Clear cell pancreatic endocrine tumor

Pancreas

Neuroendocrine neoplasms

Authors: Adam L. Booth, M.D., Raul S. Gonzalez, M.D.

Editor-in-Chief: Debra L. Zynger, M.D.

Topic Completed: 15 October 2019

Minor changes: 4 January 2021

Copyright: 2019-2021, PathologyOutlines.com, Inc.

PubMed Search: Clear cell [title] pancreatic endocrine tumor

Page views in 2020: 1,654

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Table of Contents

Cite this page: Booth A, Gonzalez R. Clear cell pancreatic endocrine tumor. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/pancreasclearcellendocrine.html. Accessed January 22nd, 2021.

Definition / general

An uncommon morphologic variant of pancreatic well differentiated neuroendocrine tumor, associated with von Hippel-Lindau syndrome (VHL) and multiple endocrine neoplasia type I (MEN I) syndrome

Essential features

Clear, vacuolated cytoplasm due to accumulation of lipid, glycogen or mucin
Characteristic “salt and pepper” nuclear chromatin features
Can be easily misdiagnosed due to morphologic similarities with primary and metastatic tumors of the pancreas

Terminology

Also known as lipid rich variant

ICD coding

ICD10: C25.4 - malignant neoplasm of endocrine pancreas

Epidemiology

Adults ages 40 - 60
No sex predilection
Syndromic patients may present at an earlier age (Pathol Res Pract 2016;212:747)

Sites

Most commonly in the head of the pancreas

Pathophysiology

In VHL, the disease results from deletions or mutations in the VHL tumor suppressor gene on chromosome 3p25.5 (Mod Pathol 2011;24:S66)
Mutations in MEN1 on chromosome 11q result in loss of function of tumor suppressor protein menin (Mod Pathol 2011;24:S66)
Sporadic tumors consistently result from allelic loss of chromosome 11q

Clinical features

Patients with VHL or MEN I may be screened following clinical suspicion
Patients may present for evaluation of abdominal symptoms or abnormal laboratory results
Some cases may be found incidentally on imaging (Mod Pathol 2011;24:S66)
Pancreatic neuroendocrine tumors in VHL or MEN I are typically non functional (Arch Pathol Lab Med 2006;130:963)

Diagnosis

Imaging may identify a suspicious mass
Definitive diagnosis is made following endoscopic biopsy or surgical resection

Radiology description

Hyperintense, enhancing mass, well circumscribed with sharp boarders on computed tomography (Radiographics 2010;30:1445)

Prognostic factors

Worse prognosis with high Ki67 proliferative index, tumor size > 2 cm, non functioning tumors, tumor necrosis and poor response to chemotherapy (J Hepatobiliary Pancreat Sci 2015;22:586, Mod Pathol 2011;24:S66)

Case reports

29 year old man with liver and pancreatic lesions (Diagn Cytopathol 2009;37:365)
32 year old woman with abdominal pain and a pancreatic mass (Cytojournal 2016;13:7)
47 year old woman presenting with a mass in the pancreatic tail (Neuro Endocrinol Lett 2017;38:83)
60 year old woman with pancreatic cysts and octreotide avid lesions (Virchows Arch 2013;463:593)
64 year old man with a nodule in the head of the pancreas (Cytopathology 2013;24:197)

Treatment

Surgical resection and chemotherapy (Mod Pathol 2011;24:S66)

Gross description

Most often solid, solitary, homogenous, tan to yellow (Am J Surg Pathol 2001;25:602)
If extensive fibrosis present, may be gray and firm (J Hepatobiliary Pancreat Sci 2015;22:586)
Hereditary syndromes may present with multiple tumors
Rarely a cystic component can be seen (Neuro Endocrinol Lett 2017;38:83)

Microscopic (histologic) description

Solitary, well circumscribed
Widely variable architectural patterns: nested, trabecular, glandular, ribbon-like, tubuloacinar, mixed patterns are common; however, there is usually a dominant pattern (Arch Pathol Lab Med 2006;130:963)
Small / medium round, polygonal cells with clear, vacuolated cytoplasm due to lipid accumulation
Central nucleus with characteristic "salt and pepper" chromatin pattern and inconspicuous nucleoli (Arch Pathol Lab Med 2009;133:350)

Microscopic (histologic) images

Contributed by Aatur Singhi, M.D., Ph.D.

Nests of tumor cells

Clear, vacuolated cytoplasm

Salt and pepper chromatin

Synaptophysin positivity

Cytology description

Isolated or small clusters of round monomorphic tumor cells (Cytopathology 2013;24:197)
Numerous small cytoplasmic vacuoles imparting a “foamy” appearance
Eccentric nuclei with fine nuclear chromatin, without prominent nucleoli (J Hepatobiliary Pancreat Sci 2015;22:586)

Cytology images

Image hosted on other servers:

Papanicolaou stain of FNA

Positive stains

Synaptophysin, chromogranin A, CD56, AE1/AE3, PAX8 (Laboratory Medicine 2009;40:417, Cytopathology 2013;24:197, Virchows Arch 2013;463:593, J Hepatobiliary Pancreat Sci 2015;22:586)

Negative stains

CK7, CK20, MelanA, CAIX, HMB45 (Mod Pathol 2008;21:1075, Cytopathology 2013;24:197, Arch Pathol Lab Med 2010;134:1080, J Hepatobiliary Pancreat Sci 2015;22:586)

Electron microscopy description

Variably sized cytoplasmic lipid globules and dense neurosecretory granules (Arch Pathol Lab Med 2009;133:350)

Molecular / cytogenetics description

von Hippel Lindau disease
- Autosomal dominant mutation in VHL tumor suppressor gene on chromosome 3p25.5 (Arch Pathol Lab Med 2010;134:1080)
Multiple endocrine neoplasia type I
- Autosomal dominant germline mutation in MEN1 tumor suppressor gene on chromosome 11q13
Sporadic tumors may arise from chromosomal alterations, epigenetic changes or functional genomic alterations

Videos

Pancreatic neuroendocrine neoplasms: overview

Sample pathology report

Pancreas, partial pancreatectomy:
- Well differentiated pancreatic neuroendocrine tumor, clear cell variant (grade 1) (see synoptic report)
- Surgical margins free of malignancy

Differential diagnosis

Metastatic
- Renal cell carcinoma, clear cell type: positive for AE1/AE3, CD10, PAX8, CAIX; negative for neuroendocrine markers (Arch Pathol Lab Med 2010;134:1080)
Primary
- Ductal adenocarcinoma with clear cell features: positive for AE1/AE3; negative for neuroendocrine markers
- Serous cystadenoma, solid variant: positive for PAS, AE1/AE3, vimentin; negative for synaptophysin
- Solid pseudopapillary neoplasm, clear cell variant: positive for beta catenin (nuclear and cytoplasmic), CD10, CD56, vimentin; variable neuroendocrine markers; loss of E-cadherin (J Hepatobiliary Pancreat Sci 2015;22:586)
- Clear cell sugar tumor / PEComa: positive for PAS, HMB45
Peripancreatic region
- Adrenocortical tumors: positive for inhibin, MelanA; weak with AE1/AE3; negative for chromogranin A (J Hepatobiliary Pancreat Sci 2015;22:586)
- Clear cell hepatocellular carcinoma: positive for Arginase1, HepPar1; negative for neuroendocrine markers

Additional references

Am J Surg Pathol 2006;30:194, Adv Anat Pathol 2004;11:202

Board review style question #1

A diagnosis should not stimulate genetic evaluation for the VHL syndrome
Frequently immunoreactive for cytokeratins
Only seen in the setting of VHL disease
Immunohistochemistry can distinguish from histologically similar metastatic clear cell renal cell carcinoma in VHL disease
Tumors associated with VHL syndrome and MEN1 syndrome are often functional tumors

Board review style answer #1

D. Immunohistochemistry can distinguish clear cell pancreatic endocrine tumors from histologically similar metastatic clear cell renal cell carcinoma in VHL disease

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Reference: Clear cell pancreatic endocrine tumor

Board review style question #2

Mutation in APC tumor suppressor gene on chromosome 5q21-22
Mutation in c-KIT proto-oncogene gene on chromosome 4q11-4q13
Mutation in CDH1 gene on chromosome 16q22.1
Mutation in MET proto-oncogene located on chromosome 17q31.1-34
Mutation in VHL tumor suppressor gene on chromosome 3p25.5

Board review style answer #2

E. Mutation in VHL tumor suppressor gene on chromosome 3p25.5

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Reference: Clear cell pancreatic endocrine tumor