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Pancreas

Superpage - Tumor

Revised: 12 December 2014
Copyright: (c) 2001-2014, PathologyOutlines.com, Inc.

Tumors

WHO classification


Reviewer: Nat Pernick, M.D. (see Reviewers page)
Revised: 30 November 2012, last major update August 2012
Copyright: (c) 2012, PathologyOutlines.com, Inc.

WHO (2010)
=========================================================================

Epithelial tumors
Benign
  8551/0 Acinar cell cystadenoma
  8441/0 Serous cystadenoma, NOS

Premalignant lesions
  8148/2 Pancreatic intraepithelial neoplasia, grade 3 (PanIN-3)
  8453/0 Intraductal papillary mucinous neoplasm (IPMN) with low- or intermediate-grade dysplasia
  8453/2 Intraductal papillary mucinous neoplasm (IPMN) with high-grade dysplasia
  8503/2 Intraductal tubulopapillary neoplasm (ITPN)
  8470/0 Mucinous cystic neoplasm (MCN) with low- or intermediate-grade dysplasia
  8470/2 Mucinous cystic neoplasm (MCN) with high-grade dysplasia

Malignant lesions
  8500/3 Ductal adenocarcinoma
  8560/3 Adenosquamous carcinoma
  8480/3 Mucinous adenocarcinoma
  8576/3 Hepatoid carcinoma
  8510/3 Medullary carcinoma, NOS
  8490/3 Signet ring cell carcinoma
  8020/3 Undifferentiated carcinoma
  8035/3 Undifferentiated carcinoma with osteoclast-like cells
  8550/3 Acinar cell carcinoma
  8551/3 Acinar cell cystadenocarcinoma
  8453/3 Intraductal papillary mucinous carcinoma (IPMN) with an associated invasive carcinoma
  8552/3 Mixed acinar-ductal carcinoma
  8154/3 Mixed acinar-neuroendocrine carcinoma
  8154/3 Mixed acinar-neuroendocrine-ductal carcinoma
  8154/3 Mixed ductal-neuroendocrine carcinoma
  8470/3 Mucinous cystic neoplasm (MCN) with an associated invasive carcinoma
  8971/3 Pancreatoblastoma
  8441/3 Serous cystadenocarcinoma, NOS
  8452/3 Solid-pseudopapillary neoplasm

Neuroendocrine neoplasms
  8150/0 Pancreatic neuroendocrine microadenoma
  8240/3 Neuroendocrine tumor G1 (NET G1) / Carcinoid
  8249/3 Neuroendocrine tumor G2 (NET G2)
  8246/3 Neuroendocrine carcinoma, NOS
  8013/3 Large cell neuroendocrine carcinoma
  8041/3 Small cell neuroendocrine carcinoma
  8241/3 Enterochromaffin cell (EC), serotonin-producing neuroendocrine tumour (NET)
  8153/3 Gastrinoma, malignant
  8152/3 Glucagonoma, malignant
  8151/3 Insulin producing carcinoma (insulinoma)
  8156/3 Somatostatinoma, malignant
  8155/3 Vipoma, malignant

Mesenchymal tumours
  9170/0 Lymphangioma, NOS
  8850/0 Lipoma, NOS
  8815/1 Solitary fibrous tumor
  9260/3 Ewing sarcoma
  8806/3 Desmoplastic small round cell tumor
  Perivascular epithelioid cell neoplasm

Lymphomas
  9680/3 Diffuse large B-cell lymphoma (DLBCL), NOS

Secondary tumours
  Secondary tumours of the pancreas

References: WHO Classification of Tumours of the Digestive System 2010, PubCan.org, Pathologe 2011;32 Suppl 2:332



Tumors

Acinar cell cystadenoma


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 25 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Either clinically recognized macroscopic or incidental microscopic (WHO)
● First described in 2002 (Am J Surg Pathol 2002;26:698)
● Rare benign cystic neoplasm of the pancreas (Pancreas 2008;37:254, Am J Surg Pathol 2012;36:1579)
● 70% women, ages 16 to 66 years
● Benign behavior

Case reports
=========================================================================

● 24 year old woman with 6 cm cystic lesion in the head of the pancreas (Case of the Week #136)
● 52 year old man with incidental tumor (Am J Clin Pathol 2002;118:211)

Treatment
=========================================================================

● Excision

Gross description
=========================================================================

● Mean 6 cm, unilocular or multilocular cysts with watery fluid, cysts usually not connected with ductal system

Gross images
=========================================================================



Various images

Micro description
=========================================================================

● Well circumscribed, mature acinar cells with abundant eosinophilic granular cytoplasm and round, basal nuclei
● Cyst lined by flattened cells resembling normal ductal epithelium, but with focal acinar cells and admixed with dilated acini
● May be adjacent to mucinous ductal epithelium
● Eosinophilic secretions form oval plugs
● No papillary projections or solid areas, no ovarian type stroma, no PanIN lesions
● No atypia, no mitotic activity, no vascular invasion, no relationship to major ductal system (Stanford University)

Micro images
=========================================================================



Case of the week #136: H&E and trypsin


Various images

Positive stains
=========================================================================

● PAS, lipase, trypsin, chymotrypsin, CK7

Negative stains
=========================================================================

● Ki-67

Electron microscopy images
=========================================================================



Case of the week 136

Differential diagnosis
=========================================================================

Acinar cell cystadenocarcinoma: more complex epithelium, nuclear atypia, prominent nucleoli; often necrosis, solid nests of tumor cells, mitotic figures, infiltration into surrounding stroma)
PanIN: no acinar cells, variable atypia



Tumors

Acinar cell carcinoma


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 24 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Malignant epithelial neoplasm composed of cells with morphological resemblance to acinar cells and with evidence of pancreatic exocrine enzyme production (WHO)
● Resembles similar tumor in parotid gland
● 1-2% of pancreatic malignancies

Clinical features
=========================================================================

● 85% men; mean age 62 years (range, 40-81 years), rare in children (Am J Surg Pathol 1992;16:815)
● 10% have lipase hypersecretion syndrome (subcutaneous fat necrosis, polyarthralgias, occasional eosinophilia, nonbacterial thrombotic endocarditis) due to tumor lipase secretion by tumor; these patients usually have liver metastases
● Tumors may also secrete alpha-fetoprotein (AFP), and most AFP+ pancreatic neoplasms are acinar cell carcinomas or pancreatoblastoma (Hum Pathol 2000;31:938)
● 50% have metastases at diagnosis (liver and regional lymph nodes)
● 5 year survival is only 10%
● Variant with intraductal polypoid growth: less aggressive behavior, fewer metastases, smaller size (Am J Surg Pathol 2010;34:1025, Int J Surg Pathol 2011;19:795)
● Poor prognostic factors: stage III/IV versus I/II (Am J Surg Pathol 2012;36:1782)

Case reports
=========================================================================

● 44 year old woman with pancreatic mass (Arch Pathol Lab Med 2002;126:985)
● 50 year old man (Arch Pathol Lab Med 2001;125:1127)

Gross description
=========================================================================

● Well circumscribed, soft/fleshy (since minimal stroma) with fibrous septa, large (mean 11 cm), hemorrhage and necrosis common

Gross images
=========================================================================


 
Cut surface displays large nodules separated by fibrous strands, with frequently necrotic foci


Soft and circumscribed tumor with abundant hemorrhage, which projects into duodenum

Micro description
=========================================================================

Note: must document pancreatic enzymes to be considered an acinar cell tumor
● Highly cellular with minimal stroma and no desmoplasia
● Solid, nesting, glandular or acinar patterns with sharp luminal space outlines
● Monotonous, uniform polarized cells with abundant eosinophilic granular apical cytoplasm due to zymogen granules (scanty in solid tumors), basal nuclei and single prominent nucleoli
● Moderate nuclear atypia, variable mitoses, no mucin
● Vascular invasion often present
● 30-50% have minor endocrine component based on immunohistochemistry
● Tumors with solid or trabecular pattern resembles endocrine tumors

Micro images
=========================================================================



Various images


Tumor is markedly cellular with gross lobulation by broad fibrous strands; stroma is scant within large tumor lobules


Mixture of acinar, trabecular and solid patterns


Nuclei are somewhat irregular in size; nuclei are polarized in acinar formations


Pure acinar pattern resembles normal pancreas


Dilated acini form "microglandular" structures


Round cells with scant cytoplasm, slightly irregular nuclei, distinct nucleoli


PAS: tumor cells have abundant, finely granular cytoplasm, which is PAS+ in apical portion


Trypsin stains tumor cells intensely (right side), normal acinar tissue is also typsin+ (right side)


Trypsin stains apical portion of tumor cells


Left: CAM 5.2+, right: synaptophysin+

Cytology description
=========================================================================

● Small to moderate-sized loose groups with numerous single cells, prominent acinar formation, little anisonucleosis and prominent nucleoli
● Background cleaner than ductal carcinoma
● Significant overlap with features of pancreatic endocrine tumors ( Diagn Cytopathol 2006;34:367)

Cytology images
=========================================================================



FNA from metastases to liver

Positive stains
=========================================================================

Note: staining is often in the apical portion of the tumor cells
● BCL10 (Virchows Arch 2009;454:133), PAS (diastase resistant) for granules, trypsin and chymotrypsin (90%+ sensitive), lipase (50% sensitive), amylase, elastase, butyrate esterase (75% sensitive, indicates lipase), keratin, 2P-1-2-1 (sensitivity and specificity 100%, J Clin Pathol 2012;65:327)
● Claudin7 (Am J Surg Pathol 2009;33:768, Arch Pathol Lab Med 2008;132:490)

Negative stains
=========================================================================

● Mucin, CD56, PAX8

Molecular / cytogenetics
=========================================================================

● Amplifications at chromosome 20q (100%) and 19p (80%) (Mod Pathol 2011;24:1229)
● Kras and p53 mutations uncommon
● Biallelic inactivation of LKB1 is associated with Peutz-Jeghers syndrome

Electron microscopy description
=========================================================================

● Well-developed microvilli, abundant granular (rough) ER, numerous mitochondria, zymogen like granules (300-600 nm, apical, homogenous), irregular fibrillary granules (up to 3500 nm with fibrillary internal structures, resemble zymogen granules in developing pancreas)

Electron microscopy images
=========================================================================



Tumor cells have many pleomorphic and rather small zymogen granules (mean 400-500 nm, range 200-1000 nm), commonly oriented towards the luminal space; they are round and lack a hole between their homogeneous dark staining contents and the granule membrane


FNA from liver metastasis

Differential diagnosis
=========================================================================

Ductal adenocarcinoma: mucicarmine+, CEA+, negative for acinar markers
IPMN: papillary variant of acinar carcinoma, compared to IPMN, has nodules with more sheetlike nature, cuboidal cells, basophilic cytoplasm, prominent nucleoli, apical granules, intraluminal crystals or pale, acidophilic secretions, and lack of mucin (Am J Surg Pathol 2007;31:363)
Pancreatic endocrine tumor: no acinar differentiation, uniform nuclear morphology, fibrous stroma, PAS-
Pancreatoblastoma: children, squamoid bodies
Solid pseudopapillary tumor: young women, cystic and hemorrhagic, solid and pseudopapillary patterns, CD56+, CD10+



Tumors

Acinar cell cystadenocarcinoma


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 25 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Typically large tumors up to 17 cm containing multiple cysts
● Marked atypia, frequent mitotic activity

Gross description
=========================================================================

● Large multilocular cystic mass with a pseudocapsule and a spongy appearance

Gross images
=========================================================================



7 kg, multiloculated cystic neoplasm of pancreatic tail/body; thick fibrous capsule surrounds mass, cysts contain serous watery fluid, vary from pinpoint to 7 cm; cysts are lined by smooth, white glistening surface; no gross pancreatic tissue is present; tumor attached to, but did not invade spleen (upper right)

Micro description
=========================================================================

● Cysts are lined by a single layer of cuboid/columnar cells
● Cytoplasm has characteristics of acinar cells, with eosinophilic granules in the apex and prominent nucleoli (Hum Pathol 2004;35:1568)

Micro images
=========================================================================


   
Numerous variably sized microcysts

Differential diagnosis
=========================================================================

Acinar cell cystadenoma: no malignant features, no invasion
Acinar cell hyperplasia: common, resembles islets, may have minor atypia, may be pre-malignant
Pancreatic endocrine neoplasm: rare mitoses, no polarization, indistinct nucleoli, amyloid stroma, trabeculae, stippled chromatin, although acinar cell may contain scattered endocrine cells and mixed tumors are common



Tumors

Mixed tumors


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 25 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Significant amount (some authors-25%) of each component
● “Collision tumours” have 2 topographically separate neoplasms, and are not considered "mixed"


Proposed classification system for mixed tumors


Mixed acinar-ductal
● Either (a) acinar component with extensive cytoplasmic or extracellular mucin pools, with positive mucin (mucicarmine, Alcian blue) and acinar (trypsin, chymotrypsin) staining or (b) ductal pattern of individual gland infiltration with desmoplasia, but acinar differentiation by IHC (WHO)
● Highly aggressive (Am J Surg Pathol 2010;34:510)


Mixed acinar-ductal carcinoma



Top-ductal elements (right) are glandular and contain intracellular mucin; acinar elements (left) are arranged in large nests
Bottom-acinar cells stain with trypsin, mucin associated with ductal cells stain with Alcian blue



Mixed acinar-endocrine tumor
● Behaves like acinar cell carcinoma
● For these tumors, diagnosis should be based on morphology, not immunohistochemistry, because endocrine tumors may routinely stain with acinar markers (Am J Surg Pathol 2002;26:893, Am J Surg Pathol 1994;18:765)
● Resembles pancreatoblastoma
Case reports: 74 year old man (Cases J 2009;2:6481)


74 year old man


Mixed ductal-endocrine
● Either (a) intermingled neoplastic ductal and neuroendocrine cells forming glandular/squamoid and solid structures, or (b) moderately differentiated neoplastic ductal structures embedded in solid neuroendocrine component (WHO)
● Must rule out trapped benign ducts within an endocrine tumor
● By definition, does not include ductal adenocarcinoma with scattered endocrine cells (see images below)
Case reports: 58 year old man with tumor types separated by fibrous band (Arch Pathol Lab Med 2000;124:284), 65 year old woman (JOP 2005;6:449), 74 year old man with mixture of tumor types (Arch Pathol Lab Med 2000;124:284)


Left: poorly differentiated carcinoma, middle: endocrine component stains with somatostain; right: PAS-diastase (purple) highlights mucin, somatostain highlights endocrine component





65 year old woman with 12 cm tumor that infiltrated spleen and splenic vessels
Line 1: ductal component is well differentiated and CA 19-9 positive
Line 2: endocrine component has irregular islands with central necrosis, is chromogranin+, synaptophysin+




Separation of tumor types by fibrous band



Various images-mixture of tumor types



Not a mixed tumor - well differentiated adenocarcinomas with scattered endocrine cells: left-synaptophysin+, right-tail tumor has numerous PP+ endocrine cells


Mixed acinar, ductal, endocrinel tumor
● Use immunohistochemistry to define
● Aggressive clinical course (Am J Surg Pathol 2010;34:510)
Case reports: 21 year old man (Pathol Int 1995;45:669), 56 year old man (Int J Clin Exp Pathol 2009;2:602)

   
56 year old man



Tumors

Ductal adenocarcinoma, NOS (not otherwise specified)


Reviewer: Deepali Jain, M.D. (see Reviewerspage)
Revised: 10 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● A malignant tumour derived from ductal epithelia, with randomly arranged epithelial elements, variable necrosis, in situ carcinoma (WHO)
● Define pancreatic tumors based on line of differentiation (ductal, endocrine or acinar), not cell of origin
● Ductal adenocarcinoma also known as Usual Ductal Adenocarcinoma (UDA); also tubular type
● 85% of pancreatic cancers are UDA
● #4 cause of cancer death in US after lung, colon, breast; in 2012, estimated 44,000 new cases, 37,000 deaths
● Currently 3 recognized precursors of invasive disease: PanIN, IPMN and Mucinous cystic neoplasm (Arch Pathol Lab Med 2011;135:716)

Risk factors
=========================================================================

● Smoking, alcohol abuse (particularly in African-Americans), obesity, beta-naphthylamine or benzidine exposure, familial relapsing pancreatitis, older age
● Uncertain risk factors: chronic pancreatitis, diabetes (may be secondary to carcinoma), male (M/F = 1.6:1)

Familial syndromes / genetics
=========================================================================

● Hereditary nonpolyposis colorectal carcinoma (MIM 114500, MLH1 or MSH2 mismatch repair genes), familial atypical mole-melanoma syndrome (MIM 600160, p16 mutations)
● Also BRCA2 (MIM 600185), Peutz-Jeghers syndrome (MIM 602216, STK11/LKB1 gene, Hum Pathol 1986;17:97), hereditary pancreatitis (MIM 276000, cationic trypsinogen gene at 7q35), ataxia telangiectasia

Sites
=========================================================================

● 60% in head, 15% in body, 5% in tail, 20% diffusely involve pancreas
● Head tumors: invades ampulla, obstructs bile flow, 50% have distention of biliary tree and progressive jaundice, 50% have pain, 85% have extension beyond pancreas at diagnosis
● Body/tail tumors: large at diagnosis since don’t cause symptoms until late, 25% have peripheral venous thrombi, metastases common at diagnosis
● Coexisting pancreatitis in 10%; may delay diagnosis while pancreatitis is treated

Clinical features
=========================================================================

● Pain, weight loss, anorexia, malaise, weakness
● Trousseau sign: migratory thrombophlebitis, in 10% due to tumor or tumor necrosis producing platelet-aggregating factors and procoagulants; causes arterial and venous thrombi, including pulmonary thromboemboli
● Serum tests: SPan-1, CA19-9

Metastases:
● Local lymph nodes (microscopic metastases found in 75% with T1 / T2 disease)
● Liver, lung, peritoneum, adrenal, bone, distal nodes
● Supraclavicular node metastases may be presenting symptom
● Tumor may track along biopsy needle path (also seminoma, pleomorphic adenoma)
● Metastases to ovary may simulate primary mucinous ovarian tumors (Am J Surg Pathol 1989;13:748)

Prognostic factors
=========================================================================

● 5 year survival 2-4%, 90% die within 1 year
● 5 year survival of 20% if localized non-metastatic (median survival 15-20 months), 6-10 months if locally advanced non-metastatic, 3-6 months if metastatic disease
● Dependent on stage, size (<4.5 cm for resectable tumors)
● Kras mutations detected by PCR in paraaortic lymph nodes is poor prognostic indicator (Am J Surg Pathol 2002;26:1578)
● MUC16 (CA125), forkhead box M1 (FoxM1) expression associated with progression and metastasis (PLoS One 2011;6:e26839)
● Low level of T-box transcription factor 4 (TBX4) associated with worse prognosis (Int J Mol Sci 2011;12:4953)

Treatment (curative)
=========================================================================

● Distal pancreatectomy for body/tail tumors, Whipple resection (subtotal pancreaticoduodenectomy) for head/periampullary tumors
● Resect retroperitoneal nerves and nodes if Stage I/II to reduce local recurrence
● Whipple perioperative mortality ~ 2%
● Most (85%) tumors are not amenable to curable surgery
● Palliative treatment includes bypass operations, radiation therapy and chemotherapy
Treatment information by stage from US National Cancer Institute

Gross description
=========================================================================

● Poorly delineated (hard to measure size), gritty, gray-white, hard masses, infiltrates locally, 25% of head tumors extend to duodenal wall
● If advanced, may be difficult to determine site of origin between pancreas, ampulla or common bile duct
● 20% have multiple tumors

Gross images
=========================================================================



1.5 cm infiltrating adenocarcinoma within head of pancreas


Whipple resection: small ductal adenocarcinoma (left) versus chronic pancreatitis (right) in head of pancreas; cannot distinguish based on gross examination


Whipple resection: ductal adenocarcinoma with invasion of ampulla and duodenal wall, obstructing common bile duct and pancreatic duct; note the ill-defined tumor demarcation


Various images


Autopsy specimen shows tumor mainly located in uncinate process, causing jaundice


Autopsy specimen shows carcinoma (arrows) in distal preampullary common bile duct; there is no tumor infiltration of adjacent pancreatic tissue

Micro description
=========================================================================

● Individual tubular glands surrounded by stroma
● Typically good architectural differentiation with marked atypia and extensive desmoplasia
● Mucin production is specific for ductal origin
● Normal pancreas may show atrophic changes, chronic inflammatory infiltrate, fibrosis, ductal dilation beyond tumor mass

Well differentiated:
● Pink apical band composed of mucin granules
● Basal cytoplasm has mucinous vacuoles
● May appear benign but has irregular shape and distribution, desmoplasia, marked nuclear pleomorphism with nucleoli, loss of polarity, mitotic figures <5/10HPF

Moderate/poorly differentiated:
● Most tumors
● Abortive tubular structures, deeply infiltrative growth pattern, >10/10HPF mitosis, irregular and abortive mucin production

Perineurial invasion:
● Present in 90%, but also associated with benign epithelial inclusions and chronic pancreatitis
● Tumor invades along nerve tract, typically with better differentiated glands
● Causes back pain, predicts poor prognosis

● Angiolymphatic invasion in 50%; vacular invasion mimicks PanIN (Am J Surg Pathol 2012;36:235)
● High grade PanIN in 20%, distant from main tumor mass or at margin; low grade PanIN in 30%
● Squamous metaplasia, pyloric gland metaplasia, focal epithelial hypertrophy are nonspecific - seen in tumors and controls
● Insular pancreas: preservation of islets while acini are destroyed due to duct obstruction

Micro images
=========================================================================


Well differentiated

Large duct-like neoplastic structures and smaller neoplastic glands are embedded in dense fibrous stroma


Atypical duct-like structures (arrows) and a carcinoma in situ lesion (asterisk) are embedded in sclerotic tissue containing remnants of acini and normal ducts; inset shows neoplastic epithelium adjacent to epithelium of a non-neoplastic duct


Tumor shows cribriform structure


Part of large duct-like structure containing papillary projections without a distinct fibrovascular stalk


Glands lined by cells with clear cytoplasm and an occasionally condensed hyperchromatic nucleus


Comparison of normal duct (left) with neoplastic gland (right); note the big, round/oval nuclei which vary in size and have a sharp nuclear membrane; some have a distinct nucleolus which is absent in the non-neoplastic duct cell nuclei


Tumor invasion into adjoining pancreatic tissue via interlobular septa, where the infiltrating duct-like tumor glands (arrows) elicit a marked desmoplastic stromal response


Carcinoma in situ component - intraductal tumor spread by severely atypical epithelium


Neoplastic glands are CEA+ (arrows), but normal ducts are CEA- (arrowheads)


Apical immunostaining for CEA (arrows)


Moderately differentiated

Medium sized duct-like and tubular structures of various shapes and arrangements


Atypical duct-like structures and small tubular complexes with a cribriform pattern


Apical cytoplasmic immunostaining for CEA


Poorly differentiated

Focus of duct-like tumor structure adjacent to poorly differentiated tumor glands


Irregularly shaped glands formed by severely atypical cells


Many tumor cells contain big bizarre nuclei with large conspicuous nucleoli


Marked variation in differentiation; duct-like glands (bottom) are seen adjacent to undifferentiated clusters of severely atypical cells


Only single tumor cells show intracytoplasmic PAS+


Keratin+ (left) and vimentin+ (right) in a number of tumor cells (arrowheads)


Comparison with chronic pancreatitis

Left: chronic pancreatitis with remnants of acini, islets, and ducts, distributed in a lobular pattern
Right: ductal adenocarcinoma characterized by unevenly distributed tumoral glands



Various images


Other features

Perineural invasion (arrow) and invasion of fatty tissue.


Intraductal tumor spread of well differentiated ductal adenocarcinoma (arrowheads): left - H&E, right: CEA+


Various immunostains

Cytology description
=========================================================================

● Duodenal secretions are 80% sensitive in head tumors, 33% sensitive in tail tumors; ERCP juice is 50-85% sensitive;, FNA is 90% sensitive
● Sensitivity and specificity of endoscopic ultrasound (EUS)-guided FNA greater than 90% and 100%, increased sensitivity with Thin Prep, brushings are 50% sensitive (repeat if inconsistent with clinical or radiologic findings, Arch Pathol Lab Med 2000;124:387)
● Aspirates are cellular, without acinar cells, with atypical ductal cells in sheets, clusters or singly; enlarged nuclei, mitotic figures
● May be adjacent to benign ductal cells

Cytology images
=========================================================================



Moderately differentiated ductal adenocarcinoma: cells are in cohesive groups and have large, pleomorphic nuclei and moderate cytoplasm

Positive stains
=========================================================================

● Maspin, S100P, and IMP-3 (all positive) and pVHL (negative) recommend to confirm diagnosis (Arch Pathol Lab Med 2012;136:601, Hum Pathol 2012 Oct 15 [Epub ahead of print])
● Mucin (gastric, small intestinal types), MUC1, MUC4, MUC5, keratin, EMA, CEA, B72.3 (cannot use to differentiate tumor from chronic pancreatitis), CA19-9, Dupan-2, CK7, CK8, CK18, CK19, CA125 (48%)
● Less common markers - human pancreatic cancer fusion #2 (HPC2), insulin-like growth factor II messenger ribonucleic acid-binding protein 3 (IMP3), plectin1 (Clin Cancer Res 2011;17:302)
● Claudin18 is early stage biomarker, positive in PanIN and carcinoma

Negative stains
=========================================================================

● CK20, estrogen receptor, MUC2, N-cadherin
● Loss of DPC4 seen in 50%; is specific for malignancy (in-situ or invasive) but only 50% sensitive (Am J Clin Pathol 2001;116:831)
● Cell polarity protein lethal giant larvae 2 diffrentiates PanIN1 and 2 (Basolateral positivity) from PanIN3 and carcinoma (lost or abnormal expression) (Hum Pathol 2010;41:902)
● HPC2 and N-cadherin together may differentiate pancreatic cancer from cholangiocarcinoma (Hum Pathol 2012;43:1583)

Electron microscopy description
=========================================================================

● Mucigen granules on EM

Electron microscopy images
=========================================================================



Well differentiated ductal adenocarcinoma: luminal surface (top) shows many microvilli; apical portion has many large mucin granules with granular contents and sometimes a dense eccentric core; cells reside on well-developed basal membrane

Molecular description
=========================================================================

● Kras mutations occur early during carcinogenesis, are present in 90% of tumors, associated with poor prognosis (Cancer 2007;109:1561)
● Kras mutation analysis of FNAs facilitates risk stratification of patients with a pancreatic mass (J Clin Gastroenterol 2007;41:906)
● 90% have point mutations at codon 12 of Kras, a signal transducer for tyrosine kinase
● 30-40% have c-myc structural alterations by immunostaining or FISH (Mod Pathol 2002;15:462)
● Other associated mutations: DPC4/SMAD4 gene (deleted in 50% of pancreatic carcinoma), p16 (#9p) in >95%, p21, Rb
● 60% have p53 mutations (present in 2/3 of PanIN lesions), 50% overexpress HER2

Differential diagnosis
=========================================================================

Chronic pancreatitis: normal architecture at low power with central ectatic branched ductules and clusters of round ductules surrounded by cuff of stroma vs. haphazard architecture of UDA with occasional glands immediately adjacent to adipocyte; UDA has cell-to-cell variability of 3-4 x difference in nuclear size, loss of cell polarity, perineurial invasion, individual cell infiltration, budding into lumen; has p53 mutations and loss of SMAD4/DPC4; IMP3 is usefu in core needle biopsies to differentiate pancreatic carcinoma from chronic sclerosing pancreatitis (Am J Surg Pathol 2011;35:873)
Bile duct adenoma (liver lesions): may contain bile but have normal architecture and uniform cytology



Exocrine tumors

Adenosquamous carcinoma


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 25 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Tumor with admiixture of malignant squamoid and glandular components (WHO), usually 30% of each
● Rare, M/F = 2:1, mean age 65 years
● Mean survival 6-12 months, poorer than usual type ductal adenocarcinoma (Mod Pathol 2001;14:443, J Surg Res 2012;174:12), but see J Gastrointest Surg 2011;15:165
● Adjuvant chemoradiation therapy improves survival, which is not affected by amount of squamous component (Hum Pathol 2010;41:113)
● Pancreatic squamous cell carcinoma may actually be adenosquamous carcinoma with exuberant squamous component
● Metastases may contain only glandular component

Gross images
=========================================================================




Micro images
=========================================================================



Various images


Squamous components


Mucoepidermoid pattern of mixing of glandular and squamoid components


Left: clear cell component; middle: rhabdoid component; right: keratin stains intermediate filaments of rhabdoid cells




45 year old man with acantholytic pattern, osteoclast-like and pleomorphic giant cells


Immunostains


Left: CAM5.2 stains glandular component; right: CK13 stains squamoid component

Cytology description
=========================================================================

● Squamous and glandular differentiation, although one component often predominates (Cancer 2003;99:372)
● Extensive necrosis with dense blue globules, squamous ghosts, anucleate squames, atypical single cells, enlarged pyknotic nuclei
● Purely squamous tumor may be metastasis or represent undersampling

Cytology images
=========================================================================


Various images

Positive stains
=========================================================================

● CK903, CD44 (Arch Pathol Lab Med 2000;124:212), CK5/6 and p63 highlight squamoid portion of tumor
● Otherwise similar immunostaining and Kras mutations as usual ductal adenocarcinoma (Mod Pathol 2009;22:651, Mod Pathol 2005;18:1193)

Differential diagnosis
=========================================================================

● Adenoacanthoma: benign squamous component
● Squamous cell carcinoma: no glandular component or mucin staining, even after extensive search



Tumors

Clear cell carcinoma


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 5 November 2014, last major update August 2012
Copyright: (c) 2001-2014, PathologyOutlines.com, Inc.

General
=========================================================================

● Variant of usual type ductal carcinoma (UDC) not well recognized in pancreas, with aggressive behavior
● Not a distinct WHO diagnosis (included under Miscellaneous)
● Clear cells are common in pancreatic adenocarcinoma (24%), due also to UDC with <75% clear cells or containing glycogen or mucin, sugar tumors, endocrine tumors, PEComa

Case reportsl
=========================================================================

● 66 year old woman (Cancer Res Treat 2009;41:175)

Micro description
=========================================================================

● Usual type ductal carcinoma with at least 75% clear cells in one study (Mod Pathol 2008;21:1075)
● Glandular, ductal or nested structures with single layer of polygonal cells, distinct cell borders and variable nuclear atypia
● Not due to accumulation of glycogen or mucin

Micro images
=========================================================================


   
Various images


66 year old woman


Well differentiated adenocarcinoma with glands lined by cells with clear cytoplasm and an occasionally condensed hyperchromatic nucleus (note: cause of cell clearing is not specified)


HNF1β staining of usual type ductal adenocarcinoma

Positive stains
=========================================================================

● Hepatocyte nuclear factor-1beta

Negative stains
=========================================================================

● PAS / PASD (glycogen), mucicarmine, HMB45, chromogranin, synaptophysin

Differential diagnosis
=========================================================================

Clear cell endocrine tumor: clear cells in nests, cords and tubules with central hemorrhage and associated thin walled vessels; stains with neuroendocrine markers
Clear cell "sugar" tumor: large epithelioid cells, clear or eosinophilic granular cytoplasm containing glycogen with nuclear pleomorphism but no mitotic activity
Ductal adenocarcinoma, usual type, with clear cells due to glycogen or mucin: positive for mucin stains or glycogen (PAS, removed by diastase), see also University of Pittsburgh Case #384
Foamy gland carcinoma: well formed glands with bland cells but subtle infiltration; cells have microvesicular (white and crisply foamy) cytoplasm with distinct pink brush border like zone at the luminal portion of the cell; nuclei are basal oriented, dense or wrinkled (raisinoid); tumor cells stain with mucicarmine and other mucin stains
PEComa: large zones of necrosis and nests of malignant cells with marked cellular pleomorphism and mitotic activity; cells are epithelioid and spindled, have clear to eosinophilic cytoplasm, large vesicular nuclei, prominent eosinophilic nucleoli; HMB45+, MelanA+
● Renal cell carcinoma, metastatic:



Tumors

Colloid (mucinous noncystic) carcinoma


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 30 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Also called pure mucinous or gelatinous carcinoma
● Infiltrating ductal epithelial neoplasm characterized by large extracellular stromal mucin pools containing suspended neoplastic cells in at least 80% of neoplasm; almost always arise in association with intestinal-type IPMN; large mucin pools partially lined by well-differentiated cuboidal to columnar neoplastic cells with clumps or strands of neoplastic cells, possibly floating signet-ring cells (WHO)
● Muconodular invasive component of 1 cm or more
● Mucin tends to be retained during histologic processing

Pathophysiology
=========================================================================

● Inverse polarization of cells (mucin glycoproteins in stroma-facing surfaces vs. luminal surface or diffuse in usual ductal adenocarcinoma), lack of external lamina or basement membrane, and expression of MUC2 (gel forming mucin) (rare in UDA) may cause accumulation of extracellular mucin, which contains tumor spread and appears to have tumor suppressor activity (Am J Surg Pathol 2003;27:571, Mod Pathol 2002;15:1087)

Prognostic factors and survival
=========================================================================

● 5 year survival 57% (vs. 5% for usual ductal carcinoma)
● Long survival even with nodal metastases, perineurial invasion, vascular invasion, but see Am J Surg Pathol 2002;26:56 (similar survival to usual ductal carcinoma using 50% as the minimal required colloid component)
● All patient deaths in one study were associated with surgical incision into the tumor or core biopsy - incisional biopsy may contribute to thromboembolism or tumor dissemination (Am J Surg Pathol 2001;25:26)

Clinical features
=========================================================================

● Mean age 61; M=F, usually in head of pancreas
● Associated with IPMN (almost always arise in association with an intestinal-type IPMN), ampullary/duodenal tubulovillous adenomas, mucinous cystic neoplasm
● Compared to UDA, are larger (5.5 cm), lower stage, better survival

Case reports
=========================================================================

● 52 year old woman with history of necrotizing pancreatitis (Arch Pathol Lab Med 2005;129:255)
● 64 year old man with 15 cm tumor (JOP 2012;13:219)

Gross description
=========================================================================

● Soft, mean 5 cm

Gross images
=========================================================================



Large, well-demarcated, associated with intestinal-type IPMN


Whipple resection specimen shows a well-demarcated tumor in the head of the pancreas with a nodular pattern and a gelatinous cut surface. The probe indicates the pancreatic duct which runs into the minor papilla

Micro description
=========================================================================

● Most of tumor consists of mucin lakes containing rare tumor cells
● Tumor cells are highly atypical and in cribriform/stellate clusters, signet-ring cells (not in stroma), small tubules
● Tumor cells may also line the mucin lakes
● Perineurial invasion and regional nodal metastases common
● Usually arise in association with IPMN or tubular/tubulovillous adenoma

Micro images
=========================================================================



Large mucin pools are partially lined by well-differentiated cuboidal to columnar neoplastic cells and contain clumps or strands of neoplastic cells


MUC2+

Cytology description
=========================================================================

● Difficult to spread thinly on slides due to abundant mucus
● Malignant cells may be rare

Cytology images
=========================================================================



Figure 1: abundant mucinous material, degenerated inflammatory cells, rare 3D fragments of benign-appearing epithelium
Figure 2: cytologic atypia with enlarged, crowded, hyperchromatic nuclei
Figure 3: numerous single cells with large solitary intracytoplasmic vacuoles consistent with mucin


Positive stains
=========================================================================

● MUC2+ (marker of indolent mucin, UDA usually MUC2-), CEA, CDX2

Negative stains
=========================================================================

● MUC1

Molecular description
=========================================================================

● Kras mutations (33%), p53 (22%)
● Microsatellite stable unlike mucinous carcinomas of colon (Mod Pathol 2003;16:537)

Electron microscopy description
=========================================================================

● Mucigen granules on stromal surface, no basement membrane

Differential diagnosis
=========================================================================

Ductal adenocarcinoma of usual type: some mucin but no mucin lakes
IPMN: smooth contours, clusters of epithelium, mucin lost in processing
Mucinous cystic neoplasms: cystic spaces lined by mucinous epithelium, ovarian type stroma, usually women, no association with IPMN



Tumors

Foamy gland pattern of pancreatic adenocarcinoma


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 27 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Deceptively benign-appearing pattern with prominent microvesicular (foamy) cytoplasm, first described in 2000 in pancreas (Am J Surg Pathol 2000;24:493)
● Also described in prostate
● Considered a ductal pattern, not a WHO variant

Clinical features
=========================================================================

● Tumors are malignant architecturally and metastasize
● Clinical course, p53 and Kras mutations similar to usual ductal adenocarcinoma
● Foamy PanIN is considered as precursor (Ann Diagn Pathol 2008;12:252)

Micro description
=========================================================================

● Well formed glands with bland cells but subtle infiltration
● Cells have abundant microvesicular (white and crisply foamy) cytoplasm with distinct pink brush border-like zone at apical/luminal portion of the cell
● Nuclei are basal oriented, dense or wrinkled (raisinoid)
● May be misinterpreted as benign mucinous ducts; apical cytoplasmic folds in benign mucinous ducts should be differentiated from brush border-like zone
● Foamy material is due to evenly sized mucigen granules that are mucin negative

Micro images
=========================================================================



Invasive glands lined by foamy cells


PanIN3 lesion (left) is Alcian blue+, as is invasive foamy gland adenocarcinoma (right)


PanIN3 lesion (left) is MUC1+, as is invasive foamy gland adenocarcinoma (right)

Cytology description
=========================================================================

● Nuclear overlap, foamy cytoplasm, loss of cohesiveness, anisonucleosis, irregular nuclear contours (Am J Clin Pathol 2004;121:893, Diagn Cytopathol 2012 Sep 25 [Epub ahead of print])

Cytology images
=========================================================================



Cells with abundant foamy cytoplasm

Positive stains
=========================================================================

● Mucicarmine, Alcian blue and high iron diamine
● CEA, CK8, p53

Negative stains
=========================================================================

Brush border-like zone: PAS, MUC2



Tumors

Intraductal oncocytic papillary neoplasm


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 2 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● First recognized in 1996 (Am J Surg Pathol 1996;20:980); also occurs in bile duct
● WHO classifies as oncocytic type of IPMN, with complex and arborizing papillae with delicate stroma; papillae are lined by 2-5 layers of cuboidal to columnar cells with abundant eosinophilic granular cytoplasm; nuclei are round, large, and fairly uniform and typically contain single, prominent, eccentrically located nucleoli (WHO)
● Mean age 62 years, no gender preference
● Low malignant potential
● Surgery may be curative
● Invasive in 20%, usually limited in extent with nested oncocytic pattern

IPMN v IOPN
=========================================================================

● IPMN more often invasive (50% v 20%)
● IPMN invades with a ductal or colloid pattern, not the oncocytic pattern of IOPN
● IPMN usually have intestinal papillae, not the pancreaticobiliary type of IOPN
● IOPN have intraepithelial lumina and are oncocytic
● IOPN does not have Kras mutation

Case reports
=========================================================================

● 76 year old man with painless jaundice (JOP 2010;11:49)
● 76 year old woman with 7.5 cm cystic mass (JOP 2007;8:206)

Gross description
=========================================================================

● Usually in head, mean 6 cm
● Mucin filled cysts with nodular papillary projections
● Often with dilated ducts communicating with main tumor

Gross images
=========================================================================



Partial gastrectomy, duodenum, pancreas, spleen, and partial omentum; pancreas shows solid area in head and multilocular lesion in tail with thick mucin and soft grey-brown luminal papillary masses (arrow); papillary mass also present in ductus choledochus (arrowhead), close to the surgical resection margin (*)


Cystic mass in body of pancreas contains coagulated blood with fibrin, mucus and nodular papillary projection

Micro description
=========================================================================

● Unilocular or multilocular papillary ducts composed of arborizing papillary structures with focal cribriform pattern, papillae lined by stratified and pseudostratified oncocytic cuboidal cells with intraepithelial lumina (highly specific, may contain mucin), abundant finely granular pink cytoplasm (due to mitochondria), prominent eccentric nuclei, microcystic spaces of 1-3 cell size (Stanford University)
● Architecturally complex with atypical cytology, mitotic figures, hyaline globules (negative for mucin) produce bud like appearance (Pathol Int 2010;60:48)
● Intraductal papillae may fuse and form large solid areas replacing the papillary architecture
● Invasive component, if present, may resemble intraductal component

Micro images
=========================================================================





Various images


Arborizing papillae and invasive areas characterized by small nests of cells with extracellular mucin accumulation; invasion front composed of cells with abundant eosinophilic cytoplasm surrounded by abundant mucin; perineural invasion exists as a peritumoral desmoplastic stromal reaction


Figure a-cyst wall lined by columnar pancreas duct epithelium with papillary projections
Figure b/c-tumor has variably complex, arborizing structures lined by plump cells with abundant eosinophilic cytoplasm
Figure d-cytoplasm is positive for anti-mitochondrial antibody



Oncocytic carcinoma: large cells with abundant, finely granular, eosinophilic cytoplasm, irregular nuclei, prominent nucleoli


MUC6+ (figure C)

Positive stains
=========================================================================

● MUC6 (Am J Surg Pathol 2010;34:364)
● Mucin in intraepithelial lumina, PTAH, 111-3 for mitochondria
● B72.3 (uniformly), CEA (focal)
● Focal apical MUC1+, dispersed MUC2+ (Am J Surg Pathol 2001;25:942)

Negative stains
=========================================================================

● p53, acinar cell markers (lipase, trypsin, chymotrypsin), neuroendocrine markers

Molecular description
=========================================================================

● No Kras, p53 or SMAD4 mutations (Am J Surg Pathol 2002;26:1071)

Electron microscopy description
=========================================================================

● Cells frequently packed with mitochondria

Electron microscopy images
=========================================================================



Oncocytic carcinoma in pancreatic tail: cells are packed with mitochondria and few glands



Exocrine tumors

Intraductal papillary mucinous neoplasm (IPMN)


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 9 December 2012, last major update December 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Proposed definition: intraductal grossly visible (1 cm or more) epithelial neoplasm of mucin producing cells, arising in main pancreatic duct or its branches; neoplastic epithelium is usually papillary; variable mucin secretion, duct dilatation (cyst formation), and dysplasia; classify based on highest degree of cytoarchitectural atypia and invasiveness as:
  • IPMN with low- to intermediate-grade dysplasia; previously called intraductal papillary mucinous adenoma
  • IPMN with high grade dysplasia; previously called intraductal papillary mucinous carcinoma, non invasive
  • IPMN with associated invasive carcinoma (WHO)
● One of three precursor lesions of pancreatic adenocarcinoma (also PanIN, Mucinous Cystic Neoplasm)

Clinical features
=========================================================================

● More common in men age 60+ at head of pancreas
● Signs and symptoms include epigastric pain, weight loss, jaundice, diabetes, pancreatitis (Arch Pathol Lab Med 1996;120:981)
● Associated with Peutz-Jegher syndrome
● IPMN component may be favorable prognostic factor in invasive disease (Hum Pathol 2001;32:834)
● Resection often requires frozen sections, since most lesions are contiguous
● Patients with branch duct involvement only: associated with mild dilation of main duct; much lower risk of invasive carcinoma; management uncertain but less aggressive (Dig Liver Dis 2012;44:257, Am J Surg Pathol 2000;24:1372)

Diagnosis
=========================================================================

● Clinical subtypes include main duct, which is symptomatic; branch duct, which is typically asymptomatic, and mixed
● Assess dysplasia (none, low/intermediate grade dysplasia, high grade dysplasia)
● Assess presence or absence of invasive carcinoma (most important prognostic factor, Hum Pathol 2012;43:1)
● Type of invasion is associated with MUC1/MUC2 pattern, see below (Mod Pathol 2002;15:1087)
● Minimal invasion does not affect survival (Am J Surg Pathol 2008;32:243)

Patterns of papillae
=========================================================================




Proposed neoplastic pathways


Gastric foveolar-type papillae:
● Low-grade lesion, occurs in small branch ducts
● Resembles gastric foveola, MUC5AC+, MUC6+, MUC2- (Am J Surg Pathol 2006;30:1561)

Intestinal-type papillae:
● More common, occurs in main duct, usually intermediate to high grade dysplasia
● Resembles colonic villous adenoma, may exhibit pale apical mucin reminiscent of gastric foveolar cells, MUC1-, MUC2+, CDX2+
● Also claudin4+ (Mod Pathol 2011;24:533)
● When invasive, associated with colloid carcinoma (also MUC1-, MUC2+)

Pancreaticobiliary type papillae:
● Complex arborizing papillae with 2-5 cell layers and cuboidal cells with prominent nucleoli, less mucinous, more cytologic atypia
● MUC1+, MUC2-/focal, MUC6+ (Am J Surg Pathol 2010;34:364)
● When invasive, associated with usual ductal adenocarcinoma (also MUC1+, MUC2-)
● Associated with invasive carcinoma more often than intestinal-type

Oncocytic type papillae (Intraductal oncocytic papillary neoplasm, IOPN):
● See IOPN topic
● MUC1+, MUC2+, MUC6+

Intraductal tubulopapillary neoplasm
● Recently recognized subtype (Am J Surg Pathol 2009;33:1164)
● See ITPN topic
● Potential origin from peribiliary cysts; tubulopapillary architecture, necrotic foci, more solid growth without visible mucin, scanty cytoplasmic mucin, no KRAS2 gene mutations
● MUC1+, MUC2-, MUC6+

Notes:
● Benign and non-neoplastic pancreas is MUC1-
● PanIN and invasive ductal NOS are usually MUC2-

Case reports
=========================================================================

● 40 year old woman with combined MCN and IPMN (Arch Pathol Lab Med 2011;135:264)

Treatment
=========================================================================

● Resect entire tumor if >3cm, symptomatic with positive cytology, dilated main duct and mural nodules
● Sample extensively (> 50 blocks) to rule out invasion or atypia

Gross description
=========================================================================

● Main duct involvement: usually diffusely dilated, tortuous and irregular, filled with mucin; usually arises in head and progresses along path of main duct, may involve entire pancreas; may involve major or minor papillae leading to mucin extrusion from Ampulla; associated with higher risk of high-grade dysplasia and invasive carcinoma than branch duct involvement; uninvoled pancreas is often pale and firm, reflecting extensive chronic obstructive pancreatitis
● Branch duct involvement: often in uncinate process; forms multicystic, grape-like structures; cystically dilated ducts are 1 to 10 cm, filled with tenacious mucin; cyst walls are usually thin with flat or papillary lining; cysts separated by normal pancreas, suggesting that cysts are separate on cut sections (WHO)

Gross images
=========================================================================



This drawing shows historical prototypes of IPMN:
Upper left, diffuse papillary tumor growth within the entire pancreatic duct system
Lower left, focal papillary growth in the main pancreatic duct
Upper right, diffuse involvement of the entire pancreatic duct system by mucin hypersecreting tumor
Lower right, focal involvement of the pancreatic duct system by a mucin hypersecreting tumor



Main duct involvement


Main duct involvement: left-sided pancreatectomy specimen with marked cystic dilatation of main duct in tail due to mucin hypersecretion; macroscopically, the duct wall shows no papillary projections


Main duct involvement: left-sided pancreatectomy specimen shows a markedly dilated main pancreatic duct filled with tumor tissue (arrows); surrounding pancreatic tissue is severely fibrotic


Branch duct involvement (arrows in figure on right are main pancreatic duct)

Micro description
=========================================================================

● Multicentric
● Complex papillary fronds of mucin-producing epithelial cells with variable atypia
● Various types of papillae described above and below
● Ductal fibrosis, acinar atrophy but well preserved islets
● Associated with PanIN (Am J Surg Pathol 2004;28:1184), chronic pancreatitis
● No ovarian-type stroma

Micro images
=========================================================================



Gastric papillae


Gastric papillae
Top-low grade (blue arrows) and intermediate grade dysplasia (black arrows)
Bottom-high grade dysplasia (black arrows) with cribriform formation and marked nuclear atypia



Intestinal papillae


Intestinal papillae (H&E and CDX2+)


Intestinal papillae: intermediate grade dysplasia (top) and high grade dysplasia (bottom)


Pancreaticobiliary papillae


Pancreaticobiliary papillae: intermediate grade dysplasia (top) and high grade dysplasia (bottom)


Comparison of subtypes: gastric, intestinal, pancreaticobiliary, oncocytic


Patient with both gastric and intestinal papillae


Various images


IPMN with loss of mismatch repair in patient with Lynch syndrome


Non-invasive (figure 4)


Invasive (colloid carcinoma, figure 9)


Cross section through main pancreatic duct shows epithelial papillary proliferations


Wall of main pancreatic duct is lined by tall columnar mucin-producing epithelium which forms varying sized papillae; tips of papillae are sectioned tangentially and appear to be free floating in mucin


PAS stain of mucin-producing tumor epithelium shows that neoplastic epithelium extends into secondary duct


Low grade dysplasia: wall of duct is lined by tall columnar epithelium which forms plump papillae; epithelial cells show apical mucin accumulation, minimal pleomorphism, and regular oval nuclei; note the goblet-like appearance of some columnar cells


Intermediate grade dysplasia: wall of duct is lined by columnar epithelium which forms irregularly shaped papillae with small fibrovascular stalks; epithelium shows focal cellular stratification and nuclear crowding


Intermediate grade dysplasia: lining epithelium of papillae is characterized by nuclear enlargement, stratification and crowding


High grade dysplasia: severely atypical epithelium forms irregular projections without any tissue stalk


High grade dysplasia: : the atypical epithelium shows branching and bridging


High grade dysplasia: cells have varying sized nuclei, some show thick nucleoli and mitoses (arrow).


High grade dysplasia and invasion: upper part shows secondary duct lined by severely dysplastic epithelium; surrounding pancreatic tissue is fibrotic and contains only some islets; lower part shows atypical ductal structures (arrows) characterizing the invasive component


Branch duct: lining by neoplastic columnar epithelium; surrounding tissue displays chronic obstructive pancreatitis with remnant of a lobulus containing an islet

Cytology images
=========================================================================



Various images

Positive stains
=========================================================================

● Varies by type of papillae (see above)
● Often S100P, MUC5AC (Hum Pathol 2010;41:824)

Molecular description
=========================================================================

● Associated with Kras mutations (Hum Pathol 2009;40:612)
● Cyst fluid shows mutations in KRAS2 and GNAS
● With increasing grades of dysplasia, see increased mutations in KRas, p53, p16, hypermethylation, reduced BRG1 (Hum Pathol 2012;43:585)
● Loss of Programmed cell death 4 (Pdcd4) and CD24 expression associated with tumor progression and proliferation (Hum Pathol 2010;41:1507, Hum Pathol 2010;41:1466)

Differential diagnosis: Mucinous cystic neoplasm (MCN)
=========================================================================


MCN               IPMN
F >> M                 M > F
Age: 40-50               60-70 years
Tail                   Head
Grossly cystic           Grossly cystic with papillae >1cm
Not in duct               In duct
Ovarian type stroma       No ovarian type stroma

● See also MCN topic

Differential diagnosis: other
=========================================================================

IOPN
PanIN: resembles small IPMN



Exocrine tumors

Intraductal tubulopapillary neoplasm (ITPN)


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 9 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Intraductal, grossly visible, tubule forming epithelial neoplasm with high-grade dysplasia and ductal differentiation without overt production of mucin; focal tubulopapillary growth may be seen (WHO)
● First described in 2009 (Am J Surg Pathol 2009;33:1164)
● ~3% of intraductal neoplasms of pancreas

Case reports
=========================================================================

● With focal invasion and stromal osseous and cartilaginous metaplasia (Pathol Int 2012;62:339)

Gross description
=========================================================================

● Solid and nodular tumor obstructing dilated pancreatic ducts; no visible mucin.

Gross images
=========================================================================



Various images

Micro description
=========================================================================

● Tubulopapillae with scant cytoplasmic mucin and high grade atypia
● Frequent necrotic foci
● Variable invasive disease

Micro images
=========================================================================



Tubulopapillary growth of neoplastic cells with eosinophilic cytoplasm, but no intracytoplasmic mucin


Staining of bile duct tumor

Cytology description
=========================================================================

● Moderately cellular with few fragments of markedly atypical epithelium
● Atypical cells have moderate cytoplasm, no intracytoplasmic mucin, enlarged eccentric nuclei, anisonucleosis and prominent nucleoli, irregular nuclear membranes, high nucleus to cytoplasmic ratio (Diagn Cytopathol 2012 Jul 16 [Epub ahead of print])

Positive stains
=========================================================================

● CK7, CK19, MUC1, MUC6


WHO table comparing staining of various IPMN related entities

Negative stains
=========================================================================

● MUC2, MUC5AC, CDX2 trypsin, chymotrypsin, p53, fascin

Molecular description
=========================================================================

● Mutations in PIK3CA were found in 3 of 11, and most cases expressed phosphorylated AKT (Am J Surg Pathol 2011;35:1812)
● Usually no abnormal expression of p53, SMAD4, beta-catenin
● Usually no KRAS or BRAF mutations

Differential diagnosis
=========================================================================

Acinar cell cystadenoma: trysin+ (Pathol Res Pract 2012;208:691)



Tumors

Large duct pattern


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 6 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Pattern seen in <10% of usual ductal adenocarcinoma; similar or slightly better prognosis (Mod Pathol 2012;25:439)
● Ducts are clustered with irregular jagged contours, may have desmoplastic and myxoid stroma, intraluminal neutrophils and granular debris; usually no cystic change
● Focal microcystic appearance may be due to marked ectasia of infiltrating neoplastic glands, particularly near duodenal muscularis propria
● May have papillary pattern (Am J Surg Pathol 2012;36:696)
● Compared to usual ductal adenocarcinoma: higher % female, higher % in tail

Gross description
=========================================================================

● White, sclerotic mass with numerous microcysts <1 cm, not detectable radiologically

Gross images
=========================================================================



Microcystic pattern

Micro images
=========================================================================



Microcystic well-differentiated neoplastic duct structures




Various images

Differential diagnosis
=========================================================================

IPMN
IOPN
Mucinous cystic neoplasm
PanIN



Tumors

Medullary carcinoma


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 12 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Sheets of carcinoma cells with abundant eosinophilic cytoplasm, large vesicular nuclei with prominent nucleoli, often intraepithelial infiltrate of lymphocytes (WHO)
● Very rare tumor associated with microsatellite instability (50%), colonic adenocarcinoma (Hum Pathol 2006;37:1498), family history of cancer at other sites
● Good prognosis

Gross description
=========================================================================

● Soft (since minimal desmoplastic stroma)

Micro description
=========================================================================

● Syncytial growth of poorly differentiated tumor cells accompanied by chronic inflammatory infiltrate, minimal desmoplastic stroma, pushing (expanding) border and extensive necrosis, associated PanIN (Am J Pathol 2000;156:1641, Stanford University)

Micro images
=========================================================================



Various images


A-extensive necrosis, B-poorly differentiated tumor with syncytial growth pattern


A-nuclear staining for MLH1; B-loss of expression of MSH2; C-loss of expression of MSH6

Molecular description
=========================================================================

● Usually no Kras mutations, but 20% have inactivation of DNA mismatch repair system



Exocrine tumors

Microglandular carcinoma


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 5 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● <20 cases, usually elderly men
● Aggressive behavior (Am J Clin Pathol 1996;105:727)
● May be best considered a growth pattern with an aggressive clinical course, not a distinct entity (Am J Surg Pathol 1996;20:1385)

Case reports
=========================================================================

● 77 year old man with mass of pancreatic head (JOP 2012;13:626)

Micro description
=========================================================================

● Neuroendrocrine features by morphology, but not by immunohistochemistry
● Small uniform cells in sheets mixed with small microglandular / cribriform structures without intervening stroma
● Scant cytoplasm, small nucleoli

Positive stains
=========================================================================

● CAM5.2

Negative stains
=========================================================================

● Chromogranin, synaptophysin, NSE, peptide hormones

Electron microscopy description
=========================================================================

● Abortive glandular lumens lined by imperfectly formed microvilli, well-developed junctional complexes
● No dense core secretory granules or zymogen granules

Molecular description
=========================================================================

● In some cases, lack the genetic abnormalities of usual type ductal adenocarcinoma (Eur J Gastroenterol Hepatol 2009;21:1373)

Differential diagnosis
=========================================================================

Pancreatic endocrine tumors (primary, metastatic): evidence of neuroendocrine differentiation by immunohistochemistry
Ductal adenocarcinoma of usual type: irregular glands, desmoplasia, mutations of Kras, p53, beta-catenin



Exocrine tumors

Mucinous cystic neoplasm (MCN)


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 9 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Benign or potentially low grade malignant cystic epithelial neoplasm composed of cells which contain intracytoplasmic mucin (WHO)
● One of three precursor lesions of pancreatic adenocarcinoma (also PanIN, IPMN)
● WHO Classification: with low- or intermediate-grade dysplasia, with high-grade dysplasia or with an associated invasive carcinoma

Clinical features
=========================================================================

● Almost always women, mean age 45 years
● Abdominal pain or mass
● <20% associated with invasive carcinoma
● Metastases usually restricted to abdominal cavity; metastases to ovary may simulate primary ovarian tumors
● Can also occur in the liver
● Rarely associated with anaplastic carcinoma (World J Gastroenterol 2008;14:132, Arch Pathol Lab Med 1997;121:1104), or sarcomatous stroma with aggressive behavior

Case reports
=========================================================================

● 65 year old man (JOP 2012;13:687)

Gross description
=========================================================================

● Large (mean 10 cm)
● Usually in body/tail, multilocular (occasionally unilocular) megacysts that don’t communicate with ductal system unless fistula are present
● Cyst wall is papillary, trabecular or thickened
● Has mucoid/watery cyst contents
● Must sample solid areas within the cyst

Gross images
=========================================================================



Unilocular cyst filled with gelatinous material; cyst on left is hemorrhagic


Invasive tumor from tail of the pancreas with adjacent spleen has conspicuous, irregular, solid protuberances projecting into cystic cavities


Invasive tumor from tail of pancreas in 36 year old woman shows large cyst with solid tumor


Multiloculated cystic lesion from tail of the pancreas is 7 cm, well demarcated, contains mucinous material; capsule shows nodular thickening; uninvolved pancreatic tissue at right (Courtesy of Dr. Klaus Riesner for AFIP fascicle)


39 year old man with multilocular cyst with thick mucin

Micro description
=========================================================================

● Lined by tall mucin-producing cells, often forming papillae
● Intestinal or gastric foveolar-type features
● Calcification common
● Ovarian type stroma is relatively specific; recapitulates fetal pancreatic mesenchyme around ducts (ER+, PR+, inhibin+)
● May have mural nodules with features of giant cell tumor, MFH or anaplastic carcinoma
● Endocrine cells often scattered among columnar lining cells
Note: must sample extensively to rule out an invasive component (Am J Surg Pathol 1999;23:1320)

Micro images
=========================================================================



Various images


Tail tumor has varying sized cysts lined by tall columnar epithelium with a few small papillae but no atypia


Cyst wall containing lobular glands with benign histology


Cyst wall with focal hyalinization and calcification in cellular stroma


Cyst wall shows mucin spillage causing chronic inflammation with a foreign body reaction


Squamous metaplasia

Dysplasia

Low grade dysplasia: intratumoral septum lined by mildly dysplastic columnar epithelium on one side and atrophic epithelium on the other; also has partly cellular, partly hyalinized ovarian-like stroma


Low grade dysplasia: lining epithelium consists of single row of tall mucin-producing columnar cells with polarized nuclei of uniform size; right side has ovarian type stroma


Intermediate grade dysplasia: cyst lining epithelium forms papillary projections with small tissue stalks composed of tall columnar epithelium with considerable mucin in apical cytoplasm and moderate nuclear atypia; some columnar cells resemble goblet cells


Intermediate grade dysplasia: lining epithelium shows focal pseudostratification with crowding of enlarged nuclei and mitotic activity


Intermediate grade dysplasia: cyst wall with ovarian-like stroma; subepithelial densely cellular layer is followed by a dense layer of collagenous connective tissue; part of epithelium is dysplastic; cellular stroma has several small daughter glands


High grade dysplasia: cyst wall and adjacent large gland are lined by severely atypical columnar cells; surrounding smaller glands lack atypia


High grade dysplasia: small and irregularly shaped papillae

Invasive disease

Invasion: lining epithelium is desquamated (top), and deeper in wall are atypical glands invading adjacent pancreatic tissue


Invasion: atypical glands from invasive component have cribriform architecture and moderate nuclear atypia


Invasion: solid tumor is a fibrosarcoma arising in wall of mucinous cystadenocarcinoma (AFIP Fascicle, Courtesy of Dr. Reinhard Kruger)


Sarcomatous stroma

Immunostains

Scattered endocrine cells are serotonin+


Squamous metaplasia

Positive stains
=========================================================================

● MUC5AC, DPC4 present in in-situ areas (usually lost in invasive disease, Am J Surg Pathol 2000;24:1544)
● Ovarian type stroma is ER+, PR+, inhibin+, CD10+
● p53, EGFR, cathepsin E (CTSE ), MET (encoding hepatocyte growth factor binding receptor), MYC, PSCA, S100P in epithelium, steroidogenic acute regulatory protein (STAR), LCK

Negative stains
=========================================================================

● MUC1 (except in invasive components, Am J Surg Pathol 2002;26:466), MUC2 (except for faint staining of goblet cells)

Molecular description
=========================================================================

● Molecular analysis suggests monoclonal origin with subsequent divergence for cases with sarcomatous stroma (Mod Pathol 2000;13:86, Am J Surg Pathol 1997;21:70)
● Kras mutations noted in in-situ or invasive areas, inactivating SMAD4 and TP53 mutations in more advanced MCNs
● Cyst fluid analysis: higher expression of microRNAs in mucinous precursors, low amylase levels

Differential diagnosis
=========================================================================

IPMN: usually head, communicates with duct system
Ovarian mucinous tumors: similar clinical and histologic appearance
Pancreatic pseudocyst: mimics MCN when MCN has denuded cyst lining; MCN cystic fluid has high CEA content and viscosity, high expression of microRNAs, lower amylase and elastase I than pseudocyst, although values may vary within different loculi of same neoplasm (Am J Clin Pathol 1993;100:425)
Pancreatic ductal adenocarcinoma, cystic



Tumors

Mucinous pancreatic tumors


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 12 December 2014, last major update August 2012
Copyright: (c) 2001-2014, PathologyOutlines.com, Inc.

General
=========================================================================

● Site of mucin helps classifies pancreatic tumors (Clin Gastroenterol Hepatol 2010;8:213)
Usual type ductal adenocarcinoma (UDA) has intracellular mucin with scattered mucicarmine positive cells
● Tumors with stromal mucin are either UDA with marked mucin formation OR colloid type adenocarcinoma with large well-defined pools of mucin and few cells
● Tumors with intraluminal mucin are either mucinous cystic neoplasms, mucinous non-neoplastic cysts or IPMN (Oncologist 2009;14:125)



Exocrine tumors

Pancreatoblastoma


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 5 November 2014, last major update August 2012
Copyright: (c) 2001-2014, PathologyOutlines.com, Inc.

General
=========================================================================

● Most common pancreatic tumor of infancy / early childhood, characterized by acinar differentiation, squamoid corpuscles, stromal bands (WHO)

Clinical features
=========================================================================

● Children: 50% cured after excision; most survive and do well with chemotherapy if no metastases, but those with metastases often die
● Children: higher survival if complete resection; 5 year overall survival is 79% (Eur J Cancer 2011;47:2347)
● Adults: mean survival 18 months

Case reports
=========================================================================

● 27 year old woman with breast, liver and lung metastases (JOP 2012;13:301)

Gross description
=========================================================================

● Partially encapsulated, often lobulated, mean 10 cm

Gross images
=========================================================================



Lobulated surface


Encapsulated tumor with nodular surface


Encapsulated heterogeneous mass with cystic components filled with serous fluid

Micro description
=========================================================================

● Mixtures of acini, squamoid corpuscles and less commonly endocrine or ductal features
● Very cellular, uniform epithelial cells in sheets and nests with acini/ducts
● Squamoid corpuscles (circumscribed whorled nests of plump spindle cells with a squamous appearance and occasional keratinization) are common and specific; note: this indicates a growth pattern, not a line of differentiation
● Pediatric cases often have hypercellular stroma, occasionally with bone/cartilage

Micro images
=========================================================================



Squamoid nests


36 year old woman: cords of primitive small cells differentiating into squamoid nests with central keratinization, with (left) and without (right) calcification


Tumor cells grow in acinar pattern and include groups of cells with pale cytoplasm ("squamoid corpuscles")


Mixed solid-glandular pattern


Solid tumor with scattered squamoid corpuscles


Nests of squamous or epidermoid tissue in a background of small, diffusely infiltrating cells


Various images


Spindle cells with sarcomatoid features


Chondroid tissue surrounded by spindle cells


Spindle cells (center), epithelial cells (right), and osteoid (left)


Metastases to liver: acinar pattern with squamous morule


CAM5.2+ tumor cells in acinar pattern; squamoid corpuscles do not stain


Various immunostains

Cytology description
=========================================================================

● Cellular smears with both epithelioid (acinar or undifferentiated) and immature mesenchymal cells (Arch Pathol Lab Med 2009;133:388)

Positive stains
=========================================================================

Note: presence of optically clear nuclei may cause false positive immunohistochemical staining with ABC (biotin) technique
● Pancreatic enzymes in acinar areas, CEA and mucin in luminal secretions of small acini
● Also keratin, alpha-fetoprotein (18%), aberrant (nuclear/cytoplasmic) expression of beta-catenin in squamous morules

Negative stains
=========================================================================

● Neuroendocrine markers (rare cells may be positive)

Electron microscopy description
=========================================================================

● Acinar cell features

Differential diagnosis
=========================================================================

Acinar cell carcinoma: no squamous corpuscles
Solid pseudopapillary neoplasm: pseudopapillae with hyalinized fibrovascular cores lined by several layers of bland fragile epithelial cells with clear to eosinophilic cytoplasm



Exocrine tumors

PanIN (pancreatic intraepithelial neoplasia)


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 9 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Most common precursor lesions of pancreatic ductal adenocarcinoma (other precursor lesions are IPMN and MCN); are microscopic papillary or flat, noninvasive epithelial neoplasms that are usually < 5 mm and confined to pancreatic ducts; composed of columnar to cuboidal cells with variable mucin, and divided into three grades according to degree of cytological and architectural atypia (WHO)
● First described in 1998 (Am J Surg Pathol 1998;22:163)

Clinical features
=========================================================================

● Associated with common and uncommon pancreatic neoplasms (Hum Pathol 2011;42:18)
● Prevalence increases with age (Am J Surg Pathol 2006;30:36)
● May be present in heterotopic pancreas (Am J Surg Pathol 2007;31:1191)

Classification
=========================================================================

● Applies only to small caliber ducts <5 mm, not the main pancreatic duct (lesions must be too small to be seen grossly or by radiologic imaging)
● Grade based on the highest grade component of a lesion
● Ki-67 immunostaining increases with PanIN grade (Figure 1, Mod Pathol 2002;15:441)


Drawings

Normal:
● Normal ductal and ductular epithelium is a cuboidal to low-columnar epithelium with amphophilic cytoplasm
● Mucinous cytoplasm, nuclear crowding and atypia are not seen

Squamous (transitional) metaplasia:
● Normal cuboidal ductal epithelium is replaced by mature squamous or transitional epithelium without atypia

PanIN-1A:
● Flat epithelial lesions composed of tall columnar cells with basally located nuclei and abundant supranuclear mucin
● Nuclei are small, round to oval
● If oval, the nuclei are perpendicular to the basement membrane
● Also designated PanIN/L-1A to reflect that the neoplastic nature of many cases is not established
● May demonstrate Kras mutations, although they are present in 70% of normal pancreata at autopsy

PanIN-1B:
● Epithelial lesions with a papillary, micropapillary or basally pseudostratified architecture, but otherwise identical to PanIN-1A

PanIN-2:
● Flat or papillary mucinous epithelial lesions with some nuclear abnormalities (some loss of polarity, nuclear crowding, enlarged nuclei, pseudo-stratification and hyperchromasia), but less than PanIN-3
● Rare mitoses are non-luminal (not apical) and not atypical
● Usually no true cribriforming luminal necrosis or marked cytologic abnormalities

PanIN-3:
● Papillary or micropapillary, rarely flat
● True cribriforming, budding off of small clusters of epithelial cells into the lumen and luminal necroses suggests PanIN-3
● Loss of nuclear polarity, dystrophic goblet cells (goblet cells with nuclei oriented towards the lumen and mucinous cytoplasm oriented toward the basement membrane), mitoses which may be abnormal, nuclear irregularities and prominent (macro) nucleoli
● References: Am J Surg Pathol 2001;25:579

Micro images
=========================================================================


● See Johns Hopkins - Classification of Duct Lesions in the Pancreas (click on links for microscopic images)


PanIN-1


PanIN-1, 2 and 3


Frozen section margins: PanIN-1, 2 and 3


PanIN2 and 3


PanIN-3


Duct is lined by severely atypical epithelium which forms an irregular papillary projection showing a cribriform pattern and lacking a fibrovascular core; this lesion was found near an invasive ductal adenocarcinoma


Severe atypia of duct epithelium which abruptly replaces benign appearing duct cells

Positive stains
=========================================================================

● MUC1, MUC5
● Ki-67 immunostaining increases with PanIN grade (Mod Pathol 2002;15:441)
● Also fascin, PSCA (prostate stem cell antigen), MMP7, survivin expression increases from PanIN1 to PanIN3 (Am J Surg Pathol 2006;30:754)

Negative stains
=========================================================================

● MUC2 (Mod Pathol 2002;15:1087)

Molecular description
=========================================================================

● Kras mutations appear to increase with severity of dysplasia (Neoplasia 2005;7:17)

Differential diagnosis
=========================================================================

Cancerization of ducts: infiltrating carcinomas can extend into pancreatic ducts and ductules, mimicking PanIN-3; infiltrating carcinoma close to a duct lesion and an abrupt transition from a highly atypical lesion to normal duct epithelium suggests cancerization of the duct or ductule
IPMN: detected clinically; larger than PanIN, usually visible grossly or by radiologic imaging; grossly visible mucin, well formed papilla; may extend into small ducts
Mucinous cystic neoplasms: large cystic masses with ovarian stroma; no connection to the duct system
● Reactive changes: have significant inflammatory cell infiltrates, particularly neutrophils
● Vascular invasion in pancreatic ductal adenocarcinoma: see Am J Surg Pathol 2012;36:235



Exocrine tumors

Tumors with rhabdoid features


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 30 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Case reports
=========================================================================

● Non-specific feature of neuroendocrine tumors (Am J Surg Pathol 2003;27:642) and carcinomas, indicative of aggressive behavior
● Not a WHO diagnosis

Case reports
=========================================================================

● 42 year old man with squamous cell carcinoma and osteoclast-like giant cells (J Clin Pathol 2006;59:1309)
● 52 year old woman with anaplastic carcinoma, apparently arising from mucinous cystadenocarcinoma (Arch Pathol Lab Med 1997;121:1104
● 59 year old man with anaplastic carcinoma (Med Mol Morphol 2007;40:168)
● 68 year old woman with anaplastic carcinoma (Pathol Int 2000;50:57)
● 75 year old man with adenosquamous carcinoma (JOP 2007;8:330)

Micro description
=========================================================================

● Sheets of monotonous tumor cells with abundant densely eosinophilic cytoplasmic inclusions that displace the nuclei toward the periphery, uniform round nuclei, dispersed chromatin
● Rhabdoid elements merge with conventional areas
● Suggested that some cases be termed "with cytokeratin aggresomes" (J Clin Pathol 2004;57:1106)

Micro images
=========================================================================



Adenosquamous carcinoma with rhabdoid features
Left-large cells with abundant eosinophilic cytoplasm with paranuclear aggregation of filaments, eccentric nuclei and prominent nucleoli
Right-cytokeratin stain highlights cytoplasmic aggregation of intermediate filaments


 
Squamous cell carcinoma with rhabdoid phenotype and osteoclast-like giant cells


Authors described as "cytokeratin aggresomes", not rhabdoid

Positive stains
=========================================================================

● Rhabdoid tumor cells: chromogranin, synaptophysin, cytokeratin

Electron microscopy description
=========================================================================

● Cytoplasmic inclusions are composed of large whorls of intermediate filaments



Tumors

Serous cystadenoma


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 12 December 2014, last major update August 2012
Copyright: (c) 2001-2014, PathologyOutlines.com, Inc.

General
=========================================================================

● Benign tumor, usually in women, composed of small cystic spaces lined by small cuboidal cells with clear cytoplasm (glycogen) (WHO)
● Also called microcystic adenoma, glycogen rich cystadenoma

Clinical features
=========================================================================

● Mean age 66, 70% women, associated with von Hippel Lindau syndrome
● Symptoms: none, local discomfort/pain, obstruction if in pancreatic head; may cause diabetes if tumor destroys enough islets
● Excision is almost always curative
● One malignant case reported, histologically benign, but metastasized to stomach and liver and invaded spleen (Am J Surg Pathol 1989;13:61)

Case reports
=========================================================================

● 47 year old woman and 53 year old man with coexisting pancreatic endocrine neoplasms (Am J Surg Pathol 1996;20:471, Arch Pathol Lab Med 2003;127:1369)
● Coexisting pancreatic adenocarcinoma (Am J Surg Pathol 1990;14:352)

Gross description
=========================================================================

● Large (mean 11 cm) multiloculated mass, sharply outlined, cysts filed with clear fluid
● Spongy
● Resembles infantile polycystic kidney
● Often has central stellate scar
● Rarely is multicentric, usually in tail or body
● Either macrocystic (megacystic, oligocystic, usually < 10 cysts, Hum Pathol 1992;23:871) or microcystic (1-3 mm)
● Large tumor size and head location predict aggressive behavior

Gross images
=========================================================================



Circumscribed, sponge-like cut surface with central stellate scar


Well demarcated cystic lesion with central stellate scar in tail of pancreas; cysts are filled with watery fluid and separated by thin septa


76 year old man with incidental pancreatic mass - contributed by Dr. Hanni Gulwani, New Delhi (India)


Solid variant

Micro description
=========================================================================

● Small cystic spaces lined by small cuboidal cells with clear cytoplasm (glycogen), minimal mucin, myoepithelial layer present, round hyperchromatic central nuclei
● Minimal papillae, has islets between lobules which may calcify (radiating pattern), tumor is vascular (seen by selective angiography)
● Occasionally has papillary features (Arch Pathol Lab Med 2001;125:1591)
● Rarely oncocytic change; rarely massive cystic degeneration resemble pseudocyst (Am J Surg Pathol 2012;36:726)
● Fluid has low CEA content compared to mucinous cystic neoplasms
● Solid variant: rare, similar microscopically to serous cystadenoma but no cystic spaces; cells arranged in nests, sheets and trabeculae separated by thick fibrous bands; has PAS+ cytoplasm (glycogen); may histologically resemble sugar tumor, clear cell carcinoma, clear cell pancreatic endocrine tumor, renal cell carcinoma, but benign behavior (Am J Surg Pathol 1996;20:1401)

Micro images
=========================================================================



Cuboidal cells with watery clear cytoplasm (due to glycogen), with round dense nuclei but no atypia; sparse stroma between cysts, cystic content has no significant staining


Cysts exhibit marked size variation (larger at periphery, smaller and uniform centrally)


Tumor cell cytoplasm is PAS+ due to glycogen


Intracystic papillary projection is formed by regular cuboidal cells


Cystic lesion is well demarcated from adjoining pancreas by small fibrous band containing some vessels


Tumor cell cytoplasm is PAS+ due to glycogen


Various images


76 year old man with incidental pancreatic mass - contributed by Dr. Hanni Gulwani, New Delhi (India)


Papillary variant


Solid variant


Serous cystadenocarcinoma
Top: 71 year old patient with metastasizing tumor resembling a serous cystadenoma, cysts of variable size, and focal papillary projections
Bottom: Lymph node metastasis of above tumor


Positive stains
=========================================================================

● EMA, low molecular weight keratin, PAS without diastase
● Alpha-inhibin, neuron-specific enolase, and MUC6 (Am J Surg Pathol 2004;28:339)
● Synaptophysin (92%), CD56 (75%, Appl Immunohistochem Mol Morphol 2011;19:141)

Negative stains
=========================================================================

● CEA, trypsin, chromogranin, S100, desmin, vimentin, Factor VIII

Electron microscopy description
=========================================================================

● Prominent microvilli, glycogen granules, epithelial cells connected by occluding junctions and belt desmosomes resting on a basement membrane
● No neurosecretory or zymogen granules

Electron microscopy images
=========================================================================



Cytoplasm has multiple glycogen particles, some mitochondria and multivesicular bodies, but no microvilli are present at the apical surface

Molecular description
=========================================================================

● May be aneuploid (Arch Pathol Lab Med 1991;115:563)

Cystic lesion is well demarcated from adjoining pancreas by small fibrous band containing some vessels

Differential diagnosis
=========================================================================

Lymphangioma: Factor VIII+, lymphocytes present, epithelial cells lack glycogen)
Mucinous cystic neoplasms: larger cystic spaces, CEA+, mucin+
Pancreatic pseudocyst: some serous cystadenomas have focal cystic degeneration resembling a pseudocyst (Am J Surg Pathol 2012;36:726)
Solid pseudopapillary tumor: pseudopapillary features

Additional references
=========================================================================

Am J Surg Pathol 1988;12:251, Am J Surg Pathol 1986;10:365



Exocrine tumors

Signet ring cell carcinoma


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 28 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Extremely rare, usually aggressive, poorly differentiated invasive adenocarcinoma with malignant glandular cells having nucleui pressed to one side by intracytoplasmic mucin (WHO)
● Must exclude breast or GI primary

Case reports
=========================================================================

● 30 year old man (Ultrastruct Pathol 1998;22:147)

Micro description
=========================================================================

● Poorly cohesive epithelial cells containing intracytoplasmic mucin that displaces nuclei towards periphery
● Infiltrates as single cells; variable extracellular mucin
● Resembles mammary lobular carcinoma and gastric carcinoma with targetoid pattern, signet ring cells, linear infiltration

Micro images
=========================================================================



Strands of relatively small tumor cells with many signet-ring cells


Typical signet-ring cells



Exocrine tumors

Solid pseudopapillary tumor of pancreas


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 3 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Low grade malignancy composed of poorly cohesive monomorphic epithelial cells forming solid and pseudopapillary structures (WHO)
● Not truly papillary or truly cystic
● Also called SPT, papillary and solid epithelial neoplasm, papillary cystic neoplasm, Gruber-Frantz tumor
● 1-2% of non-endocrine pancreatic neoplasms
● Mean age 30-35 years, 90% women, not associated with any clinical syndrome

Etiology
=========================================================================

● May be unique to pancreas (Mod Pathol 2007;20:S71)
● May derive from centroacinar cells due to DOG1 immunoreactivity in both (Hum Pathol 2011;42:817)
● Discohesive nature of cells and cystic changes may be due to abnormalities in expression of E-cadherin/catenin complex (Am J Surg Pathol 2008;32:1)

Poor prognostic factors
=========================================================================

● Venous invasion, high nuclear grade, “necrobiotic nests”
● Metastases in 10-15% to liver or peritoneum are associated with venous invasion, high nuclear grade and necrosis
● Patients usually survive even with metastases

Case reports
=========================================================================

● 33 year old woman with large, multilocular cystic mass (Case of the Week #121)
● 38 year old woman with liver metastases (Arch Pathol Lab Med 1995;119:268)
● 43 year old woman with retroperitoneal mass (Arch Pathol Lab Med 2001;125:971)
● 44 year old woman with pancreatic mass (Arch Pathol Lab Med 2002;126:985)
● Papillary cystic tumor of the pancreas (Arch Pathol Lab Med 1984;108:723)

Treatment
=========================================================================

● Wide excision, excellent prognosis (J Surg Oncol 2007;95:304)

Clinical images
=========================================================================



CT scan

Gross description
=========================================================================

● Large (mean 9 cm), usually encapsulated, hemorrhagic, necrotic, rarely multifocal (Arch Pathol Lab Med 1991;115:958)
● Tumor friable but not necrotic

Gross images
=========================================================================



Lobulated, fleshy surface showing marked hemorrhage and degenerative changes


Solid and cystic masses


Multilocular cystic mass


Whipple specimen showing large, round, well-demarcated mass in head of pancreas; tumor is partly necrotic and cystic (Courtesy of Dr. Andreas Schulz, Giessen, Germany)


Tumor invades spleen, and gave rise to liver metastases (Courtesy of Dr. Manfred Stolte, Bayreuth, Germany)


Cut surface shows uniloculated cyst with some solid areas in capsule (Courtesy of Dr. Helmut Luchtrath, Koblenz, Germany)

Micro description
=========================================================================

● Cellular tumor, resembles pancreatic endocrine neoplasm or CNS ependymoma
● Pseudopapillae with hyalinized fibrovascular cores lined by several layers of bland fragile epithelial cells with clear to eosinophilic cytoplasm, variable mucinous changes within the core, intracytoplasmic PAS+ hyaline globules
● Pseudopapillae are due to solid nests minus cells degenerating away from the small vessels; resemble rosettes in cross section
● Also round/oval nuclei, finely stippled chromatin, nuclear grooves, indistinct nucleoli, few mitoses
● Also foam cells, clusters of lipid/cholesterol crystals surrounded by foreign-body giant cells
● May have pseudocystic areas
● Tumor cells infiltrate without any stromal reaction

Micro images
=========================================================================



Pseudopapillae


Tumor cells radially arranged around delicate and somewhat hyalinized fibrovascular stalk; arrows point to small hyaline globules within and between the cells


Hyaline globules (hematoxylin phloxine saffron stain)


Solid monomorphous pattern with variable vacuoles and sclerosis


Nuclei lack conspicuous nucleolus but show indentations


Solid part of tumor has aggregate of large tumor cells with foamy cytoplasm (arrows); arrowheads point to small cyst filled with eosinophilic fluid and some foam cells


Cholesterol crystals surrounded by foreign body cells


Tumor tissue (top) is sharply demarcated from adjoining pancreatic parenchyma (bottom), but lacks a clear capsule


Margin of a malignant tumor with deep invasion into the adjacent pancreatic tissue


Aggressive histologic features


Case of the Week #121


Various images


Left to right: CD10+, CD56+, Vimentin+


Left to right: E-cadherin, β-catenin


Left to right: PR+, alpha-1-antitrypsin+, βcatenin


Intense focal immunostaining for alpha-1-antitrypsin


Diffuse immunostaining for NSE

Cytology description
=========================================================================

● Cellular, single cells, small loose clusters, and scattered intact papillary structures with delicate fibrovascular cores, fibrovascular cores may contain metachromatic material, and hyaline globules may be seen extracellularly, cells have delicate, finely granular cytoplasm (Korean J Pathol 2012;46:399)
● Chromatin is fine and nuclei are frequently grooved

Cytology images
=========================================================================



Branching vessels and cohesive cells


Various images


Comparison with pancreatic neuroendocrine tumors


Immunostains

Positive stains
=========================================================================

● Vimentin, CD10, CD56 (intense, diffuse, Am J Surg Pathol 2000;24:1361)
● Intense membranous claudin 5 and cytoplasmic claudin 2 (Am J Surg Pathol 2009;33:768, Hum Pathol 2008;39:251)
● Also estrogen and progesterone receptors, focal neuroendocrine markers
● Also chymotrypsin and trypsin (Am J Surg Pathol 1987;11:85)
● Also nuclear and cytoplasmic beta-catenin (Am J Clin Pathol 2009;132:831), cyclin D1, nuclear E-cadherin, paranuclear dot like CD99 (Am J Surg Pathol 2011;35:799),

Negative stains
=========================================================================

● Chromogranin, CEA, acinar and ductal markers (keratin may be patchy)

Electron microscopy description
=========================================================================

● Large electron dense granules with complex internal membranous and granular inclusions and alpha-1-antitrypsin

Electron microscopy images
=========================================================================



Tumor cells with abundant cytoplasm containing multiple mitochondria and a few dense bodies; nuclei have a polygonal shape (Courtesy of Dr. H.D. John, Mainz, Germany)


Large osmiophilic, zymogen-like granules of variable sizes; often is disintegration of granule content, forming multilamellated vesicles (Courtesy of Dr. H.D. John, Mainz, Germany)

Molecular description
=========================================================================

● Almost always mutations in exon 3 of the beta-catenin gene, causes abnormal immunostaining patterns for beta-catenin (nuclear and cytoplasmic, compared to membranous staining in normal pancreas) and overexpression of cyclin D1 (Am J Pathol 2002;160:1361)

Differential diagnosis
=========================================================================

Acinar cell carcinoma: typically has acinar formations, prominent nucleoli and mitotic activity, trypsin+, chymotrypsin+, lipase+ (Mod Pathol 2007;20:S94)
● Adrenal cortical tumors: positive for inhibin, keratin
Pancreatic endocrine tumor: no degenerative pseudopapillae, no clear cells, usually no intracytoplasmic hyaline globules, no longitudinal nuclear grooves; no nuclear β-catenin staining, CD10- (Am J Surg Pathol 2011;35:981)
Pancreatic pseudocyst: may be grossly similar, but no epithelial cells lining the cystic structures, even after careful search, patients are usually older and male, and have a history of pancreatitis)



Exocrine tumors

Undifferentiated carcinoma


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 26 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Carcinoma in which substantial portion has no evidence of glandular, squamous or urothelial differentiation (WHO)
● Includes anaplastic carcinoma, carcinosarcoma, sarcomatoid carcinoma
● 7% of non-endocrine pancreatic malignancies
● See also Undifferentiated with osteoclastic giant cells

Clinical features
=========================================================================

● Usually elderly patients, who present with widely disseminated disease
● Very poor prognosis

Case reports
=========================================================================

● 74 year old man with carcinosarcoma (Arch Pathol Lab Med 2002;126:1114)

Gross images
=========================================================================



Left: Whipple resection specimen shows ill-demarcated tumor in head of pancreas with large areas of central necrosis (yellow)
Right: tumor mass in tail with extensive hemorrhagic necrosis


Micro description
=========================================================================

● High grade carcinoma with no evidence of glandular, squamous or urothelial differentiation
● May have discohesive, bizarre, multinucleated giant cells (not osteoclast-like), and resemble giant cell carcinoma of lung, adrenal, liver
● Dense inflammatory infiltrate with emperipolesis (neutrophils in tumor cells)

Micro images
=========================================================================



Various images


Poorly cohesive sarcomatoid pattern of pleomorphic large cells with single or multiple nuclei, supported by scanty fibrous stroma


Tumor cells show occasional engulfment of red blood cells or other tumor cells (cannibalism)


Spindle cell sarcomatoid features


Focus of glandular differentiation within a sarcomatoid pattern


Carcinosarcoma: left-glandular component is keratin+; right-sarcomatous component is vimentin+


Left: tumor is keratin+; right: tumor is CEA+ in glandular portions, but pleomorphic cells are negative

Positive stains
=========================================================================

● EMA, keratin



Tumors

Undifferentiated carcinoma - Osteoclastic giant cell tumor


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 8 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Aggressive malignant epithelial neoplasm composed of giant cells resembling osteoclasts and atypical cells that do not display glandular or squamous differentiation (WHO)
● Different morphologically (but occasionally coexists) from anaplastic carcinoma, with better prognosis
● Tumor cells (undifferentiated) appear to induce osteoclasts
● Similar tumor in the liver
● Resembles giant cell tumor of bone (Hum Pathol 1991;22:618)

Case reports
=========================================================================

● 39 year old man with familial atypical multiple mole melanoma syndrome (Am J Surg Pathol 2008;32:1905)
● 77 year old woman with mass in tail invading spleen and adjacent bowel (J Korean Surg Soc 2011;81:146)

Gross description
=========================================================================

● Large, hemorrhagic

Gross images
=========================================================================



77 year old woman

Micro description
=========================================================================

● Contain 5 cellular components - osteoclast-like giant cells, pleomorphic large cells, histiocyte-like mononuclear cells, atypical mononuclear cells (nucleus resembles pleomorphic large cells), ductal carcinoma cells

Micro images
=========================================================================



77 year old woman


Various images


Osteoclast-like giant cells and bizarre tumor giant cells are mixed with a few spindle and smaller pleomorphic cells; osteoclast-like cells are relatively uniformly nucleated, and each nucleus has little chromatin and one small distinct nucleolus


Elongated spindle cells vary from those with small cell nuclei and relatively little chromatin to cells containing abundant chromatin; an osteoclast-like giant cell can be seen at upper left


Osteoid formation (lower right) with a few osteoclast-like giant cells, plus many small, pleomorphic, mononucleated cells


Rare small focus of adenocarcinoma


Osteoclast giant cells are LCA/CD45+; non-neoplastic macrophages and lymphocytes are also immunoreactive

Cytology images
=========================================================================



Osteoclastic giant cell tumor of pancreas

Positive stains
=========================================================================

Osteoclast-like giant cells: CD68+, keratin negative, no Kras mutation; non-neoplastic
Pleomorphic large cells (not always present): CD68-, often have Kras mutations
Histiocyte-like mononuclear cells: CD68+, keratin+, often have Kras mutations
Atypical mononuclear cells: CD68-, often have Kras mutations
Ductal carcinoma cells: CD68-, same Kras mutations as pleomorphic large cells and mononuclear cells

Electron microscopy images
=========================================================================



Various images

Molecular description
=========================================================================

● Osteoclast-like giant cells lack Kras mutations, but mononuclear cells have similar Kras mutations as ductal carcinoma cells (Am J Surg Pathol 1998;22:1247, Hum Pathol 2000;31:1223, Arch Pathol Lab Med 1998;122:266)



Exocrine tumors

Vacuolated adenocarcinoma


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 26 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Infiltrating nests of tumor cells with large vacuoles and "signet-ring" like appearance imparting a pattern resembling adipocytes (Virchows Arch 2010;457:643)
● Not a WHO diagnosis

Clinical features
=========================================================================

● Similar clinical features as ductal adenocarcinoma of usual type, except stronger association with smoking

Micro description
=========================================================================

● High grade tumors with gland-in-gland arrangement
● Tumor cells form cribriform nests with multiple large vacuoles or microcysts containing cellular debris and mucin
● May resemble fat necrosis
● Have necrotic material in lumen
Note: this pattern is rare in non-pancreatic adenocarcinomas, may be helpful in determining site of origin of metastases

Micro images
=========================================================================





Various images

Differential diagnosis
=========================================================================

● Adenomatoid tumor
● Breast or prostate cancer, metastatic-treated
● Lipogranuloma
● Mesonephric adenoma
Pancreatic adenocarcinoma, signet ring type: resembles mammary lobular carcinoma with targetoid pattern, signet ring cells, linear infiltration



Tumors

Pancreatic endocrine neoplasms - general


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 8 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Also called pancreatic endocrine tumors
● Uncommon, although most common epithelial neoplasm after ductal adenocarcinoma (3-5% of pancreatic neoplasms)
● May arise from pluripotential ductal cells with capacity to differentiate along neuroendocrine lines, so terminology "islet cell tumors" is discouraged

Clinical features
=========================================================================

● Can occur as part of 4 inherited disorders, including Multiple Endocrine Neoplasia type 1 (MEN1), von Hippel-Lindau disease (VHL), neurofibromatosis 1 (NF-1) (von Recklinghausen disease), tuberous sclerosis complex (TSC) (Cancer 2008;113:1807, J Gastrointest Oncol 2012;3:182)
● 80% occur in MEN1 patients, usually age 50-60
● Current terminology is that "functional" means they produce hormones resulting in symptoms / syndromes; of functional tumors, insulinomas are the most common, followed by gastrinomas (Endocr Relat Cancer 2008;15:409)
● Most secrete multiple hormones, but produce no symptoms (i.e. are non-syndromic, Am J Surg Pathol 1996;20:1378)
● All considered malignant except microadenomas (less than 5 mm, usually incidental at autopsy), because no histologic criteria differentiates benign and malignant (except metastases)
● Usually occurs in adults in body/tail
● Tumors are hypervascular and circumscribed with octreotide scan (highlights somatostatin receptors)
● Usually slow growing, metastases to nodes, liver, bone
● Recommend resection of metastases for palliative relief

Staging / grading
=========================================================================

● ENETS-TNM staging: Virchows Arch 2006;449:395)



●WHO grading system for neuroendocrine tumors of digestive tract is based on mitotic figures and Ki-67 staining (WHO, Pancreas 2010;39:707)
● Low grade (G1): <2 mitoses / 10 hpf AND <3% Ki67 index
● Intermediate grade (G2): 2-20 mitoses / 10 HPF OR 3%-20% Ki67 index
● High grade (G3): >20 mitoses / 10 hpf OR >20% Ki67 index

Features to report
=========================================================================

● Tumor size, location, mitotic figures, vascular or capsular invasion (Arch Pathol Lab Med 2000;124:30)

Poor prognostic factors
=========================================================================

● Tumor size > 3 cm
● Invasion of stroma, capsule, vessels or adjacent organs
● Glandular/solid pattern
● > 2 MF/10 HPF
● Aneuploidy
● Older age, high proliferation index (Ki-67 of 5% or more, Hum Pathol 1996;27:1124, Arch Pathol Lab Med 2003;127:196, Am J Surg Pathol 2011;35:853, Mod Pathol 2010;23:824, Hum Pathol 2009;40:1262)
● Also necrosis, vascular invasion, perineural invasion or CK19+(Am J Surg Pathol 2004;28:1145), loss of PAX8 expression (Am J Surg Pathol 2010;34:723)

Gross description
=========================================================================

● Pink (resembles spleen, lymph node), no well defined capsule, variable fibrous tissue, calcium, bone, cysts

Gross images
=========================================================================



Various images


Small (2 cm) intrapancreatic tumor with expansile margins showing a relatively homogeneous, deep red, hemorrhagic appearance


Large (6 cm) tumor invades the splenic capsule and contains minute foci of hemorrhage


39 year old with MEN1, Zollinger-Ellison syndrome and nonfunctioning microadenoma of pancreas (arrow)


MEN 1 associated ZES: cut section of hypertrophic gastropathy specimen reveals intramucosal tumor nodules (AFIP image, courtesy of Dr Juan Rosai)

Micro description
=========================================================================

● WHO classification: see WHO
● Nests of polygonal cells with moderate to abundant eosinophilic cytoplasm resembling carcinoid tumors due to delicate vasculature, salt and pepper chromatin
● Solid, gyriform, trabecular and glandular patterns with minimal to moderate fibrosis but NO desmoplasia
● Amyloid is produced by insulin-secreting tumors (from amylin or somatostatin)
● Cells are less polarized than acinar cell carcinoma
● Rarely exhibits true glandular formations, hyaline globules in 5% (Am J Surg Pathol 2011;35:981)
● May display endocrine atypia with marked nuclear enlargement and cytomegaly, but there is preservation of N/C ratio, even chromatin and even nuclear membranes, no necrosis or increased mitotic activity
● Rarely mucin, clear cell change, psammoma bodies, oncocytes, focal rhabdomyosarcomatous metaplasia
● Stains do NOT correlate with secretion
● Immunostains NOT necessary for diagnosis

Architecture is associated with type:
● Solid – any type
● Gyriform – alpha cells, beta cells, PP types
● Glandular – gastrin, VIP

Micro images
=========================================================================



Various images


Well demarcated, partly encapsulated growth of uniform cells forming regular microlobules; compare with islet in the lower right corner.


Nonfunctioning tumor is chromograninA+


Sheets and ill-defined nests of cells with nuclear crowding in nonfunctioning endocrine carcinoma


Blood vessel invasion by well-differentiated nonfunctioning endocrine carcinoma.


Neoplastic thrombi in a lymphatic vessel of peritumoral pancreatic tissue


Enterochromaffin cell tumor: composed of polygonal cells in solid nests.


Enterochromaffin cell tumor (left to right): serotonin+ (left), chromograninB+


Scattered Grimelius-positive tumor cells in a nonfunctioning malignant neoplasm metastatic to regional lymph nodes


MEN 1 associated ZES: cut section of hypertrophic gastropathy specimen reveals intramucosal tumor nodules surrounded by hypertrophic (left and right) and eroded (top) mucosa (Courtesy of Dr Juan Rosai)


Ki-67


CD31

Cytology images
=========================================================================



Tumor cells have round nuclei and scanty, poorly defined cytoplasm.

Positive stains
=========================================================================

● Chromogranin, synaptophysin, CEA; also, various hormones including insulin, glucagon, somatostatin, pancreatic polypeptide, gastrin, vasoactive intestinal polypeptide
● Often acinar markers (no prognostic importance, Am J Surg Pathol 2002;26:893)
● Serotonin expression correlates with trabecular pattern and large duct involvement (Hum Pathol 2012;43:1169)
● Useful panel for determining pancreatic origin is Islet1+, PAX8+, CDX2+, TTF1- (Am J Surg Pathol 2010;34:723, Mod Pathol 2011;24:412, Mod Pathol 2012;25:893, Am J Surg Pathol 2008;32:420)
● PDX1+, CDX2+, TTF1-, and CK7- may also be useful panel (Am J Surg Pathol 2012;36:737)
● High MHC-II expression related to intratumoral inflammation (Virchows Arch 2012;460:47)

Electron microscopy description
=========================================================================

● Dense-core neurosecretory granules (not specific, size overlaps with zymogen granules of acinar cell tumors), usually randomly distributed, lack the well-developed secretory apparatus of acinar cell tumors (rough ER, mitochondria)

Electron microscopy images
=========================================================================



Enterochromaffin cell tumor: irregularly shaped dense granules, characteristic of enterochromaffin cells

Differential diagnosis
=========================================================================

Chronic pancreatitis: cases with with islet cell hyperplasia resemble pancreatic endocrine neoplasms
IPMN: small, incidentally identified pancreatic endocrine tumors compress main pancreatic duct and present clinically, radiologically, and grossly as intraductal papillary mucinous neoplasm (Hum Pathol 2011;42:1034)
● Pseudoneoplastic islet cell lesions: islets aggregate while rest of pancreas atrophies; islets at tail are compact, islets in head are diffuse and may appear infiltrative, usually have trabecular pattern and are pancreatic polypeptide positive; usually no perineurial invasion)
Solid pseudopapillary neoplasm: clear cytoplasmic vacuoles on cytology, alpha1-antitrypsin+, vimentin+, CD10+, PR+, nuclear staining for beta-catenin (Am J Clin Pathol 2009;132:831)
Usual ductal adenocarcinoma: marked nuclear atypia



Pancreatic endocrine neoplasms

ACTH-secreting tumors


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 8 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Not a WHO diagnosis
● Rare pancreatic endocrine neoplasm producing adrenocorticotrophic hormone (ACTH)
● Causes Cushing syndrome: central obesity, muscle weakness, glucose intolerance, hypertension

Case reports
=========================================================================

● 41 year old woman with bilateral ovarian metastases (Int J Gynecol Pathol 2002;21:276)
● 54 year old woman with ACTH secretion only at second relapse (J Clin Endocrinol Metab 2004;89:3731)

Gross images
=========================================================================



Spleen, adrenal gland and pancreas with tumor

Micro images
=========================================================================



Rounded nests of densely packed cells with mitotic figures

 
66 year old man with ultrasound guided biopsy: H&E and ACTH antibody


ACTH producing tumor with Cushing's syndrome: moderately differentiated tumor with consistent cellular atypia, solid growth pattern, lymphatic invasion



Neuroendocrine tumors

NET G1 / Carcinoid tumors


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 28 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare, arise from Kultschitsky (serotonin secreting) cells normally present in pancreas

Terminology
=========================================================================

● Classified using similar criteria as other GI neuroendocrine neoplasms (WHO)
● Well-differentiated: cells with features similar to normal gut endocrine cell, expressing general markers of neuroendocrine differentiation (usually diffuse and intense chromogranin A and synaptophysin) and hormones (usually intense but not necessarily diffuse) according to site, with mild- to-moderate nuclear atypia and a low number of mitoses
● G1 (NET G1): mitotic count <2/10 HPF or ≤2% Ki67 index
● G2 (NET G2): mitotic count 2-20/10 HPF or 3-20% Ki67 index

Clinical features
=========================================================================

● Acceptable to supplement diagnosis to reflect the corresponding cell type (example: alpha cell/glucagon-producing NET, beta cell/insulin-producing NET, G cell/gastrin- producing NET”), but recommended to NOT use specific functional terms (glucagonoma, insulinoma, gastrinoma) unless hormonal syndrome exists
● May be associated with carcinoid syndrome (flushing, diarrhea)

Gross images
=========================================================================



Large tumor with hemorrhage and degeneration


Invasion of large vessel

 
Tumor is well demarcated from surrounding parenchyma

Micro images
=========================================================================



Trabecular and nesting patterns


Tumor cells have salt and pepper chromatin


A/B: H&E; C: chromogranin, D: keratin, E: NSE, F: synaptophysin


Organoid pattern characterized by nests and sheets


Serotonin+


Stomach: gastric carcinoid in MEN1 associated Zollinger Ellinger syndrome - mosaic-like pattern of solid cords and microlobules separated by very thin stromal septa.

Positive stains
=========================================================================

● For metastatic neuroendocrine tumors, NESP55+ and PDX1+, in the presence of negative CDX2 and TTF1, is 97% specific for pancreatic origin (Am J Surg Pathol 2009;33:626)
● Strongly argentaffinic (contains catecholamines, indolamines or related substance that reduces silver and other metallic salts to metallic silver, staining brown or black) - includes Fontana-Masson, Schmorl's

Negative stains
=========================================================================

● PAX8 (Histochem Cell Biol 2011;136:595-previous PAX8+ tumors based on cross-reactivity of polyclonal antibodies)

Electron microscopy images
=========================================================================



Stromach: argyrophil gastric carcinoid - ECL-type vesicular granules (left) and solid granules (right) with cerebroid punctate structure (atypical ECL cell granules?) in gastric carcinoids



Endocrine tumors

Clear cell pancreatic endocrine tumor


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 27 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Clear cell change is specific for von Hippel-Lindau disease, due to intracytoplasmic lipid (Am J Surg Pathol 2001;25:602)
● Rarely associated with hypercalcemia (Arch Pathol Lab Med 2003;127:241)
● Lipid rich variant of pancreatic endocrine neoplasm may also have clear cells, but is distinct variant (Am J Surg Pathol 2006;30:194, Acta Cytol 2010;54:829)

Gross description
=========================================================================

● Solid, multinodular, golden-yellow
● May be cystic

Gross images
=========================================================================



Pancreatic Endocrine Tumor from patient with von Hippel–Lindau Disease

Micro description
=========================================================================

● Clear cells in nests, cords and tubules with central hemorrhage and associated thin walled vessels
● Cords and gyriform pattern, when present, are suggestive of endocrine tumors
● Vascular invasion common
● May have adjacent serous cystadenoma-like areas

Micro images
=========================================================================



Clear cell morphology


Pancreatic neuroendocrine tumours associated with von Hippel-Lindau disease are characterized by cytoplasmic vacuolization with multiple aggregates of small lipid droplets, some of which may impinge on and indent the nucleus


Figure 1: 8 cm tumor is firm and sharply demarcated from spleen and rest of pancreas
Figure 2: Clear cells are rounded, with large vacuoles in cytoplasm, displacing the nuclei to the periphery
Figure 3: Other clear cells have smaller vacuoles
Figure 4: EM shows 150-200 nm, membrane bound, dense core neuroendocrine granules


Cytology description
=========================================================================

● Large sheets and rounded clusters of polygonal neoplastic cells with relatively abundant cytoplasm containing numerous, small, sharply-demarcated vacuoles, giving rise to "frothy" appearance (Diagn Cytopathol 2009;37:365)

Positive stains
=========================================================================

● Chromogranin, synaptophysin, pancreatic polypeptide

Differential diagnosis
=========================================================================

● Adrenal tumors
● Clear cell hepatocellular carcinoma
● Metastatic renal cell carcinoma: negative for neuroendocrine markers and neurosecretory granules
● Mucinous adenocarcinoma, low grade
Perivascular epithelioid cell tumor: HMB45+, negative for endocrine markers
Serous microcystic adenoma: small cystic spaces lined by small cuboidal cells with clear cytoplasm (glycogen), minimal mucin, myoepithelial layer present, round hyperchromatic central nuclei
Solid pseudopapillary tumors, clear cell variant: pseudopapillae with hyalinized fibrovascular cores lined by several layers of bland fragile epithelial cells with clear to eosinophilic cytoplasm, variable intracytoplasmic PAS+ hyaline globules
● Steroid secreting tumors of ovary/testis



Neuroendocrine tumors

Cystic endocrine tumors


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 1 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Distinctive subgroup of pancreatic neuroendocrine tumors that are well differentiated, with low mitotic rate and low Ki-67 proliferation index (Am J Surg Pathol 2012;36:1666)
● Up to 17% of pancreatic endocrine tumors are purely or partially cystic (J Am Coll Surg 2008;206:1154), due to cystic degeneration of solid endocrine tumors

Clinical features
=========================================================================

● Mean 5 cm, usually nonfunctional
● 25% are associated with MEN1: occur in younger patients, often multiple, in tail and express glucagon (Virchows Arch 2011;458:47)
● By imaging have peripheral hypervascular rim and images of cyst into cyst
● Confirm by octreoscan scintigraphy
● Excise since may be malignant
● Prognosis good

Case reports
=========================================================================

● 20 year old woman with incidental tumor (J Cancer Res Ther 2012;8:289)

Gross images
=========================================================================



Cut surface of an 8 cm, expansile endocrine tumor with cystic pattern


Large spherical lesion arising from head of pancreas, cyst has multiple loculations


Large cystic pancreatic endocrine neoplasm with glistening capsule and septated appearance

Micro description
=========================================================================

● Thick cyst wall with nests of neuroendocrine cells
● Also neuroendocrine cells grouped in vesicular structures surrounded a fluid filled cavity (Am J Surg Pathol 2001;25:752)

Micro images
=========================================================================



20 year old woman:
Left: cyst wall has collagenous fibrous tissue with small nests of round cells with amphophilic cytoplasm and stippled nuclear chromatin
Right: tumor cells are synaptophysin+ (a), chromogranin+ (b), NSE+(c), Ki-67 low (d), CK19- (e), CD10-(f)


Cytology description
=========================================================================

● Loosely cohesive aggregates and single cells; cells are small, plasmacytoid, with occasional cytoplasmic vacuoles; nuclei are round/oval, uniform, with finely and evenly distributed chromatin (Cancer 2009;117:203)

Cytology images
=========================================================================


conventional smear



Tumors

Gastrinoma (G cell tumor)


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 6 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Functionally active and usually malignant endocrine tumour with clinical symptoms due to inappropriate secretion of gastrin (Zollinger Ellison syndrome; ZES); either sporadic non-familial with ZES (80% of cases) or familial with ZES in the setting of MEN1 (20%) (WHO)

Clinical features
=========================================================================

● Associated with hypersecretion of gastric acid and severe peptic ulceration
● 90% have ulcers; 85% in duodenum/jejunum, 15% in stomach
● 50% have diarrhea
● Tumors usually in pancreas or duodenum (eMedicine), peripancreatic soft tissue, gastric antrum (opposite of G cell distribution)
● Also ovary, mesentery, liver, intra-abdominal lymph nodes (unclear if due to ectopic pancreatic tissue or metastases)
● 50% are locally invasive or metastatic at diagnosis
● Zollinger-Ellison syndrome tumors are usually solitary, malignant, located in pancreas
● MEN 1 cases are less likely to be malignant, arise in duodenal wall, often multicentric

Diagnosis
=========================================================================

● Glucagon provocative test is useful (Surg Today 2012 Sep 16 [Epub ahead of print])

Primary lymph node gastrinoma:
=========================================================================

● Gastrin producing tumors in lymph nodes, with no GI or pancreatic primary
● Occur with MEN1 (Am J Surg Pathol 2008;32:1101)
● Occur in “gastrinoma triangle”: from cystic and common bile ducts to the second and third portion of the duodenum to neck and body of the pancreas
● Apparently due to gastric secreting neuroendocrine cells within these nodes (Arch Pathol Lab Med 2000;124:832)
● Also due to occult duodenal microgastrinomas with lymph node metastasis (Am J Surg Pathol 2008;32:1101)

Treatment
=========================================================================

● H2 blockers; surgical resection of tumor (if cannot resect, some advocate total gastrectomy)

Gross images
=========================================================================



Lymph node: largest (2.5 cm) of 5 pancreatoduodenal lymph nodes with endocrine tumor tissue (gastrin+) found in 57 year old man with ZES; no tumor found in pancreas or duodenum; patient had Billroth II gastric resection 12 years prior

Micro description
=========================================================================

● Non-neoplastic pancreas shows large islets and nesidioblastosis
● Malignant tumors are histologically bland
● Associated with pancreatic polypeptide cell hyperplasia (Hum Pathol 1997;28:149)

Micro images
=========================================================================



Malignant tumor has trabecular pattern, hyaline and fibrous tissue between epithelial cell cords


Lobular-trabecular pattern and scattered gastrin+ cells


Duodenum: tumor cells infiltrate Brunner glands and are gastrin+


Duodenum: gastrinoma in MEN1 patient arises in deep crypts of mucosa and invades submucosa deeply (immunofluorescence)

Electron microscopy description
=========================================================================

● Granules similar to VIP, normal gastrin producing cells: small, electron dense

Electron microscopy images
=========================================================================



Tumor cells contain typical vesicular G-cell granules as well as nondiagnostic dense granules


Tumor cells contain small, nondiagnostic secretory granules



Tumors

Glucagonoma (alpha cell tumors)


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 8 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare glucagon producing endocrine neoplasm arising from alpha cells of pancreas; often displays vascular invasion and may metastasize (WHO)
● Adult females, age 40+

2 types:

(1) Glucagonoma syndrome:
● High incidence of malignancy
● Adult women with large, solitary tumors, markedly elevated serum glucagon, nondescript microscopic pattern, few immunoreactive tumor cells, atypical granules on EM
● Necrolytic migratory erythema (skin rash of legs, perineum, groin; rash becomes blisters with central clearing, heals with hyperpigmentation but without scarring in 7-14 days, Am J Surg Pathol 1986;10:445)
● Sore red tongue, angular stomatitis
● Severe weight loss, depression
● Deep venous thromboses
● May develop overwhelming infection
● Abnormal glucose tolerance test
● Normochromic, normocytic anemia

(2) Multiple small tumors with gyriform growth pattern:
● Nearly always benign
● Strongly immunoreactive for glucagon
● Typical granules on EM

Clinical images
=========================================================================



Necrolytic migratory erythema


Glucagonoma in body of pancreas at surgery

Gross images
=========================================================================



Glucagonoma of pancreatic body

Micro images
=========================================================================



70 year old woman with glucagonoma syndrome


Gyriform festoons separated by highly vascular stroma in a clinically nonfunctioning glycogen+ adenoma


Characteristic partly monolayered gyriform pattern; malignancy cannot be determined from morphology


Incidental tumor has gyriform pattern, and was glucagon+


Most tumor cells in this gyriform, nonfunctioning alpha cell adenoma contain argyrophilic granules


MEN1 patient with dysplastic lesion mostly composed of glucagon+ cells arranged in gyriform trabeculae separated by sclerotic strands of connective tissue; note close contact, in right middle, with small glucagon negative endocrine microlobule, a remnant of the original islet


MEN1 case - glucagon cell microadenoma with trabecular-gyriform structure in surviving pancreatic lobule (bottom right); islet crowding in area of exocrine tissue atrophy due to chronic pancreatitis (upper left)


MEN1 patient with nonfunctioning glucagon-producing microadenoma


Incidental tumor at autopsy is glucagon+


Minute microadenoma mainly composed of glucagon+ cells forming gyriform trabeculae


Glucagon+ tumor


Liver metastases of malignant glucagonoma with a trabecular, partly gyriform pattern


Liver metastases are chromogranin+

Electron microscopy description
=========================================================================

● Large, dense peripheral nucleoid

Electron microscopy images
=========================================================================



Characteristic alpha granules with a central dense core and a peripheral, less dense mantle


Diagnostic secretory granules with a central dense core encircled by a less dense matrix


Nondiagnostic, round, homogeneous dense granules



Neuroendocrine tumors

Neuroendocrine carcinoma, NOS


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 29 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Poorly differentiated, high grade malignant neoplasm, composed of small, intermediate or large cells, variable organoid features resembling neutroendocrine tumor, diffusely expressing neuroendocrine markers (diffuse staining for synaptophysin; faint or focal staining for chromogranin A), with marked nuclear atypia, multifocal necrosis and a high number of mitoses (> 20 per 10 HPF) (WHO)
● High grade (G3) is defined by proliferation fraction and histology
● Includes small cell carcinoma, large cell (neuro)endocrine carcinoma, poorly differentiated (neuro)endocrine carcinoma
● Genetically dissimilar from well differentiated neuroendocrine tumors (Am J Surg Pathol 2012;36:173)

Clinical features
=========================================================================

● Represents less than 3% of pancreatic neuroendocrine tumors
● May produce ACTH
● Associated with hypercalcemia

Case reports
=========================================================================

● 62 year old man with tail tumor (World J Surg Oncol 2012;10:32)

Gross images
=========================================================================



Small cell carcinoma

Micro images
=========================================================================



Large number of poorly differentiated fusiform cells and focal necrosis


High mitotic rate

Small Cell Carcinoma

Various images


Solid-diffuse pattern

 
Left: NSE+; right: scattered somatostatin-immunoreactive cells

Cytology images
=========================================================================



Metastatic pulmonary small cell carcinoma to pancreas

Differential diagnosis
=========================================================================

Acinar cell carcinoma: immunoreactive for trypsin or chymotrypsin, note: may be positive for neuroendocrine markers
Ductal adenocarcinoma, poorlly differentiated: negative for neuroendocrine markers
Metastatic carcinoma: clinical history needed
NET G1/G2: lower mitotic rate, well differentiated histology
PNET: young patients



Tumors

Insulinoma (beta cell tumor)


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 8 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Functionally active and commonly benign endocrine tumour of the pancreas with evidence of beta cell differentiation and clinical hypoglycemia due to inappropriate secretion of insulin (WHO)
● Only 7-10% have malignant behavior (perhaps because hyperinsulinemia leads to early detection)

Clinical features
=========================================================================

● Usually adults
● Whipple’s triad: symptoms of hypoglycemia (stupor, confusion, loss of consciousness), glucose < 50 mg/dl, symptoms relieved by glucose or symptoms caused by fasting or exercise
● 10-15% associated with MEN1 syndrome; age < 20 years is suggestive of MEN1 (Endocr J 2012;59:859)
● Functional status is NOT an independent prognostic factor
● Insulinomatosis: synchronous and metachronous occurrence of insulinomas, multiple insulinoma precursor lesions, and rare development of metastases, but common recurrent hypoglycemia (Am J Surg Pathol 2009;33:339)

Diagnosis
=========================================================================

● High insulin levels, intravenous tolbutamide administration detects serum proinsulin
● Use arteriography (60% successful) or ultrasound to locate small tumors

Laboratory
=========================================================================

● High insulin levels and high insulin/glucose ratio
● Hypoglycemia is mild in 80%

Case reports
=========================================================================

● Widely metastatic tumor with focal rhabdomyosarcomatous areas (Am J Surg Pathol 1989;13:422)

Treatment
=========================================================================

● Surgical exploration or subtotal pancreatectomy

Benign (90%):
  ● Solitary, encapsulated, 1.5 cm or less
  ● Solid/gyriform, no glands

Malignant (10%):
  ● Based on local invasion or metastases
  ● Usually causes more pronounced hypoglycemia

Note: amyloid may be derived from somatostatin and not amylin (Am J Surg Pathol 1998;22:360)

Gross images
=========================================================================



Tail tumor

Micro description
=========================================================================

● Solid or gyriform patterns, usually without glands
● In children are associated with nesidioblastosis (direct transformation of ductal epithelium into neoplastic islet tissue)
● Amyloid present (Arch Pathol Lab Med 1978;102:227)

Micro images
=========================================================================



Insulin immunostains


Nonfunctioning insulin-producing microadenoma in MEN1 patient


Insulinoma with concurrent pancreatic adenocarcinoma


Benign insulinoma has tumor trabeculae and microlobuli separated by abundant hyalinized stroma


Well differentiated malignant insulinoma metastatic to liver has large trabeculae and lobules


Well differentiated malignant insulinoma metastatic to liver has several cells with enlarged, hyperchromatic nuclei and conspicuous nucleoli


Amyoid deposits confirmed by Congo Red stain and polarized light, with characteristic green birefringence

Positive stains
=========================================================================

● Insulin (less than normal beta cells), proinsulin (50%), chromogranin, amylin, islet amyloid polypeptide (Islets 2011;3:344)

Electron microscopy description
=========================================================================

● Round secretory granules with irregular crystals separated from enclosing membrane by a distinct halo
● Granules do NOT imply functional activity

Electron microscopy images
=========================================================================



This tumor contains sufficient number of crystalline granules for diagnostic identification


Insulinoma with prevalence of round haloed granules of low density, plus occasional crystalloid granules (arrow)

Differential diagnosis
=========================================================================

Hyperinsulinism: diffuse hyperplasia of islets in infants of diabetic mothers
Hypoglycemia: insulin sensitivity, diffuse liver disease, glycogenoses, solitary fibrous tumor of pleura / peritoneum (tumor cells secrete insulin like growth factor II), hepatocellular carcinomas



Pancreatic endocrine neoplasms

Tumors in MEN1 patients


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 4 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Pancreatic endocrine tumors can occur in 4 inherited disorders: Multiple Endocrine Neoplasia type 1 (MEN1), von Hippel-Lindau disease (VHL), neurofibromatosis 1 (NF1) (von Recklinghausen disease), tuberous sclerosis complex (TSC) (Cancer 2008;113:1807) - discussion below focuses on MEN1
● Usually produce glucagon, insulin or pancreatic polypeptide
● Tendency towards multiple tumors in same patient, often microscopic, which often produce different hormones
● Associated with nesidioblastosis in 30% (Am J Surg Pathol 1996;20:1378)
● Loss of ATRX (alpha thalassemia/mental retardation X-linked) and DAXX (death domain-associated protein) tumor suppressor genes with alternative lengthening of telomeres is a late event in pancreatic neuroendocrine tumors associated with MEN1 syndrome (Mod Pathol 2012;25:1033, Science 2011;331:1199)
● Mutations in MEN1 and DAXX/ATRX genes associated with better prognosis
● Mutations in genes in the mammalian target of rapamycin (mTOR) pathway found in 14% of tumors

Diagrams
=========================================================================


Location of tumors



Endocrine tumors

Pancreatic polypeptide-secreting tumors


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 8 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare endocrine neoplasm with high proportion of pancreatic polypeptide (PP) cells, which typically are more frequent in posterior head of pancreas (from ventral bud)
● Not a WHO diagnosis
● Asymptomatic despite high levels of the hormone in plasma
● Note: PP cells are common in pancreatic endocrine tumors of other types

Case reports
=========================================================================

● 46 year old woman with WDHA (watery diarrhea/hypokalemia/achlorhydria) syndrome (Case Rep Gastroenterol 2008;2:238)

Gross images
=========================================================================



Various images

Micro images
=========================================================================



A: PP-oma showing abundance of PP immunoreactive cells (in black); B-predominance of PP immunoreactive cells


Nonfunctioning PP-cell tumor showing ribbons and festoons of tumor cells present throughout the neoplasm, separated by loose fibrovascular stroma


PP+ tumor has partly trabecular structure (left) with palisading of cells, and partly a solid pattern; tumor was large (5.5 cm in diameter) and associated with clinical symptoms due to local compression; tumor cells are pancreatic polypeptide+ (right)

Electron microscopy images
=========================================================================



Abundant basal accumulation of secretory granules

Differential diagnosiss
=========================================================================

● Pancreatic polypeptide cell hyperplasia: J Clin Pathol 2006;59:1087



Endocrine tumors

Sarcomatous differentiation


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 8 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Case reports
=========================================================================

● Only 1 case report to date (Mod Pathol 2001;14:1187)

Micro images
=========================================================================



Various images



Neuroendocrine tumors

Somatostatinoma


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 29 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Functionally active and usually malignant endocrine tumour with evidence of D-cell differentiation and clinical symptoms reflecting the diverse pathophysiologic effects of chronic inappropriate secretion of somatostatin (WHO)
● First reported in 1977 (Lancet 1977;1:666, N Engl J Med 1977;296:963, eMedicine)
● Also called delta cell tumors
● Note: somatostatin expression also seen in occur in gangliocytic paraganglioma, poorly differentiated neuroendocrine carcinoma and hereditary neuroendocrine tumors (MEN1)

Clinical features
=========================================================================

● Only rarely associated with somatostainoma syndrome (diabetes, cholecystolithiasis, steatorrhea, hypochlorhydria, Endocr Relat Cancer 2008;15:229)
● Hard to localize preoperatively
● May be in duodenal wall
● May have psammoma bodies

Clinical images
=========================================================================



Duodenal tumor-endoscopy

Micro images
=========================================================================



Somatostatin+ cells


3 cm, nonangioinvasive, nonfunctioning somatostatin cell tumor shows moderate nuclear crowding with distinct nucleoli; tumor recurred locally 14 years later with gross invasion and somatostatinoma syndrome


This locally invasive tumor shows a medullary pattern and no significant cellular atypia


Paraganglioma-like growth pattern


Various images

     
Duodenal tumors

Electron microscopy images
=========================================================================



D-cell granules in cells of somatostatinoma. Inset: The immunogold reactivity with somatostatin antibodies is seen



Tumors

VIPoma


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 28 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Also called Verner-Morrison tumors - tumors secrete vasoactive intestinal peptide (VIP)
● 90% of VIPomas arise from pancreas (eMedicine)

Clinical features
=========================================================================

● Diarrhea (cholera-like), hypokalemia, achlorhydria
● Neural crest tumors (ganglioneuroma, neuroblastoma, neurofibroma, pheochromocytoma) and G cell tumors produce similar symptoms
● Also contains pancreatic polypeptide, calcitonin, alpha chain of hCG
● May be locally invasive or metastastic

Case reports
=========================================================================

● 46 year old woman with 18 cm tumor (World J Surg Oncol 2008;6:80)

Gross images
=========================================================================



Pancreatic head tumor


Tumor producing 90% calcitonin, 10% VIP

Micro images
=========================================================================



Interconnecting nests and trabeculae of uniform cuboidal cells with granular cytoplasm and central round nuclei


Tumor producing 90% calcitonin, 10% VIP (left: H&E, right: VIP stain)


Small regular glands are present throughout a malignant VIPoma


Solid arrangement of uniform epithelial cells with faintly stained cytoplasm, interrupted by cystic spaces filled with weakly eosinophilic serum-like material


Trabeculae of epithelial cells with fairly abundant cytoplasm separated by loose stroma; scattered tumor cells show VIP immunostaining

Electron microscopy images
=========================================================================



Small secretory granules in a pancreatic tumor with scattered VIP-immunoreactive cells and associated WDHA syndrome


Cells with a few, round, small granules; well-developed reticulum and Golgi complex; and scattered elongated dense bodies


Abundant secretory granules of variable size, shape, and density in a pancreatic tumor with WDHA syndrome; abundant PP-and a few VIP-immunoreactive cells (inset) were detected by light microscopic immunohistochemistry



Other tumors

Inflammatory myofibroblastic tumor


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 2 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare tumor (more common in lung), that may constrict bile duct
● Cases with IgG4+ plasma cells perhaps should be classified separately as IgG4 related disorder, since they are distinct entities (Mod Pathol 2011;24:606)

Micro images
=========================================================================



19 year old man with cystic mass and splenic rupture

Micro description
=========================================================================

● Spindled cells, collagen, and variable lymphocytes and plasma cells
● Rarely has prominent eosinophils

Micro images
=========================================================================



Various images


19 year old man with cystic mass and splenic rupture


Loosely arranged spindle cells with admixed collagen bundles and scattered inflammatory infiltrate; proliferation extends into the adjacent fat and focal small lymphoid aggregates are present


Left: bland spindle cells with lymphocytes and plasma cells (arrows), but no mitotic activity; right-smooth muscle actin

Positive stains
=========================================================================

● Smooth muscle actin, vimentin, p53 (Virchows Arch 2006;448:552)
● ALK (70%, Am J Surg Pathol 2009;33:1330)

Negative stains
=========================================================================

● S100, keratin, EBV-LMP, EBER

Differential diagnosis
=========================================================================

● Follicular dendritic cell tumor
● Inflammatory fibrosarcoma



Tumors

Intraductal tubular adenoma


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 2 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare; intraductal tubular adenoma (ITA), pyloric gland type, first described in 1999 (Am J Surg Pathol 1999;23:227)
● Also called pyloric gland adenoma
● Cytologically bland nodular pancreatic intraductal epithelial proliferation with a predominantly tubular architecture (Stanford University)
● Benign tumor similar to pyloric gland type adenoma of gallbladder (Histopathology 2009;55:270)
● Either without (type A) or with (type B) associated gastric-type IPMN (Am J Surg Pathol 2005;29:607)

Gross description
=========================================================================

● Polypoid mass

Gross images
=========================================================================



Solid tumor (carcinoma) occupying main pancreatic duct with retention cyst

Micro description
=========================================================================

● Well-demarcated nodule composed of closely packed tubular glands lined by columnar, mucin-secreting cells with abundant clear cytoplasm and basally oriented nuclei
● Focal mild atypia present
● Pyloric metaplasia and focal papillary hyperplasia present in adjacent ductal epithelium
● Adjacent pancreas may show intraductal papillary-mucinous adenoma

Micro images
=========================================================================



Intraductal tubular neoplasm has closely packed glands resembling pyloric glands of stomach, lined by cuboidal to columnar cells with round nuclei and small nucleoli


Densely packed tubular glands without mucin pooling


Tumor cells proliferating in tubular fashion with irregular glandular arrangement.

Gallbladder lesions

Gallbladder: tubular glands lined by columnar cells with abundant mucin-containing cytoplasm and basal nuclei; cystically dilated gland is also seen


Gallbladder: cells with abundant eosinophilic cytoplasm similar to Warthin's tumor of salivary glands


Gallbladder: A-squamoid morule; B-cells with clear biotin-containing nuclei similar toendometrium of pregnancy


Gallbladder: with high-grade/dysplasia carcinoma in situ; closely packed glands lined by cells with large vesicular nuclei and prominent nucleoli; mitotic figures were present


Gallbladder: left-MUC6+, right-CDX2+

Positive stains
=========================================================================

● PAS with and without diastase; CK7 (Am J Surg Pathol 2004;28:233)

Negative stains
=========================================================================

● Alcian blue, chromogranin, synaptophysin

Molecular description
=========================================================================

● May have codon 12 Kras mutation of usual type pancreatic ductal adenocarcinoma and dysplasia (Am J Surg Pathol 1999;23:227)



Other tumors

Leukemia


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 28 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Case reports
=========================================================================

● 37 year old man with B-ALL and relapse in pancreas (Chin Med J (Engl) 2010;123:3364)
● 62 year old woman with plasma cell leukemia presenting as pancreatic mass (Arch Pathol Lab Med 1993;117:844)
● Man with hairy cell leukemia presenting as peripancreatic mass (Acta Cytol 2012;56:463)
● Two cases of primary granulocytic sarcoma of pancreas (World J Surg Oncol 2012;10:13)

Micro images
=========================================================================



B-ALL, relapse to pancreas, PAX5+


Granulocytic sarcoma (primary) of pancreas (H&E, CD43, CD34, myeloperoxidase)

Differential diagnosis
=========================================================================

● Adenocarcinoma: clinical features not typically found in leukemias are older age, jaundice, diabetes mellitus, B symptoms, no history of hematologic malignancy, large tumor size, high CA19-9 level (Am J Clin Pathol 2012;137:414)



Tumors

Lymphoid hyperplasia


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 30 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Case reports
=========================================================================

● Only ~5 cases reported (Clin Res Hepatol Gastroenterol 2012;36:e71)
● 57 year old woman with mass causing obstructive jaundice (Hum Pathol 1991;22:724)
● 70 year old man with incidental lesion on imaginge (Korean J Radiol 2011;12:510)

Treatment
=========================================================================

● Observation; investigate / treat any potential source of lymphoid reactivity

Micro images
=========================================================================



Various images


Hyperplastic lymphoid follicles with germinal centers; interfollicular areas are composed of mixed inflammatory cells and fibrous tissue; background pancreatic tissue shows exocrine acinar atrophy


A: H&E; B: CD79a+ B cells in lymphoid follicles and germinal centers; C: CD3+ T cells in interfollicular areas; D: germinal centers are BCL2+



Other tumors

Lymphoma


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 2 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Primary disease is rare (<200 cases reported); may originate in peripancreatic or retroperitoneal lymph nodes
● Biopsy required for diagnosis and to avoid resection, which is not required (BMC Cancer 2006;6:117)
● Only diffuse large B cell lymphoma is included in WHO classification

Clinical features
=========================================================================

● Usually in elderly
● Diffuse large B-cell lymphoma is most common (Am J Clin Pathol 2012;137:414, Diagn Cytopathol 2012;40:732)
● Present with abdominal pain and jaundice due to common bile duct obstruction or abdominal masses

Case reports
=========================================================================

● 58 year old man with follicular lymphoma invading pancreas from adjacent lymph node (JOP 2007;8:44)
● 65 year old woman with advanced angiocentric T cell lymphoma (peripheral T cell lymphoma, NOS) of pancreas and eye presenting as advanced diabetes mellitus with diabetic retinopathy (Hum Pathol 2001;32:741)

Clinical images
=========================================================================



Intraoperative findings of follicular lymphoma. a-tumor of head of pancreas; b/c-enucleation procedure for tumo; d-view after tumor enucleation

Gross images
=========================================================================



Follcular lymphoma

Micro images
=========================================================================



Angiocentric T cell lymphoma: A-pancreas is heavily infiltrated by lymphoma, with only some residual ducts and islets; B-tumor cells almost replace islet




Diffuse large B cell lymphoma


Diffuse large B cell lymphoma-65 year old man


Follcular lymphoma: a/b-central necrosis (H&E and CD20); c/d-proliferating follicules (H&E and CD20)



Other tumors

Metastatic tumors to pancreas


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 29 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Secondary pancreatic tumors usually occur by direct extension, not metastatic spread
● Primary site of metastases most commonly lung and GI tract (Virchows Arch 2004;444:527)
● Metastases usually are multifocal and lack fibrosis
● Excise metastasis if patient has low surgical risk and curative resection is possible (J Korean Surg Soc 2011;80:278)

Gross images
=========================================================================



Lung primary: adenocarcinoma

Micro images (metastases to pancreas)
=========================================================================



Breast: invasive ductal carcinoma


Kidney: renal cell carcinoma excised 5 years previously; tumor was originally diagnosed as an endocrine tumor


Lung: adenocarcinoma


Lung: small cell carcinoma


Rectum: carcinoma


Skin: Merkel cell carcinoma

Cytology images (metastases to pancreas)
=========================================================================



Left to right: prostatic adenocarcinoma, renal cell carcinoma, pulmonary small cell carcinoma, melanoma



Other tumors

PEComa


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 30 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Perivascular Epithelioid Cell tumor
● Rare, also called clear cell "sugar" tumor
● Well vascularized neoplasm composed of large, clear, epithelioid smooth muscle cells, HMB45+, MelanA+, smooth muscle actin+, keratin- (WHO)
● Concept first proposed in 1992 (Am J Surg Pathol 1992;16:307)
● Arises from perivascular epithelioid cells, which also cause lymphangioleiomyomatosis, angiomyolipoma (renal and extrarenal, Virchows Arch 2008;452:119), related tumors of falciform ligament / ligamentum teres, skin (Histopathology 2005;46:498), uterus (Mod Pathol 2005;18:1336) and other viscera and soft tissue
Origin: no known normal counterpart to perivascular epithelioid cell

Case reports
=========================================================================

● 31 year old woman with incidental mass (Virchows Arch 2005;446:555)
● 37 year old woman (Case of the Week #143)
● 49 year old man with incidental mass (JOP 2011;12:55)
● 51 year old woman withmalignant pancreatic PEComa (AIMM 2012 Published Ahead-of-Print)
● 60 year old woman (Am J Surg Pathol 1996;20:722)
● 60 year old woman with abdominal "buldge" (Am J Surg Pathol 1996;20:722)

Micro description
=========================================================================

● Large epithelioid cells, clear or eosinophilic granular cytoplasm containing glycogen with nuclear pleomorphism but no mitotic activity
● May have brown “dusty” pigment suggestive of melanin
● No glandular growth or sarcomatous features
● Malignant appearing tumors may have large zones of necrosis and nests of malignant cells with marked cellular pleomorphism and mitotic activity

Micro images
=========================================================================



Well-vascularized neoplasm composed of epithelioid smooth muscle cells with clear cytoplasm rich in glycogen




Malignant tumor


Left: HMB45, right: actin


Left to right: Well-demarcated tumor adjacent to normal pancreas (left-lower corner); tumor is composed of sheets of epithelioid to spindled cells with abundant clear to granular cytoplasm, and mild to moderate nuclear pleomorphism; MelanA+; SMA+

Positive stains
=========================================================================

● HMB45, MelanA, smooth muscle actin (Int J Surg Pathol 2010;18:243)
● Also CD1a (Pathol Int 2008;58:169), variable EMA, variable S100

Negative stains
=========================================================================

● Cytokeratin, CD68, CD45, CD117, NSE, chromogranin A, lipase, amylase, inhibin

Electron microscopy description
=========================================================================

● Membrane bound granules
● Typical melanosomes or premelanosomes and aberrant melanosomes (Pathol Int 2009;59:650, Ultrastruct Pathol 2012;36:124)

Differential diagnosis
=========================================================================

● Recommended to thoroughly sample tumor, use melanocytic markers and other immunostains, possibly molecular markers
Clear cell carcinoma
● Also alveolar soft part sarcoma, clear cell sarcoma of soft parts, GIST, leiomyosarcoma, melanoma, paraganglioma (Am J Surg Pathol 2009;33:475)



Other tumors

Phyllodes tumor


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 6 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Similar to breast tumor; metastases much more likely than pancreas primary

Case reports
=========================================================================

● First primary case reported was 37 year old man (Virchows Arch 2010;456:587)

Micro description
=========================================================================

● Cyst walls lined with a monolayer of non-atypical tall columnar epithelial cells
● Solid areas show storiform proliferation of spindle cells with round, oval or elongated nuclei; also abundant collagen fibers
● Solid areas send phylloid projections into the cystic spaces and main pancreatic duct

Micro images
=========================================================================



Case report: a-main pancreatic duct is filled with tumor; b-solid parts of lesion send phylloid projections into cystic spaces; c-margins between tumor and pancreatic tissues are well demarcated; d-small blood vessels are embedded in solid areas

Cytology images
=========================================================================



Metastatic tumor to pancreas - stromal cells show cytological atypia, with nuclear enlargement, irregular chromatin, irregular nuclear membrane

Positive stains
=========================================================================

● Diffusely positive for alpha-smooth muscle actin, desmin, h-caldesmon

Electron microscopy description
=========================================================================

● Well-developed myofilaments with dense bodies, pinocytic vesicles, basal lumina

Differential diagnosis
=========================================================================

● Gastrointestinal stromal tumor
Inflammatory myofibroblastic tumor
● Leiomyoma
● Leiomyosarcoma
Schwannoma
● Solitary fibrous tumor



Other tumors

Primitive neuroectodermal tumor (PNET)


Reviewer: Deepali Jain, M.D. (see Reviewerspage)
Revised: 2 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Small round blue cell tumor with evidence of neuroectodermal differentiation; similar to tumors at other sites
● See also Kidney tumor chapter
● Mean 18 years (range 6 to 25 years, Am J Surg Pathol 2002;26:1040)
● Usually soft tissue or bone of children/young adults, rare in pancreas (1% of pancreas sarcomas)
● At all sites, 5 year survival is 50%

Case reports
=========================================================================

● 17 year old boy (Mod Pathol 1994;7:200)
● 33 year old man with 18 cm tumor (World J Gastroenterol 2006;12:6070)
● 36 year old woman (Int J Clin Oncol 2012;17:399)
● 37 year old with 4 cm Ewing's sarcoma/PNET and multiple hepatic tumors (Intern Med 2009;48:329)

Gross description
=========================================================================

● Tumors in head of pancreas, 3.5 to 9.0 cm

Micro description
=========================================================================

● Sheets and lobules of small round cells with scant cytoplasm
● Prominent nuclear molding, frequent mitotic activity
● Often infiltrate into peripancreatic soft tissue
● Variable tumor necrosis
● Usually no rosettes

Micro images
=========================================================================



Left: sheets of small round cells with rich fibrovascular stroma; middle: rudimentary rosette; right: diffusely CD99+


Site unspecified - left: sheets of uniform, small, round, blue cells. middle: Homer-Wright rosettes; right: atypical PNET with larger cells that often have a prominent nucleolus

Positive stains
=========================================================================

● CD99 (O13/MIC2), cytokeratin, neuroendocrine markers (chromogranin, synaptophysin, NSE)

Negative stains
=========================================================================

● Desmin

Molecular description
=========================================================================

● t(11;22)(q24;q12)

Differential diagnosis
=========================================================================

● Intraabdominal desmoplastic small round cell tumor: dense fibrous stroma, strong desmin staining, different t(11;22) than PNET
● Lymphoblastic lymphoma: CD99+ but TdT+ also
● Metastatic PNET to pancreas: see Clin Imaging 1997;21:23
● Neuroblastoma: younger patients, produce catecholamines, no t(11;22)
● Neuroendocrine carcinoma
● Pancreatic endocrine neoplasm: usually adults, slow growing; no molding, negative for neuroendocrine markers
● Pancreatoblastoma: usually age 10 or less, acinar formations, squamoid corpuscles, no t(11;22)
● Rhabdomyosarcoma
● Small cell carcinoma: higher mitotic rate, numerous karyorrhectic bodies, focal glandular differentiation, no t(11;22), usually elderly



Other tumors

Sarcoma


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 30 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare (0.1%), may resemble sarcomatoid carcinoma, anaplastic carcinoma, extension of retroperitoneal or gastroduodenal sarcoma
● Leiomyosarcoma: similar morphology as other sites; recommended to resect extensively even low grade lesions, and to rule out EBV associated smooth muscle tumors with EBER testing (Am J Surg Pathol 2010;34:1849)

Case reports
=========================================================================

● 76 year old man with leiomyosarcoma causing death within 1 year (Arch Pathol Lab Med 2001;125:152
● MFH with post-operative death (Hum Pathol 1989;20:1215)

Micro images
=========================================================================



Leiomyosarcoma - various images


Leiomyosarcoma: H&E, h-caldesmon



Tumors

Schwannoma


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 24 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● May arise from extrapancreatic nerve plexus (Surgery 2012 Oct 24)
● Rare, mean age 60 years, M=F, 2/3 partially cystic, typical histology (Mod Pathol 1998;11:1178)
● 62 year old man with microcystic/reticular variant (Pathol Int 2011;61:88)

Gross images
=========================================================================



Cut surface composed of solid, myxomatous and hemorrhagic areas


Cystic tumor of pancreatic tail

Micro images
=========================================================================



Left/middle: spindle cell proliferation with interlacing and palisading patterns; right: myxoid / edematous degeneration with hemorrhage, hemosiderin and hyalinized and dilated vascular walls (Antoni B)


Giant malignant schwannoma of pancreatic body and tail, which involved transverse colon

Cytology images
=========================================================================



Cystic fluid: a-scattered spindle cells with background hemosiderin-laden histiocytes; b-tumor cells have fine granular chromatin with single prominent nucleolus; c-some tissue fragments are composed of spindle cells; d-S100+



Tumors

Features to report


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 24 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Features to report (includes endocrine tumors)
=========================================================================

● Tumor size
● Tumor location
● Histopathologic type
● Histologic grade (well, moderate, poor or undifferentiated; not necessary for endocrine tumors)
● Perineurial invasion
● Angiolymphatic invasion
● Margins (common bile duct, pancreatic duct, retroperitoneal margin [soft tissue adjacent to superior mesenteric artery], surgical margin)
● Endocrine tumors: mitotic activity, necrosis, pleomorphism, amyloid
● Involvement of adjacent structures
● Lymph nodes
● Presence of PanIN (including marginal involvement)
● Findings in remaining pancreas (pancreatitis, nesidioblastosis for endocrine tumors)

References: Arch Pathol Lab Med 2000;124:30 (endocrine tumors)



Exocrine tumors

Frozen section / exploration of possible pancreatic adenocarcinoma


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 6 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Intraoperative strategies
=========================================================================

● Surgeon should check for metastatic disease in peripancreatic nodes, liver, peritoneum
● Dilation of common bile duct and jaundice without biliary tract stones is highly suggestive of tumor
● Intraoperative FNA minimizes hemorrhage, pancreatitis, tumor seeding
● For patients with colloid carcinoma (larger tumors, typically in head, mucin lakes microscopically), avoid incisions into the tumor to prevent thromboemboli or tumor dissemination

Frozen section
=========================================================================

● Results may change extent of resection (World J Gastrointest Surg 2010;2:352)
● Look for disorganized duct distribution, variation in nuclear size of at least 4:1, incomplete duct lumen (Arch Pathol Lab Med 2002;126:1169, Am J Surg Pathol 1981;5:179)
● Minor criteria are infiltrating single cells, perineurial invasion, mitotic figures, necrotic glandular debris

Micro images
=========================================================================



Frozen section diagnosis of chronic pancreatitis versus ductal adenocarcinoma


Frozen section (left to right): normal, IPMN with low grade dysplasia, IMPN with borderline/moderate dysplasia


Frozen section: figures 2, 4-6 are pancreatic adenocarcinoma, figures 1 and 3 are chronic pancreatitis

Differential diagnosis
=========================================================================

Chronic pancreatitis: characteristic lobular arrangement at low power; limited nuclear size variation, only slight nuclear irregularity, nucleoli are inconspicuous



Tumors

Grossing


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 24 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Ink common bile duct margin, pancreatic duct margin, retroperitoneal margin, other soft tissue margins, duodenum, stomach
● Retroperitoneal margin: soft tissue adjacent to right lateral border of superior mesenteric artery, site of most local recurrences
● Margins should be sectioned perpendicular to the inked margin
References: University of Michigan, Essential Pathology, Pathology Resident Wiki

Diagrams
=========================================================================



Pancreas and duodenum

Videos
=========================================================================






Miscellaneous

Staging


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 26 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Based on AJCC Cancer Staging Manual (7th ed); same classification for clinical and pathological staging, as most patients don’t have resections
● See also WHO, Cancer Imaging 2010;10:S137

Primary Tumor (T)
=========================================================================

TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
Tis: Carcinoma in situ (includes PanIn III)
T1: Tumor limited to the pancreas, 2 cm or less in greatest dimension
T2: Tumor limited to pancreas, more than 2 cm in greatest dimension
T3: Tumor extends beyond the pancreas but without involvement of the celiac axis or the superior mesenteric artery
T4: Tumor involves the celiac axis or the superior mesenteric artery (unresectable primary tumor)

Regional Lymph Nodes (N)
=========================================================================

NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Regional lymph node metastasis

Distant metastasis (M)
=========================================================================

M0: No distant metastasis
M1: Distant metastasis

Anatomic stage / prognostic groups
=========================================================================

Stage 0: Tis N0 M0
Stage IA: T1 N0 M0
Stage IB: T2 N0 M0
Stage IIA: T3 N0 M0
Stage IIB: T1-3 N1 M0
Stage III: T4 Any N M0
Stage IV: Any T Any N M1



Miscellaneous

Pancreas transplantation


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 23 November 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Whole organ transplant
=========================================================================

● Includes pancreas transplant alone, simultaneous pancreas and kidney transplant, pancreas after kidney transplant
● Pancreas and kidney transplanted together to achieve better glycemic control, and due to significant diabetic nephropathy
● Indications of whole organ transplant: chronic pancreatitis

Islet transplant
=========================================================================

● Main indication is severe type I diabetes; also patients for whom exogenous insulin may precipitate catastrophic hypoglycemia

Clinical features
=========================================================================

Early complications: graft pancreatitis, pancreatic thrombosis, endothelialitis of capillaries and venules
Late complications: recurrence of original disease, rejection (vasculitis, obliterative endarteritis, periductal lymphocytic infiltrate), mononuclear inflammation which preferentially destroys beta cells
● Survival: 95% at one year post-transplant, 83% after 5 years (Rev Diabet Stud 2011;8:6)
Poor prognostic factors: moderate to severe acinar inflammation, acinar tissue loss, fibrosis, vascular luminal narrowing (Am J Surg Pathol 1992;16:1098)
Note: transplanted islets produce more glucagon than insulin

Rejection
=========================================================================

● Adequate biopsy requires 3 lobular areas and associated interlobular septa
● Inflammation of acini, veins, arteries, ducts; associated with acinar cell damage
● Evaluation for arteritis is critical
● >75% mixed small and large T lymphocytes, fewer mature plasma cells, variable eosinophils
● <10% atypical cells

Acute rejection:
● Usually 7-12 months posttransplant
● Necrosis, infiltration of venous walls with associated endothelialiti
● Mild (Grade I): mononuclear septal inflammation with ductulitis and venulitis
● Moderate (Grade II): multiple foci (>3 foci per lobule) of acinar inflammation with associated single cell necrosis or drop out
● Severe (Grade III): Severe acinar inflammation, moderate-severe intimal arteritis
Banff schema: Am J Transplant 2008;8:1237, Am J Transplant 2011;11:1792 (updated for antibody mediated rejection)
Additional references: Adv Anat Pathol 2010;17:202, Arch Pathol Lab Med 2007;131:1192, University of Pittsburgh

● Chronic Rejection: acinar atrophy, aparenchymal fibrosis, obliterative arteriopathy
● Antibody-mediated rejection: C4d in vessels

Micro images
=========================================================================



Acute rejection


Chronic rejection


Various images

Banff criteria images

Differential diagnosis
=========================================================================

Posttransplantation lymphoproliferative disease: distinction important since opposite treatments; nodular and expansile infiltrates, mostly atypical, plasmacytoid B cells, occasional Reed-Sternberg-like cells; involves both acini and islets; extensive infiltration of peripancreatic soft tissues is common, no involvement of arterial walls unless concurrent acute vascular rejection; EBER+ (ISH) (Hum Pathol 1998;29:569)

End of Pancreas > Superpage > Tumor


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