Multiple pulmonary melanocytic naevi presenting as peribronchiolar nodules

Abstract

Melanocytic naevi are benign neoplasms composed of melanocytes, the melanin-producing neural crest-derived cells normally located at the basal layer of the epidermis. Melanocytes are not normally present in the lower respiratory tract, and it would be surprising to encounter a primary melanocytic neoplasm in the lung. To date, less than a hundred cases of primary pulmonary melanocytic melanomas have been reported.1Deng S. Sun X. Zhu Z. et al.Primary malignant melanoma of the lung: a case report and literature review.BMC Pulm Med. 2020; 20: 94Google Scholar,2Paliogiannis P. Fara A.M. Pintus G. et al.Primary melanoma of the lung: a systematic review.Medicina (Kaunas). 2020; 56: 576Google Scholar Far rarer are the pulmonary melanocytic naevi, with only two case reports in the literature.3Tanaka M. Matsumura M. Okudela K. et al.Pulmonary melanocytic naevus - a case report with a mutation analysis of common driver oncogenes.Pathol Int. 2019; 69: 667-671Google Scholar,4Pigac B. Maric S. Masic S. Benign blue naevus of the lungs.Med Glas (Zenica). 2012; 9: 130-132Google Scholar Here, we present the first case of multiple melanocytic naevi growing along the bronchioles or alveolar septa, and clinically presenting as multiple ground glass nodules (GGNs) on thoracic computed tomography (CT) scans. A 61-year-old female never-smoker had a family history of lung cancer (her mother and aunt). Multiple pulmonary nodules and GGNs were found on low-dose chest CT scans during lung cancer screening. The largest one was a part-solid lung nodule measuring 1.4–1.5 cm in the left upper lobe. Whole body fluorodeoxyglucose-positron emission tomography (FDG-PET) showed only one mild hot area in her left upper lobe. She underwent thorough physical examination (including examination of the skin) and review of systems upon admission. There were no abnormal pigmented lesions or congenital type naevi on her skin, and she denied previous surgical history of either malignant melanoma or moles. She then received wedge resection of her largest left upper lung nodule by video-assisted thoracoscopic surgery. Grossly, a poorly defined nodule (1.3 cm in size) and some inconspicuous tiny black spots were found in the wedge resected peripheral left upper lung tissue. Histologically, the main lesion showed a lepidic-predominant adenocarcinoma positive for thyroid transcription factor 1 (TTF1) staining. Moreover, multiple foci of pigment-laden, bland-looking round cells growing along small bronchioles or alveolar septa were also noted (Fig. 1A–C). The largest focus measured 7.5 mm in the greatest dimension. These cells had uniform round to oval nuclei, inconspicuous nucleoli, absent mitotic figures, and many with cytoplasmic coarse melanin granules confirmed by Fontana-Masson stain (Fig. 1D,E). Immunohistochemically, these cells were diffusely positive for Melan-A, S100, SRY-box transcription factor 10 (SOX10), and rapidly accelerated fibrosarcoma B-type (BRAF) V600E, while negative for cytokeratin (CK) (AE1/AE3), TTF1, p40, synaptophysin, and smooth muscle actin (SMA) (Fig. 2A–D). Moreover, they were completely negative for preferentially expressed antigen in melanoma (PRAME, a marker preferentially expressed in melanoma but not in benign naevi),5Lohman M.E. Steen A.J. Grekin R.C. North J.P. The utility of PRAME staining in identifying malignant transformation of melanocytic nevi.J Cutan Pathol. 2021; 48: 856-862Google Scholar,6Lezcano C. Jungbluth A.A. Nehal K.S. Hollmann T.J. Busam K.J. PRAME expression in melanocytic tumors.Am J Surg Pathol. 2018; 42: 1456-1465Google Scholar and only very few cells were faintly positive for human melanoma black-45 (HMB45) (Fig. 2E,F). Multiple melanocytic naevi were diagnosed.Fig. 2Immunohistochemical staining. These naevus cells were positive for (A) SOX10 and (B) BRAF V600E, while negative for (C) TTF1 and (D) CK. (E) They were also totally negative for PRAME (a marker preferentially expressed in melanoma but not in benign naevi). (F) Only very few cells showed faint positivity for HMB45. (G) In contrast, the adjacent lepidic-predominant adenocarcinoma was positive for (H) TTF1.View Large Image Figure ViewerDownload Hi-res image Download (PPT) We present a very unusual case of primary multiple melanocytic naevi of the lung, clinically presenting as multiple GGNs. We searched PubMed and Embase databases from inception until January 2022 with a combination of keywords regarding pulmonary melanocytic naevus. Free-text terms were searched in complement with Medical Subject Headings (MeSH) term or EMTREE terms. Only two case reports were found. The first report in 2012 described an autopsy of a 62-year-old woman whose lung had a pulmonary blue naevus comprising spindle-shaped melanocytes with abundant melanin pigment and entwined bundles of collagen fibres in between.4Pigac B. Maric S. Masic S. Benign blue naevus of the lungs.Med Glas (Zenica). 2012; 9: 130-132Google Scholar Tanaka et al. reported another case of a pulmonary melanocytic naevus histologically resembling common type naevus of the skin in 2019.3Tanaka M. Matsumura M. Okudela K. et al.Pulmonary melanocytic naevus - a case report with a mutation analysis of common driver oncogenes.Pathol Int. 2019; 69: 667-671Google Scholar The naevus was incidentally found in a surgical specimen of mucosa-associated lymphoid tissue (MALT lymphoma), and BRAF V600E mutation was confirmed by DNA sequencing.3Tanaka M. Matsumura M. Okudela K. et al.Pulmonary melanocytic naevus - a case report with a mutation analysis of common driver oncogenes.Pathol Int. 2019; 69: 667-671Google Scholar Our case is unique because there were multiple naevi growing beneath bronchiolar epithelium or in alveolar septa, which caused alveolar wall thickening and presented as GGNs on CT scans. Despite the multifocality and the surgical margin involvement by naevus cells (Fig. 1C), our patient was uneventful during a 3-year follow-up period without adjuvant treatment. The clinical course supports that these naevi were benign in nature. The prevalence rate of primary melanocytic naevus is unknown because it may be too small to be detected on image studies or overlooked during pathological examination due to benign cytological features. The differential diagnosis of pulmonary melanocytic naevi includes neuroendocrine tumours [especially diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) and tumourlets], minute pulmonary meningothelial-like nodules (MPMNs), and metastatic melanomas. All these lesions could present as multiple small nodules. DIPNECH usually presents as multiple solid nodules with mosaic attenuation on CT scans. Microscopically, DIPNECH usually has multiple lesions including intraepithelial neuroendocrine cell hyperplasia, tumourlets, or carcinoids. These lesions rarely have pigment deposition or grow along alveolar septa. MPMNs are the most important differential diagnosis as they comprise oval to round cells growing along alveolar septa which can present as multiple nodules or GGNs on CT scans. Again, pigment deposition is not a feature of MPMNs, and they are not reactive to naeval cell markers like SOX10 or Melan-A. Metastatic (or more rarely, primary pulmonary) melanomas are high-grade malignancies with large nuclei, usually prominent nucleoli, easily observed mitotic figures, presenting as variable solid nodules on CT scans, and a rapid clinical course without appropriate treatment. Primary pulmonary melanomas are described to have a predilection for the central area of the lung,2Paliogiannis P. Fara A.M. Pintus G. et al.Primary melanoma of the lung: a systematic review.Medicina (Kaunas). 2020; 56: 576Google Scholar while the pulmonary melanocytic naevi occur at the periphery. Pulmonary melanocytic naevi are rare but still can be distinguished from above lesions with careful histological examination and proper immunohistochemical staining (Table 1).Table 1Differential diagnosis of pulmonary melanocytic naeviDiagnosisHistological featuresImmunohistochemistryPulmonary melanocytic naevi•Melanocytes with uniform round to oval nuclei, amphophilic cytoplasm, occasional coarse melanin granules, low nucleus-to-cytoplasm ratios•No nuclear atypia or brisk mitosis•Peribronchiolar distribution or along the alveolar septa•Positive: melanocytic markers (Melan-A, S100, SOX10)•Negative: cytokeratin, EMA, TTF1, neuroendocrine markersNeuroendocrine tumours (including DIPNECH and tumourlets)•Neuroendocrine cells with moderate amount of eosinophilic cytoplasm, round to oval nuclei, and a stippled (‘salt and pepper’) chromatin pattern•DIPNECH, tumourlets, and typical carcinoids: No nuclear atypia or brisk mitosis•Peribronchiolar distribution•Positive: neuroendocrine markers (synaptophysin, chromogranin, CD56, INSM1), cytokeratin, TTF1, variable SSTR2a•Negative: melanocytic markersMinute pulmonary meningothelial-like nodules•Oval or epithelioid cells with ample eosinophilic cytoplasm, indistinct cell borders, intranuclear pseudoinclusions, and whorled appearance•No nuclear atypia or brisk mitosis•Distributed in the interstitium of the alveolar septa•Positive: EMA, vimentin, SSTR2a•Negative: cytokeratin, TTF1, melanocytic markers, neuroendocrine markersMetastatic melanomas•High-grade malignancies showing large nuclei, usually prominent nucleoli, occasional coarse melanin granules, and easily observed mitotic figures•Solitary or multiple solid nodules, rarely a military pattern or a lymphangitic pattern•Positive: melanocytic markers (Melan-A, S100, SOX10, HMB45), PRAME, high Ki-67 index•Negative: cytokeratin, EMA, TTF1, neuroendocrine markersDIPNECH, diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Open table in a new tab DIPNECH, diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. There are some theories trying to explain the origin of pulmonary melanocytic tumours: (1) melanocytes or melanoblasts aberrantly migrate to the respiratory tract during embryogenesis;1Deng S. Sun X. Zhu Z. et al.Primary malignant melanoma of the lung: a case report and literature review.BMC Pulm Med. 2020; 20: 94Google Scholar,7Busuttil A. Dendritic pigmented cells within human laryngeal mucosa.Arch Otolaryngol. 1976; 102: 43-44Google Scholar (2) melanocytes may derive from neuroendocrine precursor cells in lung tissue;8Pilozzi E. Cacchi C. Di Napoli A. et al.Primary malignant tumour of the lung with neuroendocrine and melanoma differentiation.Virchows Arch. 2011; 459: 239-243Google Scholar (3) melanocytes may be metastasised from an occult primary cutaneous site, including so-called ‘benign metastasis’.9Ross A.L. Sanchez M.I. Grichnik J.M. Nevogenesis: a benign metastatic process?.ISRN Dermatol. 2011; 2011813513Google Scholar Melanocytic naevi of the skin serve as potential precursors or risk markers of malignant melanoma.10Gandini S. Sera F. Cattaruzza M.S. et al.Meta-analysis of risk factors for cutaneous melanoma: I. Common and atypical naevi.Eur J Cancer. 2005; 41: 28-44Google Scholar Progression from melanocytic naevus to malignant melanoma requires additional mutations [e.g., inactivation of cyclin-dependent kinase inhibitor 2A (CDKN2A), phosphatase and tensin homolog (PTEN) and tumour protein p53 (TP53) mutation] and the risk is very low.11Shain A.H. Yeh I. Kovalyshyn I. et al.The genetic evolution of melanoma from precursor lesions.N Engl J Med. 2015; 373: 1926-1936Google Scholar,12Tsao H. Bevona C. Goggins W. Quinn T. The transformation rate of moles (melanocytic nevi) into cutaneous melanoma: a population-based estimate.Arch Dermatol. 2003; 139: 282-288Google Scholar The incidence rate of BRAF mutations in primary pulmonary melanoma is low (11.1%) compared with their cutaneous counterpart.2Paliogiannis P. Fara A.M. Pintus G. et al.Primary melanoma of the lung: a systematic review.Medicina (Kaunas). 2020; 56: 576Google Scholar In our case, the presence of BRAF V600E mutation was confirmed by immunohistochemical staining. More studies are required to see if primary pulmonary melanoma could potentially be derived from pulmonary naevi.