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Mary Beth Beasley

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    MS 07 - Neuroendocrine Tumors other than SCLC: Pathology to Patient Management (ID 529)

    • Event: WCLC 2017
    • Type: Mini Symposium
    • Track: SCLC/Neuroendocrine Tumors
    • Presentations: 1
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      MS 07.01 - Pathology of Neuroendocrine Tumors other than SCLC (ID 7669)

      15:45 - 17:30  |  Presenting Author(s): Mary Beth Beasley

      • Abstract
      • Presentation
      • Slides

      Neuroendocrine tumors (NET) of the lung comprise approximately 20% of all primary lung carcinomas overall and consist primarily of four malignancies: Typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC) and small cell carcinoma(SCLC) using 2015 World Health Organization (WHO) nomenclature. The four tumors have historically been regarded as a spectrum; however, there are significant differences between TC/AC and LCNEC/SCLC on many levels. Additionally, while most TC and AC arise de novo, a small percentage of cases with arise in the setting of diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH), a rare pre-neoplastic condition. DIPNECH has not been associated with the development of LCNEC or SCLC. TC and AC, comprise 1-2% of primary lung cancers with the vast majority being TC. Both TC and AC may occur in either a central or peripheral location, with central tumors resulting in symptoms related to obstruction while peripheral tumors are often asymptomatic and discovered incidentally. TC is considered a “low grade” or “well-differentiated” tumor; however, 5-20% of TC are associated with regional lymph node or distant metastases. AC, considered an “intermediate grade” or “moderately-differentiated” tumor, is associated with metastases in up to 40% of cases. The five and 10 year survival for TC is approximately 90% whereas it drops to 70% and 50% for AC. By current WHO criteria, TC is defined as a neuroendocrine tumor greater than 5mm in size with fewer than 2 mitoses per 2mm[2] and lacking necrosis, whereas AC is defined as a neuroendocrine tumor with 2-10 mitoses per 2mm[2] or necrosis. As mitotic activity and necrosis may be focal, the distinction between TC and AC can generally not be made on a small sample. Both tumors classically show an organoid or trabecular pattern of growth and are composed of a relatively uniform population of round to oval cells with granular nuclear chromatin, but may show a wide range of histologic growth patterns, particularly in TC. Given that the main feature distinguishing AC from TC is mitotic activity, one would expect that proliferation markers such as Ki-67 would be of potential value in discriminating these two tumors. Numerous studies have attempted to evaluate this parameter with various cut offs being proposed; however, ultimately there is too much overlap between the Ki-67 scores of TC and AC for it to be reliably useful in discriminating between the two tumors. The Ki-67 score can be useful in separating high-grade from low-grade tumors on small distorted biopsies, and some studies have shown it to have utility as a prognostic marker in TC/AC. As such it may be used to potentially guide treatment and is included as a parameter in the European Neuroendocrine Tumor Society (ENETS) guidelines. Surgery remains the only curative treatment option for TC/AC but there is a lack of consensus in regard to treatment of un-resectable or metastatic disease. Results of the RADIANT-4 trial have led to the approval of everolimus for advanced TC/AC. There is additional evidence that somatostain analogs may be useful in selected patients. Molecular analysis of TC and AC demonstrate distinctly different molecular profiles compared to the high grade NET’s, with MEN1 alterations found essentially exclusively in carcinoids whereas alteration of RB1 cell cycle regulation genes and the PI3K/AKT/mTOR pathway were found less frequently in TC/AC and enriched in the higher grade tumors. TC/AC also tend to show frequent mutations of chromatin remodeling genes, as well as mutations of PSIP1 and ARID1A. Actionable mutations such as EGFR mutations and ALK rearrangements are not found in TC/AC and thus far evaluation of PD-L1 in carcinoids has been negative, suggesting a lack of a role for current targeted therapy or immunotherapeutic agents used in non-small cell lung carcinomas (NSCLC). Several clinical trials are either ongoing or currently recruiting to evaluate the efficacy of several small molecular inhibitors. LCNEC was originally described in 1991 and was initially included as a subtype of large cell carcinoma in subsequent WHO classification, but in the current WHO it is classified as a type of neuroendocrine carcinoma. The tumor is defined as a tumor with neuroendocrine morphology with large cell morphology and greater than 10 mitoses/2mm[2], although most cases have substantially higher mitotic rates. By definition, tumors must show evidence of neuroendocrine differentiation, usually identified by immunohistochemical methods. While distinction of LCNEC from SCLC may appear straightforward on the surface, in reality LCNEC can be heterogeneous and the distinction is not always clear cut. Currently, there is no immunostain or other definitive test to discriminate between the two and distinction ultimately rests of subjective evaluation of the tumor morphology. The extreme rarity of this tumor, combined with the tumor heterogeneity and resultant subjectivity inherent in classification has likely contributed to conflicting reports in the literature regarding prognosis, although it is generally agreed that LCNEC is a high-grade tumor with a poor prognosis. Similarly, variable results have been reported in regard to the responsiveness of LCNEC to treatment regimens typically used for SCLC leading to a lack of consensus regarding whether LCNEC should be managed similar to SCLC or similar to other non-small cell carcinomas. Molecular studies have additionally shown variable results. The majority of studies have shown overlapping features with SCLC. Some studies, however, have shown alterations characteristic of other tumor types, most notably occasional EGFR, ALK and KRAS mutations even in the absence of an overt mixed adenocarcinoma component, which have not been found in SCLC. Interestingly, in 2016, Rekhtman, et al, evaluated 45 LCNEC and pared normal tissue by NGS with 241 cancer gene analysis. This study demonstrated that LCNEC, while having some commonly altered genes, largely fell into two major and one minor subset (SCLC-like, NSCLC-like and a small number of “carcinoid like” tumors). These findings may explain the variability of results in treatment trials and may indicate that more comprehensive analysis of this rare groups of tumors may yield more optimal treatment strategies.

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