Small intestine & ampulla

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Authors: Ahmed Afifi, M.B.B.Ch., Sameer Al Diffalha, M.D., Felicia D. Allard, M.D., Devin Allison, M.D., Alaaeddin Alrohaibani, M.D., Khalid Amin, M.D., Juwairiya Arshi, M.B.B.S., Aastha Chauhan, M.D., Shefali Chopra, M.D., Kieran Doyle, M.D., David J. Escobar, M.D., Ph.D., Raul S. Gonzalez, M.D., Hanni Gulwani, M.B.B.S., Saroona Haroon, M.B.B.S., David Hernandez Gonzalo, M.D., Aaron R. Huber, D.O., Danielle Hutchings, M.D., Gagandeep Kaur, M.D., Megan Kinn, D.O., M.S., Yongchao Li, M.D., Ph.D., Tom Liang, M.D., Elias Makhoul, D.O., Haider A. Mejbel, M.D., Mohamed Mostafa, M.D., Kenechukwu Ojukwu, M.D., M.P.P., Byoung Uk Park, M.D., Krutika S. Patel, M.B.B.S., M.D., John D. Paulsen, M.D., Nat Pernick, M.D., Alexandros D. Polydorides, M.D., Ph.D., Jian-Hua Qiao, M.D., Pierre A. Russo, M.D., Jen Rytych, M.D., Hasan Samra, M.D., Divya Sharma, M.D., Archana Shenoy, M.D., Madison Swaney, M.D., Iresha Vithanage, M.B.B.S., M.D., Monika Vyas, M.D., Annika L. Windon, M.D., Mary Wong, M.D., M.B.A., Yue Xue, M.D., Ph.D., Mohamed Yakoub, M.D., Lizhi Zhang, M.D.

Editorial Board Members: Diana Agostini-Vulaj, D.O., Naziheh Assarzadegan, M.D., Raul S. Gonzalez, M.D., Catherine E. Hagen, M.D., Aaron R. Huber, D.O., Xiaoyan Liao, M.D., Ph.D., Claudio Luchini, M.D., Ph.D., Monika Vyas, M.D.

Deputy Editors-in-Chief: Raul S. Gonzalez, M.D., Catherine E. Hagen, M.D., Aaron R. Huber, D.O.

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Adenocarcinoma-ampulla Adenocarcinoma-small intestine Adenoma Adenomyoma Anatomy Atresia / stenosis Autoimmune enteropathy Behçet disease Brunner gland hyperplasia Carcinoid syndrome Celiac sprue Common variable immunodeficiency syndrome Crohn's disease Diaphragm disease Diverticula (other than Meckel) Duodenal peptic ulcer Duplication Enteritis cystica profunda Enterogenous cysts Eosinophilic gastroenterocolitis redirect Gangliocytic paraganglioma Giardia lamblia GIST Grossing & features to report Heterotopic gastric mucosa Heterotopic pancreas Histology-ampulla Histology-small intestine Hyperplastic polyp Idiopathic retroperitoneal fibrosis Ileal pouch / pouchitis Immunoproliferative small intestinal disease (ISID) Infectious disorders-general Inflammatory fibroid polyp Inflammatory myofibroblastic tumor Inflammatory polyp Intra-ampullary papillary tubular neoplasm (IAPN) Intra-ampullary papillary tubular neoplasm (IAPN) Intussusception Ischemia Ischemia Juvenile polyposis Leiomyoma Lipoma Lipomatosis of the ileocecal valve Lymphangiectasia Lymphangioma Lymphocytic enterocolitis Lymphoid hyperplasia Malabsorption-general Malignant GI neuroectodermal tumor Meckel diverticulum Meconium peritonitis Necrotizing enterocolitis Neuroendocrine carcinoma Neuroendocrine tumor Olmesartan enteropathy Peptic duodenitis Peutz-Jeghers polyp Pneumatosis cystoides intestinalis Pseudomelanosis duodeni Radiation enterocolitis Reactive nodular fibrous pseudotumor Rejection Sclerosing peritonitis Staging-ampulla carcinoma Staging-duodenal & ampullary neuroendocrine tumors Staging-small intestine carcinoma Staging-small intestine neuroendocrine tumors Ulcerative colitis Whipple disease WHO classification

Adenocarcinoma-ampulla

Table of Contents

Definition / general

Uncommon epithelial malignancy with glandular or mucinous differentiation that has an epicenter in the ampulla of Vater and displays an intestinal, pancreatobiliary or mixed phenotype
While advanced duodenal, distal common bile duct or pancreatic carcinoma may extend to involve the ampulla, only those malignancies centered on or circumferentially surrounding the ampulla are regarded as ampullary carcinomas

Essential features

Ampulla of Vater is a complex anatomical region that represents the junction of duodenal and pancreatobiliary type mucosa, resulting in a heterogenous group of malignancies that may arise from this site (Am J Surg Pathol 2012;36:1592)
Distinguishing ampullary / periampullary primaries from duodenal, distal common bile duct and pancreatic ductal primaries is based on careful gross examination to assess the tumor epicenter
Distinguishing intestinal from pancreatobiliary type tumors is an important prognostic factor; immunostains are helpful adjuncts to morphologic assessment (Int J Surg Pathol 2019;27:598)

ICD coding

ICD-O
- 8020/3 - carcinoma, undifferentiated, NOS
- 8140/3 - adenocarcinoma, NOS
- 8144/3 - adenocarcinoma, intestinal type
- 8163/3 - adenocarcinoma, pancreatobiliary type
- 8490/3 - signet ring cell adenocarcinoma or poorly cohesive carcinoma
- 8510/3 - medullary adenocarcinoma
- 8211/3 - tubular adenocarcinoma
ICD-11: 2B80.20 - adenocarcinoma of small intestine, site unspecified

Epidemiology

Rare, with an incidence of 4 - 10 cases/1 million population (Eur J Gastroenterol Hepatol 2000;12:75, J Surg Oncol 2009;100:598, Cancer Causes Control 2007;18:415, Cancer 2019;125:1489)
M:F = 1.48:1 in one large series (J Surg Oncol 2009;100:598, Am J Surg Pathol 2012;36:1592)
Commonly presents between the ages of 60 and 80 (median: 65 years) (J Surg Oncol 2009;100:598, Am J Surg Pathol 2012;36:1592)
Associated with familial adenomatous polyposis (FAP), Lynch syndrome, Gardner syndrome, Peutz-Jeghers syndrome and neurofibromatosis (Gastroenterology 2001;121:1127, Mod Pathol 2001;14:1169, Gastroenterology 1992;102:1980, Am J Med Genet 1980;6:205)

Sites

Ampullary adenocarcinomas have 4 recognized subtypes (Am J Surg Pathol 2012;36:1592)
- Periampullary carcinomas are exophytic masses that arise from the duodenal surface of the ampulla and engulf the ampullary orifice (~5%)
- Intra-ampullary carcinomas arise from intra-ampullary papillary tubular neoplasms (IAPN, ~25%)
- Ampullary ductal carcinomas arise from the portions of the distal common bile or pancreatic ducts located within the papilla of Vater and circumferentially involve the duct within the papilla (~15%)
- Ampullary carcinomas, NOS are ulceronodular tumors located at the papilla of Vater that do not show the specific features of the 3 categories listed above (~55%)

Pathophysiology

Experts theorize that the tendency for small bowel adenocarcinomas as well as familial adenomatous polyposis related adenocarcinomas to occur in the ampullary region may be related to exposure to bile and pancreatic secretions
Known precursor lesions include (Am J Surg Pathol 2012;36:1592)
- Intra-ampullary adenocarcinomas: intra-ampullary papillary tubular neoplasms
- Periampullary adenocarcinoma: intestinal type adenoma
- Ampullary ductal adenocarcinomas: some tumors show intraepithelial neoplasia; however, this is difficult to distinguish from colonization of the surface epithelium by invasive carcinoma cells
- Ampullary carcinoma, NOS: precursor lesion unclear

Etiology

For the vast majority of tumors, a specific etiology cannot be determined (Am J Surg Pathol 2012;36:1592, Am J Surg Pathol 2010;34:1731, J Clin Oncol 2013;31:1348)

Clinical features

Rare, accounting for 0.2% of gastrointestinal cancers and 6 - 9% of periampullary malignancies (Am Soc Clin Oncol Educ Book 2014:112)
Patients often present with persistent jaundice, abdominal pain, pancreatitis or weight loss
Overall 5 year survival is 39 - 45% for patients who undergo resection (Hepatobiliary Pancreat Dis Int 2018;17:443, J Surg Oncol 2009;100:598, Am J Surg Pathol 2012;36:1592)

Diagnosis

Confirmation that a tumor is an ampullary carcinoma is best done on careful gross assessment of the resection specimen to determine the tumor epicenter (Am J Surg Pathol 2012;36:1592)
It is also important to look for precursor lesions that can support the origin of a periampullary tumor: pancreatic intraepithelial neoplasms for pancreatic cancer, intestinal adenoma for duodenal cancer, biliary intraepithelial neoplasms or intraductal papillary neoplasms for biliary (distal) cancer (see Pathophysiology) (Am J Surg Pathol 2012;36:1592)

Radiology description

Endoscopic retrograde cholangiopancreatography (ERCP) is the most useful endoscopic study for diagnosing ampullary carcinoma; it permits tumor identification, biopsy and biliary decompression with a single procedure (Am J Surg 1997;174:355)
MRI plus magnetic resonance cholangiopancreatography (MRCP) has shown good performance in differentiating between malignant and benign ampullary lesions (BMC Med Imaging 2019;19:77)
MRI diagnostic accuracy for ampullary lesions has been reported to be as high as 91.17% (BMC Med Imaging 2019;19:77)

Prognostic factors

Ampullary adenocarcinomas with pancreaticobiliary histology have a much worse outcome than those with intestinal histology (J Clin Oncol 2013;31:1348, J Am Coll Surg 2008;207:210, BMC Cancer 2013;13:428, World J Surg Oncol 2022;20:406)
Decreased overall survival is associated with advanced age, tumor grade, tumor size, lymph node ratio, higher stage disease (pT3 - 4), lymph node metastasis, lymphovascular invasion, higher histologic grade tumors, perineural invasion and elevated serum CA 19-9 and CEA levels (Int J Radiat Oncol Biol Phys 2006;66:514, Ann Surg Oncol 2019;26:1079, J Am Coll Surg 2008;207:210, Am J Surg 2000;180:13, Br J Surg 2004;91:1600, Ann Surg Oncol 2003;10:1176, Pancreas 2019;48:70, J Gastrointest Surg 2008;12:1422)
Positive prognostic indicators include serum bilirubin of 75 micromol/L or less and age < 70 years (Br J Surg 2004;91:1600)
Prognosis (survival) by subtype: periampullary carcinoma > intra-ampullary > ampullary, NOS > ampullary ductal carcinoma (Am J Surg Pathol 2012;36:1592)

Case reports

11 year old boy presented with obstructive jaundice due to ampullary adenocarcinoma (youngest patient reported) (J Pediatr Surg 1997;32:636)
45 year old man who presented with abdominal pain, nausea, vomiting and a fever was found to have ampullary adenocarcinoma (Cureus 2022;14:e29398)
58 year old man with familial adenomatous polyposis presented with ampullary adenocarcinoma (Bratisl Lek Listy 2019;120:908)
74 year old man who presented with decompensated cirrhosis and choledocholithiasis associated with an ampullary adenocarcinoma (Cureus 2023;15:e37566)
77 year old man who presented with 2 rare synchornous primaries: ampullary adenocarcinoma and ileal gastrointestinal stromal tumor (World J Gastrointest Oncol 2022;14:2253)

Treatment

Management of early stage disease is primarily surgical, typically pancreatoduodenectomy (Whipple procedure) followed by adjuvant chemoradiation (Am Soc Clin Oncol Educ Book 2014:112)
- Curative resection rates for early stage disease are as high as 80 - 90% with modern techniques at high volume centers (Am Surg 1999;65:1043, J Surg Oncol 2009;100:651)
Local resection / ampullectomy is sometimes an option for patients who are poor surgical candidates / have significant comorbidities and is reported to offer lower surgical morbidity; however, recurrence rates are higher (Dig Surg 2003;20:511, Ann Surg Oncol 2005;12:971, Ann Surg 1996;224:621)
Unresectable disease is treated systemically with gemcitabine combined with a platinum compound plus radiation therapy (Am Soc Clin Oncol Educ Book 2014:112, N Engl J Med 2010;362:1273)
Small retrospective studies have suggested that patients with pancreatobiliary type carcinomas may benefit from gemcitabine therapy while those with intestinal type tumors may benefit from 5-fluorouracil (5-FU) based regimens (BMC Cancer 2008;8:170, Am J Surg Pathol 2014;38:1371)
A large, multicenter European study group for pancreatic cancer (ESPAC)-3 periampullary randomized controlled trial demonstrated no significant overall survival benefit from adjuvant chemotherapy (fluorouracil or gemcitabine) (JAMA 2012;308:147)

Gross description

Gross appearance depends on the region of the ampulla involved (Am J Surg Pathol 2012;36:1592)
- Periampullary adenocarcinomas
  - Exophytic mass arising from the duodenal aspect of the ampulla
  - Vegetating mass around the ampulla that may obscure the ampullary orifice
  - Invasive component of the lesion may extend beyond the ampulla to involve the adjacent duodenal wall
  - Large tumors: average size of 4.7 cm with a 2.4 cm invasive component
  - 50% of cases have lymph node involvement at time of resection
- Intra-ampullary adenocarcinomas
  - Arising from an intra-ampullary papillary tubular neoplasm
  - Appear as a mucosa covered bulge with a dilated ampullary orifice and bulky intraluminal growth within the ampulla
  - Average tumor size of 2.9 cm with an invasive component of 1.5 cm
  - 28% of cases have lymph node involvement at time of resection
- Ampullary ductal adenocarcinomas
  - Appear as small concentric elevations and ulcerating retractions around the ampullary orifice
  - Upon bivalving the specimen along the duct, concentric thickening with or without stricturing of the intra-ampullary duct will be seen
  - Small tumor size: average of 1.9 cm
  - Low incidence of lymph node spread
- Ampullary carcinoma, NOS
  - Tumor is grossly centered in the ampulla
  - Lacks the specific characteristics of the subtypes listed above
  - Often presents as an ulceration of the papilla with dilation of both the common bile duct and main pancreatic duct
Careful gross assessment of tumor extension into the duodenal wall and the pancreas or peripancreatic soft tissue as well as any major vessels is important for correct staging
Average gross size of tumors: 2.6 cm with invasive component measuring 1.8 cm (Am J Surg Pathol 2012;36:1592)

Gross images

Contributed by Felicia D. Allard, M.D. and Claudio Luchini, M.D., Ph.D.

Ampullary ductal carcinoma

Firm gray-white thickening

Microscopic (histologic) description

Majority are gland forming (tubular adenocarcinoma)
60% show either intestinal or biliary phenotypes while 40% have a mixed phenotype (Mod Pathol 2016;29:1575)
- Intestinal type: columnar cells with elongated, pseudostratified nuclei with scattered goblet cells and Paneth cells
- Pancreatobiliary type: cuboidal cells with pleomorphism forming small glands in desmoplastic stroma
- Mixed type: shows mix of intestinal and pancreatobiliary types
Nonglandular patterns include:
- Mucinous adenocarcinoma: > 50% stromal mucin pools containing floating tumor cells / glands with an intestinal phenotype
- Poorly cohesive cell carcinoma
- Medullary carcinoma
- Adenosquamous carcinoma: this extremely rare mixed tumor shows both morphologic and immunophenotypic evidence of both glandular and squamous differentiation (World J Surg Oncol 2015;13:287, World J Surg Oncol 2013;11:124)
- Undifferentiated carcinoma
  - Undifferentiated carcinoma with osteoclast-like giant cells: tumor that is comprised of sarcomatoid appearing mononuclear cells and contains osteoclast-like giant cells
  - Undifferentiated carcinoma with rhabdoid phenotype: discohesive tumor cells show abundant eosinophilic intracytoplasmic rhabdoid bodies and are present in a myxoid matrix (Am J Surg Pathol 2016;40:544)
Histologic features by subtype (Am J Surg Pathol 2012;36:1592)
- Intra-ampullary adenocarcinomas
  - Majority of the lesion often consists of the precursor intra-ampullary papillary tubular neoplasm
  - Majority show an intestinal phenotype
  - Growth patterns include papillary, tubular and tubulopapillary
  - Noninvasive precursor component may display a different epithelial phenotype than the invasive component
- Periampullary adenocarcinomas
  - Majority are intestinal type
  - May show mucinous or signet ring cell patterns
- Ampullary ductal carcinomas
  - Pancreatobiliary type
  - May show focal micropapillary or sarcomatoid areas
- Ampullary carcinoma, NOS
  - Lacks the specific characteristics of the above subtypes
  - Heterogenous histologic types: 45% pancreatobiliary type, 27% intestinal type, 28% mixed or other type

Microscopic (histologic) images

Contributed by Felicia D. Allard, M.D.

Intestinal type adenocarcinoma

Signet ring cell morphology

Adenocarcinoma arising from IPTN

Ampullary duct carcinoma

Pancreaticobiliary phenotype

CDX2 pancreatobiliary phenotype

CK7 pancreatobiliary phenotype

CK20 pancreatobiliary phenotype

Virtual slides

Images hosted on other servers:

Forcep biopsy periampullary mass

Cytology description

Cellular to moderately cellular preparations
Malignant cells when grouped are typically crowded and present in 3 dimensional clusters
Single pleomorphic cells are often present
Nuclei are typically enlarged and irregular with an increased N:C ratio, coarse chromatin and prominent nucleoli are often present
Necrosis can occasionally be seen (J Clin Pathol 2001;54:449, Cancer 2005;105:289)
In one study, 13/35 ampullary adenocarcinomas were identified via EUS FNA sampling (Cancer 2005;105:289)

Positive stains

Intestinal type tumors are typically positive for CK20 (50%), CDX2 (> 25% of tumor staining, 89.5%) and S100P (63%) with variable CK7 (70 - 80%) (Am J Surg Pathol 2014;38:1371, Hum Pathol 2013;44:2213, J Clin Pathol 2019;72:762)
Pancreatobiliary type tumors are positive for MUC1 (100%), CK7 (91%) (Am J Surg Pathol 2014;38:1371)
18 - 20% can be ambiguous (mixed type or a nonglandular tumor subtype) by IHC (Am J Surg Pathol 2014;38:1371, Br J Cancer 2019;120:697)
Undifferentiated carcinoma with osteoclast-like giant cells: often show mutational p53 staining pattern with giant cells showing immunoreactivity for CD68 (Am J Surg Pathol 1998;22:1247)
Undifferentiated carcinoma with rhabdoid phenotype: loss of nuclear SMARCB1 / INI1 expression (Am J Surg Pathol 2016;40:544)

Negative stains

Intestinal type tumors are typically positive for MUC2 (39.5%), MUC5AC (41%) (Am J Surg Pathol 2014;38:1371, Hum Pathol 2013;44:2213, J Clin Pathol 2019;72:762)
Intestinal type tumors are typically negative for MUC1 (EMA) (Am J Surg Pathol 2014;38:1371)
Pancreatobiliary type tumors are typically negative for CDX2 (< 25% of tumor staining), MUC2 and CK20 (Am J Surg Pathol 2014;38:1371, Hum Pathol 2013;44:2213)

Molecular / cytogenetics description

KRAS mutations are present in 30 - 40%, may be associated with worse disease free survival and are more frequently found in pancreatobiliary type tumors (Oncotarget 2016;7:58001, Br J Cancer 2019;120:697)
TP53 is also a negative predictor of survival, regardless of phenotype (Ann Surg 2018;267:149)
Microsatellite instability is present in 10 - 15%, usually in intestinal type tumors (Am J Surg Pathol 2009;33:691)
Other mutations detected include: APC, PIK3CA, SMAD4, BRAF, CDKN2A, FBXW7, TP53, APC, ELF3 and RAS mutations (Br J Cancer 2019;120:697, J Pathol Transl Med 2021;55:192, Cancer Cell 2016;29:229)
Targetable mutations have been identified in both intestinal and pancreatobiliary phenotype tumors (J Pathol Transl Med 2021;55:192, Ann Surg 2018;267:149)
- General: ERBB, WNT and PI3K
- Intestinal phenotype: PI3 / AKT
- Pancreatobiliary phenotype: RAS / RAF and PI3 / AKT
BRAF and KRAS are mutually exclusive (Br J Cancer 2019;120:697)

Sample pathology report

Pancreas, small bowel and distal common bile duct, pancreatoduodenectomy:
- Ampullary adenocarcinoma, pancreatobiliary type, poorly differentiated, invasive into the pancreatic head (pT3a) (see synoptic report)
- 3 of 15 lymph nodes positive for carcinoma and 1 tumor deposit (3/15, pN1)
- Perineural as well as extensive lymphovascular and large vessel invasion is present
- Resection margins are free of high grade dysplasia and carcinoma (closest approximation: 0.3 cm to retroperitoneal margin)
- Use ampulla pTMN for staging

Differential diagnosis

Intra-ampullary papillary tubular neoplasm:
- No invasion present
Adenomatous changes in submucosal glands / ductules simulating invasion:
- No desmoplastic stroma or single cell invasion present to indicate a truly invasive process
- Dysplastic ducts will have round, regular contours and be present in a lobular configuration in most cases
Extrahepatic cholangiocarcinoma:
- Tumor may show concentric thickening of the distal common bile duct but tumor will not be centered in the ampulla
Duodenal adenocarcinoma:
- Tumor may also arise in intestinal type adenomatous mucosa near the ampullary orifice and extend to involve the ampulla but the tumor will not be centered around the orifice

Additional references

Bosman: WHO Classification of Tumours of the Digestive System, 4th Edition, 2010, WHO Classification of Tumours Editorial Board: Digestive System Tumours, 5th Edition, 2019

Board review style question #1

The tumor shown above most likely comprises which of the following epithelial types?

Gastric
Intestinal
Pancreatobiliary
Squamous

Board review style answer #1

C. Pancreatobiliary. The image shows a mass arising at the convergence of the main pancreatic duct and the duodenal mucosal surface, circumferentially surrounding the main pancreatic duct with depression of the duodenal surface. No mass forming lesion is present within the lumen of the duct. Answers A, B and D are incorrect because the gross image is most consistent with an ampullary ductal carcinoma, and the majority of ampullary ductal carcinomas show a pancreatobiliary phenotype, histologically.

Comment Here

Reference: Adenocarcinoma - ampulla

Adenocarcinoma-small intestine

Table of Contents

Definition / general

Nonampullary primary malignant epithelial neoplasm of the small intestine showing glandular differentiation

Essential features

Small bowel adenocarcinomas are histologically very similar to colorectal adenocarcinomas, with complex glandular formations
Gross identification of the tumor epicenter is essential in duodenal tumors that involve the ampulla to exclude a primary ampullary adenocarcinoma or extension from pancreatic or bile duct malignancies
Adenocarcinomas can arise in a variety of inflammatory, autoimmune and familial conditions

ICD coding

ICD-O: 8140/3 - Adenocarcinoma, NOS
ICD-10:
- C17.0 - Malignant neoplasm of duodenum
- C17.1 - Malignant neoplasm of jejunum
- C17.2 - Malignant neoplasm of ileum
- C17.3 - Meckel diverticulum, malignant
- C17.8 - Malignant neoplasm of overlapping sites of small intestine
- C17.9 - Malignant neoplasm of small intestine, unspecified
ICD-11: 2B80.20 - Adenocarcinoma of small intestine, site unspecified

Epidemiology

30 - 40% of small intestinal cancers are adenocarcinoma and 3.3% of gastrointestinal cancers were from the small intestines in 2020 (CA Cancer J Clin 2020;70:7)
More frequently seen in men, African Americans and patients in their early to mid 60s (Cancer Causes Control 2005;16:781)

Sites

Most common locations include the periampullary region of the duodenum (50 - 64%) followed by the jejunum (18 - 20%) and finally the ileum (15%) (Ann Surg 2009;249:63, Cancer 1999;86:2693)
Patients with Crohn's disease have adenocarcinomas in a predominantly ileal location

Etiology

Inflammatory, autoimmune, genetic and familial diseases have been recognized as common risk factors:
- Crohn's disease: the cumulative risk increases after 10 years of disease and there is an absolute risk of 2.2% at 25 years
  - Risk increases with longstanding ileal inflammation, younger than average age of onset, previous immunosuppressant use, male sex and stricture and fistula formation (Dis Colon Rectum 2007;50:839, Am J Gastroenterol 2005;100:2724, Am Surg 2007;73:1181, J Crohns Colitis 2014;8:19)
- Celiac disease: there is an increased relative risk of 10 to 80 times compared with the general population in longstanding, untreated disease (QJM 2003;96:345)
  - Most adenocarcinomas occur in the jejunum
- Familial adenomatous polyposis (FAP): there is a 3 - 5% lifetime risk
  - Most tumors occur in the duodenum and periampullary regions
  - Risk increases with a higher number of polyps, larger polyps and those with poorer histologic features (Lancet 1989;2:783)
- Peutz-Jeghers syndrome: there is a 1.7 - 13% lifetime risk (Gastroenterology 2000;119:1447, Clin Cancer Res 2006;12:3209)
  - Adenocarcinomas most commonly occur in the jejunum and ileum and can arise from hamartomatous or adenomatous polyps
- Lynch syndrome: there is a 4% lifetime risk (Cancer 1998;83:240)
  - Adenocarcinomas most commonly occur in the duodenum and jejunum
Other associations and risk factors include:
- Ileal conduits / reservoirs which expose the small intestine to its nonnative milieu (Oncol Rep 2012;27:371)
- Exposure to acid and bile, especially in the vicinity of ampulla and pylorus (Int J Cancer 1997;70:512)
- Smoking, alcohol and dietary factors (low fiber, high red meat consumption, sugary drinks) (Int J Cancer 1997;70:512, Cancer Epidemiol 2015;39:265)
- Congenital bowel duplication, ileostomy, duodenal or jejunal bypass surgery (Radiographics 1998;18:379)

Clinical features

Patients are typically asymptomatic or exhibit nonspecific symptoms in the early stages of disease
Some symptoms include abdominal pain, anemia, GI bleeding, weight loss, nausea and vomiting
Intestinal obstruction may develop in ileal and jejunal cancers as the disease progresses, necessitating surgical intervention (Cancer 2004;101:518)

Diagnosis

Initial workup for primarily duodenal adenocarcinomas includes esophagogastroduodenoscopy (EGD) with endoscopic ultrasound (EUS) and biopsy for diagnosis and staging (J Natl Compr Canc Netw 2019;17:1109)
CT or MRI can be used to evaluate local tumor invasion and assess for metastatic disease
Balloon assisted and video capsule endoscopy allow for a detailed examination of entire small bowel if nonobstructed (J Natl Compr Canc Netw 2019;17:1109)

Laboratory

Complete blood count (CBC), chemistry profile, carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA) (J Natl Compr Canc Netw 2019;17:1109)

Radiology description

Distal adenocarcinomas may manifest as annular narrowing with abrupt concentric or irregular overhanging edges, a discrete tumor mass or an ulcerative lesion, while duodenal adenocarcinomas tend to be papillary or polypoid on CT scan (Radiographics 1998;18:379)

Prognostic factors

Prognosis is related to the stage of disease at diagnosis, resectability, margin status, differentiation and lymph node status (Langenbecks Arch Surg 2019;404:439, Dis Colon Rectum 2002;45:1496, Am J Surg Pathol 2014;38:1484)
Special morphologic variants (e.g. mucinous, adenosquamous) and tumor size are not strong predictors of outcome (Dis Colon Rectum 2002;45:1496)
Duodenal tumors have a worse prognosis compared with tumors occurring in the remainder of small bowel (Cancer 2004;101:518)
Mismatch repair deficient adenocarcinomas of the small bowel may present at an earlier stage of disease with lower recurrence rates (Clin Cancer Res 2021;27:1429)

Case reports

7 year old boy with Peutz-Jeghers syndrome (BMJ Case Rep 2018;11:e225076)
37 year old woman with bilateral ovarian metastasis (Gastroenterology Res 2017;10:366)
38 year old woman with coexisting ileal diverticulosis, Crohn’s disease and small bowel adenocarcinoma (In Vivo 2018;32:191)
47 year old man with adenocarcinoma arising in jejunal adenomyoma (Pathol Int 2019;69:556)
49 year old morbidly obese man with recurrent adenocarcinoma (BMJ Case Rep 2018;2018:bcr2018225273)

Treatment

Surgery is the mainstay of treatment with regional lymph node removal for stage I - III disease (J Natl Compr Canc Netw 2019;17:1109)
- Segmental resection is usually performed for jejunal, ileal and some duodenal primaries; pancreaticoduodenectomy may be indicted for some duodenal tumors that invade the pancreas or ampulla
Adjuvant chemotherapy and radiation have mixed, limited results and are still being evaluated

Clinical images

Images hosted on other servers:

Suspicious growth with jejunal stricture

Near obstructing mass distal to duodenal bulb

Irregular and ulcerated jejunal lesion (capsule endoscopy)

Gross description

A substantial number of duodenal adenocarcinomas show plaque-like growth but they can also present with polypoid growth in approximately 33% of cases (Mod Pathol 2017;30:255)
Jejunal and ileal adenocarcinomas present as large, annular, constricting apple core lesions with circumferential bowel wall involvement (Cancer 1975;36:1876)
Gross appearance can also be influenced by background mucosa in adenocarcinomas that arise in inflammatory conditions (Crohn's disease), polyposis syndromes or intestinal duplications (Virchows Arch 2018;473:265)
Frequent serosal involvement or extension into other organs is not uncommon

Gross images

Images hosted on other servers:

Jejunal
submucosal tumor
with overlying
normal mucosa

Jejunal tumor invading adherent transverse colon

Ileal tumor with ulceration

Frozen section description

Intraoperative consultation (gross or microscopic) may be requested to evaluate margin status for pancreaticoduodenectomy or segmental resection specimens
In patients undergoing surgery for inflammatory bowel disease, intraoperative findings concerning for malignancy (i.e. abscess formation, strictures, fistula tracts, perforation) may prompt a frozen section analysis
Microscopic features compatible with malignancy include complex glandular architecture, invasion, desmoplastic reaction, cellular and nuclear pleomorphism, loss of epithelial polarity and luminal necrosis

Frozen section images

Contributed by Krutika S. Patel, M.B.B.S., M.D. and Annika L. Windon, M.D.

Invasive jejunal adenocarcinoma

Microscopic (histologic) description

Adenocarcinomas, not otherwise specified, are characterized by columnar epithelial cells with elongated, pseudostratified nuclei forming complex glandular architecture with nuclear pleomorphism, loss of epithelial polarity and luminal dirty necrosis
Histologic grading system, based on the extent of glandular formation in the tumor, is recommended; grading is done as well differentiated (with more than 95% of tumor composed of glands), moderately differentiated (with 50% to 95% of tumor composed of glands) and poorly differentiated (with less than 50% of tumor composed of glands)
Additional histologic characterizations include mucinous adenocarcinoma (> 50% mucin), poorly cohesive cell carcinoma (with or without signet ring cells), medullary carcinoma, adenosquamous carcinoma (squamous and adenocarcinoma components), undifferentiated carcinoma or mixed neuroendocrine nonneuroendocrine neoplasm (MiNEN)
Signet ring cell / poorly differentiated carcinomas, presenting as late stage disease, are more common in Crohn's disease than as de novo small intestinal carcinomas (Inflamm Bowel Dis 2005;11:828)
Lynch syndrome associated small intestinal adenocarcinomas show similar features to their colorectal counterparts; tumors often show a high number of intratumoral lymphocytes and Crohn's-like lymphoid reaction (Gastroenterology 2005;128:590)
Preexisting adenoma is present in the majority of proximal tumors but sometimes cannot be identified in large distal small intestinal adenocarcinomas due to tumor overgrowth
Determining a background of Crohn's disease can sometimes be difficult because the histologic characteristics of Crohn's disease such as transmural inflammation can be caused by the tumor; oftentimes patients present without an established diagnosis of inflammatory bowel disease (J Crohns Colitis 2014;8:19)

Microscopic (histologic) images

Contributed by Krutika S. Patel, M.B.B.S., M.D. and Annika L. Windon, M.D.

Well differentiated adenocarcinoma

Moderately and poorly differentiated adenocarcinoma

Mucinous adenocarcinoma

Lymph node metastasis

Higher stage carcinomas

Ileal adenocarcinoma arising in Crohn's disease

Signet ring adenocarcinoma

Adenocarcinoma arising in a tubulovillous adenoma

Lymphovascular invasion

Perineural invasion

Cytokeratin 7

Cytokeratin 20

Cytology description

Cytopathologic analysis (FNA or brushing) is rarely used in the small intestine, except for occasionally diagnosing duodenal tumors in the ampullary or pyloric region
Malignant cells are arranged in loose 3 dimensional clusters of crowded epithelial cells without goblet cells
Alternatively, many single atypical cells with mitoses, increased nuclear to cytoplasmic ratio and marked nuclear pleomorphism are present
Reference: J Gastrointest Oncol 2012;3:285

Cytology images

Images hosted on other servers:

Duodenal adenocarcinoma and normal mucosa

Positive stains

CK7, CK20 (variable) (Am J Surg Pathol 2004;28:1352)
CDX2 in up to 70% of cases (Arch Pathol Lab Med 2017;141:1155)
SATB2 in up to 46% of cases, with patchy and weak staining in most cases, strong and diffuse staining in < 10% of cases (Arch Pathol Lab Med 2017;141:1155)
MUC1 (EMA): positive in up to 53% of cases (Am J Clin Pathol 2007;128:808)
MUC2: positive in up to 57% of cases
Villin: positive in up to 67% of cases (can be focal)
Small intestinal mucin antigen (SIMA): variably positive in up to 50% of cases
p53: strong, diffuse overexpression or completely negative (mutated phenotype) in a subset of mutated tumors
MUC5AC: focally in up to 40% of cases
MUC6: focally in up to 30% of cases

Negative stains

AMACR: usually negative (Am J Surg Pathol 2005;29:890)
CDH17 (Arch Pathol Lab Med 2017;141:1155)

Molecular / cytogenetics description

2 well defined molecular pathways are reported in small bowel adenocarcinomas, similar to colorectal adenocarcinoma tumorigenesis
First pathway includes APC, KRAS, TP53 (Int J Cancer 1997;70:390)
- Prevalence of mutations in KRAS is similar between colorectal and small bowel adenocarcinomas, typically 30 - 60%
- Prevalence of TP53 mutations is also comparable, 20 - 50%
- Fewer than 20% of small bowel adenocarcinomas have mutations in APC, in contrast to 80% of colorectal carcinomas
Second pathway includes inactivation of mismatch repair (MMR) genes, either by germline mutations (Lynch syndrome) or promoter hypermethylation (sporadic), which occurs in up to 38.5% of small bowel adenocarcinomas (Clin Cancer Res 2021;27:1429)
A number of other genetic alterations have been reported in small bowel adenocarcinomas, including mutations in CTNNB1, SMAD4, IDH1, CDH1, KIT, FGFR2, FLT3, NPM1, PTEN, MET, AKT, RET, ERBB2 (HER2), NOTCH1 and ERBB4 (Gut 2002;50:218, Scand J Gastroenterol 2004;39:748, Int J Cancer 1997;70:390, Am J Gastroenterol 2000;95:1576, Oncotarget 2015;6:20863)

Sample pathology report

Small bowel, duodenum, biopsy:
- Invasive moderately differentiated adenocarcinoma arising in a tubular adenoma; lymphovascular invasion is present (see comment)
- Comment: Mucosal colonization from an ampullary, biliary or pancreatic origin must be excluded. Clinical and radiographic correlation is recommended. Immunohistochemical testing for mismatch repair (MMR) proteins shows intact nuclear expression of MLH1, PMS2, MSH2, MSH6 in the tumor cells. Background nonneoplastic tissue / internal control shows intact nuclear expression. Based on these results, there is low probability of MSI-H (MSI = microsatellite instability; H = high).

Differential diagnosis

Metastatic adenocarcinoma (e.g. colon, breast, ovary, lung):
- Presence of preexisting adenoma or dysplasia supports a small bowel primary
- Immunohistochemistry is primarily used to exclude metastatic disease (CK7+, CK20- might be helpful to rule out metastatic colon adenocarcinomas)
Adenoma with high grade dysplasia:
- Differentiating prolapse from invasion around ampulla can be challenging
- Presence of desmoplasia and single cells supports invasion
Ectopic pancreas:
- Presence of only ducts in a small biopsy specimen may be misinterpreted as neoplasm
Endometriosis:
- Presence of endometrial stroma and ciliated epithelium helps to make this diagnosis
Ampullary adenocarcinoma:
- Advanced duodenal carcinoma may extend to involve the ampulla but only those centered on or circumferentially surrounding the ampulla are regarded as ampullary carcinomas
- Careful gross examination to assess the tumor epicenter helps in distinguishing ampullary / periampullary primary from duodenal primary

Additional references

Jpn J Clin Oncol 2009;39:54, Br J Cancer 2010;102:144, Nat Rev Clin Oncol 2013;10:534, Gastroenterol Clin North Am 2002;31:625, Gut 2003;52:1211, Hum Pathol 2010;41:1087, Ann Surg Oncol 2012;19:1439, WHO Classification of Tumours Editorial Board: Digestive System Tumours, 5th Edition, 2019

Board review style question #1

Which of the following syndromes is most associated with this tumor, arising in the small bowel?

Budd-Chiari syndrome
Cronkhite-Canada syndrome
Hereditary mixed polyposis syndrome
Juvenile polyposis syndrome
Peutz-Jeghers syndrome

Board review style answer #1

E. Peutz-Jeghers syndrome. This image illustrates a well differentiated adenocarcinoma of the small bowel. Patients with Peutz-Jeghers syndrome have a 1.7 - 13% lifetime risk of developing small bowel adenocarcinoma. It arises most commonly in jejunum and ileum and can arise from hamartomatous or adenomatous polyps.

Comment Here

Reference: Adenocarcinoma-small intestine

Board review style question #2

Which of the following statements is true regarding development of small bowel carcinoma in patients with Crohn's disease?

Carcinoma that develops in Crohn's disease is usually seen in older individuals in their 80s
Carcinoma that presents in Crohn's disease tends to present as early stage disease
Carcinomas in Crohn's disease usually are well differentiated
Risk of developing carcinoma is related to duration of disease
There is no increased risk when compared to the general population

Board review style answer #2

D. Risk of developing carcinoma is related to duration of disease. The cumulative risk of small carcinoma increases after 10 years, with an absolute risk of 2.2% at 25 years in Crohn's disease. Risk increases with longstanding ileal inflammation, younger than average age of onset, previous immunosuppressant use, male sex, strictures and fistula formation. Signet ring cell / poorly differentiated carcinomas, presenting as late stage disease, are more common in Crohn's disease than as de novo small intestinal carcinomas.

Comment Here

Reference: Adenocarcinoma-small intestine

Adenoma

Table of Contents

Definition / general

Dysplastic, premalignant lesion of ampulla of Vater

Essential features

Essentially the ampullary counterpart to colonic tubular / tubulovillous adenoma

ICD coding

ICD-10: D37.6 - Neoplasm of uncertain behavior of ampulla of Vater

Epidemiology

< 10% of periampullary neoplasms
Age range 32 - 86 years (Am J Clin Pathol 2009;132:506)
Incidence 1:1,000 - 2,000 based on autopsy studies
Generally occurs in older patients
Increased incidence in familial adenomatous polyposis syndrome

Clinical features

Usually asymptomatic but can cause gastric outlet obstruction or bleeding and rarely acute pancreatitis, biliary obstruction or intussusception
Excellent prognosis if completely excised 
Often associated with concurrent pancreatic intraepithelial neoplasia (Mod Pathol 2001;14:139)

Diagnosis

Endoscopic impression, confirmed on biopsy

Case reports

49 year old woman with intussusception (Case Rep Gastroenterol 2016;10:545)
53 year old man with common bile duct stricture (Cytojournal 2017;14:19)
74 year old man with concurrent ampullary small cell neuroendocrine carcinoma (World J Gastroenterol 2008;14:4709)
78 year old man with ampullary adenoma (J Med Case Rep 2014;8:228)
81 year old man with progression to carcinoma (Am J Case Rep 2015;16:586)

Treatment

Early or relatively confined lesions may be excised by endoscopic polypectomy or ampullectomy (Am J Clin Pathol 2009;132:506)
Otherwise, requires pancreatoduodenectomy

Clinical images

Images hosted on other servers:

Endoscopy

Gross description

Polypoid / exophytic mass

Gross images

Images hosted on other servers:

Raised lesion at ampulla of Vater

Microscopic (histologic) description

Tubular, villous or mixed, similar to adenomas in colon, with approximately half tubular and half villous (Am J Clin Pathol 2009;132:506)
Dysplastic epithelium may have only subtle changes of mild cellular stratification and fine chromatin pattern
Often contain prominent Paneth cells (with coarse, large, red-pink, refractile granules in supranuclear cytoplasm), endocrine cells (dark, red-purple, fine small granules in basal cytoplasm) and goblet cells
May show high grade dysplasia or give rise to adenocarcinoma

Microscopic (histologic) images

Contributed by Raul S. Gonzalez, M.D. and @Andrew_Fltv on Twitter

Ampullary adenoma with low grade dysplasia

Adenoma

Images hosted on other servers:

Ampullary adenoma with high grade dysplasia

Ampullary adenoma

Cytology description

Endoscopic brush cytology is sensitive and specific for adenoma / carcinoma, although diagnosis of adenoma does not exclude coexisting carcinoma (Am J Clin Pathol 1998;109:540)

Cytology images

Images hosted on other servers:

Pap

Molecular / cytogenetics description

Sporadic and familial adenomatous polyposis related adenomas show similar molecular features to colorectal adenoma, with presence of APC and KRAS mutations
BRAF mutations, p53 alterations and DNA mismatch repair abnormalities are rare (Am J Surg Pathol 2008;32:1388)

Sample pathology report

Ampulla, polypectomy:
- Ampullary adenoma (low grade dysplasia)

Differential diagnosis

Duodenal (nonampullary) adenoma:
- Anatomic site is only distinction
Intra-ampullary papillary tubular neoplasm:
- Occurs deeper within the ampulla
- May have pancreatobiliary type or intestinal type epithelium (Am J Surg Pathol 2010;34:1731)

Board review style question #1

Which of the following is true about adenomas of the ampulla of Vater?

BRAF mutations are rarely seen
Cases must be managed with pancreatoduodenectomy
Patients with Lynch syndrome are at significantly increased risk
Progression to adenocarcinoma is unusual

Board review style answer #1

A. BRAF mutations are rarely seen. KRAS and APC mutations are more common, both in sporadic cases and in those from patients with familial adenomatous polyposis.

Comment Here

Reference: Adenoma

Board review style question #2

A polypoid lesion of the ampulla is biopsied and shows the features below. Which of the following molecular mutations is most likely to be present?

BRAF
KRAS
MLH1
STK11

Board review style answer #2

B. KRAS mutations are most commonly seen in ampullary adenomas, along with APC mutations.

Comment Here

Reference: Adenoma

Adenomyoma

Table of Contents

Definition / general

Also called adenomyomatous hyperplasia
Rare, benign
Usually stomach, duodenum, jejunum
Often causes pain in right upper quadrant, radiating to back
May cause biliary obstruction and common bile duct dilation (Arch Pathol Lab Med 1987;111:388)

Case reports

55 year old woman with history of duodenal ulcers (Arch Pathol Lab Med 2001;125:701)
74 year old woman presenting as acute recurrent pancreatitis (World J Gastroenterol 2007;13:2892)

Treatment

Excision

Gross description

Mass at head of pancreas, usually 0.5 cm or more

Microscopic (histologic) description

Well circumscribed, nodular proliferation of smooth muscle cells, ducts and glands, clearly disorganized compared to normal
Ducts and glands are lined by columnar/cuboidal cells
No atypia, no mitoses, usually no pancreatic tissue

Positive stains

MUC6, focal surface positivity for MUC5AC (J Hepatobiliary Pancreat Sci 2010;17:275)

Negative stains

MUC1, MUC4

Differential diagnosis

Normal intraampullary common bile duct (normally has dense muscular layer)
Ectopic pancreatic tissue
Fibroadenoma
Brunner gland hyperplasia

Anatomy

Table of Contents

Definition / general

Small intestine extends from gastric pylorus to ileocaecal valve
6 meters long, divided into duodenum, jejunum, ileum

Ampulla

Ampulla means flask like dilatation (spreading or stretching) of a tubular structure
May refer to Ampulla of Vater or portion of fallopian tube, vas deferens, semicircular canal or colon
Vater ("fah-ter") is German anatomist Abraham Vater (1684-1751) who first described this structure
Usually refers to confluence of distal common bile duct and main pancreatic duct in second portion of duodenum near pancreatic head, although in 42% of patients, ampulla is termination of common bile duct only as the pancreatic duct enters the duodenum separately next to ampulla; in these cases, ampulla may be difficult to locate or nonexistent
Ampulla is 1.5 cm long or less, traverses duodenal wall, opens into the duodenal lumen through (major) duodenal papilla (papilla of Vater), a 0.5 cm in diameter mucosal elevation with mucosal reduplications (valves of Santorini) that probably prevent regurgitation
Minor papilla, also called accessory pancreatic duct (APD) of Santorini, is 2 cm proximal and slightly anterior to major papilla
APD is Patent in 50% cases, pancreatic tissue is noted in 80% of cases in minor papilla (Dig Surg 2010;27:137)
Ampulla is surrounded by muscular fibers of sphincter of Oddi
Reference: Dig Surg 2010;27:90

Duodenum

25 cm long, from pyloric sphincter to ligament of Treitz, mostly retroperitoneal, fixed in position
Common bile duct (CBD) and pancreatic duct enter second part of duodenum posteromedially at ampulla of Vater (eMedicine: Duodenal Anatomy [Accessed 9 February 2018)

Jejunum

240 cm long, 40% of remainder of bowel, begins at ligament of Treitz
Has prominent circular mucosal folds (folds of kerckring) that increase absorptive surface

Ileum

360 cm long, distal 60% of postduodenal bowel
Mucosa has transverse folds, prominent in proximal ileum, flat / absent at terminal ileum

Ileocecal valve

At end of small bowel
2 lip structure containing adipose tissue and lymphoid tissue

Lymph nodes

Duodenum drains to portal and pyloric nodes
Jejunum and proximal ileum drain to mesenteric nodes and nodes around superior mesenteric artery, terminal ileum drains to ileocolic nodes
Lacteals are lymphatic channels in villi for chylomicrons

Intestinal immune system

Peyer patches in ileum (ovoid lymphoid follicles, partly mucosal and partly submucosal, in antimesenteric side of terminal ileum)
Small intestinal goblet cells, which deliver low molecular weight soluble antigens from intestinal lumen to CD103+ lamina propria dendritic cells, which regulates development of T cells (Nature 2012;483:345)
M (membranous) cells, part of follicle associated epithelia (MALT) in small bowel and colon, which transfer antigen macromolecules from lumen to lymphocytes
T cells, usually CD8+ and scattered in surface epithelium
Lamina propria contains CD4+ T cells and B cells
Mucosa associated lymphoid tissue: lymphoid nodules, mucosal lymphocytes, appendiceal lymphoid follicles and mesenteric nodes (Annu Rev Cell Dev Biol 2000;16:301)

Neuromuscular function

Anterograde and retrograde peristalsis mixes food and promotes maximal contact of nutrients with mucosa
Colonic peristalsis prolongs contact with mucosa
Peristalsis is mediated via myenteric plexus and autonomic innervation (sympathetic thoracolumbar, parasympathetic vagal)
Also through interstitial cells of Cajal (pacemaker cells) and smooth muscle cells
Vagal receptors are abundant in duodenum and scattered throughout wall

Diagrams / tables

Images hosted on other servers:

Duodenum

Local anatomy (called common duct)

Papilla

Gross images

Images hosted on other servers:

Ileum and terminal ileum

Microscopic (histologic) images

Contributed by Grigory Demyashkin, M.D., Ph.D. and Suhail Muzaffar, M.B.B.S.

6 - 8 week embryo

Small intestine - normal (duodenum)

Atresia / stenosis

Table of Contents

Definition / general | Etiology | Case reports | Additional references

Definition / general

Atresia: imperforate mucosal diaphragm or string-like segment of bowel
Stenosis: narrowing of lumen; less common
Complications: perforation, meconium peritonitis, brown bowel syndrome

Etiology

Developmental failure, intrauterine vascular accidents, intussusceptions

Case reports

46 day old boy with multiple areas of jejunal atresia with apple peel deformity (twisted around an artery) associated with 22q11 abnormality (Arch Pathol Lab Med 2000;124:880)

Additional references

World J Gastroenterol 2010;16:5716

Autoimmune enteropathy

Table of Contents

Definition / general

Immune mediated disorder causing small intestinal atrophy and resulting in severe diarrhea

Essential features

Intractable diarrhea leading to malabsorption and electrolyte imbalances
Histologic findings include intestinal atrophy with variable inflammation (acute and chronic), crypt apoptosis and absence of goblet / Paneth cells
Indirect immunofluorescence on normal intestinal tissue using patient’s serum is useful in detecting circulating anti-enterocyte and antigoblet cell antibodies
Extraintestinal autoimmune manifestations are possible
Prognosis is much improved with immunomodulatory therapy

Terminology

Autoimmune enteropathy
Syndromic forms: immune dysregulation, polyendocrinopathy, enteropathy and X linked (IPEX) syndrome; autoimmune polyglandular syndrome (APS 1) also known as autoimmune phenomena, polyendocrinopathy, candidiasis and ectodermal dystrophy (APECED) syndrome

ICD coding

ICD-10: K63.9 - disease of intestine, unspecified
ICD-11: 4A01.21 - immune dysregulation syndromes presenting primarily with autoimmunity

Epidemiology

Age at diagnosis: variable, predominantly infants and young children, median age at presentation ~6 months; adult presentation documented (Mod Pathol 2014;27:543, Dig Dis Sci 2019;64:643)
< 1/100,000 children (Scand J Gastroenterol 2008;43:1102)
M > F

Sites

Small intestine, tubular gastrointestinal tract
Extraintestinal manifestations: diabetes mellitus, autoimmune hepatitis, alopecia, ectodermal dystrophy, candidiasis, hypothyroidism

Pathophysiology

Exact pathogenesis is unclear
Intestinal epithelial damage from anti-enterocyte antibodies and antigoblet cell antibodies

Etiology

Complex, multifactorial
IPEX syndrome: FOXP3 mutation leading to impaired function / number of regulatory T cells, X linked
APECED syndrome: AIRE mutation resulting in lack of suppression of autoreactive T cells, autosomal recessive
IPEX-like syndrome: mutations in genes related to regulatory T cell functions such as CD25, STAT5b, STAT1, LRBA and CTLA4 (Front Immunol 2018;9:2411)

Clinical features

Severe intractable diarrhea, unresponsive to dietary modifications (Dig Dis Sci 2020 Aug 24 [Epub ahead of print])
Failure to thrive, weight loss, growth restriction
IPEX and APECED: endocrinopathies and cutaneous manifestations (see Sites)

Diagnosis

Combination of clinical presentation, histologic findings and laboratory studies

Laboratory

Anti-enterocyte and antigoblet cell antibodies demonstrable by indirect immunofluorescence; predominantly IgG, less commonly IgM and IgA
Sequencing for known mutations

Prognostic factors

Can be fatal if untreated; advances in treatment and aggressive nutritional care have improved outcomes

Case reports

13 year old girl with autoimmune enteropathy successfully treated with infliximab (J Clin Gastroenterol 2014;48:264)
18 year old Caucasian man with APECED (BMJ Case Rep 2013;2013:bcr2012008116)
55 year old man with autoimmune enteropathy and bowel transplantation (Transplant Proc 2020;S0041:32669)

Treatment

Supportive nutrition, enteral and parenteral
Immunosuppression (steroids, immunomodulatory chemotherapeutic agents, biologic medications)
Stem cell transplant (IPEX syndrome) (Dig Dis Sci 2019;64:643)

Microscopic (histologic) description

Villous architectural abnormalities
- Villous blunting, severe villous atrophy and crypt hyperplasia
Absence of an epithelial cell subtype
- Diminished / absent goblet cells and Paneth cells
- Observed in a subset of cases; not a requisite for diagnosis (Am J Surg Pathol 2014;38:1319, Mod Pathol 2014;27:543)
Inflammation:
- Increased intraepithelial lymphocytes
- Active (acute) inflammation and cryptitis
Increased crypt apoptosis resembling graft versus host disease
Findings pronounced in duodenum / small bowel; variable findings can also be seen in the stomach and colon (Am J Surg Pathol 2014;38:1319)
Severity of histologic findings variable among individuals and reversible with therapy

Microscopic (histologic) images

Contributed by Archana Shenoy, M.D.

Duodenal biopsy

Colon biopsy

Immunofluorescence description

Indirect immunofluorescence test performed using patient’s serum on normal frozen small intestinal tissue can assist in diagnosis; positive staining of apical and basolateral borders of enterocytes or goblet cell staining indicates the presence of anti-enterocyte and antigoblet cell antibodies (Pediatr Dev Pathol 1999;2:65)

Immunofluorescence images

Contributed by Pierre A. Russo, M.D.

Indirect
immunofluorescence
test

Electron microscopy description

Not routinely used for diagnosis; if performed, helpful in eliminating congenital diarrheas that are in the differential diagnoses

Sample pathology report

Duodenum, biopsy:
- Severe villous blunting with absence of goblet cells and Paneth cells, intraepithelial lymphocytosis and increased crypt apoptosis
Duodenum, biopsy:
- Chronic active duodenitis with increased apoptosis (see comment)
- Comment: The biopsies demonstrate histologic features that raise the possibility of autoimmune enteropathy, in the correct clinical context. If celiac disease is excluded, serologic or molecular testing for autoimmune enteropathy is recommended.

Differential diagnosis

Celiac disease:
- Intact goblet and Paneth cells
- Typically more pronounced intraepithelial lymphocytes
- Typically responsive to gluten free diet
- Positive serologic tests (antiendomysial antibodies and tissue transglutaminase) for celiac disease
Very early onset inflammatory bowel disease:
- Intact goblet and Paneth cells
- Granulomas (in Crohn’s disease)
Infections:
- Stool polymerase chain reaction tests, cultures
- Acute onset of symptoms responsive to antibiotic medications
Common variable immunodeficiency:
- Paucity of lamina propria plasma cells
Congenital diarrheas:
- Tufting enteropathy:
  - Epithelial tufts, EpCAM mutations, negative EpCAM immunohistochemical stain
- Microvillus inclusion disease:
  - Absent brush border, MYO5b mutation, CD10, PAS stains highlight abnormality
- Enteroendocrine cell dysgenesis:
  - Negative chromogranin, NEUROG 3 mutations
Graft versus host disease
- History of stem cell transplant

Additional references

Virchows Arch 2018;472:55

Board review style question #1

Which of the following findings when present would distinguish autoimmune enteropathy from celiac disease?

Absence of Paneth cells and goblet cells
Cryptitis
Intraepithelial lymphocytosis
Villous blunting

Board review style answer #1

A. Absence of Paneth cells and goblet cells

Comment Here

Reference: Autoimmune enteropathy

Board review style question #2

Mutation in which of the following genes is associated with IPEX syndrome?

FOXO1
FOXP3
SS18
TFE3

Board review style answer #2

B. FOXP3

Comment Here

Reference: Autoimmune enteropathy

Behçet disease

Table of Contents

Definition / general | Case reports | Microscopic (histologic) images

Definition / general

Rare immune mediated systemic vasculitis that often presents with mucous membrane ulceration and ocular problems (Wikipedia: Behçet Disease [Accessed 12 February 2018])
GI involvement in 10% of cases, usually ileum and cecum
Punched out ulcers that may perforate
Perivascular inflammation, necrotizing and nonnecrotising lymphocytic vasculitis affecting small veins and venules is often present
Also aphthous stomatitis, genital ulcers, relapsing iritis

Case reports

30 year old man with massive GI bleeding (Korean J Gastroenterol 2007;49:400)

Microscopic (histologic) images

Images hosted on other servers:

Ulcers - site unspecified

Brunner gland hyperplasia

Table of Contents

Definition / general

Brunner gland hyperplasia (BGH) is defined as benign hyperplastic proliferation of mature Brunner glands, commonly in the duodenal bulb

Essential features

BGH clinical findings can be nonspecific; endoscopies show a polypoid / pedunculated mass that varies in size
Histologic features show proliferation of Brunner glands that extends to the submucosa
Smooth muscle proliferation and mature adipose tissue favors Brunner gland hamartoma

Terminology

Brunner gland hamartoma, Brunner gland adenoma and Brunneroma: > 0.5 cm with dilated glands and smooth muscle proliferation (Adv Ther 2021;38:2779, Rev Esp Enferm Dig 2022;114:124)

ICD coding

ICD-11: DA53.Y - other specified duodenal polyp

Epidemiology

BGH represents < 1% of all gastrointestinal tumors and ~5% of benign duodenal tumors (Int J Clin Exp Pathol 2015;8:7565)
More prevalent from 50 - 70 years old (World J Gastroenterol 2004;10:2616)
Risk factors (World J Gastroenterol 2004;10:2616)
- High gastric acid secretion
- Helicobacter pylori infection
- Chronic pancreatitis

Sites

Most common in proximal duodenum (57% in duodenal bulb) (Gastrointest Endosc 1998;47:403)

Pathophysiology

Poorly understood
Hypothesized to be embryonic dysplasia of the duodenum (Brunner gland hamartoma) (JNMA J Nepal Med Assoc 2019;57:50)
High gastric acid secretion can cause BGH, increasing alkaline mucous secretion (Scand J Gastroenterol 1990;25:165)
Relationship between H. pylori infection and BHG is not clearly understood

Etiology

Majority of cases have unclear etiology
High acid environment in the duodenum, H. pylori and chronic pancreatitis may cause duodenal mucosal injury and trigger a repair process that includes foveolar metaplasia and BGH (BMC Gastroenterol 2014;14:14)

Clinical features

Majority of patients are asymptomatic
Nonspecific symptoms (J Surg Case Rep 2018;2018:rjy305)
- Dyspepsia, nausea and vomiting
- Abdominal pain and distension
Rare cases present with gastrointestinal bleeding and iron deficiency anemia (especially in hamartomas and large lesions) (Endosc Ultrasound 2015;4:266)
Few cases present with intestinal obstructions (lesions > 2 cm) (Am J Gastroenterol 1995;90:290)
Ampullary lesions can present with biliary obstruction (Endoscopy 2000;32:998)

Diagnosis

Upper GI endoscopy (EGD)
- Some lesions (especially in posterior wall of duodenum) can be missed on EGD
- Sensitivity of EGD is 72 - 89% (Eur J Radiol 1993;16:115)
- Evaluates extent, size and origin of the lesion
- Duodenal nodule that can be covered by normal mucosa (Gastrointest Endosc 2006;64:464)
- Can mimic lipoma, endocrine tumor or gastrointestinal stromal tumor (GIST) (Trop Gastroenterol 2010;31:121)
Radiology (barium Xray and abdominal CT)
- More sensitive for larger lesions (J Comput Assist Tomogr 2010;34:543)
- See Radiology description

Radiology description

Barium Xray
- Sessile or pedunculated polypoid filling lesions (large Brunner gland hamartomas) (Gastroenterol Hepatol (N Y) 2008;4:473)
- Multiple small filling defects and cobblestone pattern (diffuse nodular BGH) (AJR Am J Roentgenol 2006;187:715)
CT (Dig Liver Dis 2021;53:134)
- Mass in the duodenum with central low attenuation
- Shows the relationship with adjacent organs

Radiology images

Images hosted on other servers:

Duodenum showing cobblestone pattern

Prognostic factors

Overall good prognosis for most lesions
Very rare cases of BGH have been reported showing dysplasia or invasive carcinoma (2% and 0.3%, respectively) (Am J Surg Pathol 2005;29:1442, J Gastroenterol 2002;37:293)

Case reports

22 year old woman presented with duodenal intussusception due to BGH (Ann Surg 1959;150:160)
33 year old woman with large BGH presented with bleeding (Case Rep Surg 2021;2021:8861308)
57 year old man with pyloric obstruction due to Brunner gland hamartoma (J Surg Case Rep 2020;2020:rjaa191)
60 year old man with BGH mimicking malignant pathology (Int J Surg Case Rep 2021;81:105827)

Treatment

Endoscopic or surgical resection
Pancreaticoduodenectomy has been reported for giant hamartomas and diffuse nodular BGH (J Korean Med Sci 2008;23:540)

Clinical images

Contributed by Hany Al Khedr, M.D.

Duodenal bulb polyp endoscopy

Microscopic (histologic) description

Brunner gland hyperplasia
- Closely packed clusters of cuboidal cells with basal round to flat nuclei and foamy cytoplasm with neutral mucin
- Features of peptic duodenitis, foveolar metaplasia or mucosal injury can be seen (Scand J Gastroenterol 1990;25:165)
Brunner gland hamartoma
- Typically, larger size: > 0.5 cm
- Smooth muscle and adipose tissue, intermixed with proliferating Brunner glands and cystically dilated ducts
- Brunner glands can be intermingled with mature adipose tissue / adipocytes
Brunner gland adenoma
- Similar morphology to Brunner gland hyperplasia or hamartoma, with cytological atypia, nuclear enlargement and mitosis (Int J Clin Exp Pathol 2015;8:7565)

Microscopic (histologic) images

Contributed by Divya Sharma, M.D.

Brunner glands in submucosa

Glands within fibrous stroma

Bland cuboidal cells

Foveolar metaplasia

Dilated ducts

Mature adipocytes

Fibrous septa

Positive stains

MUC6 (Diagn Cytopathol 2021;49:E222)

Sample pathology report

Duodenum, polyp, biopsy:
- Polypoid duodenal mucosa with prominent Brunner glands consistent with Brunner gland hyperplasia
- Negative for dysplasia or malignancy

Differential diagnosis

Gastric heterotopia:
- Commonly in first and second parts of duodenum
- Gastric oxyntic glands with foveolar epithelium on the surface
Pancreatic heterotopia:
- Variable mixture of elements of normal pancreatic tissue including acini, ducts or islet cells
Neuroendocrine tumors:
- Commonly in first and second parts of duodenum, including the ampulla
- Nests of uniform cells with round to oval nuclei with salt and pepper chromatin
- Tumor cells are positive for chromogranin A and synaptophysin
Duodenal adenoma:
- Common in the ampullary area
- Tubular or villous architecture with dysplasia of the surface epithelium
Gastrointestinal stromal tumor (GIST):
- Rare in the duodenum
- Monotonous spindle or epithelioid cells with pale cytoplasm and vesicular chromatin
- Tumor cells are positive for DOG1 and CD117
Leiomyoma:
- Incidental finding
- Can be merged with muscularis mucosa
- Positive for smooth muscle actin and desmin
Lipoma:
- Rare, submucosal
- May be ulcerated
- Needs to be distinguished from fat rich Brunner gland hamartoma

Additional references

J Investig Med High Impact Case Rep 2023;11:23247096231159811

Board review style question #1

A 52 year old man with history of dyspepsia and abdominal pain. The upper GI endoscopy showed a 0.5 cm polyp in the duodenal bulb. Which of the following is a possible etiology of the findings depicted in the image above?

Gastric atrophy
Immunosuppression
Increased duodenal acidic environment
Inflammatory bowel disease

Board review style answer #1

C. Increased duodenal acidic environment. The biopsy findings show Brunner gland hyperplasia with focal foveolar metaplasia. A possible etiology of Brunner gland hyperplasia is increased gastric acidity with compensatory increased alkaline secretion by Brunner glands in the duodenum. Answer D is incorrect due to a lack of chronic inflammation and mucosal injury. Answer B is incorrect due to lack of additional findings associated with immunosuppression like infectious agents or inflammation. Answer A is incorrect as Brunner gland hyperplasia is usually associated with gastric increased acid secretion, not gastric atrophy.

Comment Here

Reference: Brunner gland hyperplasia

Board review style question #2

The figure above is from a duodenal biopsy in a patient with duodenal polyp on upper GI endoscopy. Which of the following, if present, favors a diagnosis of Brunner gland hamartoma over Brunner gland hyperplasia?

Lesion size < 0.5 cm
Presence of foveolar metaplasia
Smooth muscle proliferation
Superficial lesion limited to the mucosa

Board review style answer #2

C. Smooth muscle proliferation. Brunner gland hamartoma is typically a larger lesion (> 0.5 cm), composed of proliferation of Brunner glands, smooth muscle and mature adipose tissue. Brunner gland hyperplasia usually presents as a small lesion (< 0.5 cm) showing only hyperplastic Brunner glands with or without foveolar metaplasia. Answer D is incorrect as both Brunner gland hamartoma and hyperplasia can extend to the submucosa. Answer A is incorrect as Brunner gland hamartoma is usually > 0.5 cm in size. Answer B is incorrect as foveolar metaplasia is mostly associated with Brunner gland hyperplasia.

Comment Here

Reference: Brunner gland hyperplasia

Carcinoid syndrome

Table of Contents

Definition / general | Symptoms | Carcinoid heart disease

Definition / general

Occurs in 1% with carcinoid tumors, 20% with widespread metastases
Elevated levels of 5-hydroxyindoleacetic acid (5-HIAA), a metabolite, are found in blood and urine
Normally liver deactivates vasoactive amines (serotonin, histamine, bradykinin, others) released from carcinoid tumors
Clinical symptoms occur if liver metastases are present or if tumor venous blood flow bypasses the liver

Symptoms

Vasomotor disturbances (cutaneous flushes, cyanosis of face and anterior chest, intermittent hypertension), palpitations, intestinal hypermotility (nausea, vomiting, diarrhea, cramps)
Also asthmatic attacks with bronchospasm, fibrosclerosis of AV and tricuspid valves, elastotic sclerosis of mesenteric vessels causing ischemia, dermal sclerosis, hepatomegaly

Carcinoid heart disease

Right sided focal or diffuse plaques of thickened valvular or mural endocardium that may extend to the great veins, coronary sinus, pulmonary trunk and main pulmonary arteries
Tricuspid and pulmonic valves are usually affected by plaque formation
Left heart and left sided valves are less frequently affected
Endocardial fibrosis is a reaction to serotonin or kinin peptide exposure
Plaques are composed of fibroblasts, myofibroblasts and smooth muscle cells embedded in a collagenous matrix, covered by a layer of endothelium
No elastic tissue is present within the plaque

Celiac sprue

Table of Contents

Definition / general

Celiac sprue / celiac disease (gluten sensitive enteropathy) is an immune mediated inflammatory disease of the small intestine seen in genetically predisposed individuals and is caused by sensitivity to prolamins, like wheat (gliadin), Barley (hordein), rye (secalin) and oats (avenin)
Innate and adaptive immune response to prolamins leads to characteristic infiltration of the lamina propria and the epithelium with chronic inflammatory cells and villous atrophy, leading to malabsorption

Essential features

Immune mediated disease characterized by intraepithelial lymphocytosis in the small bowel secondary to gluten ingestion
Partial or total atrophy of intestinal villi and hyperplasia of intestinal crypts with chronic inflammation in the lamina propria
Serologic testing in combination with biopsy confirmation required for diagnosis

Terminology

Celiac disease
Sprue
Nontropical sprue
Gluten sensitive enteropathy
Gluten induced enteropathy

ICD coding

ICD-10: K90.0 - celiac disease

Epidemiology

Seroprevalence rate: 1.4% worldwide (1.3% in South America; 1.8% in Asia) (Am J Gastroenterol 2021;116:1148)
Prevalence of biopsy diagnosed celiac disease: 0.7% worldwide (Gastroenterology 2021;160:63)
M:F = 1:1.85 (Dig Dis Sci 2018;63:184)
Mean age at diagnosis is 8.4 years
- Bimodal distribution: first at 8 - 12 months and second in third to fourth decades
Associated with autoimmune diseases (dermatitis herpetiformis, type 1 diabetes mellitus, Hashimoto thyroiditis, Graves disease, etc.), idiopathic diseases (dilated cardiomyopathy, epilepsy, multiple sclerosis, etc.) and chromosomal diseases (Down syndrome, Turner syndrome and William syndrome) (BMC Med 2019;17:142)

Sites

Small bowel

Pathophysiology

HLA class II genes HLA DQ2 and HLA DQ8 on chromosome 6 are implicated in the genetic susceptibility
- Up to 20% of the first degree relatives are affected by the disease indicating strong hereditary component
- HLA molecules on antigen presenting cells present the laminins to CD4+ T cells and activate them
Environmental trigger is the ingestion of a diet containing gluten
- Fragments of gluten peptides resistant to degradation are transported across the epithelium by transcellular pathways
- Altered intestinal permeability and release of cellular contents, including the enzyme tissue transglutaminase (tTG)
- CD71 (transferrin) receptor is found to be upregulated in active celiac disease
IFNγ and IL21 are released, which result in epithelial damage following activation of T cells by antigen presenting cells
Innate immune response by intraepithelial lymphocytes (IELs), which express NK receptors MHC class I related chain A and B and HLE on epithelial cells and lead to destruction of epithelium
- IL15 upregulates NK receptors in cytotoxic intraepithelial lymphocytes and leads to T cell receptor independent killing
Refractory sprue: where the disease persists despite avoidance of laminins, intraepithelial lymphocytes acquire a highly activated NK phenotype
- 2 types (Gastrointest Endosc Clin N Am 2012;22:639):
  - Refractory celiac disease type I:
    - Intraepithelial lymphocytes express CD3 and CD8, as well as TCRβ; similar to patients with celiac disease
    - Good prognosis when combined with immunosuppressive therapy
  - Refractory celiac disease type II:
    - Lack CD8, CD4 and TCRαβ
    - Have intracellular CD3ε and a clonal TCR gene rearrangement
    - Carry dismal prognosis

Etiology

Genetic factors: HLA DQ2 and HLA DQ8
Ingestion of gluten containing diet
Innate and adaptive immune responses
Several research studies suggested a reduction in the diversity of gut microbiota and increase in Firmicutes / Bacteroidetes (Adv Nutr 2020;11:160)

Diagrams / tables

Modified Marsh-Oberhuber classification of histologic findings in celiac disease:

Marsh type	IEL/100 enterocytes: jejunum	IEL/100 enterocytes: duodenum	Crypt hyperplasia	Villi
0	< 40	< 30	Normal	Normal
1	> 40	> 30	Normal	Normal
2	> 40	> 30	Increased	Normal
3a	> 40	> 30	Increased	Mild atrophy
3b	> 40	> 30	Increased	Marked atrophy
3c	> 40	> 30	Increased	Complete atrophy
4	> 40	> 30	Atrophic	Severe (flat)

Images hosted on other servers:

Diagnostic flowchart
in case of suspected
gluten related disorder

Diagnostic approach of refractory disease

Clinical features

Celiac disease in pediatric population is characterized by diarrhea, loss of appetite, abdominal distension and failure to thrive
Older children: diarrhea, bloating, constipation, abdominal pain or weight loss
Adults: malabsorption syndrome with chronic diarrhea, weight loss and asthenia
Extraintestinal manifestations:
- Iron deficiency anemia (microcytic)
- Macrocytic anemia due to vitamin B12 deficiency
- Osteopenia, osteoporosis due to altered absorption of calcium and vitamin D3
- Growth retardation; tooth enamel defects, aphthous stomatitis, hypertransaminasemia
Dermatitis herpetiformis
Nonspecific symptoms: headache, paresthesia, neuroinflammation, anxiety and depression
Changes in reproductive system like late menarche, amenorrhea, recurrent miscarriages, premature birth, early menopause in females and changes in number and mobility of spermatozoa in males
Refractory celiac disease (RCD) is a persistent malabsorption and villous atrophy despite strict adherence to a gluten free diet for at least 6 - 12 months in the absence of other causes and overt malignancy
- Type I and type II: severe complications like ulcerative jejunitis and enteropathy associated T cell lymphoma is seen in some patients with refractory celiac disease

Diagnosis

Gold standard for diagnosis is serology with confirmation of histology on duodenal biopsy
Serologic testing: tTGA, EMA and IgA class antigliadin antibodies (AGA) are the serologic tests
Endoscopy: hallmark endoscopic finding is patchy villous atrophy in the duodenum and is identified by magnification endoscopy or chromoendoscopy
- Scalloping or notching of mucosal folds can be seen
- Sensitivity is low
- For microscopic evaluation, 1 - 2 biopsy specimens should be taken from duodenal bulb and at least 4 specimens should be taken from postbulbar duodenum
HLA DQ association test: identifies HLA DQ2 and HLA DQ8
- Negative test essentially rules out celiac disease but is also seen in populations without celiac disease
See diagrams / tables

Laboratory

tTGA has the highest sensitivity for celiac disease (98%); specificity is 90% (Arch Pathol Lab Med 2012;136:735)
- Positive even in individuals on gluten free diet
EMA, while having a lower sensitivity, shows an almost absolute specificity (Arch Pathol Lab Med 2012;136:735)
IgA class antigliadin antibodies (AGA) is now an obsolete test (Arch Pathol Lab Med 2012;136:735)
Refractory celiac disease type 2 is characterized by loss of multiple surface T cell markers like CD3, CD7 and CD8 in more than 20% of the intraepithelial lymphocytes on flow cytometry
Flow cytometry: quantification of intraepithelial lymphocytes by flow cytometry (called IEL lymphogram), demonstrates that the IELs are antigen experienced T lymphocytes and bear the αβ (> 90%) and γδ (< 10%) receptors
- In celiac disease, the total IELs are increased, along with a permanent increase in γδ IELs and a decrease in CD3 IELs (Auto Immun Highlights 2016;7:14)

Radiology description

Fluoroscopy: small intestinal dilatation, dilution of contrast, multiple nonobstructing intussusceptions (coiled spring appearance), moulage sign (dilated jejunal loop with complete loss of jejunal folds) and flocculation (coarse clumps of disintegrated barium)
CT / MRI: jejunoileal fold pattern reversal (highest specificity); ileal fold thickening, perienteric stranding, submucosal fat deposition in longstanding cases, lymphadenopathy and ascites (Eur J Radiol 2008;65:483)

Prognostic factors

Excellent prognosis with gluten free diet
Refractory celiac disease type 2 is refractory to gluten free diet and treatment
- Poor prognosis with severe complications like ulcerative jejunitis and enteropathy associated T cell lymphoma, with an incidence of 0.06 per 100,000 person years (95% confidence interval: 0.0 - 0.12)
- Enteropathy associated T cell lymphoma is seen within 5 years in refractory celiac disease type 2 (Gut 2010;59:547)
Secondary enteropathy associated T cell lymphoma is seen in patients with long lasting, well controlled celiac disease
Enteropathy associated T cell lymphoma observed in 80 - 90% of cases in relation to celiac disease and refractory celiac disease is linked to CD56-, gain of chromosomes 1q qnd 5q
- 5 year survival rate is 8 - 20%, irrespective of subtype of enteropathy associated T cell lymphoma
- Classic type of enteropathy associated T cell lymphoma is most commonly associated with celiac disease
Higher risk of small bowel adenocarcinoma

Case reports

6 year old girl presenting with celiac disease and aplastic anemia (J Med Case Rep 2018;12:16)
9 year old boy with celiac disease and aplastic anemia (Pediatr Dev Pathol 2014;17:470)
11 year old girl with complicated primary intestinal lymphangiectasia (Waldmann disease) successfully treated with octreotide (Ann Med Surg (Lond) 2021;68:102588)
39 year old man with undifferentiated chronic pulmonary disease, chronic anemia, celiac disease, atrial fibrillation and PLA2R positive membranous nephropathy (Respir Med Case Rep 2021;33:101446)
40 year old woman with cerebral arterial and venous sinus thrombosis revealing celiac disease (BMC Gastroenterol 2020;20:327)

Treatment

Repletion of nutritional deficiencies
Prevention of bone loss
Treatment with sulfones for dermatitis herpetiformis
Gluten (laminin) free diet
Transglutaminase 2 inhibitor
Hepatitis B and pneumococcal vaccination

Gross description

Flattening or blunting of villi in the small bowel
Ulceration may be seen in severe cases

Gross images

Contributed by Erdener Özer, M.D., Ph.D.

Normal versus flattened mucosa

Microscopic (histologic) description

Histological elementary lesions (Dig Liver Dis 2011;43:S385, Semin Diagn Pathol 2014;31:124):
- Increased intraepithelial T lymphocytes (IEL):
  - 25 - 29 IEL/100 enterocytes is considered borderline
  - > 30 IEL/100 enterocytes represents a pathological lymphocytosis
- Decreased enterocyte height, flattening of enterocytes, intracytoplasmic vacuolation and reduction or absence of brush border are suggestive but not specific
- Crypt hyperplasia:
  - Extension of the regenerative epithelial crypts associated with changes in the presence of more than 1 mitosis per crypt
- Villous atrophy:
  - Decrease in villous height, normal villous:crypt ratio (3:1) until total disappearance of villi
  - This assessment requires proper orientation of the biopsies
Diagnostic categories are based on these elementary lesions:
- Modified Marsh-Oberhuber classification of histologic findings in celiac disease
- Simplified systems (Corazza & Villanaci or Ensari), which may be more reproducible (Arch Pathol Lab Med 2010;134:826, Pathol Res Pract 2016;212:1174)
Different grades of duodenal mucosal lesions:
- Grade A / type 1: increased intraepithelial lymphocytes but no villous atrophy
- Grade B1 / type 2: villi still present but shortened
- Grade B2 / type 3: complete villous atrophy

Microscopic (histologic) images

Contributed by Erdener Özer, M.D., Ph.D., Arzu Ensari, M.D., Ph.D. and Case #127

Normal versus Marsh type IIIb / IIIC

Response to gluten free diet

Collagenous sprue

56 year old woman

Flow cytometry images

Images hosted on other servers:

RCD type 2

Videos

Celiac Disease: A Fairly Advanced Lecture for Primary Healthcare Providers

Differential diagnosis

Tropical sprue:
- Variable villous blunting and contains more lamina propria eosinophils than celiac disease
- Typically involves proximal duodenum and spares terminal ileum
Autoimmune enteropathy:
- Marked villous atrophy with apoptosis at bases of crypts and lymphocytes infiltrating the crypts but not surface epithelium
- Goblet cells, paneth cells and endocrine cells may be lost
Common variable immunodeficiency:
- Apoptotic enterocytes with reduced or absent plasma cells
- Villous blunting and increased intraepithelial lymphocytes are present
Food allergy:
- Hypersensitivity to food antigens other than gluten, including cows milk, soy protein, fish, rice and chicken
- May also be associated with increased numbers of intraepithelial lymphocytes, as well as architectural changes in the form of patchy or diffuse disease
Crohn’s disease:
- Neutrophils in lamina propria and epithelium of duodenum with patchy involvement
Collagenous sprue:
- Patchy, excessive, subepithelial collagen deposits
Eosinophilic gastroenteritis:
- Dense eosinophilic and mast cell infiltrate
Inflammatory bowel disease
HIV enteropathy:
- Increased mitosis in glandular epithelial cells and increased number of apoptotic enterocytes at the surface
Giardiasis:
- Variable villous blunting with tear drop shaped organisms with paired nuclei (size similar to enterocyte nuclei)
Drugs (sartans, mycophenolate, NSAIDs):
- Serum tTg is not elevated
Intestinal lymphoma:
- Monomorphic lymphocytes with irregular nuclear membranes

Additional references

Russo: Pathology of Pediatric Gastrointestinal and Liver Disease, 2nd Edition, 2014

Board review style question #1

Which histological feature is most common in celiac disease?

Crypt hyperplasia
Granulomas
Intraepithelial lymphocytosis
Mucosal eosinophilia
Villous atrophy

Board review style answer #1

C. Intraepithelial lymphocytosis. All celiac disease patients, except for those with Marsh type 0, show intraepithelial lymphocytosis.

Comment Here

Reference: Celiac sprue

Board review style question #2

What is the immunophenotype of intraepithelial lymphocytes increased in celiac disease?

CD2+, CD3-, CD45- aberrant T cell population
CD3+, CD7+, CD103+, granzyme B and TCRαβ
CD3+, T cells with αβ and γδ receptors
CD4+, CD8+, CD3- T cells
CD4+, T cells with γε and αδ receptors

Board review style answer #2

C. CD3+, T cells with αβ and γδ receptors

Comment Here

Reference: Celiac sprue

Common variable immunodeficiency syndrome

Table of Contents

Definition / general | Clinical features | Case reports | Microscopic (histologic) description | Microscopic (histologic) images

Definition / general

Primary immune defect (usually genetic) causing reduction in B cells and most immunoglobulin classes; also frequent bacterial infections (eMedicine: Common Variable Immunodeficiency [Accessed 16 February 2018])

Clinical features

Chronic diarrhea, malabsorption, recurrent GI giardiasis

Case reports

73 year old man with nonspecific abdominal pain (Case #398)

Microscopic (histologic) description

Mucosa may resemble celiac sprue or be normal but always has reduced plasma cells and no IgA plasma cells
May have lymphoid hyperplasia or apoptotic bodies in crypts
Histologic patterns: lymphocytic colitis, collagenous enterocolitis, celiac disease, granulomatous disease, acute GVHD and IBD (Am J Surg Pathol 2007;31:1800)

Microscopic (histologic) images

Case #398

H&E images

Contributed by @RaulSGonzalezMD on Twitter

bit.ly/3wLeGIK #pathology #gipath #PathTwitter #PathOutPic"
Contributed by @RaulSGonzalezMD on Twitter (see original post here)">

Common variable immunodeficiency syndrome

Crohn's disease

Table of Contents

Definition / general

Idiopathic chronic inflammatory condition that may involve any part of the upper and lower gastrointestinal tract
Tends to involve the distal ileum and proximal large intestine

Essential features

Diagnostic criterion: segmental disease, transmural inflammation, noncaseating granulomas, deep fissuring ulcers, ileal involvement
Distal ileum is the most commonly involved part of the small intestine
Risk of colorectal carcinoma increases with duration and extent of disease

Terminology

Inflammatory bowel disease (IBD), Crohn's disease (CD), Crohn's

ICD coding

ICD-10: K50 - Crohn's disease of the small intestine

Epidemiology

Western counties, with the highest reported prevalence in Europe (322 per 100,000 in Germany) and North America (319 per 100,000 in Canada) (Lancet 2017;390:2769)
Rising incidence in newly industrialized countries in Africa, Asia and South America (Lancet 2017;390:2769)
Genetic predisposition through population and family based studies showed Crohn's disease with higher incidence among relatives with Crohn's disease, twins and Jewish population from middle European origin (Gastroenterology 2011;140:1704, Gastroenterology 1989;97:900, Med Clin North Am 1990;74:1)
Bimodal age distribution, first peak between 15 - 30 years, where the majority of patients are diagnosed; the second peak is between 50 - 80 years of age (Am J Gastroenterol 2006;101:1559, Gastroenterology 1991;100:350, Med Clin North Am 1990;74:1)
Slightly more common in women (F:M = 1.3:1)

Sites

May occur anywhere in the GI tract, from oral cavity to perianal area
Terminal ileum is the most commonly affected site (80%), with 33% having ileitis alone
50% of patients have ileocolitis (involvement of both terminal ileum and colon)
About 20% of patients have limited colon disease, of which only half will have rectal sparing
33% of patients have perianal disease
5 - 15% can have oral gastroduodenal involvement, with significantly fewer patients developing esophageal and proximal small intestinal involvement
Reference: UpToDate: Clinical Manifestations, Diagnosis, and Prognosis of Crohn Disease in Adults [Accessed 22 October 2021]

Pathophysiology

Unclear, as overall pathogenesis remains poorly understood
Inappropriate immune response has been implicated, with vast literature delineating the role of both host and microbial factors in its pathogenesis (Nat Rev Immunol 2008;8:458)
Dysregulation in epithelial barriers, immune cells and secreted mediators have been shown to play a role (J Clin Invest 1983;72:142, Gut 2013;62:1734, Gastroenterology 2009;136:1261)
Microbiota may induce inflammatory bowel disease if a concurrent underlying genetic defect is present (Nature 2012;491:119)
More than 200 loci have been identified, many of which are shared among both Crohn's disease and ulcerative colitis (UC), indicating the overlap between these 2 entities; these loci lead to modulation of protein expression, rather than amino acid change, which supports that each locus confers an increased risk of developing Crohn's disease (Nature 2012;491:119, Inflamm Bowel Dis 2015;21:1166)

Etiology

Idiopathic
Some associations have been demonstrated:
- Smoking, as shown in meta analysis studies (Mayo Clin Proc 2006;81:1462, Am J Gastroenterol 2012;107:1399)
- Physical activity is inversely related to developing Crohn's disease, with some limited data suggesting exercise can even reduce disease activity (BMJ 2013;347:f6633, Prev Med Rep 2016;3:177, Inflamm Bowel Dis 2015;21:1063)
- Sleep deprivation (Inflamm Bowel Dis 2013;19:2440, Sleep Breath 2020;24:971)
- Infection and immune response with Salmonella and Campylobacter gastroenteritis, as shown in population based cohort studies (Nat Rev Immunol 2008;8:458, Gastroenterology 2009;137:495)
- Mycobacterium paratuberculosis (Expert Opin Biol Ther 2019;19:79)
- Unclear medication association (Am J Gastroenterol 2011;106:2133, Am J Gastroenterol 2014;109:1728, Am J Gastroenterol 2010;105:2610, Lancet Gastroenterol Hepatol 2020;5:986)

Clinical features

Abdominal pain, diarrhea (bloody or nonbloody), fatigue and weight loss are classic symptoms (Am J Gastroenterol 2000;95:3458, Clin Gastroenterol Hepatol 2006;4:614, Am J Gastroenterol 2018;113:481)
Patients with distal terminal ileal involvement can present with right lower quadrant abdominal pain
Distal ileum is the most commonly involved site
Given the transmural inflammation nature in Crohn's disease, some advanced conditions can present with bowel obstruction due to fibrotic stricture formation
Extraintestinal manifestations and associations include (Inflamm Bowel Dis 2011;17:471, J Crohns Colitis 2016;10:239, J Crohns Colitis 2019;13:541):
- Joint and bones: arthropathies and osteoporosis
- Eye: iritis, uveitis and episcleritis
- Skin: erythema nodosum, pyoderma gangerosum, Sweet syndrome
- Liver: primary sclerosing cholangitis, cholelithiasis
- Kidney: nephrolithiasis
- Lung: asthma, bronchiectasis, chronic bronchitis, interstitial lung disease, bronchiolitis obliterans with organizing pneumonia, sarcoidosis, necrobiotic lung nodules and pulmonary infiltrates

Diagnosis

Multimodality approach with clinicopathologic correlation and exclusion of other differential diagnoses
Colonoscopy with ileoscopy, esophagogastroduodenoscopy (EGD) and endoscopic ultrasound are helpful in evaluating Crohn's disease as well as differentiating Crohn's disease from ulcerative colitis (Aliment Pharmacol Ther 2014;39:823)
Endoscopy also plays a pivotal role in evaluating the severity of the disease and surveillance of neoplasms
Characteristic endoscopic findings of Crohn's disease include (Med Clin North Am 1990;74:51, Gastrointest Endosc 1977;23:150, Gastrointest Endosc 1984;30:167):
- Aphthous ulcers
- Linear and serpiginous ulcers (giving a cobblestone appearance)
- Skip lesions
- Fistulas and strictures
- Isolated terminal ileum involvement, uninvolved rectum

Laboratory

May be normal
High white blood cells, anemia, elevated C reactive protein, electrolyte abnormalities, vitamin D deficiency and vitamin B12 deficiency may be found
Elevated fecal calprotectin or lactoferrin (stool inflammatory markers), which can be used as a screening tool and determine the need for endoscopy (BMJ 2010;341:c3369)

Radiology description

Not used as a primary diagnostic tool due to the wide availability of colonoscopy
Magnetic resonance imaging (MRI), computed tomography (CT) and ultrasonography have shown good diagnostic accuracy by prospective meta analysis studies (Arch Dis Child 1996;74:22, Eur J Radiol 2006;58:140, Gut 2005;54:257)

Prognostic factors

Disease course and severity may vary but is usually chronic and intermittent
50% of patients experience intestinal complications (strictures, fistula and abscess) 20 years after diagnosis (Intest Res 2015;13:19)
Involvement of terminal ileum, ileocolonic and upper GI have higher risk of developing complications (Gastroenterology 2010;139:1147)
Smoking, age < 40 years, perianal or rectal involvement and steroid requiring conditions are risk factors for disease progression (Gastroenterology 2006;130:650, Gut 2012;61:1140)
Carcinoma may develop in longstanding disease with cumulative risk of 2.9% at 10 years, 5.6% at 20 years and 8.3% at 30 years after Crohn's disease diagnosis (World J Gastroenterol 2014;20:9872)
- 2 most important risk factors: duration and extent of disease

Case reports

24 year old woman with Crohn's terminal ileitis in remission and recurrent ileal invagination (Dtsch Arztebl Int 2020;117:146)
41 year old man with Crohn's disease and mesenteric artery thrombosis (Ann Vasc Surg 2019;58:382.e15)
62 year old man with duodenal Crohn's disease with associated ampullary stenosis (Dig Dis Sci 2005;50:1118)
77 year old man with unusual initial presentation of elderly onset Crohn's disease (Cureus 2020;12:e10173)

Treatment

Multidisciplinary approach is recommended, including medications, surgery, nutritional, psychosocial support and cancer screening
Assessing disease severity using Crohn's Disease Activity Index (CDAI) is helpful in guiding treatment approach (Gastroenterology 1979;77:829, J Pediatr Gastroenterol Nutr 1991;12:439, Gastroenterology 1999;116:527)
Mild to moderately severe disease / low risk disease: sulfasalazine (colonic CD), budesonide (ileocecal CD) (Am J Gastroenterol 2018;113:481)
Moderate to severe disease / moderate to high risk disease: corticosteroids, immunomodulators (e.g. azathioprine, 6-mercaptourin, methotrexate), anti-TNF agents (e.g. infliximab, adalimumab, certolizumab pegol), agents targeting leukocyte trafficking, agents targeting IL12 / 23 (anti-p40 antibody) (Am J Gastroenterol 2018;113:481)
Severe / fulminant disease: intravenous corticosteroids, anti-TNF agents (Am J Gastroenterol 2018;113:481)
Surgery is reserved for patients with limited disease, failure to response to treatment and complications of Crohn's disease (fistula, stricture, perforation) (Gastroenterology 1999;116:527, J Pediatr Surg 1997;32:1063, J Pediatr Gastroenterol Nutr 2015;60:347, Inflamm Bowel Dis 2013;19:7, Am J Gastroenterol 2018;113:481)
Surveillance colonoscopy for dysplasia and colorectal carcinoma at 8 - 10 years after onset of symptoms with subsequent surveillance intervals of 1 - 2 years (Gastroenterol Hepatol (N Y) 2017;13:357)

Clinical images

Images hosted on other servers:

Longitudinal ulcers,
cobblestone appearance
and aphthous ulcers

Lymphoid follicles with red ring sign

Gross description

Discontinuous pattern of inflammation (segmental disease, skip lesions)
Cobblestone appearance (areas of nonulcerated mucosa separated by deep ulcers)
Adhesions, creeping fat / fat wrapping, strictures and fistulas
References: Histopathology 2012;60:1034, Virchows Arch 2014;464:511, Virchows Arch 2018;472:81

Gross images

Contributed by Elias Makhoul, D.O.

Small intestine with ulcer

Creeping fat

Stricture

Fistula

Images hosted on other servers:

Terminal ileum: mucosal (inflammatory) pseudopolyps

Terminal ileum: cobblestone change

Thickened bowel wall and fat wrapping

Microscopic (histologic) description

Features of activity: active inflammation with cryptitis, crypt abscess and ulceration
Features of chronicity: pyloric gland metaplasia, architectural distortion, crypt loss, crypt atrophy, basal lymphoplasmacytosis, fibrosis and stromal hypertrophy
Skip lesions (portions of normal appearing small intestine with scattered areas of disease)
Transmural lymphoid aggregates (beading or rosary pattern)
Noncaseating granulomas (not related to crypt injury)
Deep fissuring ulcers
Aphthous ulcers (small ulcers occurring over lymphoid aggregates)
Obliterative muscularization of submucosa (Arch Pathol Lab Med 2001;125:1331)
Dysplasia (low or high grade) and carcinoma may be present in patients with longstanding disease
Note: Some features of Crohn’s disease may also be seen in fulminant, untreated ulcerative colitis, such as aphthous ulcers, deep ulceration with transmural inflammation and superficial fissuring ulcers
References: Circulation 1965;32:332, Histopathology 2012;60:1034, Virchows Arch 2014;464:511, Virchows Arch 2018;472:81, Mod Pathol 2015;28:S30

Microscopic (histologic) images

Contributed by Mary Wong, M.D., M.B.A.

Transmural inflammation with granulomas

Noncaseating granulomas

Pyloric metaplasia

Ulceration with overlying stricture

Virtual slides

Images hosted on other servers:

Gastritis with granulomatous inflammation

Molecular / cytogenetics description

71 susceptibility loci on 17 chromosomes (Nat Genet 2010;42:1118)
Nucleotide binding oligodimerization domain 2 (NOD2) or caspase recruitment domain 15 (CARD15) on chromosome 16 (Nature 1996;379:821, Hum Mol Genet 1996;5:1679, Gastroenterology 2000;119:1483, Ann N Y Acad Sci 2006;1072:9)
Autophagy related 16-like 1 (ATG16L1) and immunity related guanosine triphosphatase family member M (IRGM) gene on chromosome 5 (Nat Genet 2007;39:596, Gut 2008;57:717)
Genetic polymorphisms in tumor necrosis factor receptors (TNFRSF1A / 1B) with differential treatment response to TNFα inhibitors (BMJ Open Gastroenterol 2019;6:e000246)

Sample pathology report

Terminal ileum and cecum, ileocecectomy:
- Segment of terminal ileum with features consistent with history of Crohn's disease, including:
  - Moderately to markedly active chronic ileitis with patchy ulcerations
  - Fibromuscular stricture with decreased luminal circumference
  - Scattered noncaseating granulomas
- No dysplasia identified
- Immunostain for CMV is negative

Differential diagnosis

Ulcerative colitis:
- Small bowel typically not involved except in case of backwash ileitis
- Absence of granulomas and segmental disease (these features are more specific for CD)
- Typically superficial inflammation with lack of transmural lymphoid aggregates
  - Deep or serosal based lymphoid aggregates may be seen adjacent to ulceration in both UC and CD
- Absence of deep fissuring ulceration
  - Superficial fissures may be seen in fulminant disease
Infectious enteritis:
- May show overlapping features of inflammatory bowel disease
- Correlation with microbiologic studies is necessary for exclusion
Drug associated enteritis (e.g. NSAIDs):
- Patchy active inflammation
- Tends to lack significant features of chronicity
Behçet disease:
- Form of vasculitis
- Recurrent aphthous stomatitis and genital ulcers may be present
Ischemia:
- Withering crypts and hyalinization of lamina propria
References: Ann Gastroenterol 2011;24:271, Curr Gastroenterol Rep 2010;12:249

Additional references

Odze: Odze and Goldblum Surgical Pathology of the GI Tract, Liver, Biliary Tract, and Pancreas, 3rd Edition, 2014

Board review style question #1

A 30 year old woman presents with abdominal pain and bloody diarrhea. The patient is refractory to medical management and a resection of the small intestine is performed. What diagnosis is most consistent with the histological findings?

Backwash ileitis
Crohn’s disease
Drug associated enteritis
Infections enteritis

Board review style answer #1

B. Crohn's disease

Comment Here

Reference: Crohn's disease

Board review style question #2

In fulminant disease, sometimes it is difficult to differentiate between Crohn's disease and ulcerative colitis. Which one of the following features can be seen in both fulminant, untreated Crohn's disease and ulcerative colitis?

Deep fissuring ulceration
Deep or serosal based lymphoid aggregates adjacent to ulceration
Granulomas
Segmental disease

Board review style answer #2

B. Deep or serosal based lymphoid aggregates adjacent to ulceration

Comment Here

Reference: Crohn's disease

Diaphragm disease

Table of Contents

Definition / general

Small bowel pathology related to NSAID use, first described in 1988 (J Clin Pathol 1988;41:516)

Case reports

46 year old woman with chronic aspirin use (Case of the Week #240)

Treatment

Cessation of NSAID use
Often surgery (Colorectal Dis 2012;14:804) or endoscopic balloon dilation (Gastrointest Endosc 2006;64:1014)

Gross description

Segmentation of ileum by incomplete mucosal diaphragms, defined as thin circumferential membranes resembling the plica circularis, composed of mucosa and submucosa with accompanying fibrosis
Also ulceration, strictures, perforation

Gross images

Case #240

Various images

Images hosted on other servers:

Various images

Microscopic (histologic) description

Thin circumferential membranes resembling plica circularis, composed of mucosa and submucosa with accompanying fibrosis
Neuromuscular and vascular hamartoma-like changes, eosinophilic enteritis and acute inflammation (Am J Clin Pathol 2008;130:518)

Microscopic (histologic) images

Case #240

H&E

Trichrome

Differential diagnosis

Cryptogenic multifocal ulcerous stenosing enteritis (CMUSE): small intestinal strictures and ulcerations of unknown origin (World J Gastroenterol 2011;17:2873), characterized as atypical vasculitis presenting with unexplained stricture and ulceration of the small bowel in young and middle aged patients but without systemic inflammation; treated with steroids

Diverticula (other than Meckel)

Table of Contents

Definition / general | Case reports | Clinical images

Definition / general

Duodenal:

Present in 1 - 2%, usually solitary and congenital, may cause obstructive jaundice, pancreatitis, fistulas, hemorrhage, perforation
Usually penetrate the pancreas
May project into lumen like a polyp

Jejunal:

Present in 0.3 - 1.4% of autopsies
Three times less frequent than duodenal but four times more likely to develop complications
Usually proximal jejunum along mesenteric border
Often multiple with thin wall
Associated with diverticula elsewhere in GI tract
Some are congenital but most are acquired
Usually asymptomatic but may cause obstruction, hemorrhage, perforation, abscess, malabsorption or vitamin B12 deficiency, possibly due to bacterial overgrowth in the diverticula

Case reports

88 year old man with acute ulcerative jejunal diverticulitis (World J Gastroenterol 2008;14:6265)

Clinical images

Images hosted on other servers:

Jejunal diverticula

Duodenal peptic ulcer

Table of Contents

Definition / general

Corrosive lesion caused by excessive gastric acid secretion, leading to defects in the mucosal surface of the duodenum

Essential features

Often results from heavy nonsteroidal anti-inflammatory drug (NSAID) use, Helicobacter pylori infection, gastric acid hypersecretion or stress
Typically presents with epigastric pain but may be asymptomatic
Histology shows ulceration and background foveolar metaplasia

ICD coding

ICD-10: K26 - duodenal ulcer
Subcodes based on hemorrhage, perforation and chronicity

Epidemiology

Incidence is 1 case per 1,000 person years (Pharmacoepidemiol Drug Saf 2011;20:718)
4 times more common than gastric ulcers (StatPearls: Peptic Ulcer Disease [Accessed 1 September 2023])
M > F (StatPearls: Peptic Ulcer Disease [Accessed 1 September 2023])
Incidence worldwide is decreasing in recent decades (Transl Res 2021;232:115)

Sites

Most commonly involves the first part of the duodenum (bulb) (> 95%) (StatPearls: Duodenal Ulcer [Accessed 1 September 2023])
Involvement of other parts of the duodenum is rare, particularly the fourth part

Pathophysiology

Duodenal ulcers develop due to a disruption in the equilibrium between aggressive factors (gastric acid) and protective factors (mucus and bicarbonate [HCO₃-]) (StatPearls: Duodenal Ulcer [Accessed 1 September 2023])
Erosion of the mucosal barrier exposes submucosal layers to gastric acid and enzymes
Most patients have a history of H. pylori infection or heavy NSAID use
H. pylori (StatPearls: Peptic Ulcer Disease [Accessed 1 September 2023])
- Inhibits somatostatin secretion, leading to increased gastrin secretion, which in turn increases hydrogen ion (H+) secretion and delivery to the duodenum
- Direct spread of H. pylori to the duodenum inhibits duodenal HCO₃- secretion, leading to increased acid without adequate neutralization
NSAIDs (StatPearls: Peptic Ulcer Disease [Accessed 1 September 2023])
- Inhibit COX1 and COX2, which decrease prostaglandin production, leading to erosion of the gastric mucosa (prostaglandins may have a protective effect, supporting blood flow and helping to maintain integrity of the mucosa)
- Decrease mucosal blood flow and mucosal cell proliferation

Etiology

H. pylori and NSAID use (see above) promote ulcer formation by interacting with additional risk factors such as smoking, heavy alcohol use, glucocorticoids and caffeine (StatPearls: Duodenal Ulcer [Accessed 1 September 2023])
Diet, stress and genetic factors also play a role (StatPearls: Peptic Ulcer Disease [Accessed 1 September 2023])
Rare causes of peptic ulcers include acid hypersecretory states (e.g., gastrinoma), non-NSAID medications (e.g., bisphosphonates), infections (e.g., cytomegalovirus [CMV]) or systemic inflammatory disease (StatPearls: Peptic Ulcer Disease [Accessed 1 September 2023])

Clinical features

Up to 70% of patients with peptic ulcer disease are asymptomatic (StatPearls: Duodenal Ulcer [Accessed 1 September 2023])
Characteristic symptoms include
- Dyspepsia: postprandial heaviness, early satiety and epigastric pain
- Epigastric pain described as burning or gnawing, often peaking during fasting periods and improving after meals
- Nausea and vomiting
- Abdominal bloating
- Weight gain due to improved symptoms after a meal
Can cause occult blood in stool or signs of internal bleeding (e.g., anemia, hematemesis, melena)
Presentation can vary based on the location and severity of the ulcer, including gastrointestinal bleeding, obstructions, perforation or fistula development

Diagnosis

Suspected in patients with dyspepsia and upper abdominal symptoms with a previous H. pylori diagnosis or a history of NSAID use
Clinical guidelines for diagnosis exist (Am J Gastroenterol 2017;112:988)
Patients < 60 years of age without red flags for dyspepsia begin with noninvasive testing for H. pylori (test and treat strategy) as successful eradication reduces unnecessary esophagogastroduodenoscopies (EGDs) and prolonged trials of acid suppression
- Urea breath test
- Stool antigen test
Patients > 60 years of age, patients with red flags for dyspepsia or patients unresponsive to medical therapy are referred directly to EGD
- Red flags indicating the need for EGD in a younger patient include dysphagia, persistent vomiting, gastrointestinal (GI) bleeding, rapid weight loss and a family history of GI malignancy
Barium endoscopy is an alternative for patients with contraindications to EGD

Laboratory

Testing for rare causes is considered in cases of recurrent ulcers or unclear etiology (J Clin Endocrinol Metab 2022;107:e2110)
- Fasting serum gastrin
- Secretin stimulation test
  - High levels in gastrinoma
- Parathyroid hormone (PTH) level (Gastroenterol Rep (Oxf) 2018;6:231)
- Testing for systemic inflammatory diseases

Radiology description

Upper gastrointestinal (UGI) series: well defined, round or oval, lucent area with a crater-like appearance, often surrounded by edema (Insights Imaging 2021;12:94)
Endoscopy (EGD): ulcer with a smooth base, rounded and regular edges, typically located on the anterior or posterior wall of the duodenal bulb, often accompanied by regular surrounding mucosa
Double contrast barium meal: provides enhanced visibility of ulcer margins, especially for smaller ulcers (Insights Imaging 2021;12:94)

Prognostic factors

Variable depending on the severity of the disease at the time of diagnosis
Duodenal ulcers caused by H. pylori require treatment to eradicate the infection, with rates of resolution varying
Duodenal ulcers caused by heavy NSAID use are treated by discontinuing the drug, with a generally favorable prognosis
Patients with ulcer complications, such as perforation, gastric outlet obstruction and severe ulceration, experience high mortality rates
Reference: StatPearls: Duodenal Ulcer [Accessed 1 September 2023]

Case reports

12 year old boy with atypical perforated duodenal ulcer (BMJ Case Rep 2014;2014:bcr2014204716)
53 year old man with leukemia and perforated duodenal ulcer (J Med Case Rep 2013;7:257)
54 year old man with perforation of gastric and duodenal ulcers (J Med Case Rep 2010;4:272)

Treatment

Treatment is based on the severity of disease at time of diagnosis
Lifestyle modifications
- Smoking cessation
- Avoid NSAIDs
- Alcohol reduction
- Stress management
Acid suppression with proton pump inhibitors (PPIs) or histamine type 2 (H2) receptor antagonists
Eradication of H. pylori infection using antibiotic regimens
- Triple therapy: 2 antibiotics (amoxicillin and clarithromycin) and 1 PPI (e.g., pantoprazole)
Effective management involves addressing underlying causes and promoting mucosal healing
Reference: StatPearls: Duodenal Ulcer [Accessed 1 September 2023]

Clinical images

Contributed by Raul S. Gonzalez, M.D.

Endoscopy

Images hosted on other servers:

Acute duodenal ulceration

Gross description

Benign peptic ulcer (StatPearls: Peptic Ulcer Disease [Accessed 1 September 2023])
- Smooth base
- Rounded, regular edges
- Regular surrounding mucosa
- Usually located on the anterior or posterior wall of the duodenal bulb
Malignant ulcer (for comparison) (Radiology 2009;252:410)
- Base reveals an ulcerated mass protruding into the lumen
- Overhanging, irregular edges
- Nodular, irregular mucosa
- Atypical location

Gross images

Contributed by Raul S. Gonzalez, M.D.

Gastroduodenal junction resection

Microscopic (histologic) description

Fibrinopurulent debris and granulation tissue at site of ulceration, extending at least into lamina propria if not into muscularis mucosae and submucosa
Underlying inflammatory changes
Severe examples may involve full thickness of wall
Adjacent duodenal mucosa may show changes of peptic injury, such as foveolar metaplasia, villous blunting and Brunner gland hyperplasia
H. pylori infection is rare within the duodenum itself and usually occurs in foveolar metaplasia (J Clin Pathol 2021;74:537)

Microscopic (histologic) images

Contributed by Raul S. Gonzalez, M.D.

Granulation tissue

Adjacent mucosa

Fibrinous ulcer

Helicobacter infection in duodenum

Videos

Severe duodenal peptic ulcer

Sample pathology report

Duodenum, ulcer, biopsy:
- Fibrinopurulent debris and granulation tissue, consistent with ulceration
- Background duodenal mucosa with foveolar metaplasia, consistent with peptic injury
- Negative for malignancy

Differential diagnosis

Celiac disease:
- Duodenal mucosa shows villous blunting, which may also occur in the setting of ulceration
- Duodenal mucosa shows increased intraepithelial lymphocytes, which should not occur in the setting of ulceration
Peptic duodenitis:
- This change can be seen in the background of an ulcer but fibrinopurulent debris and granulation tissue should be absent
Malignancy:
- Duodenal adenocarcinoma can also cause ulceration
- Microscopic examination reveals malignant glands or single cells
- Endoscopic appearance is also different (see above)
Crohn's disease:
- May also cause severe duodenal injury, including ulceration
- Lower gastrointestinal involvement should occur
- Duodenal granulomas may be present

Board review style question #1

Which of the following is a major cause of duodenal peptic ulcers?

Celiac disease
Cytomegalovirus (CMV) infection
Gastrinoma
Heavy nonsteroidal anti-inflammatory drug (NSAID) use
Stress

Board review style answer #1

D. Heavy NSAID use. Helicobacter pylori and heavy NSAID use are known to be the 2 main causes of duodenal peptic ulcers. Answers B, C and E are incorrect because CMV infection, gastrinoma elsewhere and stress are minor / uncommon causes of peptic ulcers. Answer A is incorrect because celiac disease does not generally cause peptic ulcers.

Comment Here

Reference: Duodenal peptic ulcer

Board review style question #2

Which of the following gross features suggests a duodenal ulcer is benign and peptic in nature, rather than malignant in nature?

Atypical / unusual location within the duodenum
Nodular, irregular mucosa
Overhanging, irregular edges
Smooth base
Ulcerated mass protruding into the lumen

Board review style answer #2

D. Smooth base. Benign ulcers usually have a smooth base. Answer A is incorrect because benign ulcers have a typical location, generally the anterior or posterior wall of the duodenal bulb. Answers B and C are incorrect because benign ulcers usually have rounded, regular edges with normal surrounding mucosa. Answer E is incorrect because a mass lesion should not be seen in a benign ulcer.

Comment Here

Reference: Duodenal peptic ulcer

Duplication

Table of Contents

Definition / general | Case reports | Treatment

Definition / general

Saccular to long, cystic structures which usually have shared muscular wall (so incomplete duplication)
More common in ileum, near ileocaecal valve; rare in duodenum, where choledochocele (cystic or diverticular dilatation of terminal intramural portion of the common bile duct) is more common
Present with abdominal mass, pain, vomiting and chronic rectal bleeding
Associated with gastric heterotopia but not associated with vertebral body abnormalities

Case reports

51 year old man with adenocarcinoma arising in a cystic duplication (World J Surg Oncol 2012;10:55)

Treatment

Resect entire duplication and segment of normal bowel attached to it

Enteritis cystica profunda

Table of Contents

Definition / general | Microscopic (histologic) description | Microscopic (histologic) images

Definition / general

Mucosal glands and mucinous cysts in submucosa or deeper layer (J R Soc Med 2004;97:29, Arch Pathol Lab Med 2010;134:378)
Usually asymptomatic but may cause obstruction or intussuception
Pathogenesis: herniation, implantation after ulceration, mucosal microdiverticula and reepithelialization of fistulae (e.g. in Crohn's disease)

Microscopic (histologic) description

Mucosal glands and mucinous cysts in submucosa or deeper (subserosa) layer with hemosiderin, foreign body giant cells and lamina propria around the epithelium

Microscopic (histologic) images

Images hosted on other servers:

Mucin filled cysts (PAS diastase)

Enterogenous cysts

Table of Contents

Definition / general | Microscopic (histologic) description | Additional references

Definition / general

Found in wall of small bowel, mesentery, posterior mediastinum or rectorectal space
May be associated with vertebral body abnormalities

Microscopic (histologic) description

Lined by respiratory, small intestinal or gastric epithelium
Wall composed of irregularly oriented smooth muscle

Additional references

J Indian Assoc Pediatr Surg 2012;17:68, J Pediatr Surg 2004;39:e5

Eosinophilic gastroenterocolitis redirect

Gangliocytic paraganglioma

Table of Contents

Definition / general

Rare tumor of periampullary region and second part of duodenum

Essential features

Duodenal neoplasm that rarely metastasizes
Triphasic histology (epithelioid, spindle, ganglion type cells) and immunoprofile are characteristic and distinctive

ICD coding

ICD-10: D13.2 - Benign neoplasm of duodenum

Sites

Almost all arise in the duodenum or around ampulla of Vater
May very rarely arise elsewhere (such as in the nasopharynx, Arch Pathol Lab Med 2001;125:1098)

Etiology

May derive from endodermal neuroectodermal complexes in the embryonic ventral pancreas (Am J Surg Pathol 1985;9:31)

Clinical features

15 - 84 years (mean 52 years) (BMC Cancer 2011;11:187)
M > F (1.5:1) (BMC Cancer 2011;11:187)
Presents with GI bleeding or abdominal pain but may be incidental finding
Usually benign and nonfunctional; very rarely produces hormones (J Gastrointest Oncol 2016;7:S107)
Approximately 7% metastasize to lymph nodes (BMC Cancer 2011;11:187)
- Very rarely metastasizes widely and may cause patient death (World J Clin Cases 2017;5:222)
May recur if incompletely excised

Diagnosis

Tissue diagnosis required

Radiology images

Images hosted on other servers:

CT scan

Prognostic factors

Almost always benign but distant metastases can rarely occur

Case reports

47 year old man with widely metastatic gangliocytic paraganglioma (World J Gastroenterol 2014;20:15454)
55 year old woman with gangliocytic paraganglioma of the thymus (J Pathol Transl Med 2016;50:165)
68 year old woman with gangliocytic paraganglioma metastatic to peripancreatic lymph node (Diagn Pathol 2017;12:57)
71 year old man with gangliocytic paraganglioma of the minor papilla (Intern Med 2017;56:1029)
73 year old woman with gangliocytic paraganglioma and concurrent ampullary adenocarcinoma (Intern Med 2018;57:2663)

Treatment

Endoscopic resection (Gastroenterol Hepatol 2016;39:605)

Clinical images

Images hosted on other servers:

Periampullary submucosal tumor

Gross description

Usually 1 - 3 cm, sessile or polypoid, no capsule

Gross images

Images hosted on other servers:

Tumor near ampulla

Microscopic (histologic) description

Unencapsulated submucosal lesion
Triphasic, with epithelioid, spindle cell (Schwann cell-like) and ganglion type cells of varying proportions
- May therefore resemble well differentiated neuroendocrine tumor, paraganglioma or ganglioneuroma
Variable stromal amyloid (Am J Surg Pathol 1977;1:207)

Microscopic (histologic) images

Contributed by Raul S. Gonzalez, M.D.

Submucosal tumor

Nests and trabeculae

Epithelioid cells

Spindled cells

Ganglion cells

Cytology description

All 3 cell types may be visible in aspirated material (Diagn Cytopathol 2013;41:650)

Positive stains

Epithelioid cells: pancreatic polypeptide, progesterone receptor, somatostatin, synaptophysin, chromogranin, CD56 (BMC Cancer 2015;15:269)
Ganglion cells: S100, pancreatic polypeptide, somatostatin, synaptophysin, chromogranin, CD56
Spindle cells: S100, BCL2 (67%)

Negative stains

Epithelioid cells: S100, p53 (BMC Cancer 2015;15:269)
Ganglion cells: progesterone receptor, pancytokeratin, estrogen receptor, p53
Spindle cells: pancreatic polypeptide, progesterone receptor, somatostatin, synaptophysin (25%), chromogranin, CD56, estrogen receptor, p53

Molecular / cytogenetics description

May show HIF2A gain of function mutations (Endocr Relat Cancer 2016;23:L13)

Sample pathology report

Ampulla, mass, resection:
- Gangliocytic paraganglioma (2.2 cm) (see comment)
- Margins of resection unremarkable.
- Comment: Immunohistochemical stains for S100 and synaptophysin highlight various components of this uncommon triphasic neoplasm, which is typically indolent but can rarely metastasize.

Differential diagnosis

Ganglioneuroma:
- Rare in the ampulla / duodenum
- Difficult to distinguish if ganglion cells are predominant in gangliocytic paraganglioma
Paraganglioma:
- Rare in the ampulla / duodenum
- S100+ sustentacular cells are arranged around nests of epithelioid cells, rather than forming regions of the tumor
Well differentiated neuroendocrine tumor:
- Can be difficult, depending on sampling
- Progesterone receptor and pancreatic polypeptide staining may help (Arch Pathol Lab Med 2017;141:1309)

Board review style question #1

Which of the following cell types are seen in gangliocytic paraganglioma?

Blister, ganglion and stem
Epithelioid, ganglion and spindle
Epithelioid, ganglion and sustentacular
Epithelioid, stem and spindle

Board review style answer #1

B. Epithelioid, ganglion and spindle

Comment Here

Reference: Gangliocytic paraganglioma

Board review style question #2

The following picture shows a lesion resected from the ampulla. Which of the following is true?

Similar tumors may rarely be seen outside the ampulla
The patient is at high risk for distant metastasis
The patient likely has MEN1 syndrome
This lesion usually shows translocations involving EWS

Board review style answer #2

A. Similar tumors may rarely be seen outside the ampulla. The picture shows a gangliocytic paraganglioma, which usually occurs in the ampulla but can rarely arise in other gastrointestinal or extragastrointestinal sites.

Comment Here

Reference: Gangliocytic paraganglioma

Giardia lamblia

Table of Contents

Definition / general

Protozoan disease caused by Giardia lamblia / Giardia intestinalis, a common parasite that can be detected in small bowel biopsies; it can also be detected in stool
Clinical presentation ranges from asymptomatic shedding of giardial cysts to symptomatic giardiasis (i.e., malabsorption, chronic diarrhea)

Essential features

Protozoan disease with asymptomatic colonization or acute or chronic diarrheal illness; can be histologically confirmed by visualization of the organisms

Terminology

Giardia intestinalis
Giardia duodenalis
Giardia lamblia
Beaver fever

ICD coding

ICD-10: A07.1 - giardiasis (lambliasis)

Epidemiology

Found throughout the world but less common in developed countries (Int J Parasitol 2012;42:443)
Common in areas with poor sanitation and limited water treatment facilities (Recent Pat Inflamm Allergy Drug Discov 2019;13:134)
Infection is more common in children than in adults
Equal in both sexes
Persons at increased risk are children, travelers to endemic areas, workers and children in daycare settings, individuals with immunodeficiency, cystic fibrosis patients and individuals who practice unprotected oral - anal sex (Recent Pat Inflamm Allergy Drug Discov 2019;13:134)

Sites

Found in the small intestine, classically duodenum
Jejunum, ileum and stomach are other possible sites (Scand J Gastroenterol 1997;32:48)

Pathophysiology

Giardia intestinalis infection causes enterocyte damage and loss of brush border of the epithelial cells of the small intestine, which leads to shortening of microvilli and altered epithelial barrier function (Curr Top Med Chem 2018;18:1287)
Mucosal alterations cause watery diarrhea, malabsorptive steatorrhea, nausea, abdominal pain, vomiting and weight loss
Main consequence of Giardia colonization is nutrient malabsorption
Most infections are asymptomatic

Etiology

Causative agent is flagellate protozoan Giardia intestinalis (also known as G. lamblia or G. duodenalis) (Int J Parasitol 2012;42:443)
Giardia exists in 2 forms: trophozoites and cysts
Trophozoites: motile, 4 pairs of flagellates, pear shaped organism
Cysts: elliptical infective form
Infection is transmitted through feco-oral route, frequently through ingestion of contaminated water and food or person to person transmission through contaminated surfaces or objects (Recent Pat Inflamm Allergy Drug Discov 2019;13:134)

Diagrams / tables

Images hosted on other servers:

Life cycle

Clinical features

Most infections are asymptomatic
Symptomatic infections can present as acute or chronic infection; acute infection manifests as aqueous diarrhea, nausea, vomiting and fever, whereas chronic infection is associated with loose stools, malabsorption and resultant weight loss (Int J Surg Pathol 2021;29:257)
Main consequence of Giardia colonization is nutrient malabsorption

Diagnosis

Diagnostic test of choice depends on clinical presentation and feasibility
Demonstration by microscopy of Giardia trophozoites or cysts in stool specimens (sensitivity of 50 - 70%) (J Clin Diagn Res 2014;8:DC04)
Detection of Giardia antigen in stool (sensitivity of 95 - 100%) (J Clin Diagn Res 2014;8:DC04)
PCR assay for detecting Giardia in stool
Histological demonstration of Giardia organisms in small intestinal biopsy; this is most important in chronic subset of patients

Laboratory

Stool examination: detection of Giardia trophozoites or cysts in stool specimens by microscopic examination of wet mounts and concentrated samples or after preservation with polyvinyl alcohol or 10% formalin for permanent staining with trichrome or iron hematoxylin stains
Sensitivity of stool test increases to > 90% with 3 serial specimens collected every 2 - 3 days
Direct fluorescent antibody (DFA) test detects intact organisms
Enzyme linked immunosorbent assay (ELISA) detects soluble antigens in the stool
PCR assays can detect specific genes of the parasite in stool samples
Direct aspiration of the duodenum or use of the commercially available string test (Enterotest)
Duodenal biopsy (Recent Pat Inflamm Allergy Drug Discov 2019;13:134)

Prognostic factors

Overall prognosis is good with treatment
Dehydration can be life threatening for infants and pregnant women
Chronic diarrhea might lead to rectal prolapse
Reference: Recent Pat Inflamm Allergy Drug Discov 2019;13:134

Case reports

31 year old woman with skin lesions due to giardiasis treated with antiparasitic treatment (Ann Agric Environ Med 2005;12:299)
Woman in her 40s with intestinal pseudo-obstruction caused by Giardia lamblia infection (BMJ Case Rep 2022;15:e252319)
66 year old man with an acute respiratory distress syndrome due to SARS-CoV-2 infection and hypereosinophilia due to giardiasis reactivation (Parasitol Int 2021;80:102241)

Treatment

Commonly treated by antibiotics such as metronidazole, tinidazole and nitazoxanide
Symptomatic management, such as avoiding dehydration in case of extensive diarrhea (Int J Surg Pathol 2021;29:257)

Clinical images

Images hosted on other servers:

Duodenal giardiasis on endoscopy

Gross description

Mostly normal appearing mucosa
Blunting of villi resembling celiac sprue
Congestion, erythema, erosion, nodular mucosa, rarely polyps (Int J Surg Pathol 2021;29:257)

Gross images

Contributed by Centers for Disease Control and Prevention

Giardia

Microscopic (histologic) description

Wide range of histological features
Range of normal villous architecture to variable villous blunting and expansion
Increased intraepithelial lymphocytes
Increased inflammatory cells and prominent lymphoid aggregates in the lamina propria (Int J Surg Pathol 2021;29:257)
Demonstration of organisms is diagnostic; they float freely in the lumen between the duodenal villi, adhere to the mucosal surface or are located in the cytoplasm of the epithelial cells but not invading (Hum Pathol 2009;40:323)
Organisms are pear shaped or have a falling leaves appearance and are about the size of an epithelial cell nucleus (often misinterpreted as sloughed epithelial cells or luminal contents), with 2 nuclei, mostly pale eosinophilic to translucent in crescent shaped trophozoites
If the diagnosis of giardiasis is made, the pathologist should routinely check the lamina propria for plasma cells since chronic giardiasis can be seen with CVID and a paucity of plasma cells could be a clue to this second diagnosis

Microscopic (histologic) images

Contributed by Iresha Vithanage, M.B.B.S., M.D., Saroona Haroon, M.B.B.S., Bobbi Pritt, M.D.,
Emily Fernholz, MLS (ASCP), Suhail Muzaffar, M.B.B.S. and Bilal Karim Siddiqui, M.D. (Case #157)

Normal villous morphology

Giardia organisms in intervillous spaces

Kite and pear shaped Giardia

Giardia trophozoites
along surface of
foveolar epithelial cells

Sickle shaped trophozoites

Trichrome stained stool specimen, Giardia duodenalis

Giardia trophozoites

Virtual slides

Images hosted on other servers:

Giardia trophozoite, Giemsa stain

Cytology description

Duodenal fluid aspiration cytology shows pear or teardrop shaped organisms containing multiple flagella (Am J Surg Pathol 2017;41:570)
Brush cytology of the duodenum detected giardiasis in a few cases with negative mucosal biopsy findings along with multiple negative stool examinations

Cytology images

Contributed by @JMGardnerMD on Twitter

Giardia lamblia

Positive stains

Trichrome with iron hematoxylin counterstain; methylene blue positively stains the trophozoites; Giemsa stain
CD117 / KIT immunostain is positive (Hum Pathol 2009;40:323)

Videos

Giardiasis tutorial

Sample pathology report

Duodenum, biopsy:
- Multiple pear shaped microorganisms seen on villous surface, consistent with Giardia
- Increased intraepithelial lymphocyte count noted

Differential diagnosis

Celiac disease:
- Strong morphological mimic; no Giardia organisms identified
Normal duodenal biopsy:
- Sloughed epithelial cells and extruded mucin, common in normal duodenal biopsies, are in the differential diagnosis; however, the morphology will be different

Additional references

J Pak Med Assoc 1994;44:206, J Clin Pathol 1990;43:641, Scand J Gastroenterol 1995;30:905

Board review style question #1

After a long hiking trip, most children in a large family group developed watery diarrhea, fatigue and stomach cramps along with bloating. At the hospital visit, the affected children told the doctor that they drank directly from the streams and river without the use of water purifier tablets or filters during the trip. Various tests were requested, including multiple stool samples collected over several days. Stool microscopy with direct fluorescent antibody testing (DFA) showed that the kids had giardiasis. If a duodenal biopsy is performed, which of the following is most likely to be true of the findings?

Deeper part of the small intestinal mucosa is frequently invaded by Giardia
Duodenal villous architecture can never be normal in this condition
Giardia organisms are pear shaped
Giardia organisms cannot be seen by light microscope
Immunohistochemical studies are mandatory for diagnosis

Board review style answer #1

C. Giardia organisms are pear shaped. This is the correct answer as Giardia organisms can be described as pear shaped or as having a falling leaves appearance. Answer B is incorrect because the duodenal mucosa's villous architecture can be normal with organisms only floating on the surface in giardiasis. Answer E is incorrect because immunohistochemical studies, although utilized in some cases (such as CD117), are not mandatory in routine diagnosis of Giardia in biopsies. Answer A is incorrect because the organisms are usually found floating freely in the lumen between the duodenal villi, adhered to the mucosal surface or in the cytoplasm of the superficial epithelial cells but never in deeper parts of mucosal tissue. Answer D is incorrect because Giardia organisms are identifiable on light microscopy on routine H&E stain and are similar in size to duodenal epithelial cells (Int J Surg Pathol 2021;29:257, Hum Pathol 2009;40:323).

Comment Here

Reference: Giardia lamblia

Board review style question #2

A 39 year old man presents to a general physician with malaise, episodic watery diarrhea and mild weight loss for the past 3 months. There is no significant past medical or surgical history. His vitals are stable, apart from mild tachycardia. On upper GI endoscopy, there was duodenal nodularity. Biopsy is taken with the clinical suspicion of celiac disease. The histopathological section image is given above. What is the diagnosis?

Celiac disease
Duodenal amebiasis
Duodenal giardiasis
Helicobacter pylori infection
These are nonspecific findings

Board review style answer #2

C. Duodenal giardiasis, since the photomicrograph shows many Giardia organisms on the mucosal surface of small intestinal villi. Answer A is incorrect because in celiac disease, although the histological features can be simulated, there will be no Giardia organisms. Answer B is incorrect because in duodenal amebiasis, the morphology of the organisms is different; it is also very rare. Answer D is incorrect because in Helicobacter pylori infection, there will be V shaped / sea gull shaped or curved comma shaped tiny organisms. Answer E is incorrect because there are organisms on the surface of duodenal mucosa; therefore, these findings are not nonspecific (Int J Surg Pathol 2021;29:257).

Comment Here

Reference: Giardia lamblia

GIST

Table of Contents

Definition / general

Most common mesenchymal tumor of the gastrointestinal (GI) tract
Derived from interstitial cells of Cajal

Essential features

Small bowel is second most common site of GISTs (stomach is first)
NF1 and BRAF mutated GISTs are more common in small bowel versus other sites
Prognosis depends on size, mitotic rate and location

Terminology

Gastrointestinal stromal tumor (GIST)

ICD coding

- ICD-10: C49.A3 - gastrointestinal stromal tumor of small intestine
- ICD-11: 2B5B&XH9HQ1 - gastrointestinal stromal tumor
- ICD-O: 8936/3 - gastrointestinal stromal tumor, malignant

Epidemiology

M:F = 1
Median age is 60 - 65 years; rare in children and young adults
May present in younger patients in neurofibromatosis type 1 (NF1) lesions (mean age 49 years), Carney triad (childhood), familial (middle age)
Annual incidence of GIST is between 11 and 14.5 cases per million (Int J Cancer 2005;117:289, Cancer 2005;103:821)
GISTs account for 1 - 3% of all GI neoplasms

Sites

Occurs anywhere in tubular GI tract
Small bowel is second most common site
Stomach (60%) > jejunum and ileum (30%) > duodenum (4 - 5%) > rectum (4%) > colon and appendix (1 - 2%) > esophagus (< 1%) (Semin Diagn Pathol 2006;23:70)
Extraintestinal GISTs occur in mesentery, omentum, retroperitoneum (Am J Surg Pathol 2005;29:52, Mod Pathol 2000;13:577)
- May represent a metastasis from an unrecognized primary or a detached mass from the GI tract

Pathophysiology

Sporadic - vast majority
- Somatic mutations in KIT (70 - 85%), PDGFRA (5 - 10%, mutually exclusive with KIT mutations), NF1 and BRAF (Science 2003;299:708, Cancer Res 2001;61:8118)
Sporadic tumor syndrome (nonhereditary)
- Carney triad (GIST, paraganglioma, pulmonary chondroma)
  - SDH deficient but lacking SDH germline mutations
Autosomal dominant hereditary syndromes (5 - 10% of all GISTs)
- Neurofibromatosis type 1 (NF1) - commonly small bowel and often multifocal
- Germline KIT mutations
- Germline PDGFRA mutations
- Carney-Stratakis syndrome
  - Germline mutations in SDHB, SDHC or SDHD subunit (Arch Pathol Lab Med 2020;144:655)

Etiology

Unknown, most cases are sporadic
Small subset of cases can be familial (see Pathophysiology)

Diagrams / tables

Images hosted on other servers:

Guidelines for risk assessment of primary GIST

Clinical features

Vague abdominal pain
Symptoms related to mucosal ulceration, including bleeding (47%) (Ther Clin Risk Manag 2018;14:1467)
Abdominal mass
Smaller GISTs are discovered incidentally
NF1 associated GISTs (Am J Surg Pathol 2006;30:90)
- Patients are more likely to develop multiple independent GISTs
- NF1 tumors have a strong predilection to arise in small bowel
- While NF1 associated GISTs have been estimated to account for only about 1 - 2% of tumors from all anatomic sites, they make up ~4 - 6% of small intestinal GISTs

Diagnosis

Double balloon enteroscopy (89%), CT angiography (71%) and CT (55%) are best imaging modalities (Ther Clin Risk Manag 2018;14:1467)
Endoscopy with biopsy or fine needle aspiration

Radiology description

Radiologic findings are variable, depending on size and time of presentation
CT usually shows a solid, heterogeneous mass (reflecting the presence of hemorrhage or cystic degeneration)
Endoscopic ultrasound reveals a hypoechoic solid mass
References: Front Oncol 2021;11:582847, Front Oncol 2021;11:631927

Radiology images

Images hosted on other servers:

Duodenal GIST

Jejunal GIST

Ileoileal intussusception - small bowel GIST

Prognostic factors

Prognosis depends on site, size, mitotic activity, molecular profile (Semin Diagn Pathol 2006;23:70)
Small bowel GISTs are more likely to be malignant (35 - 40%) compared with gastric GISTs (25%) (Am J Surg Pathol 2006;30:477, Am J Surg Pathol 2005;29:52)
NF1 mutated GISTs are usually grossly small and mitotically inactive, much like spontaneous low grade GISTs of the small intestine
- Their histologically benign appearance is reflected in their commonly nonaggressive clinical behavior
- NF1 associated tumors that do manifest as clinically malignant disease are generally bigger (> 5 cm in greatest dimension) and more proliferative (> 5 mitoses/5 mm²), adhering to the risk stratification provided by standard staging criteria

Case reports

58 year old woman with small bowel GIST presenting as intussusception (GE Port J Gastroenterol 2016;23:279)
68 year old woman with small bowel GIST with diffuse omental and mesenteric implants (J Surg Case Rep 2020;2020:rjaa341)
74 year old man with small bowel GIST presenting as strangulated inguinal hernia (BMJ Case Rep 2017;2017:bcr2016217273)
75 year old woman with NF1 jejunal GIST ( J Surg Case Rep 2018;2018:rjy017)

Treatment

Most GISTs are treated with surgical resection
Imatinib mesylate (Gleevec): tyrosine kinase inhibitor of KIT and PDGFRα
- Metastatic / recurrent / high risk GIST
Sunitinib malate (Sutent): a tyrosine kinase inhibitor of KIT, PDGFRα, VEGFR
- Used in imatinib resistant GIST
NF1 mutated GISTs - surgery is treatment of choice as these tumors do not respond to imatinib
BRAF mutated GISTs do not respond to imatinib and BRAF inhibitors are used for therapy if indicated
References: Am J Surg Pathol 2015;39:922, Surg Clin North Am 2017;97:437

Clinical images

Images hosted on other servers:

Small bowel GIST

Endoscopy of ulcerated mass

Gross description

Well circumscribed masses of various sizes
Cut surface may show hemorrhage, cystic change or necrosis
Usually centered in the muscularis propria
Small bowel GISTs more frequently present as external masses
Reference: Am J Surg Pathol 2009;33:1267

Gross images

Contributed by Shefali Chopra, M.D.

Adherent small bowel

Hemorrhage & cystic change

Frozen section description

Spindle cell neoplasm

Microscopic (histologic) description

3 morphologic types: spindle (70%), epithelioid (20%), mixed (10%)
Monotonous, bland cells with spindled or epithelioid cytoarchitecture, lightly eosinophilic to pale cytoplasm and vesicular chromatin residing within uniformly ovoid or round nuclei
In spindle cell GISTs, the pink cytoplasm often has a fibrillary texture with indistinct cell borders
Can show a degree of nuclear palisading reminiscent of schwannoma
Small intestinal GISTs are most often spindled
- Epithelioid morphology in small intestinal GIST portends malignant behavior, in contrast to the stomach, where epithelioid morphology is not a significant prognostic feature
Small intestine GISTs more commonly feature skeinoid fibers, stromal PAS positive globules of curved collagen fibrils, which, when present in a small intestinal tumor, correlate with less malignant clinical behavior
Treated tumors can display a widely variable histomorphology that may significantly differ from treatment naive tumors
- Tumor may be necrotic or hypocellular; the stromal component, which may be hyalinized or calcified, becomes prominent
- Cytomorphology of the tumor cells can change, usually adopting a more epithelioid and even anaplastic or sarcomatoid appearance
Histologic grade
- G1: low grade, mitoses < 5/5 mm²
- G2: High grade, mitoses > 5/5 mm²
References: Am J Surg Pathol 2017;41:577, Arch Pathol Lab Med 2020;144:655

Microscopic (histologic) images

Contributed by Shefali Chopra, M.D.

Relation to overlying mucosa

Skeinoid fibers

Spindle cell morphology

Therapy effect

CD117

DOG1

Virtual slides

Images hosted on other servers:

Duodenal GIST

Cytology description

Bland spindle and sometimes epithelioid cells
EUS-FNA with IHC staining of cell block can lead to diagnosis
- If not enough material and large tumor size, there might not be enough for genotyping to guide neoadjuvant therapy
Without enough tissue to perform immunohistochemical stains, it might be hard to get to a definitive diagnosis
Reference: Diagn Cytopathol 2021 May 18 [Epub ahead of print]

Cytology images

Contributed by Shefali Chopra, M.D.

Diff-Quik, spindle cells

Pap, spindle cells

Cell block, spindle cells

Positive stains

DOG1 - 98% (Am J Pathol 2004;165:107)
CD117 - 95% (Am J Surg Pathol 2009;33:1401)
CD34 (Am J Surg Pathol 2006;30:477)

Negative stains

S100
Desmin
CK AE1 / AE3
SMA - 34% in small bowel GISTs (Am J Surg Pathol 2006;30:477)
NF1 (loss of expression of NF1; antibody specific to C terminus) - may help in identifying NF1 associated GISTs (Mod Pathol 2018;31:160)

Molecular / cytogenetics description

See Pathophysiology

Molecular / cytogenetics images

Images hosted on other servers:

KIT mutations

Videos

Small bowel GIST

Sample pathology report

Duodenum, resection:
- Gastrointestinal stromal tumor (GIST), spindle cell type, 3.0 cm, grade 1 (see synoptic report for risk stratification as well as biomarker report)

Differential diagnosis

Low grade spindle GISTs
- Leiomyoma:
  - Eosinophilic cytoplasm, blunt ended cigar shaped nuclei
  - Cytoplasmic vacuolization present
  - Positive for desmin and negative for CD117 and DOG1
- Schwannoma:
  - Cuff of lymphocytes
  - Verocay bodies
  - Positive for S100 and negative for DOG1 and CD117
- Solitary fibrous tumor:
  - Patternless pattern
  - Collageneous stroma
  - STAT6 positive and negative for DOG1 and CD117
- Inflammatory myofibroblastic tumor:
  - Prominent inflammatory infiltrate
  - ALK positive and negative for DOG1 and CD117
High grade spindle GISTs
- Leiomyosarcoma:
  - Eosinophilic cytoplasm, blunt ended cigar shaped nuclei
  - Positive for desmin and negative for CD117 and DOG1
- Dedifferentiated liposarcoma:
  - Well differentiated component usually present
  - Positive for MDM2 amplification by FISH, negative for CD117 and DOG1
- Spindle cell carcinoma:
  - Positive for pancytokeratin and negative for CD117 and DOG1

Additional references

WHO Classification of Tumours Editorial Board: Digestive System Tumours, 5th Edition, 2019

Board review style question #1

Which of the following is true regarding gastrointestinal stromal tumors in NF1 patients?

Always associated with KIT mutation
Epithelioid in morphology with loss of SDHB immunostaining by immunohistochemistry
More aggressive than sporadic GISTs and present with metastasis
Tumor can be multiple, is spindle cell in morphology, located in small intestine and indolent in behavior

Board review style answer #1

D. Tumor can be multiple, is spindle cell in morphology, located in small intestine and indolent in behavior

Comment Here

Reference: Gastrointestinal stromal tumor (GIST)

Board review style question #2

Besides KIT and PDGFRa mutations, what other mutations can be seen more commonly in small intestinal GISTs?

BRAF
IDH
KRAS
SDH

Board review style answer #2

A. BRAF

Comment Here

Reference: Gastrointestinal stromal tumor (GIST)

Grossing & features to report

Table of Contents

Grossing | Features to report - small intestine | Features to report - ampulla | Organizations

Grossing

Ink pancreatic duct and common bile duct margins, also retroperitoneal margin
Probe common bile duct and pancreatic duct, and section along plane of both probes
Should examine at least 12 lymph nodes in a pancreaticoduodenectomy specimen

Features to report - small intestine

Tumor location
Histologic type
Histologic grade if relevant (well differentiated: > 95% glands; moderately: 50 - 95% glands; poorly: 5 - 49% glands; undifferentiated: < 5% glands)
Tumor size
Extent / depth of invasion
Margin involvement (proximal, distal, radial [soft tissue closest to deepest tumor penetration]) and distance of tumor to margin
Invasion of other structures
Obstruction, perforation, ulceration, proximal dilation
Nuclear grade, presence of necrosis
Angiolymphatic invasion
Other pathologic findings (polyps, Crohn's disease, celiac disease)
Nodal involvement (number involved, number identified)
Results of special studies

Features to report - ampulla

Specimen type
Tumor site
Presumed tumor origin (intraampullary, periampullary duodenum, mixed, common bile duct, pancreatic)
Histologic type
Histologic grade (well, moderate, poor or undifferentiated)
Tumor size (invasive carcinoma component)
Depth of invasion, local extension
Margins - invasive carcinoma; distance to closest margin and identify margin (recommended to ink posterior retroperitoneal surface of pancreas and submit sections of tumor closest to this margin)
Margins - carcinoma in situ; involvement of pancreatic duct or common bile duct margin
Margins - PanIn
Pathologic staging
Perineural invasion (for resections)
Angiolymphatic invasion (for resections)
Lymph nodes
Additional findings: PanIN / dysplasia, adenoma, inflammation, adenomyosis, pancreatitis, gastritis, other

Organizations

Features to report by organization:
Arch Pathol Lab Med 2000;124:46

Heterotopic gastric mucosa

Table of Contents

Definition / general

Mature gastric tissue found outside the stomach
Gastric fundic heterotopia represents a developmental anomaly and is frequently associated with Meckel diverticulum

Essential features

Developmental anomaly characterized by ectopic gastric mucosa outside the stomach
Histologically composed of foveolar epithelium with specialized antral glands with or without oxyntic mucosa
Clinical features can vary from asymptomatic to abdominal pain, obstruction, intussusception, perforation, palpable mass, ulceration, stricture, etc., depending on the site
Treatment is surgical removal of ectopic mucosa for symptomatic lesions

Terminology

Heterotopic gastric mucosa (HGM) or ectopic gastric mucosa

ICD coding

ICD-10:
- Q40.2 - other specified congenital malformations of stomach
- Q43.3 - congenital malformations of intestinal fixation

Epidemiology

Incidence in the duodenum varies from 0.5 to 14.3% (Pathol Res Pract 2011;207:148)

Sites

Can be found in oral cavity, esophagus, duodenum, jejunum, ileum, rectum, anal canal, gallbladder and bile duct
Occurrence in the small intestine is rare unless associated with remnants of Meckel diverticulum (Case Rep Gastroenterol 2020;14:609)
Commonly occurs in the first and second portion of the duodenum (Int J Clin Exp Pathol 2012;5:46)

Pathophysiology

Error in the differentiation of pluripotent primitive endoderm stem cells could lead to the gastric mucosa being present anywhere throughout the gastrointestinal tract
CDX2 stimulates markers of enterocyte differentiation; null mutation of CDX2 can lead to the development of ectopic lesions with a gastric phenotype in the midgut endoderm (J Cell Biol 1997;139:1553)

Etiology

Mainly a congenital malformation

Clinical features

Symptoms caused by gastric heterotopia depend on location, as well as size of the heterotopic tissue
In the majority of cases, patients are asymptomatic due to the small size of the lesion and diagnosis is made incidentally on endoscopy performed for other indications
In both small and large intestines, it can give rise to abdominal pain, obstruction, intussusception, perforation, palpable mass, ulceration, stricture, bleeding per rectum and anemia (J Pediatr Surg 2008;43:e19)

Diagnosis

These heterotopic lesions cannot be accurately diagnosed by imaging or endoscopic visualization due to lack of specific features, rendering histopathologic examination as the gold standard for precise diagnosis

Radiology description

CT scan, fluoroscopy, capsule endoscopy and 99mTc pertechnetate scan can usually detect heterotopic gastric mucosa
Capsule endoscopies have been shown to be superior compared with other radiological investigations, including barium contrast studies, computed tomographic enteroclysis, push enteroscopy and MRI
Reference: Medicine (Baltimore) 2017;96:e5854

Radiology images

Images hosted on other servers:

33 year old man with HGM in ileum

12 year old girl with extensive HGM

Prognostic factors

Patients with extensive heterotopia are at increased risk of adverse outcome, including massive hemorrhage or rarely death (Pediatr Dev Pathol 2000;3:277)

Case reports

33 year old man with heterotopic gastric mucosa in ileum (Case Rep Gastroenterol 2020;14:609)
38 year old woman with gastric heterotopia (Case Rep Gastroenterol 2015;9:233)
61 year old man with pancreatic and gastric heterotopia (Case Rep Gastrointest Med 2017;2017:3126108)

Treatment

Surgery is the treatment of choice, whether it is carried out by laparoscopy or laparotomy
Intraoperative gamma counter use has also been reported as a useful method of localizing bowel segments with nonpalpable areas of heterotopic gastric mucosa for resection (J Pediatr Surg 2001;36:1720)

Gross description

Can present as a polypoidal lesion leading to intestinal obstruction, intussusception

Gross images

Case #124

Intraluminal polyp

Images hosted on other servers:

33 year old man with HGM in ileum

14 year old boy with HGM in ileum

Microscopic (histologic) description

Lesions consist of full mucosal thickness of specialized gastric glands characterized by chief and parietal cells and surface lined by gastric foveolar epithelium
- Histologically, oxyntic mucosa may not be seen in all cases of gastric heterotopia
Prevalence and risk of malignant transformation of heterotopic gastric mucosa are not entirely understood (J Pediatr Gastroenterol Nutr 2010;50:329)
- Some reports have described heterotopic gastric mucosa progressing to malignancy in the esophagus, gallbladder and rectum (Korean J Pathol 2013;47:289)
Presence of H. pylori organism in heterotopic gastric mucosa in Meckel diverticulum is a rare histological finding; in the last 22 years, 12 published reports were found that specifically looked into the presence of H. pylori in a heterotopic gastric mucosa in a Meckel diverticulum (Clin Med Insights Case Rep 2019;12:1179547619846088)

Microscopic (histologic) images

Contributed by Khalid Amin, M.D.

Ileal polypoid lesion

Gastric glands

Jejunal polypoid lesion

Underlying antral glands

Molecular / cytogenetics description

Altered expression of cell cycle molecules (the CIP / KIP family) can be associated with heterotopic gastric mucosa (Ann Gastroenterol 2013;26:184)

Sample pathology report

Polyp, duodenum, polypectomy:
- Consistent with gastric heterotopic mucosa

Differential diagnosis

Gastric metaplasia:
- Characterized by gastric foveolar epithelium and absence of specialized antral glands seen in heterotopic gastric mucosa

Board review style question #1

Which of the following statements about gastric heterotopia is true?

Always a sequelae of chronic inflammation
Can be associated with null mutation in CDX2 gene
Microscopy shows gastric foveolar epithelium with absence of specialized gastric glands
No malignant potential

Board review style answer #1

B. Can be associated with null mutation in CDX2 gene

Comment Here

Reference: Heterotopic gastric mucosa

Board review style question #2

Which organism can colonize heterotopic gastric mucosa?

Crytosporidium
Helicobacter pylori
Tropheryma whipplei
Trypansosoma cruzi

Board review style answer #2

B. Helicobacter pylori (Am J Gastroenterol 2003;98:1266)

Comment Here

Reference: Heterotopic gastric mucosa

Heterotopic pancreas

Table of Contents

Definition / general | Gross description | Microscopic (histologic) description | Differential diagnosis | Additional references

Definition / general

Also called adenomyoma, myoepithelial hamartoma (although without pancreatic tissue)
Incidence of 1 - 14%, affects all ages but peaks in 4 - 6th decade
Most common near ampulla of Vater; also stomach, jejunum
May cause blockage of duct, leading to infection, cystic dilation and fat necrosis
Usually incidental finding at surgery submitted for frozen section but carcinoma may arise from pancreatic heterotopia (Arch Pathol Lab Med 1999;123:707)

Gross description

Submucosal nodule, intramural mass
Yellowish white, lobulated, 0.2 - 4 cm
May have central mucosal dimple

Microscopic (histologic) description

Widely separated pancreatic acini with minimally developed ducts, well formed acini may be seen (JOP 2007;8:588, Mod Pathol 2003;16:530)
Pancreatic heterotopia may be total, only ducts, only acinar cells (exocrine heterotopia), only islet cells (endocrine heterotopia)
Adenomyoma: predominance of pancreatic ducts with proliferation of thick smooth muscle bundles of the muscularis around the ducts (seen in periampullary region of the duodenum)

Differential diagnosis

Cystic change in pancreatic heterotopia from duplication
Neuroendocrine tumor from endocrine heterotopia
Well differentiated adenocarcinoma

Additional references

Arch Pathol Lab Med 2010;134:378

Histology-ampulla

Table of Contents

Definition / general

Formed by the union of the distal pancreatic duct and the intrapancreatic distal common bile duct
Opens into the major duodenal papilla

Essential features

Complex anatomical structure generally lined by pancreatobiliary-type cells

Diagrams / tables

Images hosted on other servers:

Ampulla of Vater and related structures

Ampulla, papilla and sphincters

Microscopic (histologic) description

Ampullary mucosa forms prominent papillary folds
Epithelium transitions from intestinal type (duodenal surface) to foveolar-like mucosa with occasional goblet cells (papilla) to pancreatobiliary epithelium (distal ducts) (Am J Surg Pathol 2012;36:1592)
Lamina propria has only occasional lymphocytes, plasma cells and mast cells
Small mucous glands / ductules underlie the mucosa
Smooth muscle fibers (representing sphincter of Oddi) may extend into epithelial folds
May have adjacent pancreatic acini, but usually no islets around major papillae

Microscopic (histologic) images

Contributed by Raul Gonzalez, M.D.

Normal ampullary mucosa and submucosa

Ampullary submucosal glands / ductules

Positive stains (IHC and special stains)

Ampullary biopsy performed in autoimmune pancreatitis can help to differentiate from other "mass forming" pancreatitis by IgG4+ to IgG+ ratio (Am J Surg Pathol 2008;32:1770)

Differential diagnosis

Adenocarcinoma:
- Submucosal ducts / glands may appear malignant, especially if crushed or secondarily involved by an adenoma

Additional references

Lindberg: Diagnostic Pathology: Normal Histology, 2nd Edition, 2017

Board review style question #1

Ciliated epithelium
Islets of Langerhans
Pancreatic acini
Squamous epithelium

Board review style answer #1

C. Pancreatic acini

Comment Here

Reference: Histology-ampulla

Board review style question #2

Adenocarcinoma
Gastric heterotopic
Intestinal metaplasia
Normal ampulla

Board review style answer #2

D. Normal ampulla

Comment Here

Reference: Histology-ampulla

Histology-small intestine

Table of Contents

Definition / general

Extends from gastric pylorus to ileocecal valve
Layers include mucosa, submucosa, muscularis propria (externa), subserosa and serosa (described luminal to external)
Functions relies on the structure of mucosal villi and crypts, lined by columnar cells

Essential features

Extends from gastric pylorus to ileocecal valve
Composed of duodenum, jejunum and ileum
Layers include mucosa, submucosa, muscularis propria (externa), subserosa and serosa (described luminal to external)
Villi lined by columnar absorptive cells and goblet cells
Crypts comprise the lower portion of mucosa and contain Paneth cells, endocrine cells and undifferentiated (immature) crypt cells

Terminology

Small bowel
Duodenum, jejunum, ileum

Physiology

Villi are the location for digestion and absorption of food into the columnar cells (Gastrointest Endosc Clin N Am 2017;27:1)
Crypts secrete ions and water and deliver IgA and antimicrobial peptides to the lumen
Cell division and renewal occur in crypts
Mucous cells generate adherent mucous layer that protects the epithelium and allows uptake of nutrients
Terminal ileum absorbs intrinsic factor vitamin B12 complexes

Gross description

Small intestine is approximately 6 - 7 m in length (Gastrointest Endosc Clin N Am 2017;27:1)
Duodenum:
- Retroperitoneal, except for first part
- Common bile duct and pancreatic duct enter the second part of the duodenum at the ampulla of Vater
- Suspensory duodenal ligament (ligament of Treitz) divides duodenum from jejunum
Jejunum and ileum:
- Intraperitoneal
- Transition between the jejunum and ileum is not clearly defined
- Wall of jejunum is thicker due to prominent circular mucosal folds (folds of Kerckring / plicae circulares) (Gastrointest Endosc Clin N Am 2017;27:1)
Small intestine ends at the ileocecal valve

Gross images

Contributed by Danielle Hutchings, M.D.

Jejunum

Microscopic (histologic) description

Mucosa:
- Contains villi (finger-like projections) with central blood vessels, lymphatics
- Layers are epithelium, lamina propria and muscularis mucosa
Villi:
- Tallest in the jejunum, may be shorter or show more variability in height in duodenum
- Surface lined by microvilli
- Villus to crypt length ratio is 3 - 5:1
- Lined by primarily columnar absorptive cells and goblet cells
- Scattered intraepithelial lymphocytes (T cells), usually 1 lymphocyte per 5 enterocytes
- Villi may be shorter and distorted next to lymphoid aggregates
- In a biopsy, 4 normal villi in a row suggests normal villous architecture
- Each villus contains an arteriole with capillary network, veins and a central lymphatic with numerous nerve fibers
Absorptive cells:
- Enterocytes
- Microvilli on luminal surface (brush border) and underlying mat of microfilaments (terminal web)
Microvillus:
- 1.5 - 2 µm in length and 100 nm in diameter
- PAS positive, actin myosin complexes
Goblet cells:
- Occur in crypts and surface absorptive cells
- Decrease towards villus tip, increase in frequency along small intestine (most numerous in lower ileum)
- Columnar in shape, mucus droplet in supranuclear area, secretes mucus, ions and water
Paneth cells:
- Populate crypt bases and increase in number from proximal to distal intestine
- Strongly eosinophilic, pyramidal cells with zymogenic or secretory cell characteristics
- Supranuclear Golgi complex contains large, chunky apical membrane bound eosinophilic granules
- Granules contain various proteins involved in host defenses including lysozyme, secretory phospholipase A2 and alpha defensins / cryptdins (World J Gastrointest Pathophysiol 2017;8:150)
Crypts of Lieberkühn:
- Lower 20% of epithelium, contain undifferentiated (immature) crypt cells, Paneth cells, scattered goblet cells and endocrine cells
- Surrounded by pericrypt fibroblast sheath
- Secrete ions, water, IgA, antimicrobial peptides into lumen
- Crypt cells take 3 - 8 days to migrate to surface
- Allows for rapid repair but also causes these cells to be sensitive to radiation therapy and chemotherapy
Lamina propria:
- Contains loose connective tissue, lymphocytes, plasma cells, occasional eosinophils, macrophages and mast cells
Submucosa:
- Contains connective tissue, blood vessels, lymphatics, submucosal (Meissner) plexus
- Brunner glands in duodenum
Brunner glands:
- Submucosal mucous glands in duodenum
- Secrete bicarbonate ions, glycoproteins, pepsinogen II
- Resemble gastric pylorus mucous glands
Muscularis propria (externa):
- Inner circular and outer longitudinal layer, with myenteric (Auerbach) plexus between these layers
- Plexus also contains interstitial cells of Cajal, ganglion cells, fibroblasts (Am J Surg Pathol 2003;27:228)
Serosa:
- Contains mesothelial lining, loose connective tissue
Endocrine cells:
- Contain fine eosinophilic granules with secretory proteins
- Cytoplasmic granules are subnuclear (versus supranuclear granules in Paneth cells)
Peyer patch:
- Lymphoid aggregates randomly distributed around circumference of the small intestine (partially mucosal, partially submucosal) with central germinal center
- Peyer patch germinal centers are more common in children than adults
- Increase in number distally in the small bowel and become confluent in the ileum
- Exogenous dark brown granular pigment may be present within macrophages (Hum Pathol 1987;18:50, Gut 1996;38:390)

Microscopic (histologic) images

Contributed by Danielle Hutchings, M.D.

Layers of small intestine

Villi

Paneth cells

Brunner glands

Peyer Patches

Submucosa

Muscularis propria

Microvilli and goblet cells

Positive stains

Epithelium: CK20, CDX2 (Am J Surg Pathol 2004;28:1352, Int J Dev Biol 2005;49:867)

Negative stains

Electron microscopy description

Each microvillus contains a core bundle of vertically oriented, polarized actin filaments extending from the tip of the microvillus to the base of the terminal web

Electron microscopy images

Images hosted on other servers:

Microvillus of small intestine

Videos

Small intestine: histology

Additional references

Kumar: Robbins & Cotran Pathologic Basis of Disease, 8th Edition, 2009, Noffsinger: Fenoglio-Preiser's Gastrointestinal Pathology, 4th Edition, 2017, Mills: Sternberg's Diagnostic Surgical Pathology, 6th Edition, 2015

Board review style question #1

What is the location and function of the submucosal mucous glands shown above?

Duodenum, secrete bicarbonate ions, glycoproteins, pepsinogen II
Duodenum, secrete proteins involved in host defense (e.g. alpha defensins / cryptdins)
Ileum, secrete proteins involved in host defense (e.g. alpha defensins / cryptdins)
Jejunum, secrete bicarbonate ions, glycoproteins, pepsinogen II

Board review style answer #1

A. Duodenum, secrete bicarbonate ions, glycoproteins, pepsinogen II. Brunner glands are located in the duodenum and secrete bicarbonate ions, glycoproteins and pepsinogen II.

Comment Here

Reference: Histology - small intestine

Board review style question #2

Resection of what segment of the small intestine puts the patient at risk for vitamin B12 malabsorption?

First part of the duodenum
Ileum
Jejunum
Second part of the duodenum

Board review style answer #2

B. Ileum. In the ileum, surface epithelial cells, specific receptors are present to uptake intrinsic factor vitamin B12 complexes.

Comment Here

Reference: Histology - small intestine

Hyperplastic polyp

Table of Contents

Definition / general

Nonmalignant hyperplastic proliferation of small intestine

Essential features

Extremely rare benign duodenal / ampullary polyp
Resembles microvesicular hyperplastic polyp microscopically

ICD coding

ICD-10: D13.2 - benign neoplasm of duodenum

Epidemiology

Hyperplastic polyps are extremely rare anywhere in the duodenum

Sites

Occurs in second part of duodenum and ampulla

Pathophysiology

Uncertain malignant potential

Clinical features

Mean age 52 years
Usually incidentally detected

Case reports

58 year old man with ridges in distal duodenum (J Clin Pathol 2006;59:1305)

Microscopic (histologic) description

Similar to microvesicular hyperplastic polyp of the colorectum, with elongated crypts, superficial serration and decreased goblet cells (Hum Pathol 2011;42:1953)
No evidence of basal crypt booting (as in sessile serrated adenoma of the colorectum) or gastric foveolar metaplasia

Microscopic (histologic) images

Images hosted on other servers:

Duodenal hyperplastic polyp

Positive stains

Epithelial cells express MUC2 (focal), MUC5AC and MUC6 (crypt bases)

Molecular / cytogenetics description

May harbor KRAS or BRAF mutations

Sample pathology report

Duodenum, polypectomy:
- Duodenal mucosa with bland hyperplastic and serrated architecture, most consistent with hyperplastic polyp (see comment)
- Comment: Hyperplastic polyps are rare in this location. It is unclear whether they possess premalignant potential.

Differential diagnosis

Adenoma:
- Far more common, especially in ampulla
- Dysplastic nuclei
Peutz-Jeghers polyp:
- Contains arborizing musculature

Board review style question #1

Hyperplastic polyps of the small intestine most resemble which type of colorectal polyp microscopically?

Goblet cell rich hyperplastic polyp
Microvesicular hyperplastic polyp
Mucin poor hyperplastic polyp
Sessile serrated adenoma

Board review style answer #1

B. Microvesicular hyperplastic polyp

Comment here

Reference: Hyperplastic polyp

Board review style question #2

This polyp was resected from the duodenum. Which of the following is true?

Deeper levels would show conventional cytologic dysplasia
These polyps are extremely rare in the small intestine
This must be a traditional serrated adenoma, despite the lack of abundant eosinophilic cytoplasm
This patient must have serrated polyposis syndrome

Board review style answer #2

B. These polyps are extremely rare in the small intestine. This is a hyperplastic polyp; duodenal examples resemble colonic microvesicular hyperplastic polyps.

Comment here

Reference: Hyperplastic polyp

Idiopathic retroperitoneal fibrosis

Table of Contents

Definition / general | Case reports | Gross description | Microscopic (histologic) description

Definition / general

Fibrosis which develops in retroperitoneum, often at aortic bifurcation
Associated with drug methylsergine, other fibrotic lesions (sclerosis of major bile ducts, Riedel thyroiditis, inflammatory pseudotumor of orbit)
IgG4 often involved in pathogenesis of idiopathic sclerosing lesion; associated with male gender
Associated with lymphoma, which developed in 15% of patients

Case reports

58 year old man with idiopathic sclerosing mesenteritis and retroperitoneal fibrosis (Korean J Gastroenterol 2011;58:221)
With previous sclerosing mesenteritis and small bowel obstruction (Eur J Gastroenterol Hepatol 2006;18:1285)

Gross description

Not well circumscribed

Microscopic (histologic) description

Widely scattered germinal centers and plasma cells in background of dense fibrosis
Eosinophilic infiltration and oblitertaive phlebitis in IgG4 related cases (Am J Surg Pathol 2009;33:1833)

Ileal pouch / pouchitis

Table of Contents

Definition / general | Pouchitis | Treatment | Microscopic (histologic) description | Microscopic (histologic) images

Definition / general

Pouch is formed from connecting loops of terminal ileum for patients requiring total colectomy; used to create continence in an ileostomy or to preserve anal sphincter function
Pouches are contraindicated in Crohn's disease because they are associated with fistulas and abscess
Complications: fistula, obstruction, incontinence, leaks, pouchitis

Pouchitis

Incidence 8 - 46%
Some cases are due to initially undiagnosed Crohn's disease
Nausea, vomiting, malaise, fever, cramping
Increased ileal stool that is bloody, watery, foul smelling
Often with altered bacteria

Treatment

Antibiotics, pouch excision

Microscopic (histologic) description

Decreased epithelial cell mucin, few / no lymphoid follicles
Ulcers with granulation tissue, cryptitis, crypt abscesses and patchy neutrophils
Rarely dysplasia
CD10 staining confirms biopsy site - terminal ileum (CD10+) versus colon (CD10-), although negative staining also occurs in active enteritis (Mod Pathol 2011;24:1627)

Microscopic (histologic) images

Contributed by Hanni Gulwani, M.D.

CMV pouchitis: biopsy of postcolectomy pouch in 38 year old man with ulcerative colitis

Immunoproliferative small intestinal disease (ISID)

Table of Contents

Definition / general

Also called Meditteranean lymphoma, Middle Eastern lymphoma
More common among non-European Jews, Middle Eastern Arabs, South African blacks
B cell lymphoma that arises in background of chronic diffuse mucosal plasmacytosis, with IgA heavy chain synthesis (no variable chain synthesized)

Clinical features

Many have preexisting malabsorption
May initially respond to antibiotics
Often due to Campylobacter jejuni, another human pathogen responsible for immunoproliferative states (N Engl J Med 2004;350:239)

Case reports

53 year old woman with immunoproliferative small intestinal disease (Turk J Gastroenterol 2012;23:91)

Gross description

Low grade: nonflattened mucosa
High grade: diffusely thickened folds with small nodules in distal duodenum / proximal jejunum

Microscopic (histologic) description

Low grade:

Heavy lymphoplasmacytic infiltrate by mature cells

High grade:

Resembles diffuse large cell lymphoma with plasmacytoid features
May have starry sky pattern, follicular hyperplasia

Microscopic (histologic) images

Images hosted on other servers:

Various images

Positive stains

Monoclonal kappa or lambda (not both), syndecan1, IgA heavy chain
BCL6 and p53 expression associated with advanced stage and aggressive behavior (World J Gastroenterol 2006;12:3602)

Infectious disorders-general

Table of Contents

Anisakis

Definition / general

Larvae of ascarids (Anisakidae) are found in sea animals
After ingesting contaminated raw fish or other sea food, larvae attach to mucosa of stomach or small intestine and cause ulceration, penetration or perforation

Diagrams / tables

Images hosted on other servers:

Life cycle

Case reports

37 year old woman with epigastric pain two hours after ingesting fried hake and fish ova and 200 larvae obtained by endoscopy (J Investig Allergol Clin Immunol 2010;20:437)
50 year old man with abdominal pain and peripheral eosinophilia after eating raw salmon from Pacific Ocean (Am J Surg Pathol 2003;27:1167)
Worm found in fresh salmon (Pritt: Creepy Dreadful Wonderful Parasites Blog - Case of the Week 557 [Accessed 7 September 2023])

Clinical images

Images hosted on other servers:

Larvae in terminal ileum

Larvae in fish

Larvae in a herring

Gross images

Contributed by Bobbi Pritt, M.D.

Most likely a
type I Anisakis or
Pseudoterranova

Microscopic (histologic) description

Serositis, mucosal edema, submucosal abscess with eosinophils surrounding parasite with unpaired excretory gland (renette cell), Y shaped lateral epidermal cords, no apparent reproductive system and a ventriculus (glandular esophagus)
No lateral alae, no ventricular appendage, no intestinal cecum

Microscopic (histologic) description

Contributed by Bobbi Pritt, M.D.

Most likely a type I Anisakis or Pseudoterranova: anterior boring tooth (left); mucron (terminal spicule-like structure) (right)

Images hosted on other servers:

Larva in submucosa with eosinophils and lymphocytes

Larva in jejunum

Additional references

Pritt: Creepy Dreadful Wonderful Parasites Blog - Answer to Case 557 [Accessed 7 September 2023]

Bacterial enterocolitis

Definition / general

Bacterial related disease due to either ingestion of preformed toxin (Staphylococcus aureus, Vibrio cholera, Clostridium perfringens), infection by toxigenic organisms or infection by enteroinvasive organisms which invade and destroy mucosal epithelium cells (eMedicine: Bacterial Gastroenteritis [Accessed 7 September 2023])
Bacterial adhere to mucosal epithelial cells, elaborate enterotoxins, have capacity to invade
Adhere by plasmid mediated adhesins (E. coli, V. cholera), fimbriae or pili
Adhesion destroys microvilli brush border

Clinical features

Complications due to massive fluid loss and loss of mucosal barrier include dehydration, sepsis, perforation
Salmonella: invades via transcytosis with minimal epithelial damage
Yersinia enterocolitica: penetrates ileal mucosa, multiplies in Peyer patches and regional lymph nodes
Insidious infection: Yersinia and Mycobacterium tuberculosis
Cytotoxins: Shiga toxin, enterohemorrhagic E. coli
Enterotoxins:
- Bind to cell membrane, enter cell, activates massive electrolyte secretion (cholera toxin, E. coli heat labile and heat stable toxins produce traveler's diarrhea)
- No white blood cells in stool
Bacterial invasion:
- Enteroinvasive E. coli and Shigella have plasmid that mediates epithelial cell invasion via microbe simulated endocytosis; then intracellular proliferation, cell lysis, cell to cell spread
Patients ingest preformed toxins:
- Symptoms within hours
- Explosive diarrhea and acute abdominal distress
- 1 - 2 days
- C. botulinum may produce rapid, fatal respiratory failure
Infection with enteric pathogens:
- Incubation of hours - days
- Diarrhea and dehydration (secretory enterotoxin) or dysentery (cytotoxin or enteroinvasive)
Traveler's diarrhea:
- Fecally contaminated water / food
- Begins abruptly, subsides in 2 - 3 days

Microscopic (histologic) description

Decreased epithelial cell maturation, increased mitotic figures, hyperemia and edema of lamina propria, variable neutrophils, modest villus blunting of small bowel
Late: lymphocytes, plasma cells, regenerative change

Differential diagnosis

Inflammatory bowel disease

Cryptosporidium

Definition / general

Acid fast protozoa which causes self limited disease in immunocompetent but severe watery diarrhea resistant to most therapy in immunocompromised (J Biomed Res 2012;25:1)

Diagnosis

Acid fast infective oocyst in stool

Microscopic (histologic) description

2 - 5 micron basophilic spherical structures attached to microvillus surface of epithelium
Variable villus abnormality, may have eosinophils infiltrating mucosa

Microscopic (histologic) images

Images hosted on other servers:

Small round blue organisms at the luminal border

Cryptosporidium

Positive stains

Giemsa, silver stains, PAS

Differential diagnosis

Cellular debris
Mucin

Cyclospora (pending)

[Pending]

Entamoeba histolytica

Definition / general

Dysentery causing protozoa that can also cause fulminant colitis; causes up to 100,000 deaths per year (Trop Biomed 2011;28:194)
Increased incidence in homosexual men and AIDS patients

Pathophysiology

Fecal oral spread
Amoeba invade colonic crypts, burrow into lamina propria, create flask shaped ulcer with broad base
40% invade portal vessels, embolize to liver and cause abscesses up to 10 cm
May activate apoptosis in target cells (Trends Parasitol 2011;27:254)
Rare abscesses in lung, heart, kidneys, brain

Diagrams / tables

Images hosted on other servers:

Life cycle

Microscopic (histologic) images

Contributed by Hanni Gulwani, M.D.

Amoebic colitis, numerous trophozoites of amoeba are noted

Amoebic colitis, PAS stain

Images hosted on other servers:

Ulcer seen in amebic colitis

Mice deficient for leptin or the functional leptin receptor

Giardia lamblia

See Giardia lamblia

Isospora belli

Definition / general

Coccidian parasite that infects epithelial cells of small intestine
Causes chronic diarrhea and acalculous cholecystitis in AIDS patients (Indian J Med Res 2011;134:878)

Diagnosis

Cysts in stool, biopsy (H&E or EM)

Case reports

35 year old HIV+ man (Indian J Pathol Microbiol 2010;53:824)

Microscopic (histologic) description

Cysts present in parasitophorous vacuole in lamina propria (Hum Pathol 2001;32:500)
Ovoid developmental forms are identified in and beneath epithelial cells near villus tip

Microscopic (histologic) images

Images hosted on other servers:

Oocyst of C. belli in epithelial cells of mammalian host

Positive stains

Giemsa

Microsporidia

Definition / general

Caused by Enterocytozoon bieneusi, an obligate intracellular protozoan that affects only enterocytes and Encephalitozoon intestinalis, which infects macrophages, fibroblasts, endothelial cells, enterocytes
Both cause chronic diarrhea in patients with immunosuppression, HIV

Diagnosis

Stool examination, PCR

Case reports

33 year old woman with myeloma, postautologous stem cell transplant and chemotherapy for relapse (Emerg Infect Dis 2012;18:1155)
43 year old man with pancreas / kidney transplant recipient and multiorgan system dissemination (Arch Pathol Lab Med 2004;128:e41)

Treatment

Albendozole for E. intestinalis, nothing for E. bieneusi

Microscopic (histologic) description

Minimal / no changes in mucosa but can find development spores as 1.5 mm dots in enterocytes
May be surrounded by halos
Also nucleated sporont present as 3 - 5 micron, rounded, basophilic structure often surrounded by a halo

Microscopic (histologic) images

Images hosted on other servers:

Various images

Positive stains

Giemsa

Electron microscopy description

Often helpful for diagnosis

Rotavirus

Definition / general

Primarily diarrheal illness caused by infection with rotavirus

Essential features

Rotavirus is a segmented, nonenveloped double stranded RNA virus
It is ubiquitous and infection is essentially universal first occurring in early childhood
Transmission is fecal oral either via direct contact with stool or via fomites
In the developed world, the vast majority of infections cause self limited diarrheal illness or in subsequent infections and vaccinated populations, are asymptomatic
Most cases in the developing world are similar; however, the World Health Organization estimates that in 2013 ~215,000 children under 5 years old died from rotavirus infection (WHO: Rotavirus [Accessed 7 September 2023])
Live attenuated vaccines are available and their use has resulted in a dramatic worldwide decrease of severe disease
Intestinal intussusception is a rare but well recognized potential complication of vaccination

Terminology

Rotavirus is a genus of the Reoviridae family

ICD coding

ICD-10: A08.0 - rotaviral enteritis

Epidemiology

Rotavirus is ubiquitous and infection is essentially universal in childhood in all socioeconomic groups
Transmission is fecal oral either via direct contact with stool or via fomites
Infection generally first occurs around 6 months of age as the gastrointestinal tract matures and passive immunity from breast milk wanes
Infection may occur earlier in infants fed formula and in parts of India, Asia and sub-Saharan Africa where protection from maternal antibodies appears to be less effective
Reinfection occurs throughout life and in most children older than 2 years and adults infection is minimally symptomatic or asymptomatic due to immunity either from prior infections or vaccination
In the developed world, disease was more common in winter and spring; however, whether this pattern is still valid with widespread vaccination is unclear
Transmission in the daycare and hospital setting is common
Viral particles are hardy and resistant to chlorinated drinking water although they are vulnerable to alcohol based hand sanitizer and spray disinfectants
The World Health Organization estimates that in 2013 ~215,000 children under 5 years old died from rotavirus infection, overwhelmingly in the developing world compared to 528,000 in 2000 (WHO: Global Illness and Deaths Caused by Rotavirus Disease in Children [Accessed 7 September 2023])
According to the CDC in the United States rotavirus causes over 400,000 doctor visits, 200,000 emergency room visits, 55,000 to 70,000 hospitalizations and from 20 to 60 deaths each year (CDC: Rotavirus in the U.S. [Accessed 7 September 2023])
Serologically rotavirus is classified into serogroups, subgroups and G and P serotypes
Genotypically, it is classified into electropherotypes, genogroups and G and P genotypes
There is a substantial geographic and temporal variation in strain distribution and antigenic drift as well as introduction and reassortment with animal viruses which increases genetic diversity
Epidemiologically nucleic acid testing is increasingly replacing serologic testing
Further information is available from the Rotavirus Classification Working Group's database (RotaC v2.0: Classification Tool for Rotaviruses Group A [Accessed 7 September 2023])

Sites

Infection occurs in the small intestine

Pathophysiology

Pathophysiology is complex and not fully understood
Enterocytes at villous tips are initially infected; the virus binds surface carbohydrates and penetrates the cell membrane leading to transcription of viral RNA
Damage to the mucosa leads to malabsorption
Activity of disaccharidases and peptidases in the brush border is decreased and osmosis from unabsorbed nutrients contributes to the diarrhea
Glucose cotransport of electrolytes is decreased but oral rehydration solutions are still affective (see Treatment below)
Mature enterocytes are lost and initially replaced by immature secretory cells
There is net secretion of water in part mediated by the enteric nervous system
Clearance of infection is complex and involves overlapping elements of innate, cellular and humoral immunity
Virus is usually shed for 6 to 10 days after patients become symptomatic

Clinical features

There is an incubation period of 1 - 3 days
Illness in infants and young children usually starts with vomiting and fever lasting 2 - 3 days, progressing to 4 - 5 days of profuse watery diarrhea
In symptomatic older children and adults there is 1 - 4 days of diarrhea with anorexia, crampy abdominal pain and low grade fever
Chronic infections may occur in immunosuppressed patients excepting HIV; isotonic dehydration and metabolic acidosis occur in severe cases
Viremia is uncommon; extraintestinal manifestations are rare and described in the liver and kidney
Intestinal intussusception is a rare but well recognized potential complication of vaccination
Prior intussusception is a contraindication to vaccination
Patient deaths are due to dehydration and electrolyte abnormalities that lead to cardiac failure or less commonly seizures or aspiration pneumonia

Diagnosis

Enzyme immunoassay and PCR are the mainstays
Latex agglutination is often used in resource poor areas
Viral culture and electron microscopy are largely of historical interest
Microbiologic diagnosis is rarely required

Laboratory

Severe disease may cause metabolic acidosis and high urine specific gravity
Mild elevation of transaminases and uric acid may occur
Leukocytosis is rare and stool is usually negative for white blood cells and blood

Prognostic factors

Disease is most severe in infants and young children
Immunosuppressed patients often suffer from more severe disease and cannot receive the live attenuated vaccine although patients infected with HIV do not suffer more severe disease and should be vaccinated
Infection in the developing world is more likely to lead to severe illness or death; this is related to less access to health care, malnutrition, the presence of other infections and possibly larger inoculums

Case reports

5 month old boy, 51, 54 and 71 year old men in a multiorgan transplant unit (Transpl Int 2005;18:470)
22 month old girl with opsoclonus myoclonus syndrome after rotavirus gastroenteritis (Pediatr Int 2014;56:e86)
8 year old Japanese girl with mild encephalopathy (BMJ Case Rep 2016;2016:bcr2016216895)
73 year old man with Henoch-Schönlein purpura (Am J Case Rep 2017;18:136)

Treatment

Mild to moderate disease: oral rehydration
Severe disease: intravenous lactated ringers or normal saline until oral rehydration can be tolerated
Infants: return to breast feeding or formula as soon as it can be tolerated
In the developing world, zinc supplementation and some probiotics in children older than 6 months may reduce disease duration
Diosmectite, a type of aluminum magnesium clay silica, is available in parts of Europe and controls gastroenteritis
Oral immunoglobulins have a possible role in chronic disease and for high risk patients where vaccination is unlikely to be effective (premature infants) or is contraindicated
Antibiotics are not indicated
Vaccination is recommended to commence at 2 months of age

Microscopic (histologic) description

Biopsy is rarely performed
Findings are nonspecific; villi are shortened, blunted and lined by cuboidal cells
There is crypt hyperplasia and increased mononuclear cells within the lamina propria
Apoptotic epithelial cells may be present
Disease may be patchy in distribution
Viral inclusions are not present

Electron microscopy images

Images hosted on other servers:

Multiple
rotavirus
particles

Differential diagnosis

Other causes of infectious gastroenteritis and enterocolitis

Additional references

eMedicine: Rotavirus [Accessed 7 September 2023], Bennett: Mandell, Douglas and Bennett's Principles and Practice of Infectious Diseases, 8th Edition, 2014, Kumar: Robbins and Cotran Pathologic Basis of Disease, 9th Edition, 2014

Salmonella

Definition / general

Bacterial causing food poisoning and typhoid fever (S. typhi)
Typhoid fever: systemic dissemination with bacteremia, fever, chronic infection of joints, biliary tree, bones and meninges
From contaminated milk, eggs, beef, poultry
Usually affects terminal ileum

Gross images

Case #362

Microscopic (histologic) description

Ulcers overlying Peyer patches with minimal inflammatory cells, chiefly mononuclear (plasma cells, histiocytes and lymphocytes)
Often histiocytes with erythrophagocytosis
May lead to perforation or toxic megacolon

Microscopic (histologic) images

Case #362

Strongyloides stercoralis

Definition / general

Nematode with complex life cycle that alternates between free living and parasitic cycles, with potential for autoinfection and multiplication within host

Life cycle

Larvae burrow into mucosa of duodenum and jejunum, where they mature into adults
Females lay eggs, which develop into larvae that pass into stool, where they mature and become infective
Infective larvae in soil penetrate intact skin, usually through feet
Larvae enter circulatory system, are transported to lungs, enter alveolar spaces, are carried to trachea and pharynx, are swallowed and enter intestinal tract, where process is repeated
If larvae become infective before leaving body, they may invade intestinal mucosa or perianal skin, causing autoinfection

Diagrams / tables

Images hosted on other servers:

Life cycle

Clinical features

Symptoms: none, diarrhea, malabsorption
Severe / fatal infections in immunocompromised, due to worms moving from GI tract into other organs (WormBook 2007:1)

Diagnosis

Larvae in stool
Adult female or eggs in small bowel mucosa, often with eosinophilic or granulomatous inflammation

Case reports

43 year old Honduran man with diarrhea and abdominal pain (Case #133)
66 year old man with weakness and epigastric pain (Int J Prev Med 2012;3:370)

Treatment

Antihelminths such as thiabendazole (Ann Pharmacother 2007;41:1992)
Prevent by wearing shoes in endemic areas

Microscopic (histologic) images

Contributed by Josehp Christopher Castillo, M.D. and Case #133

Small intestine

Various images

Contributed by @liverwei on Twitter

Strongyloides stercoralis

Additional references

Arq Gastroenterol 2011;48:225

Vibrio cholerae (pending)

[Pending]

Whipple disease

See Whipple disease

Board review style question #1

What is true regarding rotavirus?

Characteristic viral inclusions are diagnostic
Incidence has increased
Infection typically affects the sigmoid colon and rectum
Intussusception is a rare but recognized complication associated with vaccination
Most deaths occur in the elderly

Board review style answer #1

D. Intussusception is a rare but recognized complication associated with vaccination. However, there is broad agreement that the benefits of vaccination greatly exceed the risk.

Comment Here

Reference: Infectious disorders-general

Inflammatory fibroid polyp

Table of Contents

Definition / general

Uncommon, benign polypoid submucosal mass with CD34+ spindle cells and granulation tissue, usually in distal stomach or terminal ileum (Arch Pathol Lab Med 2011;135:1311)
Presents as obstructive mass or causing intussusception (Radiographics 1999;19:539)
True neoplasms, usually with PDGFRA mutation (Pathologe 2009;30:117)

Case reports

35 year old woman with concurrent appearance of Crohn's disease and inflammatory fibroid polyp (Ann Ital Chir 2005;76:395)

Treatment

Excision (does not recur)

Gross description

Polypoid (without stalk), submucosal mass, dumbbell shape in small intestine due to intussuception, mucosal ulceration and splitting and atrophy of muscularis propria

Gross images

Contributed by Claudia Mendez, M.D.

Inflammatory fibroid polyp

Microscopic (histologic) description

Submucosal mixture of prominent capillaries, spindle cells (occasionally concentrically arranged around vessels / onion skinning) and inflammatory cells (particularly eosinophils, plasma cells and mast cells) in granulation tissue-like stroma (Arch Pathol Lab Med 2010;134:378)
May be transmural
May have lymphoid follicles
Rare multinucleated giant cells, no atypia, no / rare mitotic figures
Histologic patterns: classical, edematous, fibrovascular, nodular, sclerotic

Microscopic (histologic) images

Contributed by Claudia Mendez, M.D.

10x

40x

Positive stains

CD34+ spindle cells
Variable calponin, cyclin D1, fascin, smooth muscle actin, vimentin, CD35

Negative stains

CD117 (although mast cells are positive)

Differential diagnosis

GIST: malignant in 30 - 50%, plump spindle cells with eosinophilic cytoplasm, variable skenoid fibers and muscular infiltration, CD117+ (Mod Pathol 2000;13:1134, Mod Pathol 2003;16:366)
Inflammatory myofibroblastic tumor: usually children, may recur, plasma cells and lymphocytes with few eosinophils, mitotic activity in cellular areas, less prominent blood vessels, smooth muscle actin+, desmin+, ALK±, CD34- (Hum Pathol 2002;33:307)
Inflammatory polyp of Crohn's or ulcerative colitis: similar histology but different clinical history and findings in remainder of bowel

Inflammatory myofibroblastic tumor

Table of Contents

Definition / general

Also called inflammatory pseudotumor; previously called inflammatory fibrosarcoma
Often in children but can occur at any age
No clinical associations
Benign but may recur; rarely has malignant behavior
Rarely behaves malignant
ALK+ tumors (22% of patients age 40 years or younger) have a more favorable prognosis (Am J Surg Pathol 2001;25:761)
Complications: obstruction, intussusception

Case reports

2 month old infant with intestinal obstruction (J Med Assoc Thai 2009;92:114)
2 year old girl with jejunal tumor (Pathol Int 2001;51:47)
29 year old woman with intramural ileal tumor showing ALK / TPM3 fusion using FISH (Hum Pathol 2006;37:112)

Gross description

Mean 3 - 4 cm, submucosal sessile polypoid mass or multiple masses with broad base
Tan gray yellow
Overlying mucosa may be ulcerated

Microscopic (histologic) description

Usually limited to submucosa
Plump ovoid myofibroblastic spindle cells with inflammatory infiltrate including plasma cells and lymphocytes
May be sparsely cellular with myxoid stroma
May have rarefaction around muscular walled blood vessels
May be infiltrative
Cellular areas may have up to 2 mitotic figures/HPF
Variable vascular component

Positive stains

Vimentin, muscle specific actin, smooth muscle actin, anaplastic lymphoma kinase (variable)

Negative stains

S100, desmin (Mod Pathol 2000;13:1134), CD117 (endothelial cells may be CD117+), CD34

Electron microscopy description

Myofibroblasts

Differential diagnosis

Fibromatosis: invades bowel secondarily

Inflammatory polyp

Table of Contents

Definition / general | Microscopic (histologic) description

Definition / general

Polypoid inflammatory mucosa associated with Crohn's disease or ulcerative colitis
Also amebiasis, schistosomiasis, ulcers, anastomotic sites

Microscopic (histologic) description

Solitary small polyps of inflamed regenerating mucosa in a fibroblastic or granulation tissue stroma
No / few mitotic figures, no atypical mitotic figures, often zonation
May have bizarre stromal changes resembling sarcoma

Intra-ampullary papillary tubular neoplasm (IAPN)

Table of Contents

Definition / general

Intra-ampullary papillary tubular neoplasm (IAPN) is the name proposed in 2010 to unify the nomenclature for mass forming preinvasive (dysplastic) lesions that arise within the ampulla of Vater (Am J Surg Pathol 2010;34:1731)

Essential features

The precursor lesion of intra-ampullary adenocarcinomas (Am J Surg Pathol 2012;36:1592)
Majority (78%) of IAPNs in one large series harbored an invasive component (Am J Surg Pathol 2010;34:1731)
Analogous to pancreatic or biliary intraductal papillary and tubular neoplasms (Am J Surg Pathol 2010;34:1731)
Must be localized within (or predominantly within) the ampulla (Am J Surg Pathol 2010;34:1731)

Terminology

Other / previous terms include intestinal type adenoma, noninvasive pancreatobiliary type neoplasm

ICD coding

ICD-O: 8210/0 - adenomatous polyp, low grade dysplasia
ICD-O: 8210/2 - adenomatous polyp, high grade dysplasia
ICD-10: C24.1 - malignant neoplasm of ampulla of Vater
ICD-11: 2E92.2 & XH3DV3 - benign neoplasm of duodenum, adenoma, NOS
ICD-11: 2E92.2 & XH8MU5 - benign neoplasm of duodenum, adenomatous polyp, NOS

Epidemiology

Mean age 64; range: 27 - 85 years (Am J Surg Pathol 2010;34:1731)
M:F = 2.4 (Am J Surg Pathol 2010;34:1731)
Estimated prevalence base on autopsy studies is 0.04 - 0.12% (World J Gastrointest Endosc 2011;3:241)

Sites

Ampulla of Vater: within the ampullary channel (common channel) or the intra-ampullary portions of the common bile duct or main pancreatic duct

Etiology

Given the prevalence of neoplasia in and around the ampulla, authors have speculated that bile acids may be carcinogenic (Mutat Res 2005;589:47)

Clinical features

Patients may be asymptomatic or present with obstructive symptoms: jaundice, weight loss, abdominal pain, nausea / vomiting, pruritus, dark urine / light stools or tarry stools (Am J Surg Pathol 2010;34:1731)
Rarely, patients present with cholangitis or pancreatitis

Diagnosis

A mass involving the ampullary region may be found on cross sectional imaging
Tissue diagnosis is often made via endoscopic retrograde cholangiopancreatography (ERCP) biopsy

Radiology description

Imaging modalities used to examine the ampulla include computed tomography (CT) and magnetic resonance imaging (MRI) (Am J Surg Pathol 2010;34:1731)
Imaging generally shows a dilated common bile duct, intra / extrahepatic ducts; an ampullary, duodenal or pancreatic mass; or enlarged or irregular papillae (Am J Surg Pathol 2010;34:1731)

Prognostic factors

Tumor size and degree of dysplasia correlate with risk of invasive component (Am J Surg Pathol 2010;34:1731)
Overall 3 and 5 year survivals in tumors without an identified invasive component is 100% (Am J Surg Pathol 2010;34:1731)
Overall 5 year survival in tumors with an invasive component is 45% (Am J Surg Pathol 2010;34:1731)
Cases showing high grade dysplasia are more likely to be associated with an invasive carcinoma (Am J Surg Pathol 2010;34:1731)

Treatment

Surgery is the mainstay of treatment: transduodenal ampullectomy or pancreatoduodenectomy (Whipple procedure)
Endoscopic resections are increasingly being used (J Clin Gastroenterol 2012;46:8, World J Gastrointest Endosc 2011;3:241, Gastrointest Endosc 2015;82:773)

Gross description

Intraluminal polypoid or papillary mass forming exophytic lesion within a dilated ampullary duct (Am J Surg Pathol 2010;34:1731)
Lesion fills and may obstruct the ampullary channel (Am J Surg Pathol 2010;34:1731)
Duodenal orifice is often widened, irregular and may be ulcerated (Am J Surg Pathol 2010;34:1731)
Average tumor size was 2.7 cm in one large series (Am J Surg Pathol 2010;34:1731)

Gross images

Images hosted on other servers:

IAPN gross / histologic correlation

Microscopic (histologic) description

Noninvasive exophytic tumor
Growth pattern often shows a mixture of papillary and tubular architecture (Am J Surg Pathol 2010;34:1731)
In one large series, cases showing predominantly papillary architecture were more likely to contain high grade dysplasia (Am J Surg Pathol 2010;34:1731)
When considering the predominant phenotype, the majority show an intestinal phenotype, with a minority showing a gastric / pancreatobiliary phenotype (74% versus 26%, respectively) (Am J Surg Pathol 2010;34:1731, Hum Pathol 2014;45:1910)
- Intestinal type: tall columnar cells with elongated nuclei and inconspicuous nucleoli; Paneth, goblet or endocrine cells may be present; appear similar to conventional colonic adenomas
- Pancreatobiliary type: cuboidal cells with round nuclei arranged predominantly in a single layer; some resemble a pyloric gland adenoma histologically
When taking into account all morphology present, 45% of cases show a mixed phenotype (Am J Surg Pathol 2010;34:1731)
Many to most do not show significant mucin production (Ann Surg 2016;263:162, Am J Surg Pathol 2010;34:1731)
At least focal high grade dysplasia is present in most cases (66.7 - 94%) (Am J Surg Pathol 2010;34:1731, Hum Pathol 2014;45:1910)
- Increased degree of architectural complexity and nuclear atypia
Lesions with a pancreatobiliary phenotype are more likely to have more extensive high grade dysplasia (Am J Surg Pathol 2010;34:1731)

Microscopic (histologic) images

Contributed by Felicia D. Allard, M.D.

Pancreatobiliary type IAPN

Intestinal type IAPN

Paneth and goblet cells

Intestinal IAPN with high grade dysplasia

Pancreaticobiliary phenotype tubular growth

Images hosted on other servers:

IAPN phenotype immune profiles

Cytology description

The majority of IAPNs are accessible to endoscopic biopsy; however, exfoliative cytology is sometimes done and can be used to diagnose dysplasia (Cytojournal 2017;14:19)

Positive stains

Intestinal phenotype: MUC2 (85%), CDX2 (94%),CK20 (93%), CK7 (63%) (Am J Surg Pathol 2010;34:1731)
Gastric / pancreatobiliary phenotype: MUC1 / EMA (89%), MUC5AC (95%), MUC6 (83%), CK7 (89%) (Am J Surg Pathol 2010;34:1731)

Negative stains

Intestinal phenotype: MUC1 / EMA (21%), MUC5AC (31%), MUC6 (24%) (Am J Surg Pathol 2010;34:1731)
Gastric / pancreatobiliary phenotype: CDX2 (39%), CK20 (39%), MUC2 (22%) (Am J Surg Pathol 2010;34:1731)

Sample pathology report

Ampulla, endoscopic ampullectomy:
- Intra-ampullary papillary tubular neoplasm, pancreatobiliary type, with multifocal high grade dysplasia
- No invasive carcinoma identified
- Resection margins are free of dysplasia

Differential diagnosis

Intraductal papillary mucinous neoplasm (IPMN):
- These lesions arise in the pancreatic ducts (main duct or side branch ducts) and generally have significant mucin production
- Proper grossing and sampling with specific location information of the tissue sampled are crucial in making the distinction between these entities, because without knowledge of the specific location of a given lesion, these can be histologically indistinguishable at microscopic level
Duodenal / periampullary adenoma:
- These lesions will generally show an intestinal phenotype (will look like a colonic adenoma)
- Proper grossing and sampling with specific location information of the tissue sampled are crucial in making the distinction between these entities, because without knowledge of the specific location of a given lesion, these can be histologically indistinguishable at microscopic level
Intra-ampullary adenocarcinoma:
- This is an adenocarcinoma that may arise from an IAPN but will show an invasive component

Additional references

WHO Classification of Tumours Editorial Board: Digestive System Tumours, 5th Edition, 2019

Board review style question #1

A 65 year old man presented with jaundice, weight loss and nausea. MRI showed a dilation of the intra and extrahepatic bile ducts with an ill defined fullness in the head of the pancreas; ERCP revealed a papillary mass in the ampullary channel. Forcep biopsy demonstrates histologic findings consistent with intra-ampullary papillary tubular neoplasm (IAPN) with high grade dysplasia including the pictured findings. The most likely immunoprofile for this lesion is

Immunoreactive for CDX2, CK20 and MUC2; negative for MUC1 and MUC5AC
Immunoreactive for CDX2, MUC1 and MUC2; negative for CK20 and MUC5AC
Immunoreactive for MUC1 and MUC5AC; negative for CDX2, CK20 and MUC2
Immunoreactive for MUC1, MUC2 and MUC5AC; negative for CDX2, CK20 and CK7

Board review style answer #1

A. Immunoreactive for CDX2, CK20 and MUC2; negative for MUC1 and MUC5AC. The question discusses a typical clinical presentation for a patient who has an intra-ampullary papillary tubular neoplasm (IAPN). The histologic image demonstrates neoplastic epithelium composed of columnar cells with elongated, hyperchromatic nuclei. Paneth cells and goblet cells are present. These findings support an intestinal phenotype; answer A contains the most common immunoprofile for an intestinal type IAPN. Answer choice C is the most common immunophenotype for a pancreatobiliary type IAPN.

Comment Here

Reference: Intra-ampullary papillary tubular neoplasm (IAPN)

Board review style question #2

A 65 year old man presented for evaluation of abdominal pain and weight loss. His wife noted that his skin and eyes were becoming yellow. Imaging revealed dilation of the main pancreatic duct and common bile duct. ERCP showed an exophytic mass filling the common channel of the ampulla; a biopsy was obtained for evaluation. Histology most likely showed a lesion comprised of which type of epithelium?

Intestinal
Oncocytic
Pancreatobiliary
Squamous

Board review style answer #2

A. Intestinal. The lesion described above is most likely an intra-ampullary papillary tubular neoplasm (IAPN). The majority (74%, in one large study) show an intestinal phenotype. The other epithelial phenotype described with IAPN is gastric / pancreatobiliary; IAPNs may show a mixture of the 2 epithelial types (45% in one large study). Oncocytic and squamous epithelial types are not seen in IAPNs.

Comment Here

Reference: Intra-ampullary papillary tubular neoplasm (IAPN)

Intra-ampullary papillary tubular neoplasm (IAPN)

Table of Contents

Definition / general

Intra-ampullary papillary tubular neoplasm (IAPN) is the name proposed in 2010 to unify the nomenclature for mass forming preinvasive (dysplastic) lesions that arise within the ampulla of Vater (Am J Surg Pathol 2010;34:1731)

Essential features

The precursor lesion of intra-ampullary adenocarcinomas (Am J Surg Pathol 2012;36:1592)
Majority (78%) of IAPNs in one large series harbored an invasive component (Am J Surg Pathol 2010;34:1731)
Analogous to pancreatic or biliary intraductal papillary and tubular neoplasms (Am J Surg Pathol 2010;34:1731)
Must be localized within (or predominantly within) the ampulla (Am J Surg Pathol 2010;34:1731)

Terminology

Other / previous terms include intestinal type adenoma, noninvasive pancreatobiliary type neoplasm

ICD coding

ICD-O
- 8210/0 - adenomatous polyp, NOS
- 8210/2 - adenocarcinoma in situ in adenomatous polyp
ICD-10
- C24.1 - malignant neoplasm of ampulla of Vater
ICD-11
- 2E92.2 & XH3DV3 - benign neoplasm of duodenum & adenoma, NOS
- 2E92.2 & XH8MU5 - benign neoplasm of duodenum & adenomatous polyp, NOS

Epidemiology

Mean age: 64 - 67 years; range: 27 - 85 years (Am J Surg Pathol 2010;34:1731, Med Sci Monit 2019;25:7332)
M:F = 2.4 in one surgical series and 42.5% men / 57.5% women in SEER analysis (Am J Surg Pathol 2010;34:1731, Med Sci Monit 2019;25:7332)
Estimated prevalence based on autopsy studies is 0.04 - 0.12% (World J Gastrointest Endosc 2011;3:241)
Incidence from SEER database study was 0.025 in 2014 (Med Sci Monit 2019;25:7332)
Incidence has been decreasing annually since 2016 (Med Sci Monit 2019;25:7332)

Sites

Ampulla of Vater: within the ampullary channel (common channel) or the intra-ampullary portions of the common bile duct or main pancreatic duct

Pathophysiology

Unknown

Etiology

Given the prevalence of neoplasia in and around the ampulla, authors have speculated that bile acids may be carcinogenic (Mutat Res 2005;589:47)

Diagrams / tables

N/A

Clinical features

Patients may be asymptomatic or present with obstructive symptoms: jaundice, weight loss, abdominal pain, nausea / vomiting, pruritus, dark urine / light stools or tarry stools (Am J Surg Pathol 2010;34:1731)
Rarely, patients present with cholangitis or pancreatitis

Diagnosis

Mass involving the ampullary region may be found on cross sectional imaging
Tissue diagnosis is often made via endoscopic retrograde cholangiopancreatography (ERCP) biopsy

Laboratory

N/A

Radiology description

Imaging modalities used to examine the ampulla include computed tomography (CT) and magnetic resonance imaging (MRI) (Am J Surg Pathol 2010;34:1731, Radiographics 2022;42:1320)
Imaging generally shows a dilated common bile duct, intra / extrahepatic ducts; an ampullary, duodenal or pancreatic mass; or enlarged or irregular papillae (Am J Surg Pathol 2010;34:1731)
Double duct sign is present in 52% of cases, with both biliary and pancreatic duct dilatation (Radiographics 2022;42:1320)
It may be challenging to identify lesions < 1 cm due to the duodenal folds (Radiographics 2022;42:1320)

Radiology images

N/A

Prognostic factors

Tumor size and degree of dysplasia correlate with risk of invasive component (Am J Surg Pathol 2010;34:1731)
Overall 3 and 5 year survival rates in patients with tumors lacking an identified invasive component is 100% (Am J Surg Pathol 2010;34:1731)
Overall 5 year survival rates in patients with tumors containing an invasive component is 45% (Am J Surg Pathol 2010;34:1731)
Cases showing high grade dysplasia are more likely to be associated with an invasive carcinoma (Am J Surg Pathol 2010;34:1731)

Case reports

61 year old woman presented with combined IAPN and ampullary neuroendocrine carcinoma (World J Clin Cases 2022;10:8045)
66 year old man presented with mucinous adenocarcinoma of the ampulla arising within an IAPN (Surg Case Rep 2021;7:25)
80 year old man presented with micropapillary adenocarcinoma of the ampulla arising within an IAPN (World J Clin Cases 2021;9:2671)

Treatment

Surgery is the mainstay of treatment: transduodenal ampullectomy or pancreatoduodenectomy (Whipple procedure)
Endoscopic resections are increasingly being used (J Clin Gastroenterol 2012;46:8, World J Gastrointest Endosc 2011;3:241, Gastrointest Endosc 2015;82:773)

Clinical images

N/A

Gross description

Intraluminal polypoid or papillary mass forming exophytic lesion within a dilated ampullary duct (Am J Surg Pathol 2010;34:1731)
Lesion fills and may obstruct the ampullary channel (Am J Surg Pathol 2010;34:1731)
Duodenal orifice is often widened, irregular and may be ulcerated (Am J Surg Pathol 2010;34:1731)
Average tumor size was 2.7 cm in one large series (Am J Surg Pathol 2010;34:1731)

Gross images

Images hosted on other servers:

IAPN gross / histologic correlation

Frozen section description

N/A

Frozen section images

N/A

Microscopic (histologic) description

Noninvasive exophytic tumor
Growth pattern often shows a mixture of papillary and tubular architecture (Am J Surg Pathol 2010;34:1731)
In one large series, cases showing predominantly papillary architecture were more likely to contain high grade dysplasia (Am J Surg Pathol 2010;34:1731)
When considering the predominant phenotype, the majority show an intestinal phenotype, with a minority showing a gastric / pancreatobiliary phenotype (74% versus 26%, respectively) (Am J Surg Pathol 2010;34:1731, Hum Pathol 2014;45:1910)
- Intestinal type
  - Tall columnar cells with elongated nuclei and inconspicuous nucleoli
  - Paneth, goblet or endocrine cells may be present
  - Appears similar to conventional colonic adenomas
- Pancreatobiliary type
  - Cuboidal cells with round nuclei arranged predominantly in a single layer
  - Some resemble a pyloric gland adenoma histologically
When taking into account all morphology present, 45% of cases show a mixed phenotype (Am J Surg Pathol 2010;34:1731)
Many to most do not show significant mucin production (Ann Surg 2016;263:162, Am J Surg Pathol 2010;34:1731)
At least focal high grade dysplasia is present in most cases (66.7 - 94%) (Am J Surg Pathol 2010;34:1731, Hum Pathol 2014;45:1910)
- Increased degree of architectural complexity and nuclear atypia
Lesions with a pancreatobiliary phenotype are more likely to have more extensive high grade dysplasia (Am J Surg Pathol 2010;34:1731)

Microscopic (histologic) images

Contributed by Felicia D. Allard, M.D.

Pancreatobiliary type IAPN

Intestinal type IAPN

Paneth and goblet cells

Intestinal IAPN with high grade dysplasia

Pancreaticobiliary phenotype tubular growth

Virtual slides

N/A

Cytology description

Majority of IAPNs are accessible to endoscopic biopsy; however, exfoliative cytology is sometimes done and can be used to diagnose dysplasia (Cytojournal 2017;14:19)

Cytology images

N/A

Immunofluorescence description

N/A

Immunofluorescence images

N/A

Positive stains

Intestinal phenotype: MUC2 (85%), CDX2 (94%), CK20 (93%), CK7 (63%) (Am J Surg Pathol 2010;34:1731)
Gastric / pancreatobiliary phenotype: MUC1 / EMA (89%), MUC5AC (95%), MUC6 (83%), CK7 (89%) (Am J Surg Pathol 2010;34:1731)

Negative stains

Intestinal phenotype: MUC1 / EMA (21%), MUC5AC (31%), MUC6 (24%) (Am J Surg Pathol 2010;34:1731)
Gastric / pancreatobiliary phenotype: CDX2 (39%), CK20 (39%), MUC2 (22%) (Am J Surg Pathol 2010;34:1731)

Electron microscopy description

N/A

Electron microscopy images

N/A

Molecular / cytogenetics description

N/A

Molecular / cytogenetics images

N/A

Videos

N/A

Sample pathology report

Ampulla, endoscopic ampullectomy:
- Intra-ampullary papillary tubular neoplasm, pancreatobiliary type, with multifocal high grade dysplasia
- No invasive carcinoma identified
- Resection margins are free of dysplasia

Differential diagnosis

Intraductal papillary mucinous neoplasm (IPMN):
- These lesions arise in the pancreatic ducts (main duct or side branch ducts) and generally have significant mucin production
- Proper grossing and sampling with specific location information of the tissue sampled are crucial in making the distinction between these entities because without knowledge of the specific location of a given lesion, these can be histologically indistinguishable at microscopic level
Duodenal / periampullary adenoma:
- These lesions will generally show an intestinal phenotype (will look like a colonic adenoma)
- Proper grossing and sampling with specific location information of the tissue sampled is crucial in making the distinction between these entities because without knowledge of the specific location of a given lesion, these can be histologically indistinguishable at microscopic level
Intra-ampullary adenocarcinoma:
- This is an adenocarcinoma that may arise from an IAPN but will show an invasive component

Additional references

WHO Classification of Tumours Editorial Board: Digestive System Tumours, 5th Edition, 2019

Board review style question #1

A 65 year old man presented with jaundice, weight loss and nausea. MRI showed a dilation of the intra and extrahepatic bile ducts with an ill defined fullness in the head of the pancreas; endoscopic retrograde cholangiopancreatography (ERCP) revealed a papillary mass in the ampullary channel. Forcep biopsy demonstrates histologic findings consistent with intra-ampullary papillary tubular neoplasm (IAPN) with high grade dysplasia including the pictured findings. What is the most likely immunoprofile for this lesion?

Immunoreactive for CDX2, CK20 and MUC2; negative for MUC1 and MUC5AC
Immunoreactive for CDX2, MUC1 and MUC2; negative for CK20 and MUC5AC
Immunoreactive for MUC1 and MUC5AC; negative for CDX2, CK20 and MUC2
Immunoreactive for MUC1, MUC2 and MUC5AC; negative for CDX2, CK20 and CK7

Board review style answer #1

A. Immunoreactive for CDX2, CK20 and MUC2; negative for MUC1 and MUC5AC. The question discusses a typical clinical presentation for a patient who has an intra-ampullary papillary tubular neoplasm (IAPN). The histologic image demonstrates neoplastic epithelium composed of columnar cells with elongated, hyperchromatic nuclei. Paneth cells and goblet cells are present. These findings support an intestinal phenotype; answer A contains the most common immunoprofile for an intestinal type IAPN. Answer C is incorrect because it is the most common immunophenotype for a pancreatobiliary type IAPN.

Comment Here

Reference: Intra-ampullary papillary tubular neoplasm (IAPN)

Board review style question #2

A 65 year old man presented for evaluation of abdominal pain and weight loss. His wife noted that his skin and eyes were becoming yellow. Imaging revealed dilation of the main pancreatic duct and common bile duct. Endoscopic retrograde cholangiopancreatography (ERCP) showed an exophytic mass filling the common channel of the ampulla; a biopsy was obtained for evaluation. Histology most likely showed a lesion comprised of which type of epithelium?

Intestinal
Oncocytic
Pancreatobiliary
Squamous

Board review style answer #2

A. Intestinal. The lesion described above is most likely an intra-ampullary papillary tubular neoplasm (IAPN). The majority (74% in one large study) show an intestinal phenotype. The other epithelial phenotype described with IAPN is gastric / pancreatobiliary; IAPNs may show a mixture of the 2 epithelial types (45% in one large study). Answers B and D are incorrect because oncocytic and squamous epithelial types are not seen in IAPNs.

Comment Here

Reference: Intra-ampullary papillary tubular neoplasm (IAPN)

Intussusception

Table of Contents

Definition / general | Case reports | Treatment | Clinical images

Definition / general

Portion of bowel (intussuscipiens) swallows another length of bowel (intussusceptum)
Usually occurs during first 5 years of life, 50% within first year (BMC Pediatr 2012;12:36)
May be due to lymphoid hyperplasia in ileocecal region secondary to adenovirus or other viral infections
In older patients, may be associated with HIV or due to pedunculated intraluminal lipoma or leiomyoma that serves as point of traction
Complications: ischemic necrosis due to compression of vessels

Case reports

75 year old man with giant ileal lipoma (Int J Surg Case Rep 2012;3:382)

Treatment

Manual reduction, barium enema, resection

Clinical images

Images hosted on other servers:

Gentle reduction of the ileoileal intussusception

Ischemia

Table of Contents

Definition / general

Decreased blood flow or lack of oxygen to the bowel that causes necrosis or damage

Essential features

Numerous arterial or venous causes of small bowel ischemia
Early histologic findings: mucosal surface damage with hemorrhagic necrosis and lamina propria hyalinization
Late histologic findings: necrosis, inflammation, loss of base crypts, crypt distortion
Important to examine the vessels for evidence of thromboembolic disease or vasculitis
Reference: Greenson: Diagnostic Pathology - Gastrointestinal, 3rd Edition, 2019

Terminology

Necrosis / necrotic bowel
Mesenteric ischemia

ICD coding

ICD-10:
- K55.01 - acute (reversible) ischemia of small intestine
- K55.02 - acute infarction of small intestine
ICD-11: DD30.1 - acute mesenteric arterial ischemia

Epidemiology

Mean age of 70 years old; less common before age 60
M:F = 1:1
Rare condition but high mortality rates (24 - 94%) (StatPearls: Bowel Ischemia [Accessed 9 August 2023])
Decrease in mesenteric arterial blood flow is the most common cause

Sites

Small bowel (duodenum, jejunum, ileum)
Often has transmural infarction due to occlusion of superior mesenteric artery

Pathophysiology

Decrease or lack of blood flow deprives the tissue of oxygen
Lack of oxygen leads to cell death and necrosis
Ischemia injury causes the release of toxic byproducts, production of free radicals and activation of neutrophils (StatPearls: Bowel Ischemia [Accessed 9 August 2023])
Thrombosis can lead to full thickness infarction

Etiology

Artery occlusion: thrombosis, embolism, atherosclerosis, vasculitis, compression (adhesions, volvulus, tumor), radiation
Venous occlusion: thrombosis (oral contraceptives, hypercoagulable states), compression (adhesions, volvulus, tumor)
Low flow states: shock (blood loss, postsurgery), dehydration, heart failure, vasospasm (medications, drugs like cocaine)
Intestinal obstruction: masses (neoplasms, diverticular disease), ileus, motility disorders
Infection: enterohemorrhagic E. coli (E. coli O157:H7), cytomegalovirus
Drugs / medications: NSAIDs, opioids, chemotherapy, digoxin, vasoconstrictors (cocaine, amphetamines, decongestants, ergot alkaloids)
Reference: Am J Surg Pathol 1998;22:773

Diagrams / tables

Not applicable

Clinical features

Abdominal pain (usually sudden onset), nausea / vomiting, hematochezia and fever

Diagnosis

History and physical is most important
Some patients have a leukocytosis
CT abdomen with or without contrast (Curr Gastroenterol Rep 2019;21:27)
Findings of underlying cause: CT angiography abdomen, magnetic resonance angiography (MRA) abdomen, infectious causes
Endoscopic findings: edema and erythema, geographic ulcers, strictures (Greenson: Diagnostic Pathology - Gastrointestinal, 3rd Edition, 2019)

Laboratory

Some patients present with a leukocytosis or other complete blood count (CBC) abnormalities (if bleeding)

Radiology description

CT abdomen with and without contrast shows evidence of intestinal ischemia by bowel wall thickening, dilatation of bowel lumen, mesenteric fat stranding and ascites, bowel wall attenuation and possibly pneumatosis

Radiology images

Contributed by Krutika S. Patel, M.B.B.S., M.D.

CT scan

Prognostic factors

Depends on the underlying cause
90% mortality for mesenteric artery thrombosis, 10% mortality for nonocclusive disease (Turk J Surg 2017;33:104)

Case reports

33 year old man presented with acute abdominal pain following amphetamine use (Radiol Case Rep 2020;15:2183)
34 year old man with history of right hepatectomy presented with diffuse abdominal pain, bloating and nausea (World J Gastrointest Pathophysiol 2019;10:29)
59 year old woman with history of peritonectomy (Int J Surg Case Rep 2020;76:247)

Treatment

Supportive treatment, hemodynamic stability and oxygen
Surgical treatment if necessary

Clinical images

Not applicable

Gross description

Infarcted bowel mucosa and wall described as dusky, which is a dark red-brown color
Bowel wall can be thin and friable, may contain bloody contents
Geographic (sharp demarcation) between infarcted bowel and normal bowel
Ulcers and pseudomembranes may be present (Greenson: Diagnostic Pathology - Gastrointestinal, 3rd Edition, 2019)

Gross images

Images hosted on other servers:

Infarcted small intestine

Marked hyperemia

Early ischemic enteritis

Resected ischemic jejunal segment

Frozen section description

Not applicable

Frozen section images

Not applicable

Microscopic (histologic) description

Early histologic findings
- Mucosal surface with hemorrhagic necrosis and loss of surface crypts
- Base of crypts can remain intact but are atrophic and withered with marked regenerative atypia
- Lamina propria hyalinization with smudgy appearance
- Edematous submucosa, edema and subsequent splaying of muscularis mucosae
- Little inflammation
- Pseudomembranes may be present
Later histologic findings
- Inflammation progresses with crypt distortion
- Hemosiderin laden macrophages
- Can have giant cells in areas of ulceration
Vessels
- Evidence of thrombi, emboli or vasculitis; most commonly in resection specimens
- Do not over interpret thrombi or inflammation in ulcer bed
Reference: Greenson: Diagnostic Pathology - Gastrointestinal, 3rd Edition, 2019

Microscopic (histologic) images

Contributed by Krutika S. Patel, M.B.B.S., M.D. and Madison Swaney, M.D.

Early ischemic changes

Ischemic changes

Virtual slides

Images hosted on other servers:

Ischemic colitis

Cytology description

Not applicable

Cytology images

Not applicable

Immunofluorescence description

Not applicable

Immunofluorescence images

Not applicable

Positive stains

Not applicable

Negative stains

Not applicable

Electron microscopy description

Not applicable

Electron microscopy images

Not applicable

Molecular / cytogenetics description

Not applicable

Molecular / cytogenetics images

Not applicable

Videos

Not applicable

Sample pathology report

Small bowel, biopsy:
- Enteric mucosa with changes consistent with ischemic type mucosal injury (see comment)
- Comment: Possible etiologies for this ischemic type mucosal injury include true ischemic colitis, infection (such as E. coli 0157:H7) and a drug reaction (including oral contraceptives, NSAIDs, digoxin and ergotamine derivatives). Clinical and endoscopic correlation is recommended.
Small bowel, resection:
- Ischemic enteritis with transmural necrosis / hemorrhage / perforation
- Resection margins are viable

Differential diagnosis

Enterohemorrhagic E. coli infection:
- History of eating undercooked meat
- Fibrin thrombi are characteristic but not specific for E. coli
Chronic inflammatory bowel disease:
- Chronic ischemia with stricture formation may look identical to quiescent Crohn's disease
- Presence of hemosiderin laden macrophages favors ischemia
- Presence of fistulae and granulomas favors Crohn's Disease
Nonsteroidal anti-inflammatory drug damage:
- Can be histologically similar to ischemia
- Clinical history is important
Dysplasia:
- Should appear top heavy; ischemia is bottom heavy
- Typically has more branched and complex architecture
- Regenerative crypts in ischemia are usually small and round
Behçet disease:
- Scattered punched out ulcers in the GI tract, no intervening normal mucosa
- Patients have urogenital and ocular manifestations, which are required for diagnosis
Clostridium difficile colitis:
- Usually, a more diffuse process than ischemia (geographic)
- Hyalinized lamina propria or withered crypts are not usually seen with C. difficile
Reference: Greenson: Diagnostic Pathology - Gastrointestinal, 3rd Edition, 2019, Am J Surg Pathol 1998;22:773

Additional references

None

Board review style question #1

Which of the following statements describes the findings associated with the small bowel biopsy shown above?

Atrophic crypts with lamina propria hyalinization
Crypt abscess with granulomatous inflammation
Lamina propria mast cells and eosinophil rich inflammation
Pseudomembrane formation

Board review style answer #1

A. Atrophic crypts with lamina propria hyalinization. Features of ischemic colitis vary depending on the extent and timing of the ischemic event. This biopsy shows features of withered and atrophic crypts and lamina propria hyalinization in the absence of acute inflammation or other significant architectural distortion. The withered crypts are a feature of ischemic pattern colitis, the etiology of which includes both ischemia and infection. Answer B is incorrect because crypt abscesses and granulomatous inflammation are typically seen in inflammatory bowel disease and are not features of ischemic colitis. Answer C is incorrect because mast cells and eosinophils are not typically seen in small bowel ischemia. These features can be seen in eosinophilic gastroenteritis, parasitic infections, mastocytosis or Langerhans histiocytosis. Answer D is incorrect because pseudomembrane formation is typically seen with C. difficile colitis.

Comment Here

Reference: Ischemia

Board review style question #2

Which of the following are clinicopathologic features that distinguish ischemic enteritis from other causes of enteritis?

Branched and complex architecture in crypts
Evidence of thrombi, emboli or vasculitis
History of eating undercooked meat
Scattered ulcers in the GI tract, ocular, oral and genital manifestations

Board review style answer #2

B. Evidence of thrombi, emboli or vasculitis, most commonly in resection specimens, can be seen in ischemic small bowel. Answer C is incorrect because E. coli infection is associated with history of eating undercooked meat. Answer A is incorrect because small bowel dysplasia is associated with branched and complex architecture in crypts. Answer D is incorrect because scattered ulcers in the GI tract, ocular, oral and genital manifestations are commonly associated with Behçet disease.

Comment Here

Reference: Ischemia

Ischemia

Table of Contents

Definition / general

Mucosal damage (initially) due to vascular occlusion or reduced blood flow associated with shunting
Usually not due to atherosclerosis because of widely anastomosing blood supply
Damage varies from none to hemorrhagic infarction
Also ulceration, mucosal plaque, strictures
Grossing bowel specimens with possible ischemia: dissect blood vessels and submit several sections to detect inflammation and thrombosis

Gross images

Images hosted on other servers:

Various images

Microscopic (histologic) description

Early: lamina propria hemorrhage, superficial epithelial necrosis, preservation of deep crypts
Later: ulceration with minimal inflammation, villous distortion, pyloric gland metaplasia progressing to full thickness infarct
Late: strictures affecting muscularis propria

Microscopic (histologic) images

Images hosted on other servers:

Various images

Differential diagnosis

Crohn's disease: marked inflammatory infiltrate, no stricture of muscularis propria, no hemosiderin

Additional references

J Med Case Rep 2012;6:48, Histol Histopathol 2010;25:277

Juvenile polyposis

Table of Contents

Definition / general

Juvenile polyposis (JP) of small intestine is a rare condition that is characterized by presence of multiple hamartomatous polyps in the small bowel typically presenting during childhood
This topic describes features of juvenile polyps in the small intestine that differ from colonic juvenile (retention) polyp

Essential features

Clinical findings of sporadic juvenile polyps can be nonspecific
Multiple juvenile polyps of small intestine with or without multiple colorectal juvenile polyps are required diagnostic criteria for juvenile polyposis syndrome (JPS)
Juvenile polyps in small intestine can present with intussusception
Histologic features show cystically dilated or branched glands with edematous and inflamed stroma with or without dysplasia
Close surveillance and genetic testing are recommended for symptomatic cases

Terminology

Hamartomatous gastrointestinal polyposis

ICD coding

ICD-11: DA98.Z - polyps of small intestine, unspecified

Epidemiology

Juvenile polyposis syndrome (JPS) has an incidence of 1 per 100,000 live births in western countries (Bull World Health Organ 1990;68:655)
Incidence of small intestine JP is very low compared to colorectal JP and is most commonly located in the duodenum, ranging between 14 and 33% (Endoscopy 2009;41:1001)
JPS is an autosomal dominant inherited disease associated with the presence of mutation in SMAD4 / DPC4 or BMPR1A genes (Clin Genet 2009;75:79)

Sites

The most common site for small intestine JPS is the duodenum (14 - 33%) (Ann Surg Oncol 1998;5:751)

Pathophysiology

Classical mutational profile in JPS involves either the bone morphogenetic protein receptor 1A (BMPR1A), located at 10q23 or SMAD4 gene, located at 18q21 (Clin Genet 2009;75:79, Gut 2008;57:623)
Juvenile polyposis of infancy shows contiguous deletion of BMPR1A and PTEN genes at chromosome 10q23 (Am J Hum Genet 2006;78:1066)
Neoplasia may arise in JPS from adenomatous epithelium within the polyp through a landscaper mechanism and abnormal stromal environment that affects TGFβ signaling (Science 1998;280:1036)
Pathophysiology and etiology of sporadic / solitary juvenile polyps in small bowel is unknown

Etiology

See Pathophysiology

Diagrams / tables

Images hosted on other servers:

Genotype phenotype correlations in JPS

Clinical features

Can be asymptomatic
Clinical presentation includes (Am J Surg 1975;129:198, Folia Med (Plovdiv) 2022;64:693)
- Abdominal pain, nausea and vomiting
- Gastrointestinal bleeding and iron deficiency anemia
- Intermittent obstruction including intussusception
Endoscopic findings
- Video capsule endoscopy
  - Minimally invasive
  - Can explore the entire small bowel
  - Diagnostic sensitivity for epithelial and subepithelial polyps ≤ 1 cm is 75% and 83%, respectively (Endoscopy 2005;37:960)
- Double and single balloon enteroscopy
  - Enables sampling and intervention
  - Diagnostic sensitivity in double balloon enteroscopy for epithelial and subepithelial polyps ≤ 1 cm is 100% and 97%, respectively (Gastrointest Endosc 2012;76:344)
JPS can present with duodenal adenocarcinoma; however, the risk analysis of cancer development in a juvenile polyp is unclear (Ann Surg Oncol 1998;5:751)

Diagnosis

Diagnostic criteria of JPS are based on these criteria (Histopathology 1988;13:619, J Pediatr Gastroenterol Nutr 2019;68:453)
- More than 3 - 5 juvenile polyps in colon or rectum
- Multiple juvenile polyps throughout gastrointestinal tract (including stomach and small intestine)
- Any number of juvenile polyps and positive family history
Diagnostic criteria of isolated or single small intestine juvenile polyps are unclear (J Pediatr Gastroenterol Nutr 2020;71:491)
Diagnosis can be reached by integrating histology, immunohistochemistry and next generation sequencing (Fam Cancer 2022;21:441)

Laboratory

Genetic testing of the following gene mutations
- SMAD4 and BMPR1A: for juvenile polyposis syndrome
- PTEN: identified in juvenile polyposis of infancy and Cowden syndrome
- STK11 / LKB1: seen in Peutz-Jeghers syndrome
Preferred for at risk patients, starting at age of 4 (Curr Mol Med 2007;7:29)
Upper and lower endoscopy surveillance starting at age 12 if symptomatic (Dis Colon Rectum 2012;55:1038)

Radiology description

Magnetic resonance enterography (MRE)
- Noninvasive
- Compared to video capsule endoscopy, magnetic resonance enterography showed comparable rates of detection for large (> 15 mm) polyps (Abdom Imaging 2012;37:279)

Radiology images

Images hosted on other servers:

Magnetic resonance enterography of ileal polyp

Magnetic resonance enterography of ileal polyp

Prognostic factors

Risk of upper gastrointestinal cancer, risk analysis is unclear

Case reports

3 year old girl presented with chronic iron deficiency anemia caused by a single painless juvenile polyp in the small intestine (J Pediatr Gastroenterol Nutr 2020;71:491)
35 year old woman presented with a juvenile polyp complicated with intussusception of the small intestine (Folia Med (Plovdiv) 2022;64:693)
50 year old woman presented with severe iron deficiency anemia and numerous stomach and jejunum polyps (Fam Cancer 2022;21:441)
73 year old woman with an isolated benign hamartomatous (juvenile-like) polyp (Am J Case Rep 2023:24:e938929)

Treatment

Screening and management for small intestine JPS are based on symptoms (Am J Gastroenterol 2015;110:223)
Goal is preventing malignancy through close surveillance and endoscopic resection if symptomatic
Sirolimus studies showed decreased disease burden in JPS and juvenile polyposis of infancy (Pediatrics 2019;144:e20182922)

Clinical images

Contributed by Milton Smith, M.D.

Juvenile polyps in duodenum

Large eroded juvenile polyp

Multiple juvenile polyps

Gross description

Multiple polyps in JPS, up to 200 polyps, with variable size reaching up to a few centimeters in some cases (J Gastroenterol Hepatol 2005;20:1634)
Surface of the polyp may show erosion or ulceration

Microscopic (histologic) description

Solitary or multiple hamartomatous polyps
Classic solitary polyps (Histopathology 1988;13:619)
- Eroded surface and reactive epithelium
- Abundant edematous stroma with inflammatory cells and granulation tissue
- Cystically dilated glands
- Hyperplastic glands can be seen
Multilobulated / atypical polyp
- Finger-like lobules
- Increased epithelial - stromal ratio
- Budding and branching glands
- Focal dysplasia can be present (Am J Surg Pathol 2011;35:530)

Microscopic (histologic) images

Contributed by Divya Sharma, M.D., Rachel Sheridan, M.D. and Sara Szabo, M.D.

Surface erosion

Inflammatory stroma

Granulation tissue

Branching glands

Glandular hyperplasia

Slit-like serrations and inflammation

Finger-like lobulation of glands

Low grade dysplasia

Ileal polyp, surface erosion

Ileal polyp, dilated glands

Negative stains

Loss of SMAD4 expression in ~50% of JPS patients with germline SMAD4 mutation (somatic inactivation of the SMAD4 wild type allele) (Clin Cancer Res 2010;16:4126)
Loss of SMAD4 is not seen in sporadic juvenile polyps or in patients with BMPR1A mutations

Molecular / cytogenetics description

Genetic testing for germline mutations in SMAD4, BMPR1A and PTEN genes

Sample pathology report

Duodenum, polyp, endoscopic resection:
- Polypoid mucosa with edematous stroma and cystically dilated glands consistent with features of juvenile polyps
- Negative for dysplasia or malignancy

Differential diagnosis

Peutz-Jeghers polyp:
- Commonly in jejunum and ileum
- Papillary villous architecture with tree-like arborization of smooth muscles and normal overlying epithelium
- STK11 / LKB1 gene mutations
Inflammatory polyp:
- Branched and cystically dilated glands with reactive atypia of the mucosa
- Lamina propria acute and chronic inflammation
Hyperplastic polyp:
- Common in second part of duodenum
- Classically a solitary polyp
- Epithelial serrations and bland cytology
- Association with BRAF V600E and KRAS
Cowden syndrome polyp:
- Dilated glands with expanded stroma
- Can be associated with intramucosal lipoma
- No dysplasia
- Histologically can be similar to juvenile polyp
- PTEN gene mutations
Cronkhite-Canada polyp:
- Ill defined polyps
- Cystically dilated glands with edematous stroma
- Mononuclear and eosinophilic infiltrate
- Histologically can be similar to juvenile polyp
- Nonhereditary
Ménétrier disease:
- Most commonly located in stomach
- Presentation with small bowel polyposis is rare
- Marked foveolar hyperplasia with no atypia
- Interstitial edema with mild inflammatory infiltrate

Additional references

Am J Surg Pathol 2014;38:1618, Best Pract Res Clin Gastroenterol 2017;31:401

Board review style question #1

Upper esophagogastroduodenoscopy (EGD) in a 12 year old patient with history of abdominal pain and nausea showed multiple polyps in the second part of the duodenum. The largest polyp was biopsied and the microscopic findings demonstrated surface erosion and cystically dilated glands. Which of the following is a criterion for a diagnosis of juvenile polyposis syndrome (JPS) in this patient?

2 colon polyps from the same patient with similar morphology to the duodenal polyp
Germline mutation in STK11 gene
Multiple duodenal polyps that are at least 10 mm in size
Positive family history

Board review style answer #1

D. Positive family history. The biopsy findings show a polyp with features suggestive of a juvenile polyp (eroded surface, inflammatory stroma and dilated glands). A diagnosis of JPS requires one of the following criteria

More than 3 - 5 juvenile polyps in colon or rectum
Multiple juvenile polyps throughout gastrointestinal tract (including stomach and small intestine)
Any number of juvenile polyps and positive family history

Answer B is incorrect as STK11 mutations are seen in Peutz-Jeghers syndrome. Answer A is incorrect because the diagnostic criteria of JPS requires the presence of more than 3 - 5 colorectal polyps. Answer C is incorrect as there is no polyp size cut off criteria for the diagnosis of JPS.

Comment Here

Reference: Juvenile polyposis

Board review style question #2

The microscopic image above is from a biopsy of a duodenal polyp. Which of the following features, if present, favors a diagnosis of juvenile polyp over an inflammatory polyp?

Clinical history of inflammatory bowel disease
Hyperplasia of the glands with gland branching and cystic dilatation
Reactive atypia of the mucosal glands
Solitary polyp and mucosal hyperemia seen on esophagogastroduodenoscopy (EGD)

Board review style answer #2

B. Hyperplasia of the glands with gland branching and cystic dilatation. These features are generally nonspecific; however, they are less likely to be seen in inflammatory polyps. Answer C is incorrect because reactive atypia in the glands can be seen in both juvenile and inflammatory polyps. Answers A and D are incorrect as these features favor a diagnosis of an inflammatory polyp.

Comment Here

Reference: Juvenile polyposis

Leiomyoma

Table of Contents

Definition / general

Benign smooth muscle tumors that arise from small bowel muscularis propria or muscular mucosa
Duodenal leiomyomas of muscular mucosa are incidental, 1 - 2 mm, merge with muscularis mucosa; those not from muscularis mucosa are also often incidental but larger, 2 - 4 cm, with firm, white, whorled cut surface

Microscopic (histologic) description

Low cellularity, no / rare mitotic figures, resembles esophageal leiomyoma

Microscopic (histologic) images

AFIP images

Esophageal leiomyomas

Positive stains

Smooth muscle actin, desmin

Negative stains

CD117, CD34

Differential diagnosis

GIST: often cytologically malignant in small bowel; CD117+, often CD34+ (Rom J Morphol Embryol 2011;52:1121, Am J Surg Pathol 2003;27:625)

Lipoma

Table of Contents

Definition / general

Rare, usually submucosal
May cause ulceration or intussusception
Lipohyperplasia often found near ileocecal valve

Case reports

45 year old man with ileocecal intussusception due to lipoma (N Engl J Med 2009;361:e55)
52 year old woman with pedunculated lesion of terminal ileum (J Med Case Rep 2010;4:51)
77 year old man with ileocecal valve lipoma (JSLS 2009;13:80)

Gross description

Bright yellow, round, encapsulated
Bulges into lumen, 5% multiple
May have hemorrhage or necrosis

Gross images

Contributed by @Andrew_Fltv on Twitter

Lipoma

Images hosted on other servers:

Large pedunculated polypoid lipoma

Microscopic (histologic) images

Contributed by @Andrew_Fltv on Twitter

Lipoma

Images hosted on other servers:

Circumscribed collection of mature adipocytes

Differential diagnosis

Lipomatosis: bowel infiltrated by mature fat

Lipomatosis of the ileocecal valve

Table of Contents

Definition / general

Mature adipocyte proliferation within the submucosal layer of the ileocecal valve not contained within a capsule (Iran J Radiol 2014;11:e4336)
Rarely extends into serosa and mesenteric fat (Iran J Radiol 2014;11:e4336)

Essential features

Diffuse infiltration of the fatty tissue mainly in the submucosal layer is characteristic
Usually asymptomatic and found incidentally
Lack of encapsulation differentiates it from lipoma
Cause of the fat deposition is not known

Terminology

Lipomatosis of the ileocecal valve
Lipohyperplasia

ICD coding

ICD-10: E88.2 - lipomatosis, not elsewhere classified

Epidemiology

M > F
Uncommon under age 40
More common with obesity

Sites

Ileocecal valve and ileum
Also can occur in cecum and ascending colon

Pathophysiology

Benign mature adipocyte proliferation within the submucosal layer of the ileocecal valve

Etiology

Unknown

Clinical features

Commonly asymptomatic
May present with
- Right lower quadrant pain
- Constipation
- Diarrhea
- Obstruction
- Bleeding
- Hemorrhage
- Intussusception
Can mimic appendicitis
Risk factors: female, obese, age > 40

Diagnosis

Incidental diagnosis of right colon resection, which usually includes terminal ileum and ileocecal valve

Radiology description

Commonly visualized on abdominal CT as well defined circumferential thickening of the lips of ileocecal valve with fat attenuation (Radiopedia: Lipomatosis of the ileocecal valve [Accessed 19 March 2019], Iran J Radiol 2014;11:e4336)
Barium enema may show smooth mass-like enlargement of ileocecal valve
Lips can be thickened with nodularity but margins are smooth (Am J Roentgenol Radium Ther Nucl Med 1973;119:323, Cancer 1972;119:323, J Korean Radiological Soc 2001;45:43)
Ultrasound can show bulky and hyperechoic ileocecal valve with intussusception if present

Radiology images

Images hosted on other servers:

Hypoechoic on ultrasound

CT with submucosal fat

Multidetector CT

Case reports

45 year old man with melena and anemia (BMJ Case Rep 2013 Jul 8;2013)
50 year old woman with intestinal symptoms, anemia and positive fecal occult blood test (Tech Coloproctol 2007;11:278)
70 year old woman with abdominal pain (Iran J Radiol 2014;11:e4336)

Treatment

Usually asymptomatic
Surgical resection if causing obstruction, significant symptoms or concern for malignancy

Clinical images

Images hosted on other servers:

Smooth ileocecal lesion

Gross description

Prominent and thickened ileocecal valve, usually an incidental finding during gross exam of right colectomy specimen

Gross images

Contributed by Jian-Hua Qiao, M.D.

Thickened ileocecal valve

Donut shaped ileocecal valve

Microscopic (histologic) description

Ileocecal valve mucosa with extensive submucosal proliferation of lipomatous mature adipocytes
Fibrous septa and vascular congestion are usually present
No surrounding fibrous capsule

Microscopic (histologic) images

Contributed by Jian-Hua Qiao, M.D.

Unencapsulated submucosal adipose

Villi resembling terminal ileum mucosa

Unencapsulated submucosal adipose

Well defined crypts resembling cecal mucosa

Immunohistochemistry & special stains

Not indicated

Sample pathology report

Right hemicolectomy
- Adenocarcinoma of ascending colon (see synoptic report)
- Lipomatosis of ileocecal valve (incidental finding)
- 20 mesenteric lymph nodes negative for metastatic tumor (0/20)

Differential diagnosis

Lipoma:
- True lipoma of ileocecal valve is rare
- Has demarcating capsule around the fatty tissue and is confined to only one of the ileocecal lips
Crohn's disease:
- Crohn's ileocolitis can be associated with lipomatosis of the ileocaecal valve
- Can cause difficulty in diagnostic imaging studies
- Gross and microscopic examination will show characteristic fissuring, skipping ulceration and transmural lymphoid aggregates
Non-Hodgkin lymphoma (NHL):
- Can involve ileocecal valve and forming obstructive mass lesion or circumferential infiltration
- Microscopic examination will show malignant lymphoma cells with specific IHC staining patterns
Adenomatous polyp:
- Can involve ileocecal valve
- Grossly, it is usually focal polypoid lesion rather than diffuse thickening
- Microscopic exam will show adenomatous tubules
Adenocarcinoma of the ileocecal valve:
- Usually an irregular mass lesion with ulceration and obstruction
- Microscopic exam will show malignant tumor glands

Additional references

Radiat Med 2007;25:480, Yonsei Med J 2003;44:359, Acta Chir Belg 2008;108:356, Radiographics 2006;26:1373, Am J Gastroenterol 1992;87:82

Board review style question #1

A middle aged man underwent a right hemicoloectomy for cecal adenocarcinoma. Grossly, the ileocecal valve was prominent and diffusely thickened but no tumor was noted. What is your diagnosis?

Crohn's disease
Lipoma of the ileocecal valve
Lipomatosis of the ileocecal valve
Non-Hodgkin lymphoma
Normal ileocecal valve

Board review style answer #1

C. Lipomatosis of the ileocecal valve. Submucosal nonencapsulated adipose tissue proliferation is diagnostic for lipomatosis of the ileocecal valve.

Comment here

Reference: Lipomatosis of the ileocecal valve

Board review style question #2

A 45 year old woman presents with sudden right lower quadrant abdominal pain. She has been experiencing on and off abdominal pain for the past 4 weeks. CT abdomen reveals small bowel obstruction near the ileocecal valve. She undergoes exploratory laparotomy and is later diagnosed with lipomatosis of the ileocecal valve by pathological examination. Which of the following is diagnostic for lipomatosis of the ileocecal valve?

Adipocyte proliferation in the muscularis propria not contained within a capsule
Adipocyte proliferation in the submucosa contained within a capsule
Adipocyte proliferation in the submucosa not contained within a capsule
Diffuse gland proliferation
Inflammatory cells predominately lymphocytes

Board review style answer #2

C. Adipocyte proliferation in the submucosa not contained within a capsule is diagnostic for lipomatosis of the ileocecal valve.

Comment here

Reference: Lipomatosis of the ileocecal valve

Lymphangiectasia

Table of Contents

Definition / general

Dilated small intestinal lacteals, which may be primary or secondary
Primary intestinal lymphangiectasia is a rare disorder resulting in lymph leakage into the small bowel lumen and responsible for protein losing enteropathy, leading to lymphopenia, hypoalbuminemia and hypogammaglobulinemia (Orphanet J Rare Dis 2008;3:5)

Essential features

Lymphagiectasia can be primary or secondary; primary intestinal lymphangiectasia is more common in children, though in rare cases it can present in early adulthood and is usually associated with malabsorption
Secondary lymphangiectasia is often seen in adults and can be associated with various obstruction / constrictive conditions (described below), though exclusion of an underlying malignancy remains the main consideration
Microscopy shows dilated lymphatic vessels in the mucosa and submucosa without significant villous atrophy or inflammation

Terminology

Waldmann disease

ICD coding

ICD-10: K63.89 - Other specified diseases of intestine

Epidemiology

Primarily affects children (generally diagnosed before 3 years of age) and young adults but may be diagnosed later in adults (Orphanet J Rare Dis 2008;3:5)
Very rare familial forms of Waldmann disease have been reported

Sites

Small intestine

Pathophysiology

To date, the etiology of primary intestinal lymphangiectasia is unknown
Several genes, such as VEGFR3 (vascular endothelial growth factor receptor 3), prospero related homeobox transcriptional factor PROX1, forkhead transcriptional factor FOXC2 and SOX18 are implicated in the development of the lymphatic system (Orphanet J Rare Dis 2008;3:5)
Mutations in the FOXC2 (MFH1) gene or deletion of the PIK3R1 gene may result in lymphangiectasia, arrested lymphatic sprouting and maturation defects (World J Gastrointest Endosc 2011;3:235)

Etiology

Etiology is unknown for primary intestinal lymphangiectasia
Syndromes associated with primary intestinal lymphangiectasia include von Recklinghausen, Turner or Noonan, Klippel-Trenaunay and Hennekam (Turk J Gastroenterol 2018;29:714)
Some secondary causes of intestinal lymphangiectasia include constrictive pericarditis, intestinal lymphoma, lymphenteric fistula, Whipple disease, Crohn's disease, sarcoidosis, intestinal tuberculosis, systemic sclerosis, radiation or chemotherapy with retroperitoneal fibrosis and human immunodeficiency virus related enteropathy (Orphanet J Rare Dis 2008;3:5)

Clinical features

Classical symptoms are bilateral or unilateral lower limb edema and intermittent diarrhea (Am J Case Rep 2016;17:512)
Some patients develop steatorrhea
Accumulation of fluids in body cavities resulting in pleural effusion or ascites has been reported
Lymphedema (Orphanet J Rare Dis 2008;3:5)
In children, primary intestinal lymphangiectasia is generally diagnosed before 3 years of age and may be complicated by fatigue, abdominal pain, nausea, vomiting and weight loss, inability to gain weight and growth retardation; malabsorption may cause fat soluble vitamin deficiencies and hypocalcemia leading to convulsions (Orphanet J Rare Dis 2008;3:5)
In secondary cases, the symptoms may be related to the underlying condition

Diagnosis

Endoscopy or capsule endoscopy can show swollen mucosa and enlarged whitish villi (World J Gastrointest Endosc 2011;3:235)
Biopsy

Laboratory

Hypoproteinemia, hypoalbunimia and hypogammaglobunimea due to protein loss (Orphanet J Rare Dis 2008;3:5)
Exudative enteropathy is confirmed by high 24-h stool alpha-1 antitrypsin clearance due to enteric protein loss
Functional absorption tests such as D-xylose test results are normal in primary intestinal lymphangiectasia

Radiology description

Ultrasonographic findings may show dilation of the intestinal loops, regular and diffuse thickening of the walls, plical hypertrophy and severe mesenteric edema and, in some cases, ascites (Orphanet J Rare Dis 2008;3:5)
CT scan can show diffuse, nodular small bowel wall thickening and edema, which are a consequence of the dilated lymphatics within the villi along with some degree of small bowel dilation with (in few cases) a halo sign due to swelling and edema (Orphanet J Rare Dis 2008;3:5)

Prognostic factors

Primary intestinal lymphangiectasia is a chronic debilitating disorder requiring constraining long term dietary control based on a low fat regimen associated with supplementary medium chain triglycerides (Orphanet J Rare Dis 2008;3:5)
Primary intestinal lymphangiectasia may be life threatening when malignant complications (lymphoma) or serous effusion(s) (pleural, pericardic) occur (Orphanet J Rare Dis 2008;3:5)

Case reports

10 year old boy with pediatric localized intestinal lymphangiectasia treated with resection (Int Med Case Rep J 2019;12:23)
30 year old woman with primary intestinal lymphangiectasia causing intussusception and small bowel obstruction (ACG Case Rep J 2019;6:e00233)
47 year old patient with marginal zone lymphoma complicated by protein losing enteropathy (Case Rep Hematol 2016;2016:9351408)
60 year old woman with Waldmann disease (Rev Esp Enferm Dig 2017;109:385)

Treatment

Low fat diet associated with supplementary medium chain triglycerides is the cornerstone of primary intestinal lymphangiectasia medical management (Orphanet J Rare Dis 2008;3:5)
Small bowel resection is useful in the rare cases in which intestinal lymphangiectasia is segmental and localized (duodenum)
Steroids were prescribed to patients with intestinal lymphangiectasia secondary to inflammatory disease with variable efficacy and also to systemic lupus erythematosus patients with protein losing enteropathy
Treatment of the underlying disease in secondary causes

Clinical images

Images hosted on other servers:

Markedly dilated lymphatics

Gross description

White granular surface (Turk J Gastroenterol 2018;29:714)
Mucosa can be swollen
May form a polypoid lesion

Microscopic (histologic) description

Moderately to severely dilated mucosal and submucosal lymphatic vessels with polyclonal normal plasma cells (Orphanet J Rare Dis 2008;3:5)
Intestinal lymphatics may be dilated in few or many villi
No histologic difference between primary and secondary lymphangiectasia

Microscopic (histologic) images

Contributed by Monika Vyas, M.D.

Ectatic lymphatics

Dilated lymphatic channels

Polypoid lesion

Irregularly dilated lymphatics

Positive stains

Lymphatic vessels are D2-40 positive

Negative stains

CD34, factor VIII

Sample pathology report

Small intestine, biopsy:
- Small bowel lymphangiectasia (see comment)
- Comment: Small bowel lymphangiectasia can be primary or secondary to other conditions such as constrictive pericarditis, intestinal lymphoma, lymphenteric fistula, Whipple disease, Crohn's disease, sarcoidosis, intestinal tuberculosis, systemic sclerosis, radiation or chemotherapy with retroperitoneal fibrosis and human immunodeficiency virus related enteropathy.

Differential diagnosis

Lymphangioma (Am J Clin Pathol 2015;144:563):
- Presents as a discrete lesion
- Most reliable histologic features distinguishing lymphangioma from lymphangiectasia are the presence of smooth muscle surrounding the lymphatic spaces and complete circumferential lining of spaces by endothelial type cells present in lymphangioma
- Lymphoid aggregates may often be seen in lymphangiomas

Board review style question #1

A 10 year old presented with bilateral edema of the legs and diarrhea. Laboratory evaluation showed hypoalbuminemia and hypogammaglobinemia. No other abnormality was identified. Capsule endoscopy performed showed white granular surface in the small intestine. A biopsy was performed which showed dilated spaces in the mucosa and submucosa. PAS stain performed is negative. What is the most likely cause of the patient's underlying condition?

Crohn's disease
Primary lymphangiectasia
Ulcerative colitis
Whipple disease

Board review style answer #1

B. Primary lymphangiectasia

Comment Here

Reference: Lymphangiectasia

Lymphangioma

Table of Contents

Definition / general

Nonencapsulated benign proliferation of lymphatic vessels

Essential features

Benign neoplasm of lymphatic origin (proved by immunohistochemical expression of lymphatic markers, such as D2-40)
Usually detected as an incidental finding during procedures performed for other reasons but can be symptomatic
Mostly presents as a sporadic single lesion and rarely can be syndromic and diffuse
Prognosis is excellent; local recurrence may occur, especially for incompletely excised lesions

Terminology

Lymphangiomatosis (in cases of diffuse organ involvement)
Lymphatic malformation / hamartoma
Hemangiolymphangioma
Simple (capillary) lymphangioma
Mesenteric lymphangioma

ICD coding

ICD-10: D18.1 - Lymphangioma, any site

Epidemiology

Mostly arises in children < 5 years old, with male predominance; rare in adults (Pediatr Radiol 2002;32:88)
Accounts for 2% of GI tumors in adults and 6% of GI tumors in children

Sites

Terminal ileum is most common GI site but can arise in any part of the GI tract (Gastrointest Endosc 2005;62:181)

Etiology

Environmental exposure: as a result of reactive lymphatic proliferation secondary to trauma
Developmental anomaly: failure of development of lymphatic channels, resulting in lymphatic channel engorgement and dilation
Genetics: Noonan syndrome, Maffucci syndrome, trisomies 13, 18, 21 and Turner syndrome (cystic hygroma)

Clinical features

Variable clinical presentation, from asymptomatic to abdominal pain with mass effect (Keio J Med 1993;42:41)
May present as an incidental finding during surgical procedures performed for other conditions (Int J Surg Case Rep 2020;66:319)
Rarely in large lesions, complications include obstruction, infarct and perforation (J Clin Diagn Res 2017;11:PD01)
May be associated syndromes (Turner, Noonan, Maffucci)
Rarely is large, multiple or involves multiple organs (lymphangiomatosis)

Diagnosis

Initial examination is by ultrasound and CT; definitive diagnosis by histopathology and ancillary studies

Radiology description

Ultrasound: cystic lesion; endoscopic ultrasound may be useful to determine depth of lesion
CT: nonenhancing cystic lesions, multiplication, may have calcifications (Acta Radiol Open 2015;4:2047981614564911)

Prognostic factors

Incompletely removed lesions may increase recurrence
Excellent prognosis

Case reports

22 year old man with lymphangioma causing intestinal malrotation (BMJ Case Rep 2013;2013:bcr2013008994)
37 year old man with recurrent intussusception (Int J Surg Case Rep 2020;75:126)
53 year old man with polypoid lymphangioma of the ileocecal valve (Saudi J Gastroenterol 2014;20:262)
57 year old woman with small intestinal lymphangioma who presented with persistent gastrointestinal bleeding (World J Gastroenterol 2012;18:2145)

Treatment

Complete surgical resection, especially for symptomatic lymphangioma
Endoscopic mucosal resection can be used for mucosal lymphangioma (Ann Surg Treat Res 2018;94:52)

Gross description

Well defined lesions, polypoid or pedunculated mass with 3.0 cm average size
Small lesions typically superficial (Gastrointest Endosc 2000;52:255)
Large lesions may have calcifications and may involve deeper layers (World J Gastroenterol 2012;18:2145)

Microscopic (histologic) description

Dilated and anastomosing thin walled blood vessels, lined by single layer of flat endothelial cells (Am J Clin Pathol 2015;144:563)
Blood vessels are surrounded by lymphoid aggregate
Lymphocytes, eosinophils and proteinaceous material often fill the vascular spaces
Smooth muscle in blood vessel wall might be seen in large lesions
No nuclear enlargement, hyperchromasia, pleomorphism or prominent nuclei should be seen in the lining endothelial cells

Microscopic (histologic) images

Contributed by Haider A. Mejbel, M.D.

Lobular contour

Dilated lymphatics

Endothelial cells

Nuclear uniformity

CD31 expression

Positive stains

Common endothelial markers: CD34, CD31 and factor VIII
More specific markers: podoplanin (D2-40), VEGFR3 and LYVE1 (J Biol Chem 2001;276:19420)

Negative stains

HHV8

Sample pathology report

Small intestine, biopsy:
- Lymphangioma

Differential diagnosis

Secondary lymphangiectasia:
- Dilated lymphatics arise in response to trauma, obstruction or radiation
- Has identical histology (dilated lymphatics)
- Clinical history and presentation is necessary for distinction (Lymphat Res Biol 2009;7:75)
Lymphangioma-like Kaposi sarcoma:
- Characteristic area of spindle cells with dissecting blood vessels diagnostic of Kaposi sarcoma should be present and HHV8 is positive
Hemangioma:
- Smaller in size, has lobular contour and has fewer associated lymphocytes
Angiosarcoma:
- Angulated and infiltrative blood vessels
- Nuclei of endothelial cells range from hyperchromatic to highly atypical with prominent nucleoli

Board review style question #1

A 34 year old man underwent upper gastrointestinal endoscopy for chronic anemia. A random biopsy from the duodenum shows dilated lymphatics lined by flatted endothelial cells. No atypia or mitosis is seen. Both CD31 and D2-40 are positive, highlighting the endothelial cells lining the lymphatic channels. HHV8 is negative. The most likely diagnosis is

Angiosarcoma
Hemangioma
Kaposi sarcoma
Lymphangioma

Board review style answer #1

D. Lymphangioma

Comment Here

Reference: Lymphangioma

Board review style question #2

What syndrome is associated with the development of large central lower neck lymphangioma (cystic hygroma)?

Angelman syndrome
DiGeorge syndrome
Klinefelter syndrome
Turner syndrome

Board review style answer #2

D. Turner syndrome

Comment Here

Reference: Lymphangioma

Lymphocytic enterocolitis

Table of Contents

Definition / general | Microscopic (histologic) images | Lymphocytic colitis related

Definition / general

Refractory sprue-like condition associated with colonic mucosal abnormalities (Can J Gastroenterol 2008;22:771)

Microscopic (histologic) images

Contributed by Hanni Gulwani, M.D.

Lymphocytic ileitis: ileal biopsy from 28 year old man with chronic diarrhea

Lymphocytic colitis related

High intraepithelial lymphocyte count in terminal ileum biopsies (Mod Pathol 2003;16:115, Am J Surg Pathol 2002;26:1484)
Normal range of ileal lymphocytes is 0 - 9 lymphocytes/100 enterocytes, decreases with age (Am J Clin Pathol 2007;127:816)
Lymphocytes are mostly suppressor T cells
Symptoms: chronic nonbloody diarrhea, relatively normal endoscopy

Lymphoid hyperplasia

Table of Contents

Definition / general

Also called lymphoid polyp; formerly called pseudolymphoma
Most common site is ileocecal region
Causes intussusception in children
Nodular lymphoid hyperplasia: nodules throughout bowel, associated with giardiasis or childhood viral infection

Case reports

60 year old woman with florid reactive lymphoid hyperplasia of terminal ileum (BMJ Case Rep 2010;2010)

Gross images

Images hosted on other servers:

Terminal ileum exhibiting
shows mucosal ulcers
due to nodular lymphoid
hyperplasia

Microscopic (histologic) description

Numerous lymphoid follicles with germinal centers in lamina propria or submucosa

Microscopic (histologic) images

Images hosted on other servers:

Various images

Positive stains

CD20, CD45; do not confuse BCL2 expression in marginal zone cells with BCL2 expression of germinal center cells in follicular lymphoma (Am J Surg Pathol 2003;27:888)

Differential diagnosis

Low grade lymphoma: often infiltrative, light chain restriction

Malabsorption-general

Table of Contents

Definition / general

Standard site for biopsies is proximal jejunum, just distal to ligament of Treitz
Mount specimen mucosal side up on solid substance, then embed perpendicular to mounting material, then step section or serial section
Small bowel is important for absorption of fats, fat soluble vitamins, proteins, carbohydrates, electrolytes, minerals, water
In U.S., most common malabsorption disorders are celiac sprue, pancreatic insufficiency and Crohn's disease
Steatorrhea: bulky, greasy stools associated with weight loss, anorexia, muscle wasting

Symptoms associated with specific deficiencies

Diarrhea, flatus, abdominal pain, weight loss, mucositis, anemia (iron, folate, vitamins B6, B12)
Bleeding / purpura (vitamin K)
Osteopenia, tetany (calcium, magnesium, vitamin D)
Amenorrhea / impotence / infertility (generalized malnutrition)
Hyperparathyroidism (calcium, vitamin D)
Edema (albumin)
Dermatitis (zinc, vitamin A, fatty acids, niacin)
Peripheral neuropathy (vitamins A, B12)

Physiologic classification of malabsorption

Disturbances related to:
- Intraluminal digestion: saliva, gastric peptic digestion, small bowel, bile salts
- Terminal digestion: hydrolysis of carbohydrates and peptides by disaccharidases and peptidases in brush border of small bowel
- Transepithelial transport: across small bowel epithelium to intestinal vasculature; fatty acids to triglycerides, cholesterol to chylomicrons
Causes of defective intraluminal digestion:
- Digestion of fats / proteins: pancreatic insufficiency due to pancreatitis or cystic fibrosis, Zollinger-Ellison syndrome
- Defective bile secretion (fat solubilization): ileal dysfunction or resection with decreased bile salt uptake, cessation of bile flow (obstruction, hepatic dysfunction), nutrient preabsorption or modification by bacterial overgrowth
Causes of abnormalities in terminal digestion or transepithelial transport:
- Disaccharidase deficiency (lactose intolerance), bacterial overgrowth, abetalipoproteinemia, defects in ileal bile acid transporter

Abetalipoproteinemia

Definition / general

Rare; due to mutations in MTP gene encoding microsomal triglyceride transfer protein (MTP); autosomal recessive (Ann Hepatol 2011;10:221)
Causes defect in synthesis and export of apoprotein B from intestinal mucosal cells
As a result, free fatty acids and monoglycerides cannot be assembled into chylomicrons and become triglycerides stored within cells, causing lipid vacuolization
Symptoms: failure to thrive, diarrhea, steatorrhea

Laboratory

Lipid profile shows no chylomicrons, no VLDL, no LDL
CBC smear shows acantholytic red blood cells (burr cells) due to lipid membrane abnormalities

Microscopic (histologic) description

Marked fat vacuoles in apical villous cytoplasm, normal villi

Positive stains

Fat stains highlight lipid vacuoles

Differential diagnosis

Celiac sprue

See Celiac sprue

Collagenous sprue

Definition / general

Subtype of refractory sprue with patchy, excessive subepithelial collagen deposits (5 of 10 patients in one study, Am J Surg Pathol 2000;24:676)
May eventually respond to gluten free diet but disease may also be fatal (Mod Pathol 2010;23:12)

Microscopic (histologic) description

Small intestinal villous and crypt atrophy, subepithelial collagen deposit thicker than 12 μm that entraps lamina propria cellular elements (Arch Pathol Lab Med 2011;135:803)

Microvillus inclusion disease

Definition / general

Also called congenital or familial microvillous atrophy
Disorder of intestinal brush border that causes intractable watery diarrhea with steatorrhea in infants
Patients require total parental nutrition and rarely live beyond age 2 years
Villous atrophy may be due to apoptotic cell loss (Hum Pathol 2000;31:1404)

Treatment

Small bowel transplant

Microscopic (histologic) description

Severe villous abnormality with crypt hypoplasia, resembling celiac sprue but without lymphocytosis
Increased enterocyte apoptosis and proliferation, bubbly vacuolated apical cytoplasm with extensive or patchy absence of brush border, absence of inflammation (Ultrastruct Pathol 2010;34:327)

Microscopic (histologic) images

Images hosted on other servers:

Duodenal section

Positive stains

CD10 (Am J Surg Pathol 2002;26:902), PAS, polyclonal CEA, alkaline phosphatase (cytoplasmic staining versus linear brush border staining in normals)
Vacuoles - PAS, CEA
Cytoplasmic CD10 staining of absorptive colonocytes can aid in the diagnosis in situations where only colonic biopsy could be obtained (Am J Surg Pathol 2010;34:970)

Electron microscopy description

Abnormal microvillus structures at luminal border of enterocytes
Apical intracytoplasmic inclusions lined by microvilli

Tropical sprue

Definition / general

Also called postinfectious sprue
Affects people living in or visiting the tropics, particularly Caribbean (not Jamaica), Africa, India, Southeast Asia, Central / South America (Case Rep Gastroenterol 2010;4:168)
Has endemic and epidemic features
May be due to E. coli or Haemophilus
Symptoms: malabsorption within weeks of acute diarrheal enteric infection

Treatment

Broad spectrum antibiotics (tetracycline), folic acid, vitamin B12
No increased risk of intestinal lymphoma

Microscopic (histologic) description

Variable villous atrophy (none, partial, total)
Injury to entire small bowel (not proximal as in celiac sprue), inflammatory infiltrate, crypt hyperplasia

Microscopic (histologic) images

Contributed by Hanni Gulwani, M.B.B.S.

40 year old man with chronic diarrhea who improved after antibiotics; marked villous atrophy in duodenal biopsy but no increase in intraepithelial lymphocytes

Images hosted on other servers:

Duodenum, superficial epithelium and lamina propria

Additional references

Gastrointest Endosc 2007;66:377, Dig Dis Sci 2011;56:161

Tufting enteropathy

Definition / general

Intractable diarrhea syndrome, sometimes familial, beginning in neonates
Also called intestinal epithelial dysplasia (Orphanet J Rare Dis 2007;2:20)
Due to epithelial cell adhesion molecule gene (EpCAM) (Gastroenterology 2008;135:429, Gut Liver 2010;4:407)

Treatment

Total parental nutrition

Microscopic (histologic) description

Variable villus abnormality, epithelial crowding, disorganization and focal tufting
No epithelial lymphocytosis

Microscopic (histologic) images

Images hosted on other servers:

Schematic of duodenal mucosa

Typical disorganization of surface enterocytes

Intestinal epithelial dysplasia

Electron microscopy description

Basement membrane abnormalities; increase in desmosome length and number; decreased number of microvilli of surface enterocytes with structural disorganization

Electron microscopy images

Images hosted on other servers:

Ultrastructural changes

Decreased number of microvilli

Malignant GI neuroectodermal tumor

Table of Contents

Definition / general

Rare malignant mesenchymal neoplasm of the gastrointestinal tract

Essential features

Mesenchymal malignancy that grows in sheets or cords and may have osteoclast-like giant cells
Positive for S100 and synaptophysin; negative for HMB45 and MelanA
Harbors EWSR1 translocation

Terminology

Also known as clear cell sarcoma-like tumor of the gastrointestinal tract

Sites

Small bowel is most common site in gastrointestinal tract, followed by stomach (Am J Surg Pathol 2012;36:857)

Clinical features

Median age 35 years; no sex predilection (Arch Pathol Lab Med 2015;139:407)
Most common symptoms are abdominal pain and intestinal obstruction
Tumor can spread to lymph nodes and liver and may cause death

Case reports

17 year old boy with stomach mass (Oncol Lett 2014;8:2687)
18 year old man with small bowel mass (Diagn Pathol 2017;12:29)

Treatment

Surgery; possible adjuvant role for c-Met / ALK inhibitors and VEGF inhibitors (Oncology 2016;91:348)

Gross description

Large mass (mean 5 cm)

Microscopic (histologic) description

Sheets or nests of oval / spindled mesenchymal cells with clear or eosinophilic cytoplasm, visible nucleoli and often mitoses
Osteoclast-like giant cells may be seen
Tumor often spans the entire wall

Microscopic (histologic) images

Contributed by Raul S. Gonzalez, M.D.

Low power

Intermediate power

High power

Positive stains

S100, SOX10, vimentin, synaptophysin

Negative stains

HMB45, MelanA, CD117, DOG1, cytokeratin

Electron microscopy description

Secretory vesicles and dense core granules

Molecular / cytogenetics description

Translocation involving EWSR1 (most commonly EWSR1-ATF1 [t(12;22)] or EWSR1-CREB1)

Sample pathology report

Jejunum, resection:
- Malignant gastrointestinal neuroectodermal tumor (6.1 cm) (see comment)
- Lymphovascular invasion present.
- Margins of resection unremarkable.
- Three of eight lymph nodes involved by metastatic tumor (3/8).
- Comment: Gastrointestinal neuroectodermal tumor is a rare malignancy that can metastasize distantly and has a poor prognosis. Immunohistochemical stains show the tumor is positive for S100 and synaptophysin.

Differential diagnosis

Alveolar rhabdomyosarcoma:
- Positive for myogenin and myoD1, harbors t(2;13) translocation
Clear cell sarcoma:
- Positive for HMB45 and MelanA
- May metastasize to gastrointestinal tract or possibly arise there
Gastrointestinal stromal tumor:
- Positive for CD117 and DOG1
Synovial sarcoma:
- Positive for keratins, harbors t(X;18) translocation

Additional references

Int J Surg Pathol 2003;11:75

Board review style question #1

Which of the following is true about malignant gastrointestinal neuroectodermal tumor?

It can demonstrate a t(12;22) EWSR1-ATF1 translocation
It most commonly occurs in the colon
Its preferred site of metastasis is the lungs
It stains positive for S100 and cytokeratin by immunohistochemistry
Most patients are in their sixth decade or older

Board review style answer #1

A. It can demonstrate a t(12;22) EWSR1-ATF1 translocation

Comment Here

Reference: Malignant GI neuroectodermal tumor

Meckel diverticulum

Table of Contents

Definition / general

Meckel diverticulum is a congenital disorder caused by incomplete obliteration of omphalomesenteric duct (also called vitelline duct), which results in a true diverticulum, typically located in the ileum within 2 feet from the ileocecal valve (Zhang: Surgical Pathology of Non-neoplastic Gastrointestinal Diseases, 1st Edition, 2019)

Essential features

Most common congenital malformation of the GI tract, affecting 2 - 4% of the population
Most common cause of GI tract bleeding in children, usually before age 2
Usually occurs within 2 feet from the ileocecal valve at the antimesenteric border of the ileum
True diverticulum that consists of all layers of intestinal wall
50% with ectopic tissue, most common is gastric mucosa and then followed by pancreatic tissue
Rule of 2s:
- Occurring in about 2% of infants
- Usually 2 inches long
- Located in the ileum approximately 2 feet from the ileocecal valve
- M:F = 2:1
- 2 types of ectopic tissue (gastric or pancreatic)

ICD coding

ICD-10: Q43.0 - Meckel diverticulum (displaced) (hypertrophic)

Epidemiology

Most common congenital malformation of the gastrointestinal tract
Difficult to determine the prevalence because many patients are asymptomatic
Estimated to be in approximately 2 - 4% of the population
63% occur in men (Ann Surg 2005;241:529)

Sites

Usually occurs within 2 feet from the ileocecal valve at the antimesenteric border of the ileum
In children under 2 years old, the average distance is 34 cm from the ileocecal valve and for adults is 67 cm (J Antibiot (Tokyo) 1978;31:3)

Pathophysiology

Remnant of the omphalomesenteric duct, which connects the yolk sac with the developing midgut in the fetal life
Normally regresses by the seventh to eighth week of gestation
Incomplete obliteration of the omphalomesenteric duct results in Meckel diverticulum
Reference: Radiographics 2004;24:565

Etiology

Congenital disorder, caused by the incomplete obliteration of the omphalomesenteric duct
Diverticulum results from fibrous obliteration of the umbilical end of the omphalomesenteric duct and complete patency of the ileal end of the duct
Diverticulum is on the antimesenteric side of the ileum and may connect to the umbilicus by a fibrous band if the fibrous portion of the duct fails to be completely obliterated and absorbed

Clinical features

16% of patients may be symptomatic; among symptomatic patients, M:F ≈ 3:1 (Ann Surg 2005;241:529)
Most frequent complications are bleeding from ectopic gastric mucosa and bowel obstruction due to the intussusception, volvulus or adhesive band
Other uncommon complications include ulceration, diverticulitis, perforation and tumors
Can also be present in an external hernia, typically on the right side, known as a hernia of Littre
May be associated with other congenital anomalies

Diagnosis

Asymptomatic Meckel diverticulum is often incidentally diagnosed during laparoscopy or laparotomy
However, preoperative diagnosis is still challenging
Technetium 99m pertechnetate scan, also called Meckel scan, detecting gastric mucosa, has become the most common and accurate noninvasive test to diagnose Meckel diverticulum in children, with a 95% specificity and 85% sensitivity
- However, this test is only 9% specific and 62% sensitive in adults (Clin Anat 2011;24:416)

Radiology description

Identified as a saccular, blind ending structure located on the antimesenteric border of the ileum
- Antimesenteric location can be confirmed from the position of the diverticulum, which faces away from the axis of the root of the small intestinal mesentery (Br J Surg 1980;67:417)
Junction of the diverticulum with the ileum may show a mucosal triangular plateau or triradiate fold pattern, which represents the site of omphalomesenteric duct attachment to the ileum (AJR Am J Roentgenol 1980;134:925)
Technetium 99m pertechnetate scan, also called Meckel scan, can detect gastric mucosa in Meckel diverticulum (Clin Anat 2011;24:416)

Radiology images

Images hosted on other servers:

Barium examination

Technetium 99m pertechnate scan (Meckel scan)

Case reports

6 year old boy with desmoplastic small round cell tumor arising in Meckel diverticulum (J Clin Oncol 2007;25:3372)
11 year old boy with a giant Meckel diverticulum in distal ileum (Radiol Case Rep 2020;16:400)
16 year old girl with Meckel diverticulum presenting with necrotic diverticulitis attached to the bladder dome (Medicina (Kaunas) 2021;57:495)
64 year old man with Meckel diverticulum presenting with acute appendicitis (Int J Surg Case Rep 2021;83:105994)
70 year old man with Meckel diverticulum initially presented with left strangulated inguinal hernia (Int J Surg Case Rep 2021;79:271)

Treatment

Treatment for symptomatic Meckel diverticulum is surgical resection
Prophylactic diverticulectomy is recommended for incidental asymptomatic Meckel diverticulum (Ann Surg 2005;241:529)

Gross description

Small bowel with blind pouch or diverticulum on antimesenteric aspect
Average length is 3 cm but can be longer than 10 cm; giant Meckel diverticulum refers to those longer than 5 cm (Radiographics 2004;24:565)
Diameters are usually smaller than ileum
Other lesions may also be identified, such as umbilical bands or omphalomesenteric duct cyst
Grossly specimen should be examined for evidence of perforation or presence of tumor (J Med Case Rep 2010;4:264)

Gross images

Contributed by Lizhi Zhang, M.D.

Giant Meckel diverticulum

Antimesenteric location

Luminal connection

Images hosted on other servers:

Meckel diverticulum with perforation

Microscopic (histologic) description

True diverticulum that consists of all layers of intestinal wall
Common abnormalities in symptomatic Meckel diverticulum are ectopic tissue, diverticulitis, enterolith and tumors
Most common ectopic tissue seen in Meckel diverticulum is gastric mucosa, which may consist of gastric foveolar or oxyntic glands
- Helicobacter pylori has also been seen in the ectopic gastric mucosa (Pathology 1998;30:7)
Second most common ectopic tissue is pancreatic tissue
Other rare ectopic tissue includes jejunal, duodenal mucosa or Brunner tissue, colonic mucosa, endometriosis or hepatobiliary tissue
Tumors can occur in the ectopic tissue: the most common tumor is neuroendocrine tumor (Ann Med Surg (Lond) 2019;43:75)
Other rare tumors include adenocarcinoma, gastrointestinal stromal tumor, intraductal papillary mucinous neoplasm or pancreatic intraepithelial neoplasm (within pancreatic heterotopia), leiomyosarcoma, peripheral nerve sheath tumor and desmoplastic small round cell tumor (Ann Med Surg (Lond) 2019;43:75)

Microscopic (histologic) images

Contributed by Lizhi Zhang, M.D.

All layers of intestinal wall

Ectopic gastric mucosa

Ectopic pancreatic tissue

Sample pathology report

Small bowel, ileum, segmental resection:
- Meckel diverticulum identified measuring 3 x 1 cm
- Located 50 cm from the ileocecal valve
- Ectopic pancreatic tissue identified within the diverticulum, otherwise unremarkable

Differential diagnosis

Intestinal duplication or duplication cyst:
- Tubular or cystic
- Located at the mesenteric side
Small bowel bleeding or perforation:
- No outpouching structures at the site of bleeding or perforation
- No ectopic tissue

Board review style question #1

A 2 year old boy presented with abdominal pain and bloody stool. He has otherwise been healthy and growing normally. On physical exam, the patient is irritable, with guarding of the right lower quadrant of the abdomen. Based on clinical suspicion, a technetium 99m pertechnetate scan demonstrates increased uptake in the right lower abdomen. Which of the following embryologic structures is associated with this patient’s condition?

Allantois
Ductus arteriosus
Metanephric mesenchyme
Omphalomesenteric duct
Paramesonephric duct

Board review style answer #1

D. Omphalomesenteric duct. Meckel diverticulum is a remnant of the omphalomesenteric duct, which connects the yolk sac with the developing midgut in the fetal life. It normally regresses by the seventh to eighth week of gestation. The incomplete obliteration of the omphalomesenteric duct results in Meckel diverticulum.

Comment Here

Reference: Meckel diverticulum

Board review style question #2

Regarding the histologic finding in the section from a Meckel diverticulum, which of the following statements is true?

Atypical glands suspicious for a malignancy
Clinically not significant
Commonly seen in Meckel diverticulum
Metaplastic change
Small bowel mucosa with no significant pathological changes

Board review style answer #2

C. Commonly seen in Meckel diverticulum. The picture shows ectopic gastric mucosa, which is the most common ectopic tissue in Meckel diverticulum, followed by pancreatic tissue. The most frequent complication of Meckel diverticulum is bleeding from ectopic gastric mucosa. Benign and malignant tumors can rarely occur in the ectopic tissue but the pyloric glands and rare oxyntic glands in this case are totally benign.

Comment Here

Reference: Meckel diverticulum

Meconium peritonitis

Table of Contents

Definition / general

Rare prenatal complication in 1 per 30,000 live births
GI perforation releases meconium into abdominal cavity, inducing sterile inflammatory reaction and calcium deposition
Perforation may be due to anoxia leading to bowel ischemia, atresia, congenital bands, Hirschprung disease, internal hernia, meconium ileus, stenosis, volvulus or idiopathic
Presents with fetal distress, maternal polyhydramnios, abdominal distention or a mass
Newborns with perforation should be evaluated for cystic fibrosis (Pediatr Surg Int 2003;19:75)

Radiology description

Prenatal ultrasound shows dilated bowel, ascites, polyhydramnios, intra-abdominal calcifications (Prenat Diagn 2005;25:676)
Ultrasound findings have prognostic value (Fetal Diagn Ther 2003;18:255, Prenat Diagn 2007;27:960)

Case reports

35 week old girl with intrauterine distress (Case of the Week #106)

Treatment

Surgical
Gestational age at diagnosis does not predict postnatal outcome (J Pediatr Surg 1995;30:979)

Gross description

Organized peritonitis with fibrosis, calcifications, dense intestinal adhesions
Meconium pseudocyst (fibrous wall) may form

Gross images

Case #106

Abdominal cavity

Small intestine

Microscopic (histologic) description

Peritoneal surface shows fibrinous exudate with microcalcifications, bile pigment-like debris, histiocytes, chronic inflammatory cells

Microscopic (histologic) images

Case #106

Peritoneal surface

Differential diagnosis

Vernix caseosa peritonitis: cheesy white exudate coats the visceral organs after cesarean section (J Obstet Gynaecol 2007;27:660)

Necrotizing enterocolitis

Table of Contents

Definition / general

Acute, necrotizing inflammation of small bowel and colon in patients with myelosuppression
Also called typhlitis, neutropenic enterocolitis, ileocecal syndrome
Most common acquired GI emergency of neonates (eMedicine: Necrotizing Enterocolitis [Accessed 13 February 2018])
Common in premature or low birth weight infants, particularly when they start on oral foods at 2 - 4 days
Also adults with various myeloproliferative disorders, solid malignancies, posttransplant immunosuppression (eMedicine: Neutropenic Enterocolitis [Accessed 13 February 2018])
Affects terminal ileum, ascending colon

Etiology

Intestinal bacteria invade immature intestinal epithelium, causing subsequent inflammation and tissue necrosis
Bacteria in food produce more cytokines and injure mucosa
May be due to TNF receptor 1 dependent depletion of mucus which occurs in immature small intestine (Am J Physiol Gastrointest Liver Physiol 2011;301:G656)
May also be due to deranged intestinal blood flow (J Pediatr Surg 2011;46:1023)

Diagrams / tables

Images hosted on other servers:

TLR4 signaling in pathogenesis of necrotizing enterocolitis

Clinical features

Symptoms: mild GI disturbance or fulminant illness with intestinal gangrene, perforation, sepsis, shock
Complications: short bowel syndrome, malabsorption (due to ileal resection), strictures, recurrence

Treatment

Fluids and surgery if gangrene / perforation

Gross images

Images hosted on other servers:

Various images

Microscopic (histologic) description

Early: mucosal edema, hemorrhage, necrosis
Late: hemorrhagic and gangrenous bowel wall, fibrous strictures; often pneumatosis cystoides intestinalis
After recovery, Paneth cell hyperplasia; colon also shows metaplastic Paneth cells (Pediatr Res 2011;69:217)

Microscopic (histologic) images

Images hosted on other servers:

Various images

Additional references

Pediatr Res 2011;69:183, J Pediatr Gastroenterol Nutr 2011;52:140

Neuroendocrine carcinoma

Table of Contents

Definition / general

Usually fatal

Case reports

50 year old man with obstructive jaundice with an ampullary mass: collision tumor-mixed adenoneuroendocrine carcinoma (Case #322)
52 year old man with collision tumor of primary adenocarcinoma and neuroendocrine carcinoma of duodenum (Rare Tumors 2012;4:e20)
55 year old woman with large cell neuroendocrine carcinoma with glandular differentiation (J Clin Pathol 2004;57:1098)
73 year old woman with large cell neuroendocrine carcinoma with squamous cell and glandular components (Jpn J Clin Oncol 2011;41:434)
74 year old man with small cell neuroendocrine carcinoma with villous adenoma (World J Gastroenterol 2008;14:4709)
74 year old with large cell neuroendocrine carcinoma (Arch Pathol Lab Med 2003;127:221)

Clinical features

Ampullary tumors are rare, present with progressing jaundice
- Aggressive with poor prognosis (Hepatobiliary Pancreat Dis Int 2008;7:422)
Small cell carcinoma is rare; in few cases reported, prognosis better than for small cell lung tumors (Arch Pathol Lab Med 2003;127:e357, J Clin Oncol 2004;22:2730, J Clin Pathol 2010;63:620)

Microscopic (histologic) description

Marked pleomorphism, large irregular hyperchromatic nuclei, prominent nucleoli, tumor necrosis, frequent mitotic figures
Large cell carcinoma:
- Islands and trabeculae of large cells with brisk mitotic activity and extensive necrosis
- Cells have more cytoplasm than small cell carcinoma, irregular chromatin, frequent nucleoli
Small cell carcinoma:
- Sheets and nests of small, round cells with scanty cytoplasm, hyperchromatic nuclei, stippled chromatin, indistinct nucleoli, numerous mitotic figures and apoptotic cells
- Foci of necrosis and vascular invasion common
- Resembles pulmonary tumor
- Pure or mixed with adenocarcinoma

Microscopic (histologic) images

Case #322

Mixed adenoneuroendocrine carcinoma
Line 2: CDX2 (left); chromogranin (middle); synaptophysin (right)

Images hosted on other servers:

Large cell neuroendocrine carcinoma

Small cell neuroendocrine carcinoma

Nests of small cells
with uniform round
nuclei with classic salt
and pepper chromatin

Electron microscopy description

Small cell carcinoma: membrane bound dense core granules

Neuroendocrine tumor

Table of Contents

Definition / general

Well differentiated duodenal, jejunal and ileal epithelial neoplasms with neuroendocrine differentiation
Subtypes:
- Neuroendocrine tumor, grades 1 - 3
- Gastrinoma, NOS
- Somatostatinoma, NOS
- Enterochromaffin cell carcinoid

Essential features

Neuroendocrine tumors (NETs) of the small intestine and ampulla are rare, although the incidence is increasing
Majority of tumors are nonfunctioning; functional (hormone secreting) neuroendocrine tumors are rare
Histologic features include monotonous tumor cells with finely stippled chromatin arranged in nests, trabeculae or tubuloglandular architecture
Grading is based on mitotic rate and Ki67 index

Terminology

Intestinal NET: carcinoid (not preferred), well differentiated neuroendocrine tumor

ICD coding

ICD-O: 8240/3 - neuroendocrine tumor, NOS
ICD-11: 2B80.01 - neuroendocrine neoplasm of duodenum

Epidemiology

Prevalence increased from 0.006% in 1993 to 0.048% in 2012
NETs are more prevalent in women than in men (2.5:1)
Incidence of GI-NET 3.56 per 100,000 population
- Incidence of small intestinal NET 1.05 per 100,000 persons
References: World J Gastrointest Oncol 2020;12:791, JAMA Oncol 2017;3:1335

Sites

> 95% duodenal NETs located in part 1 or 2 (those in part 2 are predominantly in the ampullary region)
- Gastrin expressing NETs: duodenum
- Somatostatin expressing NETs: ampulla
Majority of jejunoileal NETs are located in the distal ileum, with only 11% of jejunal origin:
- Serotonin expressing enterochromaffin cell NETs: Meckel diverticula

Pathophysiology

Poorly understood at this time

Etiology

Etiology of sporadic intestinal NETs is unknown
Minority of NETs arise in setting of hereditary cancer predisposition syndromes
- Multiple endocrine neoplasia (MEN) type 1: develop multiple duodenal gastrinomas (Neuroendocrinology 2017;104:112)
- 10% of ampullary somatostatinomas arise in the setting of neurofibromatosis type 1 (NF1) (J Gastrointest Surg 2010;14:1052)

Clinical features

Nonfunctioning NETs: patients may present with symptoms of mass effect (small bowel obstruction, jaundice)
Functioning NETs: can cause symptoms related to hormone secretion
- Gastrinomas: cause Zollinger-Ellison syndrome (hypergastrinemia, gastric hypersecretion, refractory peptic ulcer disease, diarrhea) (Int J Endocr Oncol 2017;4:167)
  - Patients with Zollinger-Ellison syndrome have worse prognosis and higher rate of metastasis
- Somatostatinomas: rarely cause somatostatinoma syndrome (diabetes mellitus, diarrhea, steatorrhea, hypohydrea or achlorhydia, anemia, gallstones) (Endocr Relat Cancer 2008;15:229)
- Carcinoid syndrome (diarrhea, bronchospasms, flushing, tricuspid valve fibrosis) occurs in < 10% of cases and only if liver metastasis is present (Endocr Relat Cancer 2008;15:229)

Diagnosis

Most small intestine and ampullary NETs are detected on endoscopy and diagnosed with biopsy

Laboratory

Well differentiated NETs are associated with elevated serum chromogranin A
- Increases with larger tumor burden
- Not recommended as a screening test due to low specificity
- May be used to assess disease progression, response to therapy or recurrence in patients with established advanced NET
- Clinical importance decreasing due to day to day variation in chromogranin levels and lack of a standard assay
24 hour urinary excretion of 5-HIAA is the preferred initial diagnostic test for carcinoid syndrome (sensitivity > 90%, specificity 90%)
- 5-HIAA is the end product of serotonin metabolism
- Most useful for jejunoileal, appendiceal and ascending colon NETs because they secrete the highest levels of serotonin

Radiology description

CT or MRI considered mandatory for radiologic staging of NETs
CT and MRI have poor sensitivity for detection of primary small bowel NETs
Somatostatin receptor scintigraphy has been used for decades to image and survey small intestinal NETs
Currently, PET and concomitant CT with 68Ga-DOTA somatostatin analogs (SSAs) are preferred, given the better detection of distant metastases

Radiology images

Images hosted on other servers:

PET / CT

Prognostic factors

Ampullary NETs:
- 5 year survival rate of 82%; 10 year survival rate 71% (Arch Pathol Lab Med 2010;134:1692)
- Tumors < 2 cm or limited to ampulla have better prognosis
- Lymph node metastases are frequent but do not influence overall and disease free survival rates (Langenbecks Arch Surg 2012;397:933)
- Liver is the most common site of metastasis
Small intestine NETs:
- Often present with metastatic disease (locoregional lymph nodes and liver most common)
- Most have prolonged survival due to low proliferative rate (World J Surg 2012;36:1419)
  - Localized disease 5 year overall survival rate: 70 - 100%
  - Distant metastasis 5 year overall survival rate: 35 - 60%
Long term recurrence rates are ~50% (HPB (Oxford) 2010;12:427)
- Nodal metastasis, mesenteric involvement, lymphovascular invasion and perineual invasion increase risk of recurrence

Case reports

38 year old woman with occult duodenal microgastrinoma with lymph node metastases (Am J Surg Pathol 2008;32:1101)
53 year old woman undergoing papillectomy for ampullary adenoma found to have accompanying ampullary NET (World J Gastroenterol 2016;22:3687)
58 year old man diagnosed with ampullary NET, pheochromocytoma and multiple gastrointestinal stromal tumors as first manifestation of NF1 (Diagn Pathol 2019;14:77)
60 year old man with periampullary neuroendocrine tumor presenting with acute pancreatitis (Am J Case Rep 2018;19:1063)

Treatment

Surgical excision of tumor and regional lymph nodes

Clinical images

Images hosted on other servers:

Ampullary NET on endoscopy

Gross description

Duodenal and periampullary NETs are small polypoid lesions within the submucosa (usually < 2 cm); rarely can be large and infiltrating
Jejunoileal NETs can be multifocal; deep infiltration of muscularis propria and subserosa is common

Gross images

Contributed by Megan Kinn, D.O., M.S.

Ileal neuroendocrine tumor

Liver metastasis

Microscopic (histologic) description

Composed of uniform tumor cells showing round to oval nuclei with salt and pepper chromatin
Varying architectural patterns
- Gastrin expressing G cell NETs: trabecular growth pattern
- Somatostatin expressing D cell NETs: tubuloglandular pattern; may have psammoma bodies
- Serotonin expressing EC cell NETs: nests of tumor cells with peripheral palisading, often minor pseudoglandular component
Grading:
- Well differentiated neuroendocrine neoplasms:
  - Neuroendocrine tumor, grade 1: low grade, < 2 mitoses/2 mm², Ki67 index: < 3%
  - Neuroendocrine tumor, grade 2: intermediate grade, 2 - 20 mitoses/2 mm², Ki67 index: 3 - 20%
  - Neuroendocrine tumor, grade 3: high grade, > 20 mitoses/2 mm², Ki67 index: > 20%

Microscopic (histologic) images

Contributed by Megan Kinn, D.O., M.S.

Ileal NET extending to mucosa

Nests of tumor cells

Salt and pepper chromatin

Ki67

Contributed by Wei Zheng, M.D., Ph.D.

Ampullary NET

Trabecular and glandular architecture

Psammoma bodies

Positive stains

AE1 / AE3, CAM5.2
Chromogranin A, synaptophysin
- Somatostatin expressing NETs less likely to express chromogranin A
CDX2 and SSTR2A are positive in serotonin producing EC cell NETs

Negative stains

Mucin, CK7, CK20, TTF1

Electron microscopy description

Well formed, membrane bound, dense core secretory granules

Molecular / cytogenetics description

Sporadic duodenal and ampullary neuroendocrine tumor: no molecular data available
Small intestinal NETs have a complex genomic landscape:
- 60 - 90% of jejunoileal NETs show chromosome 18 deletion (Mod Pathol 2005;18:1079)
- Chromosome 14 gain in advanced lesions and metastases (Endocr Relat Cancer 2009;16:953)
- CDKN1B mutations in ≤ 10% of ileal NETs (Ann Surg Oncol 2015;22:S1428)
- Epigenetic changes are common (Epigenomics 2015;7:1245)
  - > 50% of ileal NETs are CpG island methylator phenotype
  - Substantial epigenetic dysregulation found in 70 - 80% of tumors
- 3 molecular subgroups with potential prognostic impact (Clin Cancer Res 2016;22:250):
  - Favorable prognosis: small intestinal NET with chromosome 18 loss (55%)
    - Correlates with CpG island methylator phenotype negativity and CDKN1B mutation
  - Intermediate prognosis: small intestinal NET with no whole arm copy number variation (19%)
    - Correlates with CpG island methylator phenotype positivity
  - Poor prognosis: small intestinal NET with multiple whole arm copy number variations (26%)

Sample pathology report

Ileum, resection:
- Well differentiated neuroendocrine tumor (2.4 cm), WHO grade 2 of 3 (see synoptic report)
- Ki67 proliferation index: 6%
- Tumor involves mucosa up to subserosa
- Lymphovascular invasion present
- Resection margins are negative for tumor
- 10 lymph nodes, negative for tumor

Differential diagnosis

Neuroendocrine carcinoma:
- Poorly differentiated neoplasm with sheets of tumor cells or poorly formed trabeculae or nests that is almost exclusive to the ampullary region
  - Pleomorphic cells with large cell or small cell patterns
- Chromogranin A and synaptophysin may be negative
- Loss of RB1 and aberrant p53 expression support the diagnosis of neuroendocrine carcinoma
Mixed neuroendocrine - nonneuroendocrine neoplasms (MiNENs):
- Exocrine (usually adenocarcinoma) and neuroendocrine components, each ≥ 30%
Adenocarcinoma:
- Negative or focally positive for neuroendocrine markers
- More prominent nuclear atypia
Gangliocytic paraganglioma:
- Triphasic (neuroendocrine, Schwannian and ganglion cell-like components)
- Predominantly in ampullary region

Additional references

WHO Classification of Tumours Editorial Board: Digestive System Tumours, 5th Edition, 2019

Board review style question #1

A 49 year old woman presented with epigastric abdominal pain, diarrhea and significant weight loss in the last 2 years. Clinical examination revealed the presence of a few café au lait spots located on the upper limbs, large, poorly circumscribed areas of hyperpigmentation on the trunk, bilateral axillary freckling and multiple asymptomatic, soft, flesh colored, sessile or dome shaped cutaneous tumors 1 - 2 cm in diameter, nonadherent to the underlying structures, distributed on the trunk and limbs. An abdominal MRI revealed an infiltrative duodenal mass. Microscopy and immunohistochemistry uncovered a well differentiated neuroendocrine tumor (Ki67 = 1%) with psammoma bodies. A mutation in which of the following genes is most likely responsible for the patient’s disease?

MEN1
RET
MLH1
APC
NF1

Board review style answer #1

E. NF1. The patient’s clinical examination (the presence of a few café au lait spots located on the upper limbs, large, poorly circumscribed areas of hyperpigmentation on the trunk, bilateral axillary freckling and multiple asymptomatic, soft, flesh colored, sessile or dome shaped cutaneous tumors, 1 - 2 cm in diameter, nonadherent to the underlying structures, distributed on the trunk and limbs) and well differentiated neuroendocrine tumor with psammoma bodies (somatostatinomas) in the duodenum are highly suggestive of neurofibromatosis type 1 (NF1).

MEN1 (answer A) is incorrect because mutations in the MEN1 gene cause multiple endocrine neoplasia type 1 (MEN 1). MEN1 is a hereditary syndrome characterized by hyperplasia or sometimes adenomas of the parathyroid glands, pancreatic neuroendocrine tumors or pituitary gland tumors. RET (answer B) is incorrect because the RET proto-oncogene mutations are responsible for multiple endocrine neoplasia (MEN) type 2. MEN2 syndrome is divided into three subtypes (MEN2A, MEN2B and FMTC). People with all subtypes of MEN2 syndrome have an increased risk of medullary thyroid cancer, pheochromocytoma and parathyroid gland cancer. MLH1 (answer C) is incorrect because MLH1 is one of the mismatch repair gene mutations that have been implicated in the development of hereditary nonpolyposis colon cancer (Lynch) syndrome. This patient does not have colon cancer. APC (answer D) is incorrect because the autosomal dominant APC gene mutation is responsible for familial adenomatous polyposis (FAP). This condition causes multiple adenomatous polyps in the colon of affected individuals.

Comment Here

Reference: Neuroendocrine tumor

Olmesartan enteropathy

Table of Contents

Definition / general

A sprue-like enteropathy associated with olmesartan, initially reported in 2012 by Rubio-Tapia et al (Mayo Clin Proc 2012;87:732)
Although less frequent, it can be seen with other angiotensin II receptor antagonists

Essential features

Reversible sprue-like enteropathy with chronic diarrhea and weight loss
Negative celiac serology
Variable villous atrophy (with or without collagen deposition), increased intraepithelial lymphocytes, crypt hyperplasia and variable active inflammation
No clinical response to gluten free diet
Fast clinical and histologic improvement after suspension of olmesartan

Terminology

Sprue-like enteropathy associated with olmesartan

ICD coding

ICD-10: K63.9 - disease of intestine, unspecified

Epidemiology

Frequency not really known; in a large study done by DeGaetani et al, several cases of unclassified sprue were later reclassified as olmesartan enteropathy (Am J Gastroenterol 2013;108:647)

Sites

Mainly duodenum but stomach (lymphocytic or collagenous gastritis) and colon (lymphocytic or collagenous colitis) also can be involved (Mayo Clin Proc 2012;87:732)

Pathophysiology

IL15 expression is increased in response to olmesartan medoxomil treatment
ZO-1, a tight junction protein, is disrupted in olmesartan medoxomil treated Caco-2 cells (human colonic epithelial line) (Aliment Pharmacol Ther 2015;42:1303)

Etiology

Olmesartan medoxomil (trade names of Benicar, Benicar HCTZ, Azor and Tribenzor)
Most taking 40 mg/day before onset of diarrhea (mean: 3.1 years) (Mayo Clin Proc 2012;87:732)

Clinical features

Severe diarrhea (often following a dose increase; sudden onset in some cases), steatorrhea, weight loss, nausea, vomiting, abdominal pain, bloating and fatigue (Virchows Arch 2017;470:245)

Diagnosis

High index of suspicion is needed; diagnosis can be made in hypertensive patients on olmesartan who have clinical, endoscopic and histologic sprue-like enteropathy who have negative celiac serology and no clinical improvement following a gluten free diet
May be misdiagnosed as refractory celiac disease if medication induced injury is not considered
May be misdiagnosed as refractory celiac disease if medication list is not reviewed by the pathologist

Laboratory

Negative IgA tissue transglutaminase antibody testing
Negative endomysial antibodies
Anti-enterocyte antibody can be rarely positive (linear / apical pattern)
HLA DQ2 more frequently positive than in general population (68% versus 25%) (Mayo Clin Proc 2012;87:732)
Normocytic normochromic anemia
Hypoalbuminemia
Small bowel bacterial overgrowth can be seen in a subset of cases

Radiology images

Images hosted on other servers:

Thickened bowel wall

Prognostic factors

No patients have recurrence of symptoms after restarting a diet containing gluten once olmesartan is discontinued

Case reports

59 year old Caucasian man admitted to the hospital with complaints of intractable diarrhea, vomiting and considerable weight loss (Am J Case Rep 2019;20:111)
68 year old Caucasian woman with a history of hypertension with recurrent episodes of acute intermittent diarrhea, nausea, vomiting, renal failure and 15 lbs weight loss (BMJ Case Rep 2018 Oct 2;2018)
72 year old woman with a 6 month clinical history of nonbloody diarrhea and weight loss (Eur J Case Rep Intern Med 2019;6:001093)
74 year old woman who presented with mainly upper gastrointestinal symptoms (BMJ Case Rep 2018;11:pii:e226133)
84 year old woman with 15 months of chronic diarrhea without improvement despite multiple empiric treatments (BMJ Case Rep 2015 Sep 14;2015)

Treatment

Discontinuation of olmesartan
Antibiotics not helpful even if small bowel bacterial overgrowth is noted

Clinical images

Images hosted on other servers:

Normal colonoscopy

Duodenal villous atrophy

Duodenal fold attenuation

Gross description

Mucosal scalloping of duodenal mucosa can be seen (World J Gastroenterol 2013;19:6928)

Microscopic (histologic) description

Partial or total villous atrophy
Increased intraepithelial lymphocytes (> 25 - 30 IEL/100 enterocytes)
Crypt hyperplasia
Variable active inflammation
With or without thick band of subepithelial collagen deposition (collagenous sprue pattern)

Microscopic (histologic) images

Contributed by David Hernandez Gonzalo, M.D.

Moderate villous atrophy and crypt hyperplasia

Increased intraepithelial lymphocytes

Focal active inflammation

Complete histologic recovery

Positive stains

H&E is sufficient for the diagnosis
- Significant increase in the numbers of CD8+ cells and the number of cells that are FoxP3+ (Aliment Pharmacol Ther 2015;42:1303)

Sample pathology report

Duodenum, biopsy:
- Duodenal mucosa with (mild / moderate / severe) villous blunting, crypt hyperplasia, increased intraepithelial lymphocytes and increase in lymphoplasmacytic infiltrate within lamina propria (see comment)
- Comment: The above histopathologic findings are in keeping with a malabsorption pattern of injury. The findings can be seen in medication induced injury (such as olmesartan, NSAIDs, methotrexate, azathioprine, colchicine), gluten sensitive enteropathy, reactive duodenopathy, bacterial overgrowth, tropical sprue, chronic malnutrition, hypersensitivity reaction to nongluten proteins (cow's milk, soy, egg, etc.) and immune related disorders (including CVID and autoimmune enteropathy). Correlation with the clinical, endoscopic and serologic findings (including IgA TTG antibodies in non-IgA deficient patients) is needed.

Differential diagnosis

Gluten sensitive enteropathy
- Responds to gluten free diet
- Celiac serology frequently positive, particularly tTGA (sensitivity: 98%)
Tropical sprue
- GI symptoms with temporal relationship to travel history to tropical regions
- Responds to antibiotics
Collagenous sprue
- Can be a pattern of injury seen in olmesartan enteropathy (exclusion of celiac disease is key)
Autoimmune enteropathy
- Marked reduction of goblet cells or Paneth cells
- Crypt apoptoses more prominent
- Anti-enterocyte antibody can be positive in both entities
- Responds to immusuppressive agents
Common variable immunodeficiency
- 2/3 of patients show loss of plasma cells in duodenal biopsy
- Prominent lymphoid aggregates commonly seen
- Immunoglobulin replacement indicated (does not improve olmesartan enteropathy)
Medication associated injury (eg. mycophenolate mofetil, NSAIDs)
- Mycophenolate mofetil most prominent feature is increase in apoptotic bodies, while celiac-like features are unusual in duodenal biopsies (12%); history of kidney heart or liver transplant is key (Am J Surg Pathol 2009;33:1355)
- NSAIDs are associated with mucosal erosions and ulcerations in jejunum and ileum and GI bleeding

Board review style question #1

An 84 year old woman presents to your hospital with chronic watery diarrhea (15 months) and 30 lbs of unintentional weight loss. Celiac serology is negative. The patient is on 20 mg on Benicar (olmesartan medoxomil) 1 tablet by mouth daily for her hypertension. She tried a gluten free diet for one year with no response. A duodenal biopsy demonstrates the following findings (see image). After switching to valsartan the patient has a dramatic improvement of her diarrhea within days. Which of the following is true about this entity?

Histopathologic findings can mimic gluten sensitive enteropathy
HLA DQ2 is always negative in these patients
IgA tissue transglutaminase antibody testing is positive in most patients
Onset of diarrhea is typically within days or weeks after initiation of olmesartan

Board review style answer #1

A. Histopathologic findings can mimic gluten sensitive enteropathy. Villous atrophy, increased intraepithelial lymphocytes and crypt hyperplasia can be seen in duodenal biopsies, mimicking celiac disease. Answer B is incorrect because HLA DQ2 appears to be more frequently positive in these patients than in the general population. Answer C is incorrect because IgA tissue transglutaminase antibody testing is negative. Answer D is incorrect because the onset of diarrhea is typically within months or years after initiation of olmesartan.

Reference: Small intestine - Olmesartan enteropathy

Comment here

Board review style question #2

Which of the following is true about olmesartan enteropathy?

Clinical and histologic resolution is slow and it takes years for the duodenal mucosa to recover after discontinuation of olmesartan
It is an important diagnostic consideration in patients with presumed refractory celiac disease
Olmesartan associated injury can only be seen in duodenum
Subset of patients with bacterial overgrowth respond to antibiotics

Board review style answer #2

B. It is an important diagnostic consideration in patients with presumed refractory celiac disease. It is important for the pathologist to correctly diagnose these patients. You can change the patient's life just by checking the medication list. Gluten free diet can be miserable for many patients. Answer A is incorrect because clinical and histologic recovery is fast compared with celiac disease patients. Answer C is incorrect because changes can be seen in duodenum, stomach and colon. Answer D is incorrect because a subset of patients on olmesartan can demonstrate bacterial overgrowth. These patients don't respond to antibiotic treatment.

Comment Here

Reference: Small intestine - Olmesartan enteropathy

Peptic duodenitis

Table of Contents

Definition / general

Histologic findings indicative of duodenal mucosa injury as a result of chronic exposure to increased gastric secretion

Essential features

Primarily involves proximal duodenum
Histologic features include gastric foveolar metaplasia and Brunner gland hyperplasia
Usually mild and regresses with treatment

Terminology

Also termed chronic nonspecific duodenitis

ICD coding

ICD-10: K29.80 - duodenitis without bleeding

Epidemiology

Median age: 58 years (Hum Pathol 2010;41:1593)
Foveolar metaplasia can be seen in up to 26.3% of patient population (Lab Invest 2016;96 Suppl 1:187A)

Sites

Duodenum, usually proximal segment

Pathophysiology

Chronic exposure of the duodenal mucosa to excessive gastric acidity in proportion to duodenal bicarbonate contents, resulting in injury to the lining mucosa (Monogr Pathol 1990;31:69)

Etiology

Medications (in particular NSAIDs) (Aliment Pharmacol Ther 2012;36:48)
Helicobacter pylori infection (though recent data suggests H. pylori might not be implicated as much as it was believed) (Hum Pathol 2010;41:1593, Lab Invest 2016;96 Suppl 1:187A)
Idiopathic (Aliment Pharmacol Ther 2013;38:946)

Clinical features

May be asymptomatic (incidental finding) or cause dyspepsia, abdominal pain, hematemesis
In advanced cases: symptoms related to gastric outlet obstruction or acute abdominal pain (clinical features of peritonitis) secondary to duodenal perforation

Diagnosis

Endoscopy with biopsy

Laboratory

Negative celiac sprue serology (antitissue transglutaminase, endomysial antibodies, deamidated gliadin peptide)

Endoscopic findings

Mucosal erythema
Mucosal nodularity (Mod Pathol 2005;18:1134)
Mucosal erosion and ulceration

Prognostic factors

Good prognosis as most cases regress with treatment

Case reports

56 year old man with foveolar gastric metaplasia of atypical appearance (J Med Case Rep 2016;10:355)
72 year old man with duodenal obstruction secondary to Brunner gland hyperplasia (Pathologica 2017;109:414)
80 year old man with carcinoma arising from gastric foveolar metaplasia in the duodenum after 9 years of observation (Clin J Gastroenterol 2018;11:391)

Treatment

Stop the offending medication
Proton pump inhibitors
Treat underlying infection, like H. pylori (Histopathology 2006;48:417)
Surgical intervention for perforated peptic duodenitis or gastric outlet obstruction

Microscopic (histologic) description

Foveolar metaplasia of the surface duodenal epithelium
Brunner gland hyperplasia (Brunner glands seen above the muscularis mucosae)
Expansion of the lamina propria by mixed inflammatory cell infiltrate, including few neutrophils that usually do not infiltrate the epithelium
Mildly increased intraepithelial lymphocytes, usually corresponding to Marsh 1 lesion (Mod Pathol 2005;18:1134)
Mild villous blunting can be seen (World J Gastroenterol 2005;11:686)
Severe cases may show mucosal erosion, ulceration or regenerative changes, like mucin depletion, nuclear hyperchromasia and increased mitotic activity
H. pylori very rarely present in metaplastic epithelium

Microscopic (histologic) images

Contributed by Mohamed Mostafa, M.D.

Surface foveolar metaplasia and Brunner gland hyperplasia

Foveolar metaplasia and lamina propria expansion

H. pylori associated peptic duodenitis

Surface foveolar metaplasia

Contributed by @RaulSGonzalezMD on Twitter

Helicobacter pylori colonizing foveolar metaplasia in the duodenum? bit.ly/38K3WT0 #pathology #PathTwitter #PathOutPic"
Contributed by @RaulSGonzalezMD on Twitter (see original post here)">

Peptic duodenitis

Sample pathology report

Duodenum (D1 / D2), biopsy:
- Duodenal mucosa with preserved villous architecture and gastric metaplasia, suggestive of peptic injury

Differential diagnosis

Celiac sprue:
- Positive celiac serology
- Marked increased intraepithelial lymphocytes and prominent villous blunting
- Improvement with gluten elimination
- May also show concomitant peptic injury / gastric metaplasia
Crohn’s disease:
- Nonnecrotizing granulomas
- Involvement of other locations in the gastrointestinal tract

Additional references

J Clin Pathol 1997;50:54, Can J Gastroenterol Hepatol 2019;2019:6340565

Board review style question #1

Which of the following histologic findings are most likely to be encountered in peptic duodenitis?

Cryptitis and crypt abscess formation
Lamina propria expansion and nonnecrotizing granulomas
Marked intraepithelial lymphocytosis and moderate villous blunting
Scattered lymphoid follicles in the lamina propria
Surface foveolar metaplasia and Brunner gland hyperplasia

Board review style answer #1

E. Surface foveolar metaplasia and Brunner gland hyperplasia

Comment Here

Reference: Peptic duodenitis

Board review style question #2

Regarding peptic duodenitis, which one of the following is true?

Affects primarily duodenal mucosa distal to ampulla of Vater
Always associated with Helicobacter pylori gastritis
Histologic findings result from excessive bile reflux
Medication is always a culprit
Presents with mild symptoms and regresses with treatment

Board review style answer #2

E. Presents with mild symptoms and regresses with treatment

Comment Here

Reference: Peptic duodenitis

Peutz-Jeghers polyp

Table of Contents

Definition / general

Hamartomatous polyp associated with Peutz-Jeghers syndrome (PJS) and characterized by papillary architecture with arborizing compact bundles of smooth muscle

Essential features

> 90% of patients with Peutz-Jeghers polyposis syndrome have an autosomal dominant germline mutation in STK11 (formerly LKB1) (Clin Genet 2007;72:568)
Most commonly affects the small bowel but can occur anywhere along the GI tract
Morphologically characterized by central cores of arborizing smooth muscle that divide lobules of relatively normal glandular mucosa
Moderate to high lifetime cumulative risk of malignancies in Peutz-Jeghers syndrome, with a variable risk for malignancy of the GI tract, breast, pancreas, ovary, lung, cervix, uterus and testes (Gastroenterology 2000;119:1447, Am J Gastroenterol 2010;105:1258)

Terminology

Peutz-Jeghers polyp (PJP)
Peutz-Jeghers polyposis syndrome (PJPS)

ICD coding

ICD-10: Q85.8 - other phakomatoses, not elsewhere classified
ICD-11: LD2D.0 - Peutz-Jeghers syndrome

Epidemiology

Peutz-Jeghers polyposis syndrome is an autosomal dominant syndrome with variable penetrance and an incidence of 1 case in 50,000 - 200,000 births (Clin Gastroenterol Hepatol 2006;4:408)
~67% of patients present in the second to third decades of life and 33% present in first decade of life

Sites

Small bowel (in ~95% of patients with Peutz-Jeghers polyposis syndrome), most commonly in jejunum and ileum
Colon and stomach (in ~25% of patients with Peutz-Jeghers polyposis syndrome) (Am J Gastroenterol 2000;95:596, Int J Surg Pathol 2016;24:185)
Rarely, these polyps can be seen in the respiratory tract, urogenital tract and gallbladder (Int J Colorectal Dis 2000;15:118)

Pathophysiology

Direct precursor is unknown
May represent a genetic predisposition to epithelial prolapse and polyp formation (Gut 2006;55:1)
Dysplasia in Peutz-Jeghers polyps is rare; however, sections of unaffected colon in Peutz-Jeghers syndrome patients have shown protracted clonal evolution in the crypts which may explain increased cancer risk (Gut 2012;61:839)

Etiology

Autosomal dominant inheritance pattern
Germline mutations in tumor suppressor gene serine / threonine kinase 11 (STK11) (formerly called LKB1) located on gene 19p13.3 are found in up to 90% of cases (J Med Genet 2006;43:e18)
~25% of cases are sporadic and are likely due to de novo STK11 mutations or low penetrance variants (Gastroenterology 2000;119:1447)
STK11 gene is postulated to be involved in cell polarity, chromatin remodeling, cell cycle arrest and Wnt signaling; mutations in STK11 lead to dysregulation of mTOR pathway
Rare cases of Peutz-Jeghers polyp in patients that do not meet criteria for Peutz-Jeghers syndrome

Clinical features

Mucocutaneous hyperpigmented macules around the lips, eyes, nostrils, perianal area, mouth and of the buccal mucosa
Often presents with abdominal pain due to polyp related obstruction, intussusception or prolapse (Curr Mol Med 2007;7:29)
May also develop chronic gastrointestinal bleeding, hematochezia, hematemesis and anemia

Diagnosis

Diagnosis of a Peutz-Jeghers polyp requires endoscopy with polypectomy and histologic evaluation
WHO diagnostic criteria for Peutz-Jeghers syndrome includes:
- ≥ 3 histologically confirmed Peutz-Jeghers polyps
- Any number of Peutz-Jeghers polyps with a family history of Peutz-Jeghers syndrome
- Characteristic, prominent mucocutaneous pigmentation with a family history of Peutz-Jeghers syndrome
- Any number of Peutz-Jeghers polyps and characteristic, prominent mucocutaneous pigmentation
Reference: Gut 2010;59:975

Radiology description

Variably sized polyps that often occur in clusters
Larger polyps commonly have a more lobular appearance

Radiology images

Images hosted on other servers:

Axial T1 weighted image - enhancement of rounded PJP

Prognostic factors

Prognosis for Peutz-Jeghers syndrome is mostly determined by the associated cumulative risk of malignancy, with the lifetime cumulative risk for all types of cancer being > 90%
Most common sites of developing malignancy are colorectum (39% cumulative risk), stomach (29%), small intestine (13%), pancreas (100x risk, 11 - 36%), breast (32 - 54%), ovary (21%), cervix (10 - 23%), uterus (9%), testis (9%), lung (7 - 17%) (Gastroenterology 2000;119:1447)
Unusual gonadal lesions such as sex cord tumor with annular tubules (SCTAT), calcifying Sertoli cell tumor of the testes and HPV independent gastric type adenocarcinoma of the cervix (formerly known as adenoma malignum) are associated with Peutz-Jeghers polyposis syndrome (Am J Gastroenterol 2005;100:476)

Case reports

7 year old boy with Peutz-Jeghers syndrome and jejunoileal intussusception with invasive adenocarcinoma (BMJ Case Rep 2018;11:e225076)
33 year old woman with Peutz-Jeghers syndrome and bilateral ovarian SCTATs (J Obstet Gynaecol Res 2022;48:492)
36 year old woman with Peutz-Jeghers syndrome and gastric type cervical adenocarcinoma (Obstet Gynecol Sci 2019;62:474)
60 year old man with a Peutz-Jeghers polyp of the appendix (Case Rep Pathol 2019;2019:7584070)

Treatment

U.S. Multi-Society Task Force (USMSTF) recommends polypectomies when seen on endoscopy, are symptomatic or are ≥ 10 mm on imaging (Gastroenterology 2022;162:2063)
Also recommended are scheduled surveillance of GI tract, breast, pancreas, ovaries, testes and lungs
Genetic testing of all asymptomatic first degree relatives

Clinical images

Images hosted on other servers:

Hyperpigmented macules of the perioral area

Lobular duodenal polyp

Gross description

Variable size of polyps; small polyps can be sessile
Larger polyps are usually pedunculated with a multilobulated / cerebriform smooth surface and a thick stalk

Gross images

Images hosted on other servers:

Duodenal dilatation, arborizing polyps

Arborizing polyps, pedunculated and sessile

Intraluminal polyp

Microscopic (histologic) description

Peutz-Jeghers polyps of the small bowel have distinctive papillary villous architecture with tree-like arborization of compact smooth muscle bundles and relatively normal overlying epithelium (Mod Pathol 2013;26:1235)
Epithelial component is usually arranged in a distinct lobular configuration, separated by cores of smooth muscle
Epithelium often shows glandular dilation and distortion
Secondary erosion and ulceration can be present
Epithelial misplacement (pseudoinvasion) can be seen in the submucosa, muscularis propria and even to the serosa due to prolapse and peristaltic kneading; pseudoinvasion is commonly associated with pedunculated polyps
- This can be mistaken for invasive carcinoma
Dysplasia is rare in Peutz-Jeghers polyps but if present, is characterized by complex cribriform architecture, nuclear hyperchromasia, loss of polarity, nuclear crowding and nuclear stratification extending to the surface

Microscopic (histologic) images

Contributed by Krutika S. Patel, M.B.B.S., M.D. and @SueEPig on Twitter

Jejunal Peutz-Jeghers polyp

Tree-like arborization of smooth muscle

Distinct lobular configuration of epithelium

Bland epithelial component

Surface erosion

Epithelial misplacement

Peutz-Jeghers polyp

Virtual slides

Images hosted on other servers:

Jejunum, Peutz-Jeghers polyp

Molecular / cytogenetics description

Cytogenetic evaluation for STK11 mutation via germline sequencing may be helpful in subtle cases

Videos

Small bowel, Peutz-Jeghers polyp

Sample pathology report

Small bowel, jejunum, polypectomy:
- Hamartomatous polyp, Peutz-Jeghers type (see comment)
- Comment: Histologic sections show a hamartomatous polyp with arborizing smooth muscle cores dividing lobular compartments of mucosa, consistent with Peutz-Jeghers polyp. There are no adenomatous changes or malignancy identified.

Differential diagnosis

Mucosal prolapse polyp:
- More common in rectosigmoid colon
- Smooth muscle shows more disarray and is less compact than Peutz-Jeghers polyp
- Smooth muscle wrapping around individual crypts favors mucosal prolapse
Juvenile polyp:
- Loose, edematous lamina propria with inflammation is a characteristic feature
- Smooth muscle arborization is not a prominent feature
- Marked cystic dilation of epithelial component is more common
- Genetic testing shows germline mutations in SMAD4 or BMPR1A
Inflammatory polyp:
- Usually associated with branching and cystic dilatation of epithelial component with regenerative mucosa with reactive atypia
- Edematous lamina propria with acute and chronic inflammatory infiltrate
Sporadic hyperplastic polyp:
- Uncommon, typically occurs in the second portion of the duodenum
- Histologically resembles colonic microvesicular hyperplastic polyps with epithelial serrations, crypts with narrow bases, mucin droplets and bland cytology
- Small case series showing association with mutations in BRAF V600E and KRAS (Hum Pathol 2011;42:1953)
In addition to histology, clinical and family history often aid in the diagnosis; for Peutz-Jeghers polyps, as for other hamartomatous polyps with syndromic considerations, consultation with genetic counseling is recommended to gather family history and consider germline mutation analysis

Additional references

Clin Cancer Res 2006;12:3209, Gastrointest Tumors 2015;2:65, Orphanet J Rare Dis 2014;9:101

Board review style question #1

Which of the following is true about the syndrome associated with the jejunal polyp shown above?

Associated with autosomal recessive inheritance pattern
Associated with germline mutations in SMAD4
Dysplasia is seen in a majority of these polyps
Histology is characterized by papillary architecture with arborizing compact bundles of smooth muscle
More commonly seen in the sigmoid colon

Board review style answer #1

D. Histology is characterized by papillary architecture with arborizing compact bundles of smooth muscle. The image is of a Peutz-Jeghers polyp, which is morphologically characterized by tree-like arborizing smooth muscle cores dividing lobules of relatively normal glandular villous epithelium. Peutz-Jeghers polyposis syndrome patients have autosomal dominant germline mutation in STK11 (formerly LKB1). It most commonly affects the small bowel. Dysplasia is rare in Peutz-Jeghers polyps.

Comment Here

Reference: Peutz-Jeghers polyp

Board review style question #2

The above small intestinal polyp is removed from a patient after an episode of intussusception. They are also noted to have perioral hyperpigmented spots. In which gene does this patient likely have a germline mutation?

APC
PTEN
SMAD4
STK11 (formerly LKB1)

Board review style answer #2

D. STK11 (formerly LKB1). The above polyp is consistent with a Peutz-Jeghers type polyp. Germline mutations in tumor suppressor gene serine / threonine kinase 11 (STK11 - formerly called LKB1) are found in up to 90% of cases and is inherited in an autosomal dominant fashion. Patients with this syndrome often have perioral hyperpigmented macules. SMAD4 mutations are associated with juvenile polyps. APC mutations are seen in familial adenomatous polyposis. And PTEN mutations are associated with Cowden syndrome.

Comment Here

Reference: Peutz-Jeghers polyp

Pneumatosis cystoides intestinalis

Table of Contents

Definition / general

Submucosal gas filled cysts in GI tract
Called mucosal pseudolipomatosis if it resembles lipomatosis

Clinical features

Part of differential diagnosis of acute abdomen (World J Gastroenterol 2012;18:453)
In infants, associated with necrotizing enterocolitis and may be fatal; also associated with cystic fibrosis, congenital heart defects
In adults, either idiopathic or varied clinical settings including chemotherapy, chronic lung disease, drugs, ischemic colitis, obstruction, scleroderma (World J Gastroenterol 2011;17:4932, Arch Pathol Lab Med 2010;134:378)
Often indolent clinical course, although radiographically resembles carcinoma
Considered a finding, not a diagnosis

Case reports

6 year old girl with ulcerative colitis (Arch Pathol Lab Med 1999;123:354)
32 year old woman with idiopathic myointimal hyperplasia of mesenteric veins and pneumatosis intestinalis (J Crohns Colitis 2011;5:239)
73 year old woman with dysplasia in perforated intestinal pneumatosis (World J Gastroenterol 2009;15:4189)

Clinical images

Images hosted on other servers:

Endoscopy

Gross description

Polypoid grape-like masses protrude through mucosa
Soft, bluish and often sessile, "bubble wrap" crackling noise while handling the specimen

Gross images

Images hosted on other servers:

Various images

Microscopic (histologic) description

Submucosal cysts lined by multinucleated giant cells
Mucosa contains cryptitis, crypt abscesses, granulomas
May also resemble lipomatosis

Microscopic (histologic) images

Images hosted on other servers:

Various images

Differential diagnosis

Crohn's disease

Pseudomelanosis duodeni

Table of Contents

Definition / general | Case reports | Microscopic (histologic) images

Definition / general

Brownish black pigment in lamina propria macrophages of proximal duodenum
Also known as melanosis duodeni
Due to iron and sulfur (J Formos Med Assoc 1995;94:632) and may be associated with oral iron intake, hypertension, diabetes or end stage renal disease (Endoscopy 2008;40:165, World J Gastroenterol 2012;18:1414)
Not associated with laxative abuse (J Clin Gastroenterol 1988;10:127)
Not associated with lipofuscin pigment, which is identified in melanosis coli
Often identified at endoscopy
Pigment may originate in atmosphere or diet
No known clinical significance

Case reports

94 year old woman with GI bleed and spotty hyperpigmentation at endoscopy (Case #231)

Microscopic (histologic) images

Contributed by @liverwei on Twitter

Pseudomelanosis duodeni

Case #231

Various images

Images hosted on other servers:

Various images

Radiation enterocolitis

Table of Contents

Definition / general | Clinical features | Gross description | Microscopic (histologic) description | Microscopic (histologic) images

Definition / general

Observed acutely or years after radiation therapy for cervical carcinoma, Wilms tumor, lymphoma or other peritoneal tumors

Clinical features

Acute: anorexia, cramps, diarrhea due to mucosal injury and malabsorption
Chronic: may present as inflammatory colitis or indolent; also vascular injury, ischemic fibrosis, stricture
Treatment: resection if severe

Gross description

Thickened bowel wall

Microscopic (histologic) description

Acute:

Varies from mild epithelial damage to massive necrosis and ulceration (BMC Surg 2004;4:10)
Loss of columnar shape and nuclear polarity of enterocytes, nuclear pyknosis, bizarre nuclei, mucin depletion and decreased mitoses
Also fibroblasts and endothelium with submucosal edema but low nuclear to cytoplasmic ratio, preservation of architecture
No desmoplasia, no infiltrative pattern

Chronic:

Atrophic and ulcerated mucosa, ectatic blood vessels, fibrosis of submucosa and muscular wall, vascular wall thickening, vascular stenosis
Possible fistula formation, atherosclerosis-like changes of vasculature (subintimal lipid laden macrophages, calcification, thrombosis), hyalinization of lamina propria

Microscopic (histologic) images

Images hosted on other servers:

Acute changes (mice)

Reactive nodular fibrous pseudotumor

Table of Contents

Definition / general

First described in 2003 in 5 patients (4 men), mean age 56 years (Am J Surg Pathol 2003;27:532)
May present as obstruction (Am Surg 2011;77:790) but otherwise benign clinical course

Gross description

Firm, tan white, 4 - 6 cm, solitary / multiple, in small bowel or colon

Microscopic (histologic) description

Low / moderate cellularity
Spindled fibroblasts arranged haphazardly or in intersecting fascicles
Often infiltrative borders
Stroma rich in wire-like, keloidal or hyalinized collagen
Peripheral lymphoid aggregates

Positive stains

Vimentin, CD117 or muscle specific actin (80%), smooth muscle actin or desmin (60%) (Int J Surg Pathol 2004;12:365)

Negative stains

CD34, S100, ALK1

Differential diagnosis

Fibromatosis

Rejection

Table of Contents

Definition / general

Small bowel transplantation is a surgical option for patients who have intestinal failure and have failed parenteral nutrition
Rejection of the transplanted bowel occurs through cellular or antibody mediated mechanisms and is responsible for a significant portion of graft failures

Essential features

Rejection is a major complication of small bowel transplantation, with 30 - 40% of patients developing an episode of acute cellular rejection (ACR) within the first year
ACR is characterized by increased crypt apoptotic figures, increased lamina propria mixed inflammation and epithelial injury
Repeated episodes of ACR can lead to chronic rejection and graft dysfunction, which shows nonspecific histologic findings, including ischemic changes and lamina propria fibrosis

Terminology

Acute cellular rejection (ACR)
Antibody mediated rejection (AMR)
Chronic rejection

ICD coding

ICD-10
- T86.850 - intestine transplant rejection
- T86.851 - intestine transplant failure
ICD-11: NE84 - failure or rejection of transplanted organs or tissues

Epidemiology

Small bowel transplants are uncommon; < 100 performed in the U.S. per year since 2019 (Am J Transplant 2023;23:S264)
30 - 40% of adult transplants develop acute cellular rejection within the first year posttransplant (Am J Transplant 2021;21:1705)
Chronic rejection was documented in 15% of transplants in 1 series (Ann Surg 2009;250:567)
Rejection is the primary cause of graft loss in ~13% of cases (sepsis causes ~50% and cardiac complications account for ~8%) (Am J Transplant 2015;15:210)

Sites

Transplants performed as small intestine only, with liver or multivisceral (with liver, stomach, pancreas, colon, spleen or kidney)

Pathophysiology

Direct pathway
- Donor antigen presenting cells using donor major histocompatibility complex (MHC) class II and class I molecules present allogenic molecules from the graft to recipient CD4+ and CD8+ lymphocytes
- Activated CD4+ and CD8+ lymphocytes are predominantly responsible for early acute cellular rejection occurring within the first several months posttransplant
Semidirect pathway
- Donor membrane bound MHC molecules are transferred to recipient antigen presenting cells and presented to CD4+ and CD8+ lymphocytes without processing
- Responsible for delayed acute cellular rejection occurring years after transplant
Indirect pathway
- Donor MHC antigens are internalized and processed by recipient antigen presenting cells and presented to recipient CD4+ lymphocytes
- Responsible for antibody mediated rejection and delayed acute cellular rejection
Inverted direct pathway
- Donor CD4+ T cells are activated by recipient B cells presenting recipient MHC class II molecules
- Responsible for early antibody mediated rejection
Reference: Int J Mol Sci 2023;24:4541

Etiology

Rejection of allograft through cellular mediated response or antibody mediated response involving activation of CD4+ and CD8+ lymphocytes (Int J Mol Sci 2023;24:4541)

Clinical features

Symptoms are typically nonspecific: fever, diarrhea / increased ostomy output, nausea and abdominal pain
Acute cellular rejection
- Onset is typically between 1 and 9 weeks posttransplant
Antibody mediated rejection
- Typically occurs during the first 2 weeks posttransplant
- Detection of lymphocytotoxic antibodies by serologic testing
Chronic rejection
- Typically occurs after repeated episodes of acute cellular rejection
- Also associated with nutritional deficiency and generalized edema (associated with protein losing enteropathy)
Reference: Arch Pathol Lab Med 2012;136:761

Diagnosis

Mucosal biopsies of the graft are the only current reliable method (Scand J Gastroenterol 2021;56:13)

Laboratory

No specific laboratory markers are routinely used to diagnose or monitor rejection
Biomarkers such as decreased serum citrulline and increased fecal calprotectin are seen in moderate to severe rejection but are nonspecific (Scand J Gastroenterol 2021;56:13)
Detection of lymphocytotoxic antibodies may support antibody mediated rejection

Radiology description

Imaging findings are nonspecific
- Noncontrast computed tomography (CT): diffuse wall thickening, mucosal hyperenhancement or hypoenhancement and moderate ascites
- Magnetic resonance imaging (MRI): wall thickening and mucosal hyperenhancement with contrast on T1 sequence
- Fluoroscopy: wall thickening, loss of mucosal fold patterns and hypomotility
Reference: Br J Radiol 2018;91:20180173

Radiology images

Images hosted on other servers:

Acute cellular rejection (CT)

Acute cellular rejection (MRI)

Prognostic factors

Increased number of episodes of ACR, higher grade of ACR and earlier onset of ACR are associated with an increased risk of chronic rejection (Pediatr Dev Pathol 2003;6:240)
5 year graft survival for patients < 18 years old is better than adults (62% versus 43%) (Am J Transplant 2023;23:S264)

Case reports

18 year old man with small bowel transplant and acute cellular rejection (World J Gastroenterol 2005;11:5332)
19 year old woman with small bowel transplant and severe acute rejection (Dig Dis Sci 2010;55:3336)
20 year old woman with a history of small bowel transplant and severe late onset acute cellular rejection (Transplant Proc 2019;51:3181)
20 year old man with small bowel transplant and acute cellular rejection associated with an elevation of donor specific HLA antibodies (Transplant Proc 2016;48:525)
31 year old woman with small bowel transplant, acute cellular rejection with white exudates on endoscopy (Transplant Proc 2017;49:2419)

Treatment

Induction immunosuppression with antithymocyte globulin or interleukin 2 receptor blocking antibody
Maintenance immune suppression with tacrolimus and mycophenolate mofetil or corticosteroids
Reference: Am J Transplant 2023;23:S264

Clinical images

Images hosted on other servers:

Endoscopic appearance of ACR

Gross description

Endoscopically, acute cellular rejection shows an erythematous and friable mucosa with or without erosion or ulceration
No endoscopic / macroscopic findings have been identified that are specific for chronic ACR or AMR
Reference: Am J Transplant 2021;21:1705

Microscopic (histologic) description

Standardized histologic criteria were developed at the pathology workshop of the VIII International Small Bowel Transplant Symposium (Transplant Proc 2004;36:335)
Acute cellular rejection
- Grading based on apoptotic bodies per 10 consecutive crypts, amount of lamina propria mixed inflammation (lymphocytes, eosinophils and neutrophils) and amount of epithelial injury (crypt dropout, erosions or ulceration) (see table below)
- Other features include edema, villous blunting, reactive epithelial changes and vascular congestion
Antibody mediated rejection
- Capillaritis, lamina propria inflammation, mucosal erosion / ulceration, fibrin thrombi within lamina propria vasculature and edema (Am J Transplant 2018;18:2250)
Chronic rejection
- Nonspecific findings: mild ischemic changes, apoptotic bodies (< 6/10 consecutive crypts) and mild fibrosis of the lamina propria

Grading of acute cellular rejection (adapted from Arch Pathol Lab Med 2012;136:761, Transplant Proc 2004;36:335)

Grade	Apoptotic bodies / 10 consecutive crypts	Crypt dropout	Amount of lamina propria inflammation	Surface epithelial damage	Additional findings
0 (no ACR)	< 2	None	Not increased	None	Unremarkable mucosa
Indeterminate (grade ind)	< 6	None	Focal minimal	None	Focal mild villous blunting
Mild (grade 1)	≥ 6	None	Mild	Focal damage / erosion	Mucin depletion, nuclear enlargement and hyperchromasia
Moderate (grade 2)	≥ 6; possibly confluent	Focal	Moderate to severe	Erosion	Moderate to marked architectural distortion and villous blunting, edema and congestion
Severe (grade 3)	Variable	Extensive	Moderate to severe	Extensive erosion / ulceration	Moderate to marked architectural distortion, granulation tissue formation

Microscopic (histologic) images

Contributed by Jen Rytych, M.D.

Mild ACR, mild inflammation

Focal villous blunting

Few apoptotic figures

Erosion and crypt dropout

Many apoptotic figures

Extensive ulceration

Positive stains

Complement 4d (C4d) is usually positive in antibody mediated rejection (not routinely performed) (Am J Transplant 2018;18:2250)

Negative stains

Cytomegalovirus, adenovirus and Epstein-Barr virus stains

Sample pathology report

Small intestine, transplant, biopsy:
- Moderate mixed lamina propria inflammatory cells, increased crypt apoptotic figures and foci of crypt distortion, crypt loss and ulceration, consistent with moderate, acute cellular rejection (see comment)
- Comment: Up to 8 crypt apoptotic figures per 10 consecutive crypts are identified. This finding, in combination with lamina propria inflammatory infiltrate and focal epithelial injury, is compatible with moderate acute cellular rejection.

Differential diagnosis

Infectious enteritis (Arch Pathol Lab Med 2012;136:761):
- Most commonly caused by adenovirus and cytomegalovirus (CMV); other etiologies including bacteria, other viruses, fungi and protozoa are possible
- Apoptotic figures are generally less prominent, viral inclusions may be seen
- Positive immunohistochemistry for adenovirus or CMV useful for confirmation
- Correlation with cultures and serologic studies may be helpful
Medication effect (commonly mycophenolate mofetil) (Transplant Proc 2010;42:82):
- Can display increased crypt apoptotic figures, increased lamina propria inflammation and epithelial erosion / ulceration
- Will affect both transplanted and native bowel
- Correlation with medication history and supportive endoscopic findings is helpful
Graft versus host disease (Nat Rev Gastroenterol Hepatol 2017;14:711):
- Commonly affects multiple sites: skin, liver, gastrointestinal tract
- Small bowel involvement characterized by increased crypt apoptotic figures and crypt dropout
- Only affects the native tissues (bowel)

Additional references

Wallace: Practical Atlas of Transplant Pathology, 1st Edition, 2016

Board review style question #1

A 35 year old patient with a history of small bowel transplantation presents with diarrhea, abdominal pain and weight loss. Out of concern for acute cellular rejection (ACR), endoscopic biopsies of both the transplanted small bowel and segment of native small bowel are obtained. Histologic examination of the transplanted bowel shows the findings displayed in the representative photomicrograph. What additional findings, if present, would be most supportive of the diagnosis of acute cellular rejection of the transplant bowel in this patient?

Identification of eosinophilic nuclear inclusions
Increased mitotic rate
Occasional crypt dropout and apoptotic figures in the native small bowel
Occasional crypt dropout and erosion of the surface epithelium in the transplanted small bowel

Board review style answer #1

D. Occasional crypt dropout and erosion of the surface epithelium in the transplanted small bowel. The histological findings described, including ≥ 6 apoptotic bodies per 10 consecutive crypts, when combined with the additional findings of occasional crypt dropout and focal erosion, are indicative of moderate acute cellular rejection (grade 2) in transplanted small bowel. Grade 2 rejection is characterized by ≥ 6 apoptotic bodies per 10 consecutive crypts, moderate to extensive inflammation in the lamina propria, focal crypt dropout and focal erosion of the epithelium. Answer B is incorrect because an increased mitotic rate is not specifically associated with acute cellular rejection. Answer A is incorrect because identification of viral mediated cellular changes, such as Cowdry-like nuclear inclusions, would be more suggestive of infectious etiologies affecting the transplanted bowel. Answer C is incorrect because identification of crypt apoptosis, crypt injury and epithelial injury in the native small bowel may suggest medication induced injury (such as mycophenolate), infection or graft versus host disease.

Comment Here

Reference: Rejection

Board review style question #2

Which of the following factors is a known risk factor for the development of chronic rejection in small bowel transplant recipients?

Frequent surveillance biopsies
History of multiple acute cellular rejection episodes
Long term immunosuppressive therapy
Short duration of cold ischemia time during transplant surgery
Younger age at transplant

Board review style answer #2

B. History of multiple acute cellular rejection episodes. The development of chronic rejection is typically preceded by episodes of acute cellular rejection (ACR). Increased number of episodes of ACR, higher grade of ACR and earlier onset of ACR are all associated with an increased risk of chronic rejection. Answers A and C are incorrect because frequent surveillance biopsies and long term immunosuppressive therapy are necessary for the maintenance and surveillance of the health of the graft and are not associated with the development of chronic rejection. Answer E is incorrect because patients < 18 years old at transplant have an improved 5 year graft survival compared to adults and age at transplant is not associated with chronic rejection. Answer D is incorrect because shorter ischemic times have been associated with improved graft outcomes and ischemic time is not directly related to the development of chronic rejection.

Comment Here

Reference: Rejection

Sclerosing peritonitis

Table of Contents

Definition / general

Inflammatory and fibrosing process affecting visceral peritoneum that can encase small bowel (World J Gastroenterol 2012;18:1999)
Infiltrates mesentery at attachment site with peritoneum
Usually spares retroperitoneum
Associated with dry eyes and itchy scaly skin lesions

Clinical features

Associated with beta blockers; chronic peritoneal dialysis
Rare causes include abdominal surgery, abdominal tuberculosis, cirrhosis, dermoid cyst rupture, endometriosis, familial Mediterranean fever, fibrogenic foreign material, GI malignancy, intraperitoneal chemotherapy, liver transplantation, luteinized ovarian thecomas, pertioneoventricular shunting, protein S deficiency, recurrent peritonitis, sarcoidosis, subclinical primary viral peritonitis

Case reports

76 year old woman with rectal cancer and a suspected enteric duplication cyst in the distal ileum (Case of the Month #482)
Sclerosing peritonitis associated with luteinized adult granulosa cell tumor (Int J Gynecol Pathol 2012;31:141)

Clinical images

Images hosted on other servers:

Encapsulating thick,
white adherent
membrane encasing
small bowel

Gross images

Contributed by Sajna V. M. Kutty, M.D. (Case of the Month #482)

Right colon limited resection for possible enteric duplication cyst in the distal ileum

Microscopic (histologic) images

Contributed by Sajna V. M. Kutty, M.D. (Case of the Month #482)

Board review style question #2

Sclerosing encapsulating peritonitis most often involves what intraperitoneal organ?

A. Colon
B. Ovary
C. Small bowel
D. Stomach

Board review style answer #1

C. Small bowel

Reference: Small bowel (small intestine) - Sclerosing peritonitis

Comment here

Staging-ampulla carcinoma

Table of Contents

Pathologic TNM staging of carcinomas of the Ampulla of Vater, AJCC 8th edition

Definition / general

All carcinomas of the Ampulla of Vater or the duodenal papilla, including poorly differentiated neuroendocrine carcinomas, are covered by this staging system
Not covered by this staging system are well differentiated neuroendocrine tumors at this location (use the neuroendocrine tumor staging system instead)

Essential features

AJCC 7th edition staging was sunset on December 31, 2017; as of January 1, 2018, use of the 8th edition is mandatory

ICD coding

ICD-10: C24.1 - malignant neoplasm of ampulla of Vater

Diagrams / tables

Images hosted on other servers:

Regional lymph nodes of the Ampulla of Vater

Pancreas / Ampulla of Vater staging

Primary tumor (pT)

TX: primary tumor cannot be assessed
T0: no evidence of primary tumor
Tis: carcinoma in situ
T1: tumor limited to Ampulla of Vater of sphincter of Oddi or tumor invades beyond the sphincter of Oddi (perisphincteric invasion) or into the duodenal submucosa
- T1a: tumor limited to Ampulla of Vater of sphincter of Oddi
- T1b: tumor invades beyond the sphincter of Oddi (perisphincteric invasion) or into the duodenal submucosa
T2: tumor invades into the muscularis propria of the duodenum
T3: tumor directly invades into the pancreas (up to 0.5 cm) or tumor extends more than 0.5 cm into the pancreas or extends into peripancreatic or periduodenal tissue or duodenal serosa without involvement of the celiac axis or superior mesenteric artery
- T3a: tumor directly invades the pancreas (up to 0.5 cm)
- T3b: tumor extends more than 0.5 cm into the pancreas or extends into peripancreatic tissue or periduodenal tissue or duodenal serosa without involvement of the celiac axis or superior mesenteric artery
T4: tumor involves the celiac axis, superior mesenteric artery or common hepatic artery, irrespective of size

Regional lymph nodes (pN)

NX: regional lymph nodes cannot be assessed
N0: no regional lymph node involvement
N1: metastasis to one to three regional lymph nodes
N2: metastasis to four or more regional lymph nodes

Notes:
- Regional lymph nodes include peripancreatic, hepatic artery and portal vein nodes
- Minimum of 12 lymph nodes must be recovered for lymph node staging to be considered accurate in curative resections

Distant metastasis (pM)

M0: no distant metastasis
M1: distant metastasis

Prefixes

y: preoperative radiotherapy or chemotherapy
r: recurrent tumor stage

Stage grouping

Stage 0:Tis N0 M0
Stage I:T1a N0 M0
Stage IB:T1b - T2 N0 M0
Stage IIA:T3a N0 M0
Stage IIB:T3b N0 M0
Stage IIIA:T1a - T3b N1 M0
Stage IIIB:T4 any N M0
any T N2 M0
Stage IV:any T any N M1

Registry data collection variables

Tumor size
Lymph node status
Margin status
Histologic differentiation
Histologic subtype
Preoperative or pretreatment CEA
Preoperative or pretreatment CA 19 - 9
Adjuvant therapy

Histologic grade

GX: grade cannot be assessed
G1: well differentiated
G2: moderately differentiated
G3: poorly differentiated

Histopathologic type

Carcinoma in situ
Adenocarcinoma
Adenocarcinoma, invasive intestinal type
Adenocarcinoma, pancreatobiliary type
Clear cell adenocarcinoma
Hepatoid adenocarcinoma
Mucinous carcinomas
Signet ring cell carcinoma
Squamous cell carcinoma
Adenosquamous carcinoma
Neuroendocrine carcinoma
Large cell neuroendocrine carcinoma
Small cell neuroendocrine carcinoma
Mixed adenoneuroendocrine carcinoma
Undifferentiated carcinoma
Undifferentiated carcinoma with osteoclast-like giant cells
Noninvasive pancreatobiliary papillary neoplasm with high grade dysplasia
Papillary carcinoma, invasive

Board review style question #1

To qualify as pT3b disease, an ampullary carcinoma must extend at least how far into the pancreas?

0.2 cm
0.5 cm
1.0 cm
2.0 cm

Board review style answer #1

B. 0.5 cm

Comment Here

Reference: Staging-ampulla carcinoma

Staging-duodenal & ampullary neuroendocrine tumors

Table of Contents

Pathologic TNM staging of neuroendocrine tumors of the duodenum and ampulla of Vater, AJCC 8th edition

Definition / general

Well differentiated neuroendocrine tumors of the ampulla ("carcinoids") and of the duodenum are covered by this staging system
Not covered by this staging system are poorly differentiated neuroendocrine carcinomas at this location (use the adenocarcinoma staging system instead)

Essential features

AJCC 7th edition staging was sunset on December 31, 2017; as of January 1, 2018, use of the 8th edition is mandatory
Hormone secretion by the tumor (gastrin, somatotatin, etc.) is not incorporated into staging

Terminology

"Carcinoid” is no longer an acceptable term

ICD coding

ICD-10: C7A.019 - Malignant carcinoid tumor of the small intestine, unspecified portion

Primary tumor (pT)

TX: primary tumor cannot be assessed
T1: tumor invades the mucosa or submucosa only and is ≤ 1 cm (duodenal tumors); tumor ≤ 1 cm and confined within the sphincter of Oddi (ampullary tumors)
T2: tumor invades the muscularis propria or is ≥ 1 cm (duodenal); tumor invades through sphincter into duodenal submucosa or muscularis propria or is ≥ 1 cm (ampullary)
T3: tumor invades the pancreas or peripancreatic adipose tissue
T4: tumor invades the visceral peritoneum (serosa) or other organ
Notes: Tis is not a valid category under AJCC 8th edition staging for these tumors

Regional lymph nodes (pN)

NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node involvement
N1: Regional lymph node involvement
Notes: Regional lymph nodes include duodenal, hepatic, pancreatoduodenal, infrapyloric, gastroduodenal, pyloric, superior mesenteric and pericholedochal nodes

Distant metastasis (pM)

M0: No distant metastasis
M1: Distant metastasis
- M1a: Metastasis confined to liver
- M1b: Metastasis in at least one extrahepatic site (e.g., lung, ovary, nonregional lymph node, peritoneum, bone)
- M1c: Both hepatic and extrahepatic metastases

Prefixes

r: recurrent tumor stage

Stage grouping

Stage I: T1 N0 M0
Stage II: T2 - T3 N0 M0
Stage III: T4 N0 M0
any T N1 M0
Stage IV: any T any N M1

Registry data collection variables

Size of tumor
Maximum depth of invasion
Number of tumors
Lymph node status
Grade
Mitotic count
Ki67 labeling index
Perineural invasion
Lymphovascular invasion
Margin status
Functional status
Genetic syndrome
Location in duodenum
Type of surgery
Preoperative chromogranin A level
Preoperative pancreastatin level
Preoperative neurokinin level
Age of patient
Histologic variants

Histologic grade

Grading is not formally part of the staging system
Most pathologists use the ENETS / WHO grading criteria:
- G1: mitotic rate < 2 per 10 high power fields and Ki67 rate < 3%
- G2: mitotic rate 2 - 20 per 10 high power fields or Ki67 rate 3 - 20%
- G3: mitotic rate > 20 per 10 high power fields or Ki67 rate > 20%

Histopathologic type

Well differentiated neuroendocrine tumor
Glandular duodenal neuroendocrine tumor (i.e., somatostatinoma)
Gangliocytic paraganglioma

Board review style question #1

T1 only
T1 and T2
T1, T2, and T3
T2, T3, and T4

Board review style answer #1

B. T1 and T2

Comment Here

Reference: Staging-duodenal & ampullary neuroendocrine tumors

Staging-small intestine carcinoma

Table of Contents

Pathologic TNM staging of carcinomas of small bowel, AJCC 8th edition

Definition / general

Carcinomas, including neuroendocrine carcinomas, of the duodenum, jejunum and ileum are covered by this staging system
Use this system for duodenal / ampullary neuroendocrine tumors and this system for jejunum / ileum neuroendocrine tumors

Essential features

AJCC 7th edition staging was sunset on December 31, 2017; as of January 1, 2018, use of the AJCC, 8th Edition, 2018 is mandatory

ICD coding

C17.9: malignant neoplasm of small intestine, unspecified

Primary tumor (pT)

TX: primary tumor cannot be assessed
T0: no evidence of primary tumor
Tis: high grade dysplasia / carcinoma in situ
T1: tumor invades the lamina propria or submucosa
- T1a: tumor invades the lamina propria
- T1b: tumor invades the submucosa
T2: tumor invades the muscularis propria
T3: tumor invades through the muscularis propria into the subserosa or extends into nonperitonealized perimuscular tissue (mesentery or retroperitoneum) without serosal penetration
T4: tumor perforates the visceral peritoneum or directly invades other organs or structures (e.g., other loops of small intestine, mesentery of adjacent loops of bowel and abdominal wall by way of serosa; for duodenum only, invasion of pancreas or bile duct)

Notes:

For jejunal / ileal pT3 tumors, the nonperitonealized perimuscular tissue is part of the mesentery
For duodenal pT3 tumors in areas lacking serosa, the nonperitonealized perimuscular tissue is part of the interface with the pancreas

Regional lymph nodes (pN):

NX: regional lymph nodes cannot be assessed
N0: no regional lymph node metastasis
N1: metastasis in one or two regional lymph nodes
N2: metastasis in three or more regional lymph nodes

Notes:

Regional lymph nodes for the nonampullary duodenum include the retropancreatic, hepatic artery, inferior pancreaticoduodenal and superior mesenteric nodes
Regional lymph nodes for the jejunum or ileum include the mesenteric and superior mesenteric nodes; for the terminal ileum, the cecal and ileocolic nodes are also included

Distant metastasis (pM)

M0: no distant metastasis
M1: distant metastasis

Stage grouping

Stage 0:Tis N0 M0
Stage I:T1 - 2 N0 M0
Stage IIA:T3 N0 M0
Stage IIB:T4 N0 M0
Stage IIIA:any T N1 M0
Stage IIIB:any T N2 M0
Stage IV:any T any N M1

Registry data collection variables

Primary tumor site (duodenum, jejunum, ileum)
Number of lymph nodes examined
Presurgical CEA
LVI
Microsatellite instability
Tumor grade
Presence of disease
Personal or family history of familial GI malignancies (familial adenomatous polyposis, Lynch syndrome, Peutz-Jeghers syndrome)

Histologic grade

GX: grade cannot be assessed
G1: well differentiated
G2: moderately differentiated
G3: poorly differentiated

Histopathologic type

Adenocarcinoma
Mucinous adenocarcinoma
Mucin producing adenocarcinoma
Adenocarcinoma in adenomatous polyp
Adenocarcinoma in villous adenoma
Adenocarcinoma in tubulovillous adenoma
Signet ring cell carcinoma
Carcinoma, NOS
Adenosquamous carcinoma
Squamous cell carcinoma
Large cell neuroendocrine carcinoma (NEC)
Small cell neuroendocrine carcinoma (NEC)
Mixed adenoneuroendocrine carcinoma
Undifferentiated carcinoma
Medullary carcinoma
High grade dysplasia

Board review style question #1

Based on AJCC eighth edition criteria, a jejunal adenocarcinoma extending through the muscularis propria into the adjacent mesentery but without perforating the serosa would be staged as which of the following?

Board review style answer #1

C. pT3

Comment Here

Reference: Staging-small intestine carcinoma

Staging-small intestine neuroendocrine tumors

Table of Contents

Pathologic TNM staging of neuroendocrine tumors of the jejunum and ileum, AJCC 8th edition

Definition / general

Well differentiated neuroendocrine tumors of the jejunum and ileum are covered by this staging system
Not covered by this staging system are well differentiated neuroendocrine tumors of the ampulla or duodenum (use ampulla staging) or poorly differentiated neuroendocrine carcinomas of the small intestine (use small bowel carcinoma staging)

ICD coding

C7A.011: malignant carcinoid tumor of the jejunum
C7A.012: malignant carcinoid tumor of the ileum

Primary tumor (pT)

TX: primary tumor cannot be assessed
T0: no evidence of primary tumor
T1: invades lamina propria or submucosa and ≤ 1 cm in size
T2: invades muscularis propria or > 1 cm in size
T3: invades through the muscularis propria into subserosal tissue without penetration of overlying serosa
T4: invades visceral peritoneum (serosa) or other organs or adjacent structures

Regional lymph nodes (pN)

NX: regional lymph nodes cannot be assessed
N0: no regional lymph node metastasis
N1: regional lymph node metastasis in < 12 nodes
N2: large mesenteric masses (> 2 cm) or extensive nodal deposits (≥ 12), especially those that encase the superior mesenteric vessels

Notes:

Regional lymph nodes include superior mesenteric and mesenteric nodes; posterior cecal nodes also apply for terminal ileum lesions
2 cm cutoff for including mesenteric masses in N categorization may be suboptimal (Mod Pathol 2018 May 24 [Epub ahead of print])

Distant metastasis (pM)

M0: no distant metastasis
M1: distant metastasis
- M1a: metastasis confined to liver
- M1b: metastasis in at least one extrahepatic site (e.g., lung, ovary, nonregional lymph node, peritoneum, bone)
- M1c: both hepatic and extrahepatic metastasis

Prefixes

(m): multiple primary lesions (provide stage for the most advanced lesion)
r: recurrent tumor stage

Stage grouping

Stage I:T1 N0 M0
Stage II:T2 - 3 N0 M0
Stage III:T4 N0 M0
any T N1 - 2 M0
Stage IV:any T any N M1

Registry data collection variables

Size of tumor (value or unknown)
Tumor focality (unifocal or multifocal)
Depth of invasion
Nodal status and number of nodes involved, if applicable
Sites of metastasis, if applicable
NKA (neurokinin A) level
Pancreastatin level
Ki67 index
Mitotic count
Histologic grading (from Ki67 and mitotic count): G1, G2, G2

Histologic grade

Grading is not formally part of the staging system
Most pathologists use the European Neuroendocrine Tumor Society (ENETS) / WHO grading criteria:
- Grade 1: mitotic rate < 2 per 10 high power fields and Ki67 rate < 3%
- Grade 2: mitotic rate 2 - 20 per 10 high power fields or Ki67 rate 3 - 20%
- Grade 3: mitotic rate > 20 per 10 high power fields or Ki67 rate > 20%

Histopathologic type

Neuroendocrine tumor (NET) G1 (carcinoid)
Neuroendocrine tumor (NET) G2

Board review style question #1

A patient undergoes resection for jejunal neuroendocrine tumors. Three tumors are present – one smaller than 1 cm, one larger than 1 cm and invading the muscularis propria and one larger than 1 cm and invading the subserosa. Using AJCC 8th edition criteria, how would the pathologic T category be reported for this patient?

Separate complete staging for each primary focus
pT1/T2/T3
pT1(1)T2(1)T2(1)
pT3(m) or pT3(3)

Board review style answer #1

D. pT3(m) or pT3(3)

Comment Here

Reference: Staging-small intestine neuroendocrine tumors

Ulcerative colitis

Table of Contents

Definition / general | Backwash ileitis | Microscopic (histologic) images

Definition / general

Severe UC is associated with contiguous backwash ileitis and appendix involvement
UC also associated with postcolectomy pouchitis
Rarely diffuse duodenitis is associated with ulcerative colitis but it does not behave as Crohn's disease (Am J Surg Pathol 2000;24:1407)
Diffuse chronic duodenitis in ulcerative colitis patients who have colectomy is a strong predictor of pouchitis (Am J Surg Pathol 2010;34:1672)

Backwash ileitis

Recommended to restrict use of term to active enteritis involving ileum contiguously from cecum that has a similar or greater degree of active inflammation; mild cases predominantly involves the superficial mucosa in a contiguous pattern
Focal isolated ileal erosions, mucous gland metaplasia or patchy edema with mild active inflammation are features of Crohn's disease (Am J Clin Pathol 2006;126:365)

Microscopic (histologic) images

Images hosted on other servers:

Mild backwash ileitis in moderately active cecal chronic ulcerative colitis resection specimen; mucosa
of distal ileum is edematous and villi are slightly wider and flatter than normal; most of the active colitis
stops abruptly at transition point between the two mucosae; the two most distal villi have the greatest
degree of injury, including blunting, edema and neutrophils in the lamina propria and surface epithelium

Moderate backwash ileitis

Severe backwash ileitis

Terminal ileum inflammation: (A) grade
1, cryptitis; (B) grade 2, scattered
crypt abscesses; (C) grade 3, numerous
crypt abscesses; (D) grade 4, ulcer

Whipple disease

Table of Contents

Definition / general

Rare systemic infection caused by intracellular rod shaped actinobacterium Tropheryma whipplei

Essential features

Whipple disease is a rare, multisystem infection due to Tropheryma whipplei that most commonly affects the small bowel but may involve any part of the gastrointestinal tract
Histologically, small intestinal biopsies show infiltration of the lamina propria by foamy macrophages containing PAS positive, AFB negative bacteria
Electron microscopy shows intact and degenerated rod shaped bacterial forms
PCR for 16S ribosomal genes of T. whipplei is often diagnostically useful and can be performed on fresh or paraffin embedded, formalin fixed tissue
Treatment consists of long term antimicrobial therapy

Terminology

Tropheryma whipplei is also known as the Whipple bacillus
- Formerly called Tropheryma whippelii
Historical term: intestinal lipodystrophy (Clin Gastroenterol Hepatol 2004;2:849)

ICD coding

ICD-10: K90.81 - Whipple disease

Epidemiology

M:F = 8:1
More common in middle aged white males
Extremely rare, annual incidence of approximately 1 - 6 new cases per 10,000,000 persons per year worldwide (Scand J Gastroenterol 1997;32:52)

Sites

Multisystem infection
- Most often involves gastrointestinal tract
  - Small intestine > esophagus / stomach / appendix / colorectum
- May involve mesenteric lymph nodes, joints, heart, lungs, eyes and central nervous system

Pathophysiology

Many individuals carry antibodies against Tropheryma whipplei, despite the extremely low incidence of Whipple disease
Disease presumably develops in individuals with predisposing immune factors
- Patients with Whipple disease often have immunomodulatory conditions, such as alcohol abuse, sarcoidosis, ankylosing spondylitis, Crohn's disease and rheumatoid arthritis (Am J Surg Pathol 2012;36:1066)
Association with HLA-B27 (Eur J Clin Invest 1979;9:385)
Organism laden macrophages mechanically compress lymphatics in small bowel, leading to malabsorption

Etiology

Causative agent is Tropheryma whipplei
- Actinomycete, related to mycobacteria

Clinical features

Clinical presentation is highly variable
- Most common symptoms are malabsorption, weight loss, diarrhea, arthralgias and abdominal pain
- Generalized lymphadenopathy may be present (particularly in the abdomen)
- Often referred to as protean and the great mimicker, like syphilis, because of nonspecific clinical presentation (Am J Surg Pathol 2012;36:1066)
- Approximately 15% of patients do not have typical symptoms
Neurological symptoms (such as cognitive changes, ophthalmoplegia, nystagmus and myoclonia) present in ~24% of patients (Medicine (Baltimore) 2015;94:e714)
Tropheryma whipplei accounts for ~6.3% of culture negative endocarditis (J Clin Microbiol 2012;50:216)
Rarely, can present in retroperitoneum, mimicking a neoplasm (Braz J Infect Dis 2014;18:346)
Esophagogastroduodenoscopy findings:
- Unremarkable (majority of cases) (Medicine (Baltimore) 2015;94:e714)
- Pale yellow, shaggy mucosa
- Thickened mucosal folds
- Yellow-white plaques
- Erosions, erythema, friability

Diagnosis

Upper endoscopy with biopsies of small intestine
- H&E histology
- Periodic acid-Schiff (PAS) staining
- PCR on paraffin embedded, formalin fixed tissue for 16S ribosomal genes of Tropheryma whipplei
  - PCR testing can also be performed on fresh tissue, vitreous fluid and cardiac valves (N Engl J Med 1992;327:293, N Engl J Med 1995;332:363, J Infect Dis 2004;190:935)
  - PCR can be negative after antibiotic treatment (Ann Intern Med 1997;126:520)
- Immunohistochemical stain: polyclonal rabbit antibody against T. whipplei, available from reference center, such as Centers for Disease Control and Prevention (Am J Clin Pathol 2002;118:742)
- Electron microscopy
Cerebrospinal fluid and synovial fluid
- Cytology
- PAS staining
- PCR

Laboratory

Laboratory abnormalities seen in chronic inflammatory conditions are common (Medicine (Baltimore) 2015;94:e714):
- Anemia (81% of patients)
- Leukocytosis (48% of patients)
- Thromobocytosis (56% of patients)
- Elevated C reactive protein (69% of patients)

Radiology description

Radiological findings are nonspecific (Clin Gastroenterol Hepatol 2004;2:849)
Abdominal computed tomography and magnetic resonance imaging:
- Thickened small bowel mucosal folds
- Mesenteric lymphadenopathy
Small bowel contrast radiology may also show thickened mucosal folds

Radiology images

Images hosted on other servers:

Contrast study

Prognostic factors

Response to antimicrobial treatment is unpredictable
Relapse is common after treatment

Case reports

4 year old girl with chronic bloody diarrhea and growth retardation (Intest Res 2021;19:119)
49 year old man with weakness, loss of appetite, weight loss and joint pain (Med Princ Pract 2020;29:90)
52 year old man with diarrhea, marked weight loss and vision changes (GE Port J Gastroenterol 2020;27:283)

Treatment

Antimicrobial treatment (Clin Microbiol Rev 2017;30:529)
Optimal treatment regimen is uncertain and without consensus but most regimens involve an initial phase followed by a maintenance phase
- Initial phase (2 - 4 weeks): ceftriaxone or penicillin G
- Maintenance phase (one year): trimethoprim sulfamethoxazole
Doses and durations of therapy depends on presence or absence of central nervous system disease or endocarditis

Clinical images

Images hosted on other servers:

Endoscopic findings

Microscopic (histologic) description

Lamina propria expanded by foamy macrophage infiltrate (Am J Surg Pathol 2012;36:1066)
- Infiltrate may be diffuse or patchy
Blunt or distended villi (Dig Dis Sci 2019;64:213)
Scattered dilated lacteals (Am J Surg Pathol 2012;36:1066)
Fat vacuoles within lamina propria (Dig Dis Sci 2019;64:213)
Overlying enterocyte vacuolization due to intracytoplasmic lipid accumulation
Acute inflammation (variable)
Mononuclear inflammation usually absent
Epithelioid granulomas (minority of cases) (Virchows Arch A Pathol Anat Histol 1979;382:227)

Microscopic (histologic) images

Contributed by John D. Paulsen, M.D. and Alexandros D. Polydorides, M.D., Ph.D.

Lamina propria macrophage infiltrate

Foamy macrophages

Positive PAS stain

Negative AFB stain

Negative GMS stain

Cytology description

Limited clinical utility
Cytospin stained with PAS reagent may be used for fluid samples (i.e. cerebrospinal fluid [CSF], synovial fluid)
- Histiocytes with numerous intracellular PAS positive, granular particles
- Intracellular particles may appear sickle shaped, resulting in sickleform particle containing (SPC) cells (Gastroenterology 1997;113:434)
- CSF cytology may be positive in patients without neurological symptoms (Gastroenterology 1997;113:434)

Cytology images

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CSF cytospin with PAS

Positive stains

PAS and PASD (granular staining)
- Stains the glycoprotein wall of the bacteria
- Can stain both viable and nonviable organisms
Tropheryma whipplei immunostain (granular staining) (Am J Clin Pathol 2002;118:742)
- Can stain both viable and nonviable organisms

Negative stains

Acid fast stains
GMS

Electron microscopy description

Rod shaped bacterium (bacillary bodies) within macrophages and lamina propria
Intracellular forms may be associated with phagocytic vacuoles (Am J Surg Pathol 1981;5:507)
After treatment, bacterial breakdown products and degenerating organisms may be seen

Electron microscopy images

Images hosted on other servers:

Whipple disease, duodenum

T. whipplei bacteria

Bacterium (arrowhead)

Molecular / cytogenetics description

PCR for 16S ribosomal genes of T. whipplei is an important diagnostic tool for diagnosing Whipple disease
- In patients with histologically confirmed disease: sensitivity 96.6% and specificity 100% (Ann Intern Med 1997;126:520)
Conversion from positive to negative PCR results can occur before histologic resolution of disease because bacterial remnants and cell wall structures often persist in macrophages after treatment (Gastroenterology 1996;110:1735)
Positive PCR can be seen in asymptomatic colonization of patients without disease

Molecular / cytogenetics images

Images hosted on other servers:

Gel electrophoresis of PCR products

Sample pathology report

Duodenum, endoscopic biopsy:
- Duodenal mucosa with abundant foamy macrophages in lamina propria (see comment)
- Special stains for PAS and PAS with diastase (PASD) show strong, granular positivity within macrophages
- AFB stain (Ziel-Neelsen method) is negative
- Comment: In the appropriate clinical setting, the findings are concerning for Whipple disease. Immunohistochemical stain for Tropheryma whipplei as well as PCR on the paraffin embedded block have been requested, results of which will be reported in a follow up addendum.

Differential diagnosis

Mycobacterium avium intracellulare complex:
- Lamina propria macrophage infiltrate containing intracellular acid fast bacilli
- Acid fast stain positive
- PAS positive (pitfall)
Histoplasmosis:
- Lamina propria macrophage infiltrate containing small, intracellular yeast forms with narrow based budding and halos
- GMS positive
- PAS positive
Malakoplakia:
- Lamina propria macrophage infiltrate showing targetoid Michaelis-Gutmann bodies (PAS positive, von Kossa positive)
- False positivity with Tropheryma whipplei immunostain has been documented (Am J Surg Pathol 2020;44:1251)
Rhodococcus:
- Lamina propria macrophage infiltrate containing intracellular coccobacillary organisms
- Gram positive on tissue Gram stain
- PAS positive (typically more granular than T. whipplei)
- T. whipplei immunostain negative
Gaucher disease:
- Lamina propria macrophage infiltrate with fibrillary cytoplasm (tissue paper-like)
- PAS positive
- Electron microscopy shows elongated lysosomes with tubular inclusions
Crushed Brunner glands:
- Interpret in context of adjacent more intact Brunner glands
- PAS positive

Board review style question #1

A 54 year old man presents to his primary care physician with a 5 month history of diarrhea and abdominal pain. He is referred for esophagogastroduodenoscopy, which demonstrates diffuse yellow-white plaques of the duodenal mucosa. Multiple biopsies are performed. Representative H&E of the duodenal biopsy is shown above. Which of the following pairs of ancillary stains would be most helpful in establishing a diagnosis?

AFB and CD68 immunostain
GMS and AFB
PAS and AFB
PAS and CD68 immunostain
PAS and GMS

Board review style answer #1

C. PAS and AFB. The photograph shows a single small intestinal villous containing numerous foamy macrophages in the lamina propria. The primary histologic differential diagnosis includes Mycobacterium avium intracellulare complex and Whipple disease. The most useful pair of stains for distinguishing these 2 entities is PAS and AFB given that Mycobacterium avium intracellulare complex is PAS positive and AFB positive, whereas Whipple disease is PAS positive and AFB negative. GMS does not help distinguish Mycobacterium avium intracellulare complex and Whipple disease. GMS highlights histoplasmosis; however, no intracellular yeast forms are seen on H&E stain in this case. CD68 immunostain highlights foamy lamina propria macrophages; however, it would not help distinguish the 2 entities.

Comment Here

Reference: Whipple disease

Board review style question #2

A 45 year old man presents to the emergency department with a 6 month history of weight loss, diarrhea and joint pain in both his left knee and right elbow. He is admitted for further work up, including esophagogastroduodenoscopy (EGD), which reveals a pale shaggy mucosa in the duodenum. A diagnosis of Whipple disease is confirmed on biopsy. Which of the following is true regarding the patient's diagnosis?

In a majority of patients with confirmed Whipple disease, EGD is unremarkable
On H&E stain, infiltration of the duodenal lamina propria by macrophages is pathognomonic of Whipple disease
PASD stain is usually negative due to the glycogen containing cell wall of the causative organism
PCR for 16S ribosomal genes of Tropheryma whipplei cannot be performed on paraffin embedded formalin fixed tissue
Stomach biopsies are superior to duodenal biopsies for establishing a tissue diagnosis

Board review style answer #2

A. In a majority of patients with confirmed Whipple disease, EGD is unremarkable. In the duodenum, a lamina propria infiltrate of macrophages can be seen in a variety of settings, including Whipple disease, Mycobacterium avium intracellulare complex infection, histoplasmosis, Rhodococcus infection, malakoplakia and Gaucher disease. Therefore, ancillary studies (such as PAS stain, PASD stain, AFB stain[s], PCR or electron microscopy) must be performed to confirm a diagnosis of Whipple disease on biopsy. Both PASD and PAS stains are positive on biopsies involved by Whipple disease due to the glycoprotein (not glycogen) present in the cell wall of T. whipplei. The glycoprotein does not get digested away by diastase and the organisms are therefore PASD positive. PCR for 16S ribosomal genes of T. whipplei can be performed on paraffin embedded formalin fixed tissue as well as fresh tissue, cerebrospinal fluid, synovial fluid, vitreous fluid and cardiac valves. Whipple disease most commonly involves the small bowel; therefore, biopsies of the small bowel, including duodenum, provide the best diagnostic yield.

Comment Here

Reference: Whipple disease

WHO classification

Table of Contents

Definition / general | WHO (2019)

Definition / general

WHO classification of tumors of the small intestine and ampulla
Currently on 5th edition, published in 2019
Based on histologic appearance, not molecular characteristics

WHO (2019)

Benign epithelial tumors and precursors

ICD-O codes

Adenomatous polyp, low grade dysplasia 8210/0
Adenomatous polyp, high grade dysplasia 8210/2
- Intestinal type adenoma, low grade 8144/0
- Intestinal type adenoma, high grade 8144/2
- Serrated dysplasia, low grade 8213/0
- Serrated dysplasia, high grade 8213/2
- Noninvasive pancreatobiliary papillary neoplasm with low grade dysplasia 8163/0
- Noninvasive pancreatobiliary papillary neoplasm with high grade dysplasia 8163/2
- Intra-ampullary papillary tubular neoplasm

Malignant epithelial tumors

ICD-O codes

Adenocarcinoma, NOS 8140/3
- Mucinous adenocarcinoma 8480/3
- Signet ring cell carcinoma 8490/3
- Medullary carcinoma, NOS 8510/3
- Adenocarcinoma, intestinal type 8144/3
- Pancreatobiliary type adenocarcinoma 8163/3
- Tubular adenocarcinoma 8211/3
Neuroendocrine tumor, NOS 8240/3
- Neuroendocrine tumor, grade 1 8240/3
- Neuroendocrine tumor, grade 2 8249/3
- Neuroendocrine tumor, grade 3 8249/3
- Gastrinoma, NOS 8153/3
- Somatostatinoma, NOS 8156/3
- Enterochromaffin cell carcinoid 8241/3
- Extra-adrenal paraganglioma, NOS 8693/3
Neuroendocrine carcinoma, NOS 8246/3
- Large cell neuroendocrine carcinoma 8013/3
- Small cell neuroendocrine carcinoma 8041/3
Mixed neuroendocrine - nonneuroendocrine neoplasm (MiNEN) 8154/3

Recent Small intestine & ampulla Pathology books

Albores-Saavedra: 2016

Cheng: 2023

Greenson: 2019

IARC: 2019

Lamps: 2015

Montgomery: 2017

Odze: 2022

Srivastava: 2023

Yantiss: 2021

Find related Pathology books: GI, liver, molecular

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