Primary RET-mutated lung neuroendocrine carcinoma in MEN2B: response to RET-targeted therapy.

Multiple endocrine neoplasias (MENs) are genetic syndromes distinguished by specific patterns of benign and malignant tumors of endocrine glands. MEN2 is caused by autosomal dominant inheritance of a gain-of-function mutation in the RET proto-oncogene on chromosome 10 (Mulligan & Ponder 1995, Santoro et al. 1995) and is further subclassified into three syndromes based on clinical phenotype: MEN2A (medullary thyroid cancer (MTC), pheochromocytoma, primary parathyroid hyperplasia); MEN2B (MTC and pheochromocytoma), and familial medullary thyroid cancer (MTC only). MEN is first suspected when an index patient presents with one or more tumors specific to that syndrome. Of all MEN2B cases, 95% are represented by a germline point mutation affecting codon 918 (exon 16) resulting in a methionine to threonine alteration (M918T), inducing constitutive activation of the intracellular tyrosine kinase domain of the encoded RET receptor tyrosine kinase (RTK) (Alberti et al. 2003). Tumor formation occurs in the neuroendocrine organs where constitutively activated RET is expressed. Although neuroendocrine carcinoma (NEC) of the lung has been described in MEN 1 (Farhandi et al. 1987), it has not been described in the MEN2 syndromes. Treatment of MEN-associated tumors primarily involves surgical excision of the neoplasm. In MEN2, prophylactic thyroidectomy is recommended for family members who carry the germline mutation, ideally within the first year of life in patients with MEN2B due to the high penetrance, morbidity, and mortality of MTC associated with the M918T mutation (Skinner et al. 2005). Standard cytotoxic chemotherapy and radiotherapy are not effective in MTC (Orlandi et al. 2001); however, novel targeted therapies have been developed that inhibit the activated RET RTK, including cabozantinib (Elisei et al. 2013). In 1994, a 40-year-old healthy, nonsmoking, Caucasian male experienced a hypertensive crisis