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Pancreas

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

Positive stains
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● 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
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● 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
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● Mucigen granules on EM

Electron microscopy images
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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
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● 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
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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

End of Pancreas > Tumors > Ductal adenocarcinoma, NOS


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