Melanoma of Unknown Primary - A Comprehensive Review of Immune-Mediated Pathogenesis and Therapies

Sep 28, 2026

Uploaded by Mary Man

Melanoma of unknown primary (MUP) is a rare melanoma subtype with low incidence, creating difficulty in clinical management. This systematic review summarizes recent advances on MUP pathogenesis, molecular characteristics, and therapeutic strategies. It discusses immune-driven spontaneous regression involving T cells and natural killer cells, and links UV-damage mutational patterns shared with cutaneous melanoma while highlighting distinct recurrent genomic alterations. Current treatments mirror advanced melanoma approaches but targeted-therapy efficacy in MUP remains underdefined.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages6

Reading Time15 min

AccessFree to download

Abstract

Introduction

Spontaneous regression

Implications for Practice

Melanoma of unknown primary: a comprehensive review of immune-mediated pathogenesis and therapies Wanling Xu1,, Jianping Gui2, Pengna Guo2, Yiqun Zhang2, Di Wu*,2, 1Department of Emergency, The First Hospital of Jilin University, Changchun, 130021, China 2Cancer Center, The First Hospital of Jilin University, Changchun, 130021, China *Corresponding author: Di Wu, Cancer Center, The First Hospital of Jilin University, 1 Xinmin St, Changchun, 130021, China ([wudi1971@jlu.edu.cn](wudi1971@jlu.edu.cn)) . Abstract Melanoma of unknown primary (MUP) is a rare subtype of melanoma, with its low incidence posing challenges for clinical management. This systematic review integrates recent advances in MUP research, with a focus on pathogenesis, molecular characteristics, and therapeutic strategies. The proposed pathogenesis involves spontaneous regression of the primary lesion, potentially driven by sequential immune responses mediated by T cells and natural killer cells. At the molecular level, whole-exome/genome analyses reveal that MUP and cutaneous melanoma share a highly concordant UV damage-driven mutational landscape; nevertheless, MUP exhibits distinct genomic alterations, including recurrent mutations in the telomerase reverse transcriptase promoter, protein phosphatase 6 catalytic subunit, and isocitrate dehydrogenase 1. Current therapeutic approaches are similar to those for advanced melanoma, encompassing surgery, immune checkpoint inhibitors (ICIs), and targeted therapies. While ICIs have demonstrated significant improvements in survival, the clinical efficacy of targeted therapies in MUP remains to be fully established. By consolidating current knowledge, this review provides insights to guide diagnosis, treatment, and future research in MUP. Key words: melanoma of unknown primary; spontaneous regression; cellular immunity; molecular genetic signature; therapeutics. Introduction Malignant melanoma, a highly aggressive neoplasm arising from melanocytes, continues to show a rising global incidence and mortality. In 2020 alone, approximately 325 000 new cases of cutaneous melanoma (CMM) were diagnosed worldwide, resulting in over 56 000 deaths.1 Among these, 2%-3% of melanomas present without an identifiable primary lesion, constituting a distinct clinical entity termed melanoma of unknown primary (MUP) . MUP typically peaks in incidence during the fourth and fifth decades of life and demonstrates a notable male predominance.2,3 First documented in 1952,4 and formally defined by Das Gupta in 1963, MUP is diagnosed when melanoma is identified in subcutaneous tissue, lymph nodes, or visceral organs in the absence of a primary cutaneous, ocular, or mucosal lesion.5 Its diagnosis relies on a thorough clinical evaluation, including a full-body dermatologic examination, inspection of the oral cavity and genitourinary tract, ophthalmologic assessment, andotolaryngologic evaluation, often supplemented by endoscopic procedures. Histopathological confirmation requires immunohistochemical staining for melanocytic markers such as SOX10, S-100, Melan-A, and HMB45, as well as molecular profiling of common driver mutations, including v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) and neuroblastoma RAS viral oncogene homolog (NRAS) . As a diagnosis of exclusion, MUP necessitates a multimodal diagnostic approach. Recent advances in high-throughput sequencing have yielded new insights into its pathogenesis, particularly the hypothesis of spontaneous regression of the primary lesion, and have uncovered unique molecular features that distinguish MUP from conventional melanoma. This review integrates the current understanding of MUP’s pathogenic mechanisms, molecular characteristics, and therapeutic strategies, aiming to support the development of precision diagnostics and personalized treatment approaches. Spontaneous regression Hypotheses regarding the pathogenesis of MUP primarily include (1) spontaneous regression o

FAQs

What makes melanoma of unknown primary (MUP) clinically challenging?

MUP is rare and occurs without an identifiable primary lesion, which complicates diagnosis and management. The low incidence also limits clear evidence-based guidance.

Which immune mechanisms are proposed to drive MUP spontaneous regression?

The review proposes that sequential immune responses, particularly mediated by T cells and natural killer cells, may cause spontaneous regression of the primary lesion. MUP is also described as having an immunogenic microenvironment with CD8+ T-cell and NK-cell infiltration.

How do current treatments for MUP compare with treatments for advanced melanoma?

Therapeutic approaches for MUP generally resemble those for advanced melanoma, including surgery, immune checkpoint inhibitors, and targeted therapies. Immune checkpoint inhibitors have improved survival, while targeted-therapy effectiveness in MUP is not yet fully established.

Sep 28, 2026

Uploaded by Mary Man