Well Differentiated Pancreatic Endocrine Neoplasm

Definition

• Neoplasm of pancreas resembling normal islet cells with an organoid growth pattern, measuring at least 0.5 cm in greatest dimension

Alternate/Historical Names

• Islet cell tumor
• Pancreatic endocrine tumor
• Well-differentiated endocrine carcinoma
• Various names based on functional status or secreted product (see Clinical)

Diagnostic Criteria

• Tumor composed of endocrine cells resembling normal islet cells
  • Chromogranin, synaptophysin, and/or CD56 positive
  • Round regular nuclei
  • Stippled “salt and pepper” chromatin
    • Nucleoli may be seen in some cases
  • Granular eosinophilic cytoplasm in most cases
    • If abundant, may be termed oncocytic
• Generally grossly circumscribed
  • May infiltrate surrounding tissues and organs
  • Perineural and vascular invasion may be seen
  • May entrap normal ducts
    • Has been termed ductuloinsular tumor
      • Misnomer as the ducts are not neoplastic
  • May rarely be predominantly cystic
    • Multilocular or unilocular
• At least 0.5 cm in maximum dimension
  • Non-functioning tumors <5 cm are designated endocrine microadenomas
• Mitotic figures no more than 10/10 HPF (50/50 HPF)
• Varying architectural patterns
  • Most common: rounded organoid nests of tumor
    • Set within a dense hyalinized stroma
  • Trabecular, gyriform, and rosette-like patterns also seen
  • Admixtures of patterns are often found within the same tumor
• Amyloid deposition may be seen
  • Typically in insulin-producing tumors
• Calcification, rarely psammomatous, may be seen
• Rare Morphologic Variants
  • Clear cell variant
    • Abundant clear foamy cytoplasm
    • Predominantly seen in patients with von Hippel Lindau syndrome
  • Pleomorphic variant
    • Extensive nuclear pleomorphism, enlargement and hyperchromasia
    • No increased mitotic activity or necrosis
    • No prognostic significance
  • Lipid-rich variant
    • Numerous cytoplasmic vacuoles within the tumor cell cytoplasm
    • Thought to represent a degenerative phenomenon
  • Pigmented, black variant
    • Due to lipofuscin accumulation
    • Melanoma markers negative
  • Rhabdoid variant
    • Prominent dense cytoplasmic inclusion
      • Inclusion is keratin positive, desmin negative
      • Displaces nucleus
    • May displace neuroendocrine marker staining to adjacent cytoplasm
    • No clear clinical significance
  • Oncocytic
    • Hormonally inactive
    • Most are aggressive
  • Spindle cell
  • Hepatoid carcinomas considered by some to be related
    • HepPar1 positive with bile and canaliculi
    • Some have an endocrine component
    • Aggressive
• Sporadic cases usually solitary
• Syndromic cases frequently multiple
  • MEN1
    • Pancreatic tumors in 60%
  • von Hippel Lindau
    • May be conventional or clear cell
  • Neurofibromatosis type 1
    • Intra-pancreatic tumors rare
    • More common is ampullary psammomatous somatostatinoma
  • Tuberous sclerosis - rare

Reetesh Pai MD
Robert V Rouse MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting/updates : 2/1/08, 3/18/09, 6/18/10

Supplemental studies

Immunohistology

• Chromogranin, synaptophysin, CD56 or CD57 positive in >95% of cases
  • Chromogranin and synaptophysin more specific
  • Synaptophysin most sensitive
• Specific polypeptides may be identified
  • Both normal islet and ectopic polypeptides
  • Staining frequently but not always correlates with clinical syndrome and secreted product
  • Frequent staining for more than one peptide
  • Staining may be negative even in the presence of a secreted and active product
• CK7 and CK20 usually negative
• CK19 expression has been reported to be an independent marker of less favorable prognosis
  • Applies only to WHO groups of Uncertain Behavior and Well Differentiated Pancreatic Endocrine Carcinoma
• Acinic markers trypsin, chymotrypsin and lipase may be focally positive (<25% of cells)
  • If >25%, designate as mixed acinar-endocrine carcinoma

Laboratory studies

• Measurement of secreted peptide/hormone may be useful than immunohistochemistry for defining clinical syndrome

Differential diagnosis

• Acinar cell carcinoma
• Solid-pseudopapillary neoplasm
• Pancreatoblastoma

Clinical

• These names depend on the functional status of the tumor
  • Defined by clinical plus serologic findings and not by immunohistochemistry
  • Except for PPoma (see below)
  • Neoplasms that are positive for a peptide product by immunohistochemistry but lack the corresponding clinical syndrome are designated beta-cell neoplasms, alpha-cell neoplasms etc.
• Insulinoma
  • 30-40% of functional tumors
  • Elevated serum insulin, pro-insulin and C-peptide
  • Symptoms of hypoglycemia w/ relief after glucose administration
  • Most insulinomas are benign, but between 5-10% associated with metastasis
• Gastrinoma
  • 12.5% of functional tumors
  • 80% present with duodenal ulcer (Zollinger-Ellison syndrome)
  • Serum gastrin levels >1000 pg/mL are diagnostic
  • Between 30-50% have metastatic disease at presentation
    • Can metastasize while still very small
  • 50% 10 year survival
  • May cause secondary gastric endocrine cell hyperplasia and neoplasia
  • Most gastrinomas are extra-pancreatic (duodenal) in origin
• Glucagonoma
  • 8-13% of functional tumors
  • Necrolytic migratory erythema (70%), stomatitis, weight loss, diabetes mellitus (50%)
  • Elevated fasting plasma glucagon
  • Between 60-70% have metastatic disease at presentation
• VIPoma
  • 10% of functional tumors
  • Watery diarrhea with hypokalemia and achlorhydria (Verner-Morrison syndrome, pancreatic cholera)
  • VIP may also be secreted by neurogenic neoplasms
  • 60% 5 year survival
• Somatostatinoma
  • 2-3% of pancreatic endocrine neoplasms
  • Diabetes mellitus, hypochlorhydria, cholelithiasis, diarrhea, anemia, weight loss
  • 50% 10 year mortality
• Pancreatic polypeptide cell-oma (PPoma)
  • No clinical syndrome
  • Recognized by immunohistochemistry (>50% of cells positive)
  • Elevated serum PP is not sufficient as it is commonly elevated with other peptides
  • 44% metastatic rate
• Serotonin secreting pancreatic endocrine neoplasm
  • Alternate name: pancreatic carcinoid tumor
  • Rare
  • Carcinoid syndrome
    • Flushing, diarrhea, bronchoconstriction
    • Usually present only if metastatic to liver
  • Elevated serum 5-HT and/or urine 5-HIAA
  • Extra-pancreatic primary must be ruled out
• Rare neoplasms secrete other hormones
  • ACTH, parathyroid hormone, growth hormone, calcitonin
• Multiple endocrine neoplasia 1 (MEN1) syndrome
  • Over half have a pancreatic endocrine neoplasm
    • Microadenomas are frequent and multiple
    • Most common types are gastrinoma, insulinomas and PPoma
    • Rare types are VIPoma and glucagonoma
• von Hippel Lindau syndrome
  • 5-10% have a pancreatic endocrine neoplasm
    • May show clear cell change
    • Most nonfunctional

Grading/Staging/Report

• Two currently accepted grading schemes for pancreatic endocrine tumors:
  • WHO System
    • Well-differentiated pancreatic endocrine tumor
      • “Benign” behavior: confined to pancreas, no vascular or perineural invasion, <2 cm, and <2 MF/10 HPF
      • Uncertain behavior: confined to pancreas, vascular and/or perineural invasion, >2cm, or 2-10 MF/10 HPF
    • Well differentiated pancreatic endocrine carcinoma
      • Gross local invasion or metastases
  • Memorial Sloan Kettering System
    • Low grade pancreatic endocrine neoplasm
      • No necrosis and <2 MF/50 HPF
    • Intermediate grade pancreatic endocrine neoplasm
      • Necrosis or between 2 to 50 MF/50 HPF
• Same TNM staging as exocrine pancreas, based on:
  • Size (2 cm)
  • Extrapancreatic extension
  • Invasion of adjacent structures
• Relevant prognostic features that should be reported
  • Size
    • 2 and 4 cm have been proposed as significant cutoffs
  • Presence or absence of extra-pancreatic invasion
  • Presence or absence of vascular invasion
  • Lymph node status
  • Functional status, if known

Lists

Pancreatic Carcinomas

• Acinar cell carcinoma
• Adenosquamous carcinoma
• Colloid carcinoma
• Ductal adenocarcinoma
• Neuroendocrine carcinoma, poorly differentiated
• Well differentiated neuroendocrine (islet cell) tumors
• Hepatoid carcinoma
• Medullary carcinoma
• Micropapillary carcinoma
• Pancreatoblastoma
• Serous cystadenocarcinoma
• Signet ring cell carcinoma
• Undifferentiated carcinoma
• Undifferentiated carcinoma with osteoclast-like giant cells

Pancreatic Endocrine Tumors

• Islet cell hyperplasia / aggregation
• Pancreatic neuroendocrine microadenoma
• Poorly differentiated pancreatic neuroendocrine carcinoma
• Well differentiated pancreatic neuroendocrine (islet cell) tumor
• Mixed acinar-endocrine carcinoma

Bibliography

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