Neuroendocrine neoplasms

Clear cell pancreatic endocrine tumor

Editor-in-Chief: Debra L. Zynger, M.D.
Adam L. Booth, M.D.
Raul S. Gonzalez, M.D.

Last author update: 16 February 2021
Last staff update: 29 August 2022

Copyright: 2019-2023,, Inc.

PubMed Search: Clear cell pancreatic endocrine tumor pathology

Adam L. Booth, M.D.
Raul S. Gonzalez, M.D.
Page views in 2022: 1,914
Page views in 2023 to date: 1,680
Cite this page: Booth AL, Gonzalez RS. Clear cell pancreatic endocrine tumor. website. Accessed September 21st, 2023.
Definition / general
  • 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
  • Also known as lipid rich variant
ICD coding
  • ICD-10: C25.4 - malignant neoplasm of endocrine pancreas
  • Most commonly in the head of the pancreas
  • 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 nonfunctional (Arch Pathol Lab Med 2006;130:963)
  • Imaging may identify a suspicious mass
  • Definitive diagnosis is made following endoscopic biopsy or surgical resection
Radiology description
Prognostic factors
Case reports
Gross description
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.
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Nests of tumor cells

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Clear, vacuolated cytoplasm

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Salt and pepper chromatin

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Synaptophysin positivity

Cytology description
Cytology images

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Papanicolaou stain of FNA

Electron microscopy description
Molecular / cytogenetics description
  • Von Hippel-Lindau disease
  • 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

Pancreatic neuroendocrine neoplasms: overview

Sample pathology report
  • Pancreas and duodenum, Whipple procedure:
    • Clear cell pancreatic neuroendocrine tumor, WHO grade 1 (see synoptic report and comment)
    • Comment: The patient's clinical history of von Hippel-Lindau syndrome is noted. The clear cell variant of pancreatic neuroendocrine tumor is more common in this setting. Immunohistochemical stains for synaptophysin and chromogranin are positive and the Ki67 index is approximately 2.0%.
Board review style question #1
    Which of the following statements regarding clear cell pancreatic endocrine tumor is true?

  1. A diagnosis should not stimulate genetic evaluation for the VHL syndrome
  2. Frequently immunoreactive for cytokeratins
  3. Immunohistochemistry can distinguish from histologically similar metastatic clear cell renal cell carcinoma in VHL disease
  4. Only seen in the setting of VHL disease
  5. Tumors associated with VHL syndrome and MEN1 syndrome are often functional tumors
Board review style answer #1
C. Immunohistochemistry can distinguish clear cell pancreatic endocrine tumors from histologically similar metastatic clear cell renal cell carcinoma in VHL disease

Comment Here

Reference: Clear cell pancreatic endocrine tumor
Board review style question #2
    A patient is diagnosed with a clear cell pancreatic endocrine tumor. What genetic mutation is likely to be present?

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

Comment Here

Reference: Clear cell pancreatic endocrine tumor
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