Well-Differentiated Neuroendocrine Tumors with a Morphologically Apparent High-Grade Component: A Pathway Distinct from Poorly Differentiated Neuroendocrine Carcinomas.
OBJECTIVE
Most well-differentiated neuroendocrine tumors (WD-NET) of the enteropancreatic system are low-intermediate grade (G1, G2). Elevated proliferation demonstrated by either a brisk mitotic rate (>20/10 high power fields) or high Ki-67 index (>20%) defines a group of aggressive neoplasms designated as high-grade (G3) neuroendocrine carcinoma (NEC). High-grade NEC is equated with poorly differentiated NEC (PD-NEC) and is associated with a dismal outcome. Progression of WD-NETs to a high-grade neuroendocrine neoplasm very rarely occurs and their clinicopathologic and molecular features need to be characterized.


METHODS
We investigated 31 cases of WD-NETs with evidence of a component of a high-grade neoplasm. The primary sites included pancreas, small bowel, bile duct, and rectum. Histopathology of the cases was retrospectively reviewed and selected IHC and gene mutation analyses performed.


RESULTS
The high-grade component occurred either within the primary tumor (48%) or at metastatic sites (52%). The clinical presentation, radiographic features, biomarkers, and the genotype of these WD-NETs with high-grade component remained akin to those of G1-G2 WD-NETs. The median disease-specific survival (DSS) was 55 months (16-119 months), and 2-year and 5-year DSS was 88% and 49%, respectively-significantly better than that of a comparison group of true PD-NEC (DSS 11 months).


CONCLUSIONS
Mixed grades can occur in WD-NETs, which are distinguished from PD-NECs by their unique phenotype, proliferative indices, and the genotype. This phenomenon of mixed grade in WD-NET provides additional evidence to the growing recognition that the current WHO G3 category contains both WD-NETs as well as PD-NECs.
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. tangl@mskcc.org.
Laura H
LH
Tang
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
Brian R
BR
Untch
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Diane L
DL
Reidy
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Eileen
E
O'Reilly
Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California.
Deepti
D
Dhall
Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California.
Lily
L
Jih
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
Olca
O
Basturk
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
Peter J
PJ
Allen
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
David S
DS
Klimstra
D000368:Aged; D004252:DNA Mutational Analysis; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000235:genetics / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D016896:Treatment Outcome