Lung-only melanoma: UV mutational signature supports origin from occult cutaneous primaries and argues against the concept of primary pulmonary melanoma

Abstract

Primary pulmonary melanoma (PPM) is an entity recognized by the thoracic WHO classification. However, given the absence of native melanocytes in the lung and the known phenomenon of regression of cutaneous melanomas, the existence of PPM has remained controversial. Herein we investigate clinicopathologic and genomic features of lung-only melanomas with the goal to clarify their site of origin. We identified 10 melanomas involving exclusively lung with no current or previous cutaneous, uveal, or mucosal primaries. Four patients had solitary lesions with mean size of 5.1 cm (range 3.0-10.1 cm), meeting the criteria of PPM. Four patients had 2-3 lesions and 2 patients had >10 lesions. All cases underwent targeted next-generation sequencing interrogating up to 468 cancer genes, which revealed mean tumor mutation burden of 42.6 per megabase (range 1.8 to 126) and frequent mutations involving BRAF, NRAS, NF1, KIT, and KRAS - a genomic profile typical of UV-associated cutaneous melanoma. Mutational signature was assessable for eight cases harboring >20 mutations. This revealed that all evaluable cases harbored a dominant UV signature. In addition, one nonevaluable case harbored a GG > AA TERT promoter variant that is highly specific for UV-mutagenesis. As control groups, using the same methodology, a dominant UV signature was identified in 97% (470/486) of cutaneous melanomas, whereas no lung adenocarcinoma (n = 291) exhibited this signature. Notably, the clinical and pathologic features of solitary melanomas, especially those with large size and epithelioid morphology, closely mimicked primary lung carcinomas, highlighting a major potential for misdiagnosis. In conclusion, presence of a UV signature provides direct evidence that nearly all lung-only melanomas in this series, including solitary lesions meeting the strict criteria of PPM, represent metastases from occult cutaneous melanomas. This suggests that lung-only melanomas should be considered as likely metastatic even in the absence of a known primary melanoma elsewhere.

Fig. 1. Radiologic and macroscopic features of lung-only melanomas.

Computed tomography (CT) images of three cases: (a) a 10.1 cm centrally located solitary lung mass; (b) a 3.2 cm solitary lung mass; and (c) multiple bilateral lung lesions. d Serial sections of a solitary lung mass exhibiting tan-yellow cut surfaces with central necrosis and hemorrhage. e, f Two separate lesions in one patient also demonstrate tan-yellow cut surfaces with central necrosis and hemorrhage.

Fig. 2. Microscopic features of lung-only melanomas.

Majority of cases show predominant epithelioid cytomorphology, which may mimic non-small cell carcinoma (a, b), and some cases have spindle cell morphology (c). Expression of SOX10 and HMB45 is illustrated in insets in (a) and (c), respectively. An example (d) showing pigmented melanoma cells involving the bronchial epithelium in small nests (arrow: melanoma cells in bronchial epithelium). e and f illustrate H&E stain and S100, respectively, of involvement of bronchial epithelium adjacent to a lung-only melanoma. Arrows: melanoma cells in bronchial epithelium.

Fig. 3. OncoPrint of mutations in lung-only melanomas.

Shown are mutations relevant to melanoma. MAPK: Mitogen-activated protein kinase.

Fig. 4. UV signature in lung-only melanoma with cutaneous melanoma and lung adenocarcinoma as control groups.

Two cases (case ID 4 and 7) had <20 total mutations and were excluded from this analysis (see Fig. 3). a Contribution of various signatures to each evaluable case of lung-only melanoma. Each bar represents a single case, and Y-axis represents fraction contributed by each mutational signature in individual case. b Fraction of evaluable cases characterized by various dominant signatures for lung-only melanoma vs. cutaneous melanoma vs. lung adenocarcinoma. c Dot plots showing percentage of UV-related mutations in each sample as a continuous variable. Dotted line at 40% indicate a threshold for “dominant signature”.