Abstract
Simple SummaryNeuroendocrine carcinomas (NECs) represent the most aggressive subgroup of neuroendocrine neoplasms. Around 90% of NECs arise from the lung. The minority of NECs originating outside of the lung are called extra-pulmonary (EP)-NECs. Most patients with EP-NECs are diagnosed at an advanced stage (incurable) and have a life expectancy of months; platinum-based chemotherapy or best supportive care are the only options for these patients. However, response to platinum-based chemotherapy and prognosis vary largely within this patient population. Previous studies have shown that such variability depends on the site of origin and the Ki-67 index (which is an indicator of how quickly cancer cells proliferate). The present study found that the morphological subtype—small cell (SC) or non-small cell (non-SC)—is another contributing factor. In fact, patients with an advanced-stage non-SC EP-NEC respond less to platinum-based chemotherapy and have shorter survival than patients with an advanced-stage SC EP-NEC. Alternative treatments should be considered for this subgroup.Extra-pulmonary neuroendocrine carcinomas (EP-NECs) are lethal cancers with limited treatment options. Identification of contributing factors to the observed heterogeneity of clinical outcomes within the EP-NEC family is warranted, to enable identification of effective treatments. A multicentre retrospective study investigated potential differences in “real-world” treatment/survival outcomes between small-cell (SC) versus (vs.) non-SC EP-NECs. One-hundred and seventy patients were included: 77 (45.3%) had SC EP-NECs and 93 (54.7%) had non-SC EP-NECs. Compared to the SC subgroup, the non-SC subgroup had the following features: (1) a lower mean Ki-67 index (69.3% vs. 78.7%; p = 0.002); (2) a lower proportion of cases with a Ki-67 index of ≥55% (73.9% vs. 88.7%; p = 0.025); (3) reduced sensitivity to first-line platinum/etoposide (objective response rate: 31.6% vs. 55.1%, p = 0.015; and disease control rate; 59.7% vs. 79.6%, p = 0.027); (4) worse progression-free survival (PFS) (adjusted-HR = 1.615, p = 0.016) and overall survival (OS) (adjusted-HR = 1.640, p = 0.015) in the advanced setting. Within the advanced EP-NEC cohort, subgroups according to morphological subtype and Ki-67 index (<55% vs. ≥55%) had significantly different PFS (adjusted-p = 0.021) and OS (adjusted-p = 0.051), with the non-SC subgroup with a Ki-67 index of <55% and non-SC subgroup with a Ki-67 index of ≥55% showing the best and worst outcomes, respectively. To conclude, the morphological subtype of EP-NEC provides complementary information to the Ki-67 index and may aid identification of patients who could benefit from alternative first-line treatment strategies to platinum/etoposide.
Highlights
Extra-pulmonary neuroendocrine carcinomas (EP-NECs) are aggressive epithelial cancers with immunohistochemical expression of neuroendocrine (NE) markers, and a proliferation (Ki-67)index of >20% [1]
When chemotherapy was administered with curative intent in combination with surgery or radiotherapy (n = 27), platinum/etoposide was the most commonly chosen regimen (18/27; 66.7%)
A number of studies have attempted to elucidate the molecular landscape of EP-NECs over the past few years [21,22,23,24,25], as these cancers have been gaining more attention in the scientific community
Summary
Extra-pulmonary neuroendocrine carcinomas (EP-NECs) are aggressive epithelial cancers with immunohistochemical expression of neuroendocrine (NE) markers (chromogranin A, synaptophysin or neuron cell adhesion molecule), and a proliferation (Ki-67)index of >20% [1]. EP-NECs lack the typical organoid-like growth pattern of low-grade, well-differentiated neuroendocrine tumours (WD-NETs) and are defined as poorly differentiated. Similar to their pulmonary counterparts, EP-NECs can exhibit a “small-cell” (SC) morphology; diffuse sheets of cells with scant cytoplasm and fusiform nuclei with inconspicuous nucleoli and finely granular chromatin or a “large-cell”. Patients with an EP-NEC diagnosis mostly have metastatic disease at presentation and have an average life expectancy of less than 12 months [2] Treatment options for these patients are limited; surgery remains the mainstay of treatment in the localised setting; platinum-based chemotherapy is the only standard-of-care first-line palliative treatment and has not changed for the past three decades [4]. Several chemotherapy regimens have been investigated after the failure of platinum-based chemotherapy in small retrospective studies or non-randomised trials [7], but none have become standard practice so far
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