Pathology, classification, and grading of  neuroendocrine 

tumors arising in the digestive system

The terminology of gastroenteropancreatic (GEP) neuroendocrine neoplasms has evolved over the past two decades to reflect a separation into two major categories:
Well-differentiated neuroendocrine tumors (NETs) show a solid, trabecular, gyriform, or glandular pattern, with fairly uniform nuclei, salt-and-pepper chromatin, and finely granular cytoplasm. These tumors were traditionally referred to as carcinoid and pancreatic neuroendocrine (islet cell) tumors. Although carcinoid tumors and pancreatic NETs may have similar characteristics on routine histologic evaluation, they have a different pathogenesis and biology.
Poorly-differentiated neuroendocrine carcinomas, which are high-grade carcinomas that resemble small cell or large cell neuroendocrine carcinoma of the lung . Poorly differentiated neuroendocrine carcinomas are often associated with a rapid clinical course, while well-differentiated NETs generally have a much better prognosis, with an overall five-year survival of approximately 67 percent 

Histologic appearance of the spectrum of neuroendocrine tumors arising in the gastrointestinal tract


Well-differentiated NET shows an organoid pattern and difficult-to-find mitotic activity on H&E stain (panel A),

( Panel C) the proliferative rate (as measured by the Ki67 labeling index) is very low  (<1 percent="" span="">

poorly-differentiated neuroendocrine carcinoma shows frank features of carcinoma with numerous mitotic figures and tumor necrosis on H&E stain (panel B),the Ki67 labeling index is very high (>80% in this case) (panel D).

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Interesting Case

Clinical History:

53 years male,History of hypertension and tachycardia,MRI abdomen:-Left adrenal mass:- size 5.8 cm Right renal mass:- size-3.0cm Microscopic examination of the renal mass showed vascular tumor with diffuse sheets of clear cells having Fuhrman grade III nuclei. There was no evidence of necrosis within the tumor. There was no evidence of extraparenchymal invasion.
Gross examination of the left adrenal gland revealed cortically centered, solid and multinodular mass measuring 6.5 x 6.0 x 5.0 cm and weighing 122 grams. The tumor was encapsulated but showed evidence of extraparenchymal penetration. The tumor had golden brown cut surface with areas of hemorrhage and necrosis. The partial nephrectomy showed 3.0cm x 3.0cm x 3.0 cm yellow solid mass which did not invade into the perinephric adipose tissue.
Microscopically, the adrenal mass had predominant diffuse sheets and focal trabecular arrangements. The former pattern was present in about third of tumor. The cells had clear cytoplasm and round to ovoid nuclei with conspicuous nucleoli. Mitotic rate was 9/50 HPF and included atypical forms. Gross necrosis and capsular invasion were documented microscopically. There was no evidence of lymphovascular invasion. Considering the above mentioned features, a Weiss histopathologic score2 of 7/9 was applied.


The differential diagnosis included Renal Cell Carcinoma (RCC) with contralateral adrenal metastasis, Adrenocortical carcinoma (ACC) with contralateral renal metastasis, synchronous RCC and ACC or synchronous RCC and adrenocortical adenoma. A panel of immunohistochemical stains was performed to sort out the diagnosis. Adrenal tumor demonstrated strong Vimentin positivity and is negative for CK7, CK20, E1/AE3, EMA, Synaptophysin and S100.Renal cell carcinoma was positive for CK7, AE1/AE3, EMA (weak) and Vimentin. It was negative for CK20, Synaptophysin and S100. The difference of immunoprofile between the two tumors documented that they originated from two different primaries.

Final Diagnosis:

The diagnosis of synchronous RCC and ACC rather than metastasis influences the prognosis.


The longest disease free interval after removal of contralateral adrenal metastasis was 12.1 years8 and the longest crude survival was 14.3 years. In contrast non metastazing RCC has an excellent prognosis if no metastasis developed.