Table of ContentsDefinition / general | Terminology | Essential features | Epidemiology | Sites | Etiology | Diagrams / tables | Grading | Prognostic factors | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Molecular / cytogenetics description | Differential diagnosis | Board review style question #1 | Board review answer #1
Cite this page: Sopha S. Neuroendocrine carcinoma. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/pancreasneuroendocrinecarcinoma.html. Accessed September 20th, 2020.
Definition / general
- Poorly differentiated neoplasms with high grade morphology that convincingly express neuroendocrine markers (synaptophysin, chromogranin A, NCAM / CD56, protein gene product [PGP])
- Synaptophysin is strongly and diffusely expressed in most lesions; chromogranin A is focal / patchy
- CD56 and PGP are considered less specific
- Site specific markers include PDX1 and ISL1
- "Neuroendocrine carcinoma" is now reserved for poorly differentiated, obviously malignant neoplasms; "neuroendocrine tumor" refers to well differentiated lesions with a "carcinoid" morphology, regardless of grade
- Neoplasms with both neuroendocrine and nonneuroendocrine components, formerly known as MANEC (mixed adenocarcinoma and neuroendocrine carcinoma), have a WHO 2018 classification of MENEN (mixed endocrine and nonendocrine neoplasm); the neuroendocrine component may be a tumor or a carcinoma
- Immature or finely speckled chromatin (as seen in pulmonary small cell carcinoma or acute myeloid leukemia [AML]), nuclear molding
- High rate of cellular turnover: high mitotic rate, high apoptotic rate
- Small cell variant of poorly differentiated neuroendocrine carcinoma, WHO grade 3: high nucleus to cytoplasm ratio (Am J Surg Pathol 2014;38:437)
- Large cell variant of poorly differentiated neuroendocrine carcinoma, WHO grade 3: prominent nucleoli or vesicular chromatin (Am J Surg Pathol 2014;38:437)
- Average patient age 59 years
- Male: female ratio 1.4
- Most poorly differentiated neuroendocrine carcinomas, WHO grade 3 are of the large cell variant (Am J Surg Pathol 2014;38:437)
- Lesions may be anywhere in the pancreas (Am J Surg Pathol 2014;38:437)
- No known environmental factors
- Poorly differentiated neuroendocrine carcinomas of WHO grade 3 are thought to arise from squamous carcinoma or adenocarcinoma
Diagrams / tables
- Neuroendocrine carcinomas are effectively always WHO grade 3, based on high mitotic rate and high Ki67 index
- Well differentiated neuroendocrine tumors can be grade 3 in the pancreas but this alone does not make them carcinomas (Am J Surg Pathol 2015;39:683, Clin Cancer Res 2016;22:1011, Endocr Pathol 2014;25:65)
- Much worse prognosis than well differentiated neuroendocrine tumors
- Ki67 index and mitotic count, as described above under WHO grading
- Retention of neuroendocrine morphology
- Response to chemotherapy
- Surgical resection is the mainstay
- Chemotherapy (no established protocol)
- Tan yellow, fleshy, areas of necrosis
- Indications of aggressive behavior: invasion of fibroadipose tissue (as satellite nodules), invasion of adjacent organs, invasion of large vessels
Microscopic (histologic) description
- Poorly differentiated neuroendocrine carcinoma, WHO grade 3, small cell variant: immature or finely speckled chromatin (as seen in pulmonary small cell carcinoma or AML), nuclear molding, high nucleus to cytoplasm ratio in the (Am J Surg Pathol 2014;38:437)
- Poorly differentiated neuroendocrine carcinoma, WHO grade 3, large cell variant: prominent nucleoli or vesicular chromatin (Am J Surg Pathol 2014;38:437)
- High rate of cellular turnover (high mitotic rate and high apoptotic rate)
Microscopic (histologic) images
- Two patterns (small and large cell variants):
- Small cell variant: small cells with large nuclei (high N/C ratio), nuclear molding, dark chromatin with inconspicuous nucleoli; prominent background degeneration and crush artifact with nuclear streaming
- Large cell variant: large undifferentiated cells with bizarre forms or syncytial aggregates, irregular overlapping nuclei with prominent nucleoli, variable chromatin (fine or coarse) and abundant cytoplasm (delicate, dense or granular)
- Synaptophysin: generally diffuse (Proc Natl Acad Sci U S A 1986;83:3500)
- Chromogranin A: 20% stain and have patchy / variable positivity (Am J Surg Pathol 1984;8:607)
- Neuron specific enolase (NSE): less specific, limited utility (Gastroenterology 1982;83:902)
- S100 (Am J Surg Pathol 2005;29:1194)
- Protein gene product 9.5: less specific, limited utility (Histopathology 1985;9:147)
- CK8 / 18
- CK AE1 / 3: labels 50% of cases (Virchows Arch A Pathol Anat Histopathol 1986;409:609)
- Trypsin: labeling can be seen but if > 25%, the lesion is classified as mixed acinar-endocrine carcinoma (Am J Surg Pathol 1994;18:765, Am J Surg Pathol 2002;26:893, Dig Dis Sci 2002;47:2254)
- Dupan-2 and CA 19-9: labeling with these markers of ductal differentiation can be seen in foci with pseudoglandular architecture but this is insufficient for a diagnosis of mixed ductal endocrine carcinoma (J Clin Oncol 2002;20:2633, Dig Dis Sci 2002;47:2254)
- Hormone expression (insulin, glucagon, gastrin, somatostatin, VIP, pancreatic polypeptide): may be seen but is not sufficient for diagnosis of a specific neoplasm type
- Useful panel for determining pancreatic origin is ISL1, PAX8+, CDX2+, TTF1- (Am J Surg Pathol 2010;34:723, Mod Pathol 2011;24:412, Mod Pathol 2012;25:893, Am J Surg Pathol 2008;32:420)
Molecular / cytogenetics description
- Poorly differentiated neuroendocrine carcinoma, WHO grade 3: defined by inactivation of p53, inactivation of Rb / p16 or SMAD4 (Am J Surg Pathol 2016;40:1192, Am J Surg Pathol 2012;36:173)
- Molecular findings seen in well differentiated neuroendocrine tumor, WHO grade 3 (loss of DAXX or ATRX, Am J Surg Pathol 2016;40:1192, Am J Surg Pathol 2012;36:173) are not seen in poorly differentiated neuroendocrine carcinomas
- High grade neuroendocrine carcinomas of other sites
- TTF1+ in lung, TTF1+ / NKX3.1+ in prostate, CDX2+ / SATB2+ in lower GI tract, CDX2- / SATB2+ in upper GI tract, both pancreas and small bowel primaries can be PAX8+
- Leukemia / lymphoma
- Often positive for CD3, CD20, CD45, CD79a
Board review style question #1
Which of the following statements concerning neuroendocrine neoplasms of the pancreas and GI tract is false?
- Apoptosis is a feature not considered in the WHO classification.
- Molecular features of poorly differentiated neuroendocrine tumors, WHO grade 3 are similar to those of poorly differentiated neuroendocrine carcinomas, WHO grade 3 (inactivation of p53, Rb / p16 or SMAD4).
- Molecular features of poorly differentiated neuroendocrine tumors, WHO grade 3 are similar to those of well differentiated neuroendocrine tumors, WHO grades 1 - 2 (loss of DAXX or ATRX).
- Neuroendocrine neoplasms which retain neuroendocrine morphology and show a Ki67 proliferation index of 20 - 50% are now classified as poorly differentiated neuroendocrine tumors, WHO grade 3.
- Similar to the lung, both large and small cell variants exist.
Board review answer #1
B. Molecular features of poorly differentiated neuroendocrine tumors, WHO grade 3 are similar to those of poorly differentiated neuroendocrine carcinomas, WHO grade 3 (inactivation of p53, Rb / p16 or SMAD4).