Synapse - Undifferentiated and dedifferentiated metastatic melanomas masquerading as soft tissue sarcomas: Mutational signature analysis and immunotherapy response

Undifferentiated and dedifferentiated metastatic melanomas masquerading as soft tissue sarcomas: Mutational signature analysis and immunotherapy response Journal Article

Authors:	Kasago, I. S.; Chatila, W. K.; Lezcano, C. M.; Febres-Aldana, C. A.; Schultz, N.; Vanderbilt, C.; Dogan, S.; Bartlett, E. K.; D'Angelo, S. P.; Tap, W. D.; Singer, S.; Ladanyi, M.; Shoushtari, A. N.; Busam, K. J.; Hameed, M.
Article Title:	Undifferentiated and dedifferentiated metastatic melanomas masquerading as soft tissue sarcomas: Mutational signature analysis and immunotherapy response
Abstract:	The distinction between undifferentiated melanoma (UM) or dedifferentiated melanoma (DM) from undifferentiated or unclassifiable sarcoma can be difficult and requires the careful correlation of clinical, pathologic, and genomic findings. In this study, we examined the utility of mutational signatures to identify patients with UM/DM with particular attention as to whether this distinction matters for treatment because the survival of patients with metastatic melanoma has dramatically improved with immunologic therapy, whereas durable responses are less frequent in sarcomas. We identified 19 cases of UM/DM that were initially reported as unclassified or undifferentiated malignant neoplasm or sarcoma and submitted for targeted next-generation sequencing analysis. These cases were confirmed as UM/DM by harboring melanoma driver mutations, UV signature, and high tumor mutation burden. One case of DM showed melanoma in situ. Meanwhile, 18 cases represented metastatic UM/DM. Eleven patients had a prior history of melanoma. Thirteen of 19 (68%) of the tumors were immunohistochemically completely negative for 4 melanocytic markers (S100, SOX10, HMB45, and MELAN-A). All cases harbored a dominant UV signature. Frequent driver mutations involved BRAF (26%), NRAS (32%), and NF1 (42%). In contrast, the control cohort of undifferentiated pleomorphic sarcomas (UPS) of deep soft tissue exhibited a dominant aging signature in 46.6% (7/15) without evidence of UV signature. The median tumor mutation burden for DM/UM vs UPS was 31.5 vs 7.0 mutations/Mb (P < .001). A favorable response to immune checkpoint inhibitor therapy was observed in 66.6% (12/18) of patients with UM/DM. Eight patients exhibited a complete response and were alive with no evidence of disease at the last follow-up (median 45.5 months). Our findings support the usefulness of the UV signature in discriminating DM/UM vs UPS. Furthermore, we present evidence suggesting that patients with DM/UM and UV signatures can benefit from immune checkpoint inhibitor therapy.(c) 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.
Keywords:	sarcoma; nerve sheath tumor; double-blind; malignant-melanoma; gene fusions; alveolar rhabdomyosarcoma; pleomorphic; ultraviolet-radiation; open-label; undifferentiated; diagnostic utility; mutational signature; undifferentiated melanoma; dedifferentiated melanoma; immunotherapy response; pleomorphic sarcomas; h3k27 trimethylation
Journal Title:	Modern Pathology
Volume:	36
Issue:	8
ISSN:	0893-3952
Publisher:	Nature Research
Date Published:	2023-08-01
Start Page:	100165
Language:	English
ACCESSION:	WOS:000984230200001
DOI:	10.1016/j.modpat.2023.100165
PROVIDER:	wos
PUBMED:	36990277
PMCID:	PMC10698871
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK author: Meera Hameed -- Source: Wos