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Pancreas

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

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

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

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

Differential diagnosis
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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

End of Pancreas > Tumors > Pancreatic endocrine neoplasms - general


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