Pancreas
Exocrine tumors
Ductal adenocarcinoma, NOS (not otherwise specified)

Editorial Board Member: Raul S. Gonzalez, M.D.
Wei Chen, M.D., Ph.D.

Topic Completed: 1 October 2017

Minor changes: 6 March 2020

Copyright: 2003-2020, PathologyOutlines.com, Inc.

PubMed Search: Ductal adenocarcinoma [title] pancreas

Wei Chen, M.D., Ph.D.
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Cite this page: Chen W. Ductal adenocarcinoma, NOS. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/pancreasductal.html. Accessed May 30th, 2020.
Definition / general
Essential features
Terminology
  • Also called tubular adenocarcinoma, usual ductal adenocarcinoma (UDA)
ICD coding
Epidemiology
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
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
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.
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Arising in IPMN

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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.
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4x Anisonucleosis

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Glands next to vessel

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Perineural invasion

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Gland in adipose

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Moderately differentiated

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Poorly differentiated


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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

AFIP
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Moderately differentiated ductal adenocarcinoma:
cells are in cohesive groups and have large,
pleomorphic nuclei and moderate cytoplasm
Positive stains
Negative stains
Electron microscopy description
  • Mucigen granules
Electron microscopy images

AFIP
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Well differentiated
Molecular / cytogenetics description
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)
Board review style question #1
Among the entities below, which one is not considered a precursor lesion for invasive ductal adenocarcinoma of pancreas?

  1. Intraductal papillary mucinous neoplasm
  2. Mucinous cystic neoplasm
  3. Pancreatic intraepithelial neoplasia
  4. Solid pseudopapillary neoplasm
Board review answer #1
D. Solid pseudopapillary neoplasm

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Reference: Ductal adenocarcinoma, NOS
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?

    1. Intraductal papillary mucinous neoplasm
    2. Pancreatic ductal adenocarcinoma
    3. Pancreatic intraepithelial neoplasia, high grade
    4. Pancreatic intraepithelial neoplasia, low grade
Board review answer #2
B. Pancreatic ductal adenocarcinoma

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Reference: Ductal adenocarcinoma, NOS
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