Malignant melanoma (MM) is primarily a highly aggressive non-epithelial tumor affecting skin tissue. Patients often have a history of skin melanocytic nevi and may present with cutaneous ulcerations. Although MM is typically associated with the skin, it can also occur in other sites, including the esophagus, oral cavity, anus and vagina (1). The clinical diagnosis of MM typically relies on histopathological examination and immunohistochemical markers such as sry-box transcription factor 10 (SOX10), melan-A and human melanoma black-45 (HMB-45), which are essential for differentiating it from other malignancies. Primary pulmonary malignant melanoma (pPMM) is an extremely rare manifestation, accounting for ~0.001% of primary malignant lung tumors and 0.4% of all malignant melanomas (1). Due to its rarity, pPMM poses diagnostic challenges and is often misdiagnosed as other malignancies, such as malignant peripheral nerve sheath tumors (MPNSTs) or metastatic melanoma. The absence of a cutaneous or mucosal primary site further complicates the diagnostic process. H3K27Me3 is a post-translational modification associated with transcriptional repression and tumor suppressor gene silencing (2). Loss of H3K27Me3 has been implicated in the progression of various aggressive tumors, such as MPNSTs and glioblastoma (2,3). The present study discusses a unique case of pPMM characterized by H3K27Me3 loss, examining its genomic profile, pathogenesis and natural history, along with relevant literature. Notably, this case was initially misdiagnosed as a MPNST based on overlapping histopathological and immunohistochemical features. This case underscores the challenges in diagnosing rare malignancies, particularly when they mimic more common entities. The case highlights the importance of comprehensive histological, immunohistochemical and molecular evaluations in achieving a definitive diagnosis, especially in cases with overlapping features.

MM, typically a highly aggressive tumor, is predominantly found in the skin. Patients often present with a history of melanocytic nevi and may have skin ulcerations. Although PMM is usually metastatic from skin lesions (6), pPMM is exceptionally rare. The median age of diagnosis is ~59.1 years, with no significant sex differences reported. Unlike for numerous lung cancers, smoking is not considered a risk factor for pPMM. Most cases are incidentally discovered during routine physical examinations, often appearing as solitary lung nodules on imaging (1).

Histologically, pPMM shares feature with melanomas from skin or mucosal sites, including epithelioid and spindle-shaped cells with significant nuclear atypia and melanin deposits. Distinguishing between pPMM and metastatic melanoma can be challenging due to the tendency of skin melanomas to degenerate after metastasis (7). The accurate diagnosis of pPMM requires a thorough evaluation of clinical, imaging and pathological findings. Previous studies (8,9) have proposed specific criteria for diagnosing pPMM. Jensen and Egedorf (8) suggested the following six criteria: i) No prior skin tumors removed; ii) no prior ocular tumors removed; iii) a solitary lung tumor; iv) morphology consistent with a primary tumor; v) no involvement of other organs; and vi) absence of primary MM demonstrated in other organs, particularly in the skin or eyes, confirmed by biopsy. According to the pathological diagnostic criteria for pPMM by Allen and Drash (9), the diagnosis of MM is based on bronchial epithelium invasion by melanoma cells, junctional changes such as ‘dropping off’ or ‘nesting’ just beneath the bronchial epithelium, and confirmation of melanoma cells through immunohistochemical staining (S-100, HMB-45 and Melan-A) or electron microscopy. The present case met all these clinical and pathological criteria, leading to a diagnosis of pPMM.

The key differential diagnosis in the present case was MPNST, due to the rare presentation of MM in the pulmonary region, and as both MPNST and MM can exhibit melanin deposits and similar morphological features, making differentiation difficult (10,11). The biphasic differentiation in the present case, with both epithelioid and spindle cell characteristics, added complexities to the diagnosis. H3K27Me3 is a crucial epigenetic marker of gene silencing, intricately associated with heterochromatic regions; it plays a significant role in inflammation, DNA damage repair, cell proliferation, metastasis, regulatory cell death, ferroptosis and angiogenesis, thereby influencing various epigenetic mechanisms in the pathogenesis of multiple cancer types, such as glioblastoma (2). H3K27me3 is frequently observed to be lost in MPNST (3) and has also been documented in MM (12), indicating that this marker alone is insufficient to distinguish between the two. The correct identification of pPMM had significant clinical implications, as the treatment strategies for MM and MPNSTs differ substantially. Accurate diagnosis enabled the initiation of appropriate therapy, including targeted and immune-based treatments tailored to MM, which contributed to an improved clinical outcome for the patient. Differentiation from other malignancies, such as pulmonary sarcomatoid carcinoma, epithelioid inflammatory myofibroblastic sarcoma, angiosarcoma and leiomyosarcoma, is also crucial. Negative immunohistochemical markers for AE1/AE3, EMA, SMA, ALK and others helped rule out these diagnoses in the present study.

Genomic analysis of this pPMM revealed mutations similar to those found in mucosal and esophageal melanomas, contrasting with the common mutations seen in skin melanoma (13–15). In the present patient, NGS identified mutations in TP53, NTRK3, NF1 and BCL2L11, while BRAF and KIT mutations, typically associated with skin melanoma, were absent. Research indicates that NF1 mutations are prevalent in primary esophageal melanomas (13), supporting the idea that different anatomical locations may have distinct mutational profiles.

The prognosis for patients with pPMM is generally poor (4). However, the present patient has achieved long-term disease-free survival for 72 months, possibly indicating a potential cure following surgical resection. This favorable outcome may be attributed to the incidental nature of the diagnosis, absence of clinical symptoms, early detection and H3K27Me3 loss, which has been suggested in previous studies to correlate with a more favorable prognosis in melanoma (16,17). High H3K27Me3 expression is associated with more aggressive melanoma cell phenotype and poorer outcomes (18), emphasizing the significance of this biomarker in assessing melanoma prognosis and possible therapeutic approaches based on the gennomic findings.

There are some limitations to the present study. The report is based on a single case, which limits the generalizability of the findings and the exploration of potential treatment strategies for pPMM. Given the rarity of the condition, discussing possible treatment options based on the genomic findings would have been beneficial. Therefore, more cases are needed to validate the observations and conclusions in future studies.

In conclusion, the current study presents a rare case of pPMM, initially misdiagnosed as MPNST, characterized by H3K27me3 loss and a histological profile displaying both epithelial and spindle cell features. The case findings highlight the complexities involved in diagnosing pPMM and the critical importance of comprehensive clinical and pathological evaluation.