Neoadjuvant Chemotherapy in Extra-Pulmonary Neuroendocrine Carcinoma

Extrapulmonary neuroendocrine carcinoma (EP-NEC) have been found in most organs, but the most common sites are the gastrointestinal tract, cervix uteri and urogenital tract (Strosberg et al., 2010, Walenkamp et al., 2009). Recently it has been defined as a pathological entity in breast cancer (Tavassoli et al., 2003). Additionally, in up to 30% of EPNEC cases, no primary site can be identified (Kloppel et al., 1996). In the prior 2000 WHO classification, these tumours were known as poorly differentiated endocrine carcinoma (PDEC) (Solcia et al., 2000). In the 2010 WHO GI classification PDEC the nomenclature has been altered, and these tumours are now called neuroendocrine carcinoma (NEC) (Bosman et al., 2010). NEC tumours have a much higher proliferation rate than well-differentiated endocrine tumours. The terms poorly differentiated high-grade and neuroendocrine carcinoma are used synonymously and encompass mainly two histological entities: smallcell neuroendocrine carcinoma (SCNEC) and large-cell neuroendocrine carcinoma (LCNEC) (Bosman et al., 2010). LCNEC is morphologically distinguished from SCNEC by cytological features of a non–small cell carcinoma, including large cell size, low nuclear to cytoplasm volume ratio, coarse chromatin, and frequent nucleoli. They are both characterised by markers of neuroendocrine differentiation with synaptophysin, neuron-specific enolase, chromogranin and CD56 being the primary stains. They are also characterised by a high mitotic rate (defined as >10 mitotic figures per 10 high-power fields or a ki-67 > 20% in the gastrointestinal (GI) tract and other extrapulmonary sites and often with extensive necrosis. Most carcinomas in this family exhibit substantially more mitoses than these thresholds, typically in the range of 40 to 70 mitoses per high-power fields. Up to 40% of NECs contain elements of non-NECs, usually adenocarcinoma or squamous cell carcinoma. Often the diagnosis of a NEC tumor is after surgery on examination of the histological specimen. NECs are characterised by a high proclivity for metastatic dissemination even in patients with clinically localised tumours. This principle is validated by retrospective studies confirming that surgery alone is rarely curative (Brenner et al.,2004a). In devising treatment strategies for extrapulmonary NEC, many authors refer to the extensive literature surrounding high-grade neuroendocrine carcinoma of the lung (Brenner et al., 2004a, Walenkamp et al., 2009). Several series have, however, questioned the rationale for this, and point out many differences between pulmonary small-cell carcinoma and SCNEC (Brennan et al., 2010, Brenner et al., 2004a, Brenner at al., 2007, Ku et al., 2008). Differences include aetiology (less smoking history in SCNEC), frequency of brain