Pancreas
Exocrine tumors / carcinomas
Ductal adenocarcinoma, NOS
Author: Wei Chen, M.D., Ph.D.
Editorial Board Member: Raul S. Gonzalez, M.D.
Topic Completed: 1 October 2017
Minor changes: 11 June 2020
Copyright: 2003-2020, PathologyOutlines.com, Inc.
PubMed Search: Ductal adenocarcinoma [title] pancreas
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Laboratory | Radiology description | Prognostic factors | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Electron microscopy description | Electron microscopy images | Molecular / cytogenetics description | Differential diagnosis | Additional references | Board review style question #1 | Board review answer #1 | Board review style question #2 | Board review answer #2Cite this page: Chen W. Ductal adenocarcinoma, NOS. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/pancreasductal.html. Accessed August 6th, 2020.
Definition / general
- An infiltrating epithelial neoplasm with glandular (ductal) differentiation, usually demonstrating luminal or intracellular mucin and without a predominant component of any other histological type (Bosman: WHO Classification of Tumours of the Digestive System, 4th Edition, 2010)
Essential features
- Poor prognosis: 5 year survival rate 6% (Cancer Res 2014;74:2913); 90% die within 1 year
- An adenocarcinoma derived from pancreatic ductal epithelia, with randomly arranged epithelial elements, in situ carcinoma, intense stromal desmoplasia and variable necrosis
- Currently, there are three recognized precursors of invasive ductal adenocarcinoma: pancreatic intraepithelial neoplasia / PanIN, intraductal papillary mucinous neoplasm / IPMN and mucinous cystic neoplasm / MCN (Bosman: WHO Classification of Tumours of the Digestive System, 4th Edition, 2010)
Terminology
- Also called tubular adenocarcinoma, usual ductal adenocarcinoma (UDA)
ICD coding
- ICD-10: C25.3
Epidemiology
- Fourth leading cause of U.S. cancer death after lung and colon (CA Cancer J Clin 2017;67:7); projected to be second (after lung cancer) by 2020 (Am Soc Clin Oncol Educ Book 2016;35:e205)
- Estimated 53,670 new cases, 43,090 deaths in 2017 (CA Cancer J Clin 2017;67:7)
- Male to female ratio = 1.6:1
Sites
- Head of the pancreas: 60% - 70%; body: 5 - 15%; tail: 10 - 15%
- Head tumors: 50% have distention of biliary tree and progressive jaundice; 85% have extension beyond pancreas at diagnosis
- Body / tail tumors: typically larger at diagnosis since these tumors do not cause symptoms until late; 25% have peripheral venous thrombi; metastases common
- Rarely arises from heterotopic pancreatic tissue in the gastrointestinal tract
Pathophysiology
- Invasive ductal adenocarcinoma arises in association with precursor lesions: PanIN, IPMN or MCN (Bosman: WHO Classification of Tumours of the Digestive System, 4th Edition, 2010)
Etiology
- Risk factors: smoking, alcohol abuse (particularly in African Americans), obesity, high intake of dietary saturated fat, chronic pancreatitis, diabetes
- Hereditary syndromes: Peutz-Jeghers syndrome, hereditary pancreatitis, familial atypical multiple mole melanoma (FAMMM), familial pancreatic cancer, Lynch syndrome, familial breast cancer and other Fanconi anemia genes, familial adenomatous polyposis / FAP (Bosman: WHO Classification of Tumours of the Digestive System, 4th Edition, 2010)
Clinical features
- Back pain, weight loss, malaise, jaundice, diabetes mellitus
- Trousseau sign: migratory thrombophlebitis in 10% due to tumor or tumor necrosis producing platelet aggregating factors and procoagulants; causes arterial and venous thrombi
- Coexisting pancreatitis 10%
- Metastases:
- Local lymph nodes (microscopic metastases found in 75% with T1 / T2 disease)
- Liver, lung, peritoneum, adrenal, bone, distal nodes
- Supraclavicular node metastasis may be presenting symptom
- Tumor may track along biopsy needle path
- Metastases to ovary may simulate primary mucinous ovarian tumors (Am J Surg Pathol 1989;13:748)
Diagnosis
- Preoperative / pretreatment by endoscopic ultrasound guided fine needle aspiration (EUS-FNA)
- Surgical resection specimen
Laboratory
- Serum tests: CA19-9, CEA
Radiology description
- Hypodense mass on CT imaging in 92% of cases
- “Double duct” sign (dilation of both the biliary and pancreatic ducts) in pancreatic head mass
Prognostic factors
- Dependent on stage and tumor size
- Resectable and < 4.5 cm are favorable factors
- Perineural invasion and vascular invasion are adverse prognostic factors (Eur J Surg Oncol 2007;33:892)
- High histologic grade (grades 3 and 4) unfavorable
- Any squamous component indicates poorer prognosis (median survival 7 - 11 months) (Bosman: WHO Classification of Tumours of the Digestive System, 4th Edition, 2010)
Treatment
- Most (85%) tumors are not amenable to curable surgery
- For head / periampullary tumors: Whipple resection (subtotal pancreaticoduodenectomy), perioperative mortality ~ 2%
- For body / tail tumors: distal pancreatectomy
- Resect retroperitoneal nerves and nodes if stage I / II to reduce local recurrence
- Palliative treatment includes bypass operations, chemotherapy (gemcitabine) and radiation therapy
Gross description
- White gray, sclerotic, poorly defined mass
- > 75% of ductal adenocarcinoma are solid tumors
- 25% of head tumors extend to duodenal wall
- If advanced, may be difficult to determine site of origin between pancreas, ampulla and common bile duct
- 20% have multiple tumors
Gross images
Contributed by Wei Chen, M.D., Ph.D.
Arising in IPMN
Arising in high grade PanIN
Microscopic (histologic) description
- Infiltrating well to poorly formed glandular / ductal structures surrounded by remarkably desmoplastic stroma
- Mucin production is specific for ductal origin vs. acinar or neuroendocrine differentiation
- Perineural invasion present in 90%, typically with better differentiated glands
- Angiolymphatic invasion in 50%; vacular invasion may mimic PanIN (Am J Surg Pathol 2012;36:235)
- Well differentiated: pink apical band composed of mucin granules, may appear benign but has irregular shape and distribution; desmoplasia, marked nuclear pleomorphism with nucleoli, loss of polarity, mitotic figures
- Moderately to poorly differentiated: seen in most tumors; abortive tubular structures, deeply infiltrative growth pattern, frequent mitosis, irregular and abortive mucin production
- TNM histologic grading system, recommended by College of American Pathologists, is based on the extent of glandular differentiation: G1=well differentiated, ( > 95% tumor composed of glands), G2=moderately differentiated (50 - 95% glands), G3=poorly differentiated ( < 49 glands), G4=no or minimal differentiation
- Klöppel grading system: G1 (well) to G3 (poorly differentiated) based on four criteria: degree of glandular differentiation, mucin production (lower grade more mucin), mitosis ( < 5/10HPF, 6-10/10HPF, > 10/10HPF) and nuclear features (Histopathology 1985;9:841)
- Background pancreas may show high grade PanIN, atrophic changes, chronic inflammatory infiltrate, fibrosis, ductal dilation beyond tumor mass
- Non-WHO variants:
- Clear cell: not uncommon in ductal adenocarcinoma (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; overexpression of HNF-1β by IHC
- Foamy gland: deceptively benign appearing pattern with prominent microvesicular (foamy) cytoplasm, first described in pancreas (Am J Surg Pathol 2000;24:493); also prostate; 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); foamy material is due to evenly sized mucigen granules that are mucin negative; foamy PanIN proposed to be the precursor lesion (Ann Diagn Pathol 2008;12:252)
- Large duct: seen in < 10% of usual ductal adenocarcinoma (Mod Pathol 2012;25:439); ducts are clustered with irregular jagged contours, diameter of most ducts is 0.5 mm to 1 cm; may have desmoplastic and myxoid stroma, intraluminal neutrophils and granular debris; 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
- Vacuolated: high grade tumors with clusters of tumor cells containing large vacuoles imparting cribriform architecture or reminiscent of adipocytes or signet ring cells; microcysts contain cellular debris and mucin; can resemble fat necrosis or lipogranulomas in lymph node; recognizing the atypical, enlarged, hyperchromatic nuclei is key (Virchows Arch 2010;457:643)
Microscopic (histologic) images
Contributed by Wei Chen, M.D., Ph.D.
Anisonucleosis
Glands next to vessel
Perineural invasion
Gland in adipose
Moderately differentiated
Poorly differentiated
Foamy gland pattern
Cytology description
- EUS-FNA has sensitivity and specificity of > 90% and 100%, increased sensitivity with ThinPrep, 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 ("drunken honeycomb"), clusters or singly; anisonucleosis (4:1 variation)
- Signet rings cells and mitotic figures are helpful when present, but may be absent
- Papanicolaou Society of Cytopathology's six tiered system for pancreatobiliary cytology: non diagnostic, negative for malignancy, atypical, neoplastic, suspicious and positive / malignant (Cytojournal 2014;11(Suppl 1):3)
- Duodenal secretions are 80% sensitive in head tumors, 33% sensitive in tail tumors; ERCP juice is 50 - 85% sensitive
Cytology images
Contributed by Regina Plummer, D.O.
Abundant inspissated mucin
Transition into drunken honeycomb
Anisonucleosis (4:1 variation)
AFIP
cells are in cohesive groups and have large,
pleomorphic nuclei and moderate cytoplasm
Positive stains
- Maspin, placental S100 (S100P) and IMP3 (all positive) and pVHL (negative) staining pattern present in > 90% UDA vs. reactive ducts (opposite results) (Arch Pathol Lab Med 2012;136:601, Hum Pathol 2013;44:503)
- p53 expressed in most cases
- CK7, CK8, CK18, CK19, MUC1, MUC3, MUC4, MUC5AC, CEA, B72.3, CA19-9, CA125 (48%)
Negative stains
- Loss of DPC4 seen in 55%; specific for malignancy (in situ or invasive) (Am J Clin Pathol 2001;116:831)
- CK20, MUC2, vimentin, synaptophysin, chromogranin, trypsin, chymotrypsin, lipase
Electron microscopy description
- Mucigen granules
Electron microscopy images
AFIP
Molecular / cytogenetics description
- Four key driver gene mutations (Arch Pathol Lab Med 2011;135:716, Hum Pathol 2009;40:612, Cancer Cell 2017;32:185)
- KRAS: > 95%, early event during carcinogenesis (Cancer 2007;109:1561)
- CDKN2A (p16): 95%
- TP53: 50 - 80%
- SMAD4: 55%
- 50% overexpress HER2
- Many core signaling pathways involved
- ~10% of pancreatic cancers have a familial basis
Differential diagnosis
- Ampullary adenocarcinoma: epicenter at ampulla, presence of preinvasive component at ampulla
- Chronic pancreatitis: lobular architecture at low power with central ectatic branched ductules and clusters of round ductules surrounded by cuff of stroma (Arch Pathol Lab Med 2009;133:382)
- Features of UDA to differentiate above (Arch Pathol Lab Med 2015;139:848):
- UDA has anisonucleosis (4:1 variation), loss of cell polarity, perineurial invasion, individual cell infiltration, budding into lumen; has p53 mutations and loss of SMAD4 / DPC4
- UDA has haphazard architecture and glands at abnormal locations in interlobular areas, next to vessels and "naked glands" in fat
- Distal bile duct adenocarcinoma: epicenter at bile duct, circumferential / symmetrical involvement of the bile duct, presence of in situ component (BilIN or biliary intraductal papillary neoplasm)
Additional references
Board review style question #1
Among the entities below, which one is not considered a precursor lesion for invasive ductal adenocarcinoma of pancreas?
- Intraductal papillary mucinous neoplasm
- Mucinous cystic neoplasm
- Pancreatic intraepithelial neoplasia
- Solid pseudopapillary neoplasm
Board review answer #1
Board review style question #2
- The above microphotograph demonstrates a section from peripancreatic adipose tissue in a patient with pancreatic ductal adenocarcinoma. What is the lesion in the center of the microphotograph?
- Intraductal papillary mucinous neoplasm
- Pancreatic ductal adenocarcinoma
- Pancreatic intraepithelial neoplasia, high grade
- Pancreatic intraepithelial neoplasia, low grade
Board review answer #2
