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Updated: Jun 14, 2025
Comparative Lesions Analysis Through a Targeted Sequencing Approach
Published on: November 5, 2019
Morphologic and immunophenotypic characterization of conventional FLCN-mutated tumors (FMT) compared to a series of 8
Sounak Gupta1, Surendra Dasari2, Wei Shen1
1Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
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.
