Morphologic and immunophenotypic characterization of conventional FLCN-mutated tumors (FMT) compared to a series of 8 non-conventional FMT

IF 2.7 2区医学 Q2 PATHOLOGY

Human pathology Pub Date : 2025-06-01 DOI:10.1016/j.humpath.2025.105813

Sounak Gupta , Surendra Dasari , Wei Shen , Hussam Al-Kateb , Emily G. Barr Fritcher , Nate R. Torell , Leah M. Nelson , Yelena Kalugina , Kingsley Ebare , Melissa L. Stanton , Santosh Menon , Burak Tekin , Rumeal D. Whaley , Loren P. Herrera Hernandez , Aditya Raghunathan , Rafael E. Jimenez , Benjamin R. Kipp , Lori A. Erickson , John C. Cheville

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引用次数: 0

Abstract

Background

Recent studies suggest that hybrid oncocytoma/chromophobe tumors in Birt-Hogg-Dubé Syndrome (BHD) may instead represent unique tumors. We performed histologic assessment of FLCN-mutated tumors (FMT) to better separate conventional (c-FMT) from non-conventional tumors (nc-FMT), as the latter can behave aggressively.

Methods

Histologic features of c-FMT were compared to 8 nc-FMT. Immunohistochemistry (IHC) of representative FMT and morphologic mimics was quantified using H-scores (range: 0–300). Molecular profiling of nc-FMT included NGS, chromosomal microarrays, and FISH for TFE3/TFEB.

Results

A single c-FMT was identified in the setting of Smith-Magenis Syndrome (germline terminal 17p microdeletion associated with a second hit of FLCN). nc-FMT accounted for a minority of FMT in 25 patients (8/89, 9 %), had a mean size of 8.0 cm, and they exhibited papillary and microcystic features in 3/8 (38 %) patients, each. Germline FLCN alterations were confirmed in 4 BHD patients with nc-FMT, and biallelic FLCN inactivation was documented for 7/8 (88 %) nc-FMT. Screening IHC showed inconsistent results in nc-FMT compared to c-FMT for SOX9 (mean H-score: 60 vs 208) as opposed to mean H-scores for L1CAM (187 vs 176) and GPNMB (266 vs 267). Two nc-FMT with variable levels of TFEB gain/amplification showed aggressive behavior. Positivity for markers such as cathepsin K/melan A was only seen for a TFEB-amplified nc-FMT, suggesting that such markers may have a role in screening for aggressive nc-FMT.

Conclusions

Our results can serve as a framework for the development of essential diagnostic criteria for c-FMT, and their separation from nc-FMT which can occasionally show aggressive behavior associated with TFEB amplification.

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常规flcn突变肿瘤（FMT）与一系列8个非常规FMT的形态学和免疫表型特征比较

背景：最近的研究表明，在birt - hogg - dub综合征（BHD）中，混合型嗜癌细胞瘤/憎色瘤可能是一种独特的肿瘤。我们对flcn突变肿瘤（FMT）进行了组织学评估，以更好地区分常规（c-FMT）和非常规肿瘤（nc-FMT），因为后者具有侵袭性。方法：将c-FMT与8 nc-FMT的组织学特征进行比较。采用h评分（范围0-300）对代表性FMT和形态模拟物的免疫组织化学（IHC）进行量化。nc-FMT的分子分析包括NGS、染色体微阵列和FISH检测TFE3/TFEB。结果：在Smith-Magenis综合征（种系末端17p微缺失与FLCN的第二次撞击相关）的情况下，鉴定出单个c-FMT。nc-FMT占25例FMT的少数（8/ 89,9%），平均大小为8.0 cm, 3/8（38%）的患者分别表现为乳头状和微囊状特征。在4例伴有nc-FMT的BHD患者中证实了种系FLCN的改变，7/8（88%）患者的双等位基因FLCN失活。筛查IHC显示，与SOX9的c-FMT相比，nc-FMT的结果不一致（平均h分数：60 vs 208），而L1CAM的平均h分数（187 vs 176）和GPNMB的平均h分数（266 vs 267）。两个具有不同TFEB增益/放大水平的nc-FMT表现出攻击行为。组织蛋白酶K/黑色素A等标记物的阳性仅见于tfeb扩增的nc-FMT，这表明这些标记物可能在筛选侵袭性nc-FMT中起作用。结论：我们的研究结果可以作为c-FMT基本诊断标准的制定框架，以及它们与偶尔表现出与TFEB扩增相关的侵袭性行为的nc-FMT的分离。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Human pathology 医学-病理学

CiteScore

5.30

自引率

6.10%

发文量

206

审稿时长

21 days

期刊介绍： Human Pathology is designed to bring information of clinicopathologic significance to human disease to the laboratory and clinical physician. It presents information drawn from morphologic and clinical laboratory studies with direct relevance to the understanding of human diseases. Papers published concern morphologic and clinicopathologic observations, reviews of diseases, analyses of problems in pathology, significant collections of case material and advances in concepts or techniques of value in the analysis and diagnosis of disease. Theoretical and experimental pathology and molecular biology pertinent to human disease are included. This critical journal is well illustrated with exceptional reproductions of photomicrographs and microscopic anatomy.