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  • Surgical Pathology Criteria
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    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
    • 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 of the Pancreas Well Differentiated Pancreatic Neuroendocrine (Islet Cell) Tumor
    Granular PASd+ cytoplasm PASd negative
    Basal nuclear polarization Centrally located nuclei
    Vesicular nuclei with prominent nucleoli Salt and pepper stippled chromatin
    BCL10, trypsin, chymotrypsin positive BCL10, trypsin, chymotrypsin negative
    Synaptophysin and chromogranin positivity <25% in pure tumors, mixed tumors may have more Synaptophysin or chromogranin positivity widespread, over 25%

     

    Well Differentiated Pancreatic Neuroendocrine (Islet Cell) Tumor Solid Pseudopapillary Neoplasm of the Pancreas
    Lacks pseudopapillary architecture Frequent pseudopapillary architecture
    Chromogranin usually strongly positive Chromogranin focal to negative
    Keratin positive Keratin variable
    Galectin 3 negative Galectin 3 positive (small numbers)
    Vimentin, CD10 negative Vimentin, CD10 positive
    Nuclear beta catenin negative Nuclear beta catenin positive
    No PAS+ granules in cytoplasm PAS+ granules may be present
    CD99 variable but not paranuclear dots CD99 paranuclear dots (one report)
    Solid pseudopapillary neoplasm may be synaptophysin positive

     

    Pancreatoblastoma Well Differentiated Pancreatic Neuroendocrine (Islet Cell) Tumor
    Trypsin, chymotrypsin positive Trypsin, chymotrypsin negative
    Squamoid nests always present Lacks squamous differentiation
    Usually prominent nucleoli Salt and pepper chromatin
    Chromogranin, synaptophysin scattered positive Chromogranin or synaptophysin widespread staining
    Islet polypeptide markers negative or very focal Islet polypeptide markers frequently positive
    Cellular stroma frequent Lacks cellular stroma

    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

    Pancreatic Endocrine Tumors

    Bibliography

    • Hruban RH, Pitman MB, Klimstra DS. Tumors of the Pancreas, Atlas of Tumor Pathology, AFIP Fourth Series, Fascicle 6, 2007.
    • Klimstra DS. Nonductal neoplasms of the pancreas. Mod Pathol. 2007 Feb;20 Suppl 1:S94-112.
    • Hochwald SN, Zee S, Conlon KC, et al. Prognostic factors in pancreatic endocrine neoplasms: an analysis of 136 cases with a proposal for low-grade and intermediate grade groups. J Clin Oncol 2002; 20: 2633-2642.
    • Zee SY, Hochwald SN, Conlon KC, Brennan MF, Klimstra DS. Pleomorphic pancreatic endocrine neoplasms: a variant commonly confused with adenocarcinoma. Am J Surg Pathol. 2005; 29:1194-200.
    • Singh R, Basturk O, Klimstra DS, Zamboni G, Chetty R, Hussain S, La Rosa S, Yilmaz A, Capelli P, Capella C, Cheng JD, Adsay NV. Lipid-rich variant of pancreatic endocrine neoplasms. Am J Surg Pathol. 2006;30:194-200.
    • Smith AE, Levi AW, Nadasdy T, Campbell KA, Fishman EK, Hruban RH. The pigmented "black" neuroendocrine tumor of the pancreas: a question of origin. Cancer. 2001 Oct 1;92(7):1984-91.
    • Schmitt AM, Anlauf M, Rousson V, Schmid S, Kofler A, Riniker F, Bauersfeld J, Barghorn A, Probst-Hensch NM, Moch H, Heitz PU, Kloeppel G, Komminoth P, Perren A.  WHO 2004 criteria and CK19 are reliable prognostic markers in pancreatic endocrine tumors.  Am J Surg Pathol. 2007 Nov;31(11):1677-82.
    • Bordeianou L, Vagefi PA, Sahani D, Deshpande V, Rakhlin E, Warshaw AL, Fernández-del Castillo C. Cystic pancreatic endocrine neoplasms: a distinct tumor type? J Am Coll Surg. 2008 Jun;206(3):1154-8.
    • Capelli P, Martignoni G, Pedica F, Falconi M, Antonello D, Malpeli G, Scarpa A. Endocrine neoplasms of the pancreas: pathologic and genetic features. Arch Pathol Lab Med. 2009 Mar;133(3):350-64.
    • van Eeden S, de Leng WW, Offerhaus GJ, Morsink FH, Weterman MA, de Krijger RR, Klöppel G, Klimstra DS. Ductuloinsular tumors of the pancreas: endocrine tumors with entrapped nonneoplastic ductules. Am J Surg Pathol. 2004 Jun;28(6):813-20.
    • Scarpa A, Mantovani W, Capelli P, Beghelli S, Boninsegna L, Bettini R, Panzuto F, Pederzoli P, delle Fave G, Falconi M. Pancreatic endocrine tumors: improved TNM staging and histopathological grading permit a clinically efficient prognostic stratification of patients. Mod Pathol. 2010 Jun;23(6):824-33.
    • Verbeke CS. Endocrine tumours of the pancreas. Histopathology. 2010 May;56(6):669-82.
    • Ligneau B, Lombard-Bohas C, Partensky C, Valette PJ, Calender A, Dumortier J, Gouysse G, Boulez J, Napoleon B, Berger F, Chayvialle JA, Scoazec JY. Cystic endocrine tumors of the pancreas: clinical, radiologic, and histopathologic features in 13 cases. Am J Surg Pathol. 2001 Jun;25(6):752-60.
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