Dr. Ralph H. Hruban
Dr. Günter Klöppel
Case 5 -
Poorly differentiated neuroendocrine carcinoma of the pancreas producing somatostatin
Dr. Günter Klöppel
48-year-old male patient. Admission to hospital because of continuously increasing jaundice of
one-week duration. Laparotomy because of suspected carcinoma in the head of the pancreas. Removal of
Case 5 - Figure 1
Multiple lymph node metastases in the tissue between the pancreatic head and the hilus of the liver.
The individual lymph nodes have a diameter of up to 2 cm.
Lymph node tissue that is almost totally replaced by solid and anastomosing tumor cell complexes. The
tumor cell have round to oval nuclei and sparse eosinophilic cytoplasm. The chromatin of the nuclei is
dense, but a distinct nucleus is rarely seen. There are many mitoses in multiple necrotic areas. The
tumor tissue is supported by cords of connective tissue.
The tumor cells stain for synaptophysin and chromogranin. They also express cytokeratin 8 and 18 to a
variable extent, occasionally with a dotlike staining pattern. Somatostatin is expressed in about 50% of
the cells, while there is no staining for gastrin and serotonin.
Poorly differentiated neuroendocrine carcinoma of the pancreas producing somatostatin.
The differential diagnosis of poorly differentiated neuroendocrine carcinomas includes all poorly
differentiated and undifferentiated solid carcinomas of nonneuroendocrine tissues. The most important
are undifferentiated pancreatic carcinoma, leiomyosarcoma, gastrointestinal stromal tumor (GIST),
peripheral neuroectodermal tumor (PNET), malignant peripheral nerve sheath tumor (MPNST) and metastases
of malignant melanoma. All these tumors are negative for neuroendocrine markers such as synaptophysin
and chromogranin. This makes the differential diagnosis rather easy. The only ones that may show some
positivity for synaptophysin are PNET, MPNST and GIST; however, this never as strong and even as it is
for the neuroendocrine carcinoma. Moreover, they consistently lack chromogranin positivity.
The WHO classification of endocrine tumors of the pancreas distinguishes between well differentiated
endocrine tumors with benign or uncertain behavior, low grade malignant well differentiated endocrine
carcinomas and high grade malignant poorly differentiated endocrine carcinomas. Most pancreatic
endocrine tumors (PET) belong to the groups of well differentiated endocrine tumors and well
differentiated endocrine carcinomas. They account for at least 95% of cases.
Poorly differentiated endocrine carcinomas are very rare. They are usually carcinomas with a solid
pattern, small necrotic areas, mitotic activity >10/10 HPF and proliferative activity of 30-50%. When
stained for the neuroendocrine markers synaptophysin and chromogranin, they show distinct positivity for
synaptophysin and no or only very weak positivity for chromogranin. The expression of cytokeratin 8 and
18, which is always found in these tumor cells, occasionally shows a dotlike staining pattern, which is
seen in neuroendocrine carcinomas such as small cell lung carcinomas or Merkel cell carcinomas of the
skin, but may also be observed in poorly differentiated neuroendocrine carcinomas of the pancreas. In
contrast to well differentiated PET, they often show nuclear expression of p53.
Poorly differentiated neuroendocrine carcinomas rarely express hormones. Therefore the production of
somatostatin in this tumor is an exception. Since the patient had no symptoms of a somatostatinoma
syndrome (diabetes, cholelithiasis, steatorrhea), the term somatostatinoma cannot be applied.
Poorly differentiated neuroendocrine carcinomas follow a rapid course, with early metastases to the
lymph nodes, the liver and extrahepatic organs. They usually respond to chemotherapy. Patients with
poorly differentiated neuroendocrine carcinomas usually fare better than patients with undifferentiated
carcinomas of the exocrine pancreas.
- DeLellis RA, Lloyd RV, Heitz PU, Eng C (2004) Pathology and genetics: tumours of endocrine organs. WHO classification of tumors. IARC Press, Lyon
- Klöppel G, Heitz PU (2000) Tumors of the endocrine pancreas. In: CDM Fletcher (ed) Diagnostic histopathology of tumors, 2nd ed. Churchill Livingstone, London, pp 1083-1098
- Solcia E, Capella C, Klöppel G (1997) Tumors of the pancreas. AFIP Atlas of Tumor Pathology, third series, fascicle 20. Armed Forces Institute of Pathology, Washington, D.C.