视网膜母细胞瘤辅阻遏物 1（RB）和细胞周期蛋白依赖性激酶抑制剂（CDKN）作为一个多基因panel，用于区分转移性神经内分泌癌的肺来源和非肺来源。

Retinoblastoma co-repressor 1 (RB) and cyclin-dependent kinase inhibitor (CDKN) as a multi-gene panel for differentiating pulmonary from non-pulmonary origin in metastatic neuroendocrine carcinomas.

机构信息

A.M. Rywlin, MD Department of Pathology, Mount Sinai Medical Center, Miami Beach, FL 33140, USA.

Medical Oncology, Mount Sinai Medical Center, Miami Beach, FL 33140, USA.

出版信息

Pathol Res Pract. 2020 Sep;216(9):153051. doi: 10.1016/j.prp.2020.153051. Epub 2020 Jun 10.

DOI:10.1016/j.prp.2020.153051

PMID:32825935

Abstract

BACKGROUND

Neuroendocrine carcinomas (NECs) arise from neuroendocrine cells present throughout the body, and often present with metastases even with small and undetectable primary tumors. Additionally, neuroendocrine differentiation can be seen in carcinomas of non-neuroendocrine origin further complicating the landscape of metastatic NECs. Organ specific immunohistochemical markers such as TTF1, CDX2 and PAX8 are often lost in high grade tumors and may be non-contributory in localizing the primary site. Though NECs share a common cellular origin, they exhibit great variability in biologic behavior, prognosis and treatment based on the primary organ of origin.

DESIGN

Twenty one cases of metastatic NECs were retrieved from our archives and were classified based on location of the primary tumor derived from clinical and radiological findings. Next generation sequencing data was retrieved and analyzed for recurrent genetic abnormalities in these cases. Statistical analysis was performed using IBM SPSS25 software.

RESULTS

RB1 mutations were exclusive to NECs metastasizing from lung primary and were detected in 5 of 12 (41.6 %) cases (p = 0.04). CDKN gene family (CDKN1B and 2 A) mutations were limited to metatstatic NECs of non-pulmonary origin and were detected in 4 of 9 (44.4 %) cases (p = 0.02).

CONCLUSION

The location of the primary tumor in metastatic NECs appears to have significant prognostic and therapeutic implications. But due to the morphological homogeneity, higher grade of tumor, variable sensitivity of immunohistochemical markers, and small, often undetectable primary tumors, the localization of the primary tumor in cases of metastatic NECs is a challenge. In this study, RB1 and CDKN gene family mutations are identified as possible markers for differentiating pulmonary and non-pulmonary origin in metatstatic NECs.

摘要

背景

神经内分泌癌（NEC）起源于全身各处的神经内分泌细胞，即使原发肿瘤较小且无法检测到，也常伴有转移。此外，非神经内分泌来源的癌中也可见神经内分泌分化，这使得转移性 NEC 的起源变得更加复杂。组织特异性免疫组化标志物，如 TTF1、CDX2 和 PAX8，在高级别肿瘤中常丢失，对定位原发灶可能无帮助。虽然 NEC 具有共同的细胞起源，但基于原发器官的不同，其生物学行为、预后和治疗存在很大差异。

设计

从我们的档案中检索了 21 例转移性 NEC 病例，并根据原发肿瘤的位置（源自临床和影像学发现）进行分类。检索并分析了这些病例的下一代测序数据中是否存在复发性遗传异常。使用 IBM SPSS25 软件进行统计分析。

结果

RB1 突变仅存在于源自肺部原发灶的转移性 NEC 中，在 12 例（41.6%）中检测到 5 例（p=0.04）。CDKN 基因家族（CDKN1B 和 2A）突变仅限于非肺部起源的转移性 NEC，在 9 例（44.4%）中检测到 4 例（p=0.02）。

结论

转移性 NEC 中原发灶的位置似乎具有重要的预后和治疗意义。但由于形态学上的同质性、肿瘤分级较高、免疫组化标志物的可变敏感性以及原发灶较小且常无法检测，转移性 NEC 中原发灶的定位仍然具有挑战性。在这项研究中，RB1 和 CDKN 基因家族的突变被确定为区分转移性 NEC 中肺来源和非肺来源的可能标志物。