Pancreatic Endocrine Tumour

 

Epidemiology and Etiology:

    • All ages
      • Peak 30-60y
    • M=F
    • 1-2% of pancreatic neoplasms

 

Common sites:

    • insulinoma:
      • anywhere in the pancreas
    • gastrinoma:
      • pancreas
      • duodenum
      • peripancreatic soft tissues

 

Gross features:

    • 1-5cm
      • microadenoma is < 0.5cm
      • insulinoma < 2cm usually
      • non-functioning often > 5cm
    • solitary usually
      • MEN-1 associated gastrinomas are usually multiple
    • encapsulated
    • white-yellow or pink-brown
    • solid
      • rarely cystic

 

Histologic features:

    • relatively monotonous population
    • solid, trabecular, glandular, gyriform, tubuloacinar, pseudorosette arrangements
      • varying amount of stroma / fibrosis
    • round to ovoid, smoothly contoured nuclei
      • salt and pepper chromatin pattern
      • centrally located
    • finely granular amphophilic cytoplasm
      • varies in quantity and density
      • may see:
        • clear cells
        • vacuolated lipid-rich cells
        • oncocytes
        • “rhabdoid” cells
    • look like “giant islets”
    • atypia is not reliable to predict malignancy
    • malignant criteria:
      • unequivocal:
        • lymph node mets
        • liver mets
        • gross invasion of adjacent organs
      • suggestive:
        • high mitotic count (> 4 / 10 HPF)
          • ~80% specificity, ?low sensitivity
        • tumour necrosis
        • vascular invasion
        • perineural invasion
        • infiltration into pancreatic parenchyma
        • significant atypia
        • size:
          • <2cm generally indolent
          • 2-3cm increased risk
          • > 3cm usually malignant
          • > 10cm highly likely to be malignant
        • insulinoma generally benign
        • other types of functioning tumours generally malignant (85-90%)
          • some are tumours of uncertain behaviour (10-15%)
        • Non-functioning are generally malignant (90-95%)
    • insulinoma:
      • amyloid deposits (specific for insulinoma)
    • somatostatinoma of periampullary duodenum:
      • glandular structures containing psammoma bodies commonly (specific for somatostatinoma)
    • poorly differentiated:
      • hard to recognize as endocrine on H&E
      • require immunohistochemical examination to reveal neuroendocrine phenotype
        •  
      • solid sheets usually
      • pleomorphic cells with hyperchromatic nuclei
      • high mitotic activity (>10 per 10HPF)

 

Immunophenotype:

Marker:

Sensitivity:

Specificity:

 Insulin, other hormones

 

 

Synaptophysin

More sensitive for poorly differentiated tumours

Any neuroendocrine tumour, SPPT (some)

Chromogranin

May be negative in poorly differentiated tumours

Any neuroendocrine tumour

Protein gene product (PGP)

Any neuroendocrine tumour

Neuron specific enolase (NSE)

Low

CK 8, 18, 19
    • Multiple hormones may be produced
    • Immunohistochemical staining may not correspond to clinical syndrome
    • Metastases may produce hormones other than those found in the primary

 

 

Molecular features:

    • Sporadic:
      • Little is known
      • Somatic MEN1 mutations (21%)
        • Not in insulinomas
      • CGH:
        • Amplifications are uncommon
        • Losses > gains
        • Gains:
          • Early : 9q
          • 4pq, 5q, 7pq, 12q, 14q, 17pq, 20q
        • losses :
          • early : 1p, 11q
            1. 11q13 and/or more distal parts of 11q loss (68%)
              1. less in insulinomas
          • 3p, 6q, 10pq, Y, X
        • Total number of genomic changes is associated with tumour size and stage
        • Insulinomas and especially gastrinomas exhibit fewer genetic alterations than other tumour types
    • Familial:
      • MEN 1
      • VHL

 

Other features:

    • benign or malignant
      • malignant tend to have remarkably slow progression (except poorly differentiated)
        • mets may develop years after primary resection
        • survival 5-10y after liver mets is not uncommon
        • hormonal effects tend to be more life threatening
    • functioning or non-functioning (non-syndromic) (dictated by clinical signs/symptoms, not lab results or immunohistochemistry)
      • insulinoma
      • glucagonoma
      • somatostatinoma
      • gastrinoma
      • VIPoma
      • Others
      • PP secreting tumours do not cause a distinct hormonal syndrome – therefore non-functioning (non-syndromic)
      • < 0.5cm (microadenomas) are as a rule non-functioning
    • insulinomas:
      • most common type
      • only 10% of  are malignant
      • EM – distinctive round granules containing polygonal or rectangular dense crystals
      • High insulin levels
        • Hypoglycemia may be life-threatening
      • High insulin:glucose ratio
    • 60-90% of other functioning and non-functioning tumours are malignant
    • gastrinomas:
      • 90-95% have hypersecretion of gastric acid with severe peptic ulceration
        • intractable jejunal ulcers should raise red flags
        • may be life-threatening
      • >50% have diarrhea
      • over half are locally invasive or have already metastasized at the time of diagnosis
      • 25% occur with MEN-1 syndrome (and are frequently multifocal)
    • clinical syndromes:
      • insulinoma:
        • hypoglycemia
        • neuropsychiatric disturbances
      • gastrinoma:
        • Zollinger-Ellison syndrome
          • Abdominal pain
          • Ulcer disease
          • Diarrhea
          • GI bleeding
      • multiple endocrine neoplasia
      • glucagonoma:
        • mild DM
        • necrolytic migratory erythema (skin rash)
        • anemia
        • stomatitis
      • somatostatinoma
        • DM, cholelithiasis, steatorrhea, hypochlorhydria
      • VIPoma – watery diarrhea, hypokalemia, achlorhydria (WDHA syndrome)
        • May be life-threatening
      • Pancreatic polypeptide (PP)-secreting (PP-oma)
        • Clinically silent
      • Pancreatic carcinoid (serotonin-producing) – carcinoid syndrome
        • Flushing
        • diarrhea
      • ACTH secretion
      • Melanocyte-stimulating hormone
      • Vasopressin
      • Norepinephrine

 

References:

    • Robbins 2005
    • WHO Tumours of Endocrine Organs (2004)