FINAL DIAGNOSIS Mixed Adenoneuroendocrine Carcinoma- Signet Ring Type
RIGHT COLON, HEMICOLECTOMY-
MOLECULAR ANATOMIC PATHOLOGY TESTING:
Colorectal carcinoma with neuroendocrine differentiation (CRC-NE) may present as a pure neuroendocrine carcinoma or as a component of a combined carcinoma (mixed adeno-neuroendocrine carcinoma, MANEC). Neuroendocrine carcinomas are malignant neoplasms composed of small or intermediate-to-large cells that express general markers of neuroendocrine differentiation, such as synaptophysin, chromogranin, neuron-specific enolase, and CD56.1 By definition, they are high-grade neoplasms with >20 mitoses per 10 HPF and/or >20% Ki-67 proliferative index. MANECs have a phenotype that is morphologically recognizable as both epithelial gland-forming and neuroendocrine. According to the WHO 2010 classification, at least 30% of either component must be identified to qualify for this definition.
2 MANECs are rare entities known to be associated with biological aggressiveness and poor patient survival, but otherwise remain incompletely characterized.3
In a recent study that compared CRC-NE to conventional colorectal carcinoma, CRC-NE was more frequently located in the right colon (76% vs. 46%), more often presented with metastasis (59% vs. 18%) and often had perineural (68%), lymphatic (97%), and venous (62%) invasion and high tumor budding (71%). BRAF V600E mutation was more common in CRC-NE compared with conventional CRC (53% vs. 12%). Neuroendocrine differentiation, high stage, BRAF mutation without microsatellite instability, and signet ring histology were all associated with poor overall survival.4
In the same study, CRC-NE was further divided into large cell neuroendocrine carcinoma (LCNEC), MANEC composed of LCNEC and conventional adenocarcinoma (MANEC-conventional type), and MANEC composed of LCNEC and signet ring cell carcinoma (MANEC-signet ring type). MANEC-signet ring type more often had BRAF V600E mutation compared with LCNEC and MANEC-conventional type (73% vs. 14% vs. 50%). KRAS mutations were identified in 0% of MANEC-signet ring type, 25% of LCNEC, and 43% of MANEC-conventional type. LCNEC, MANEC-conventional type, and MANEC-signet ring type all had a worse overall survival compared to conventional CRC.4
The patient in this case presented with metastatic MANEC-signet ring type involving the right colon with perineural invasion, lymphovascular invasion, and high tumor budding. The tumor was also microsatellite stable, positive for the BRAF V600E mutation, and negative for mutations in KRAS. This constellation of features is indicative of a highly aggressive malignancy with very poor prognosis. Approximately 10 months following resection, the patient developed bilateral lung metastases and pleural effusions and ultimately died a few months later at the age of 73.
Contributed by Dane C. Olevian, MD and Reetesh K. Pai, MD