Neuroendocrine tumors of the thymus and mediastinum

Neuroendocrine tumors of the thymus (tNET) are very rare, only accounting for about 5% of all tumors in the thymus and mediastinum, and have an estimated incidence of 1 per 5 million people (1-3). Despite some differences in etiology (e.g., role of cigarette smoking), epidemiology, and genetics, the nomenclature of tNET traditionally followed that of their pulmonary counterparts. Thus, in the most recent fascicle of the World Health Organization (WHO) classification of tumors of the lung, pleura, thymus and heart (4), neuroendocrine tumors of the thymus and lung are separated into typical (low grade) and atypical (intermediate grade) carcinoid tumors, large cell neuroendocrine carcinomas (LCNEC) (5), and small cell carcinomas (SCC) (Table 1). Like in most other organs (6), “low/intermediate grade” typical and atypical carcinoids (TC and AC) on the one hand and “high grade” LCNEC and SCC are believed to be unrelated tumors and not to represent successive stages of de-differentiation, in spite of some overlapping genetic features (7). Defining characteristics of TC and AC and LCNEC include neuroendocrine morphology on H & E stainings, “neuroendocrine blood vessels”, and expression of neuroendocrine markers. Of note, the diagnosis of SCC is primarily based on H & E morphology and does not require demonstration of neuroendocrine markers by immunohistochemistry. Since the current definition of LCNEC (non-small cell morphology and >10 mitoses/10 HPF) includes tumors with just 11 mitoses as well as tumors with >100 mitoses, it is likely that this category comprises a (so far undefined) subgroup of “large cell NET” tumors with a lower mitotic rate and an intermediate prognosis, as emerging also in other organ systems