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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.


● 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)



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

End of Pancreas > Tumors > Pancreatic endocrine neoplasms - general

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