The initial symptoms of PMLL are often cough, hemoptysis, difficulty breathing, chest pain (6). Usually, the sensitivity and specificity of CT, MRI, and 18F-FDG PET CT in describing melanoma depend on size and location. However, there are currently no indications for imaging in primary diagnosis (7). Black phlegm is considered an important indicator for the diagnosis of malignant melanoma. Black phlegm is caused by diffuse infiltration of melanoma cells in the lungs, as well as secondary pigment deposition by macrophages and bronchial epithelial cells (8). At present, the pathogenesis of PMML is still controversial. There are several theories that can explain its occurrence (9–11): (1) melanocytes exist throughout the body as dispersed neuroendocrine system cells; (2) Melanocytes migrate to the respiratory tract during embryonic formation and transform into malignant cancer cells in the respiratory tract; (3) Melanocytes may originate from melanocytes and produce PMML, as they share the same origin as other melanocytes located in the trachea, esophagus, and pharynx (12); (4) Melanoma cells may originate from pluripotent stem cells. More research is needed to elucidate the pathogenesis of PMML.

The pathological manifestations of PMLL are consistent with the morphological features of malignant melanoma of the skin, mainly characterized by the presence of melanin particles in the cytoplasm and between cells. Commonly used immunohistochemical markers include HMB-45, Melan-A, and S-100 (8, 13). HMB-45 is very specific for melanocytic tumors, but its sensitivity for melanoma is lower (70%-90%) than that in S100. Melan-A has a sensitivity of 85%-97% for primary and 57%-92% for metastatic melanoma and a specificity of 95%-100%. S-100 was the first marker that proved to be useful in the diagnosis of melanoma. The sensitivity is very high (93%-100%), and S100 should be used in association with other markers (14). For the diagnosis of primary malignant melanoma of the lung, the diagnostic criteria proposed by Wilson et al. have been adopted in recent years (4): (1) solitary lung tumor; (2) Pathologically confirmed malignant melanoma; (3) No history of skin, mucosal or eye surgery or electrocautery; (4) Central lung injury; (5) At the time of diagnosis, there were no tumors in other parts.

At present, there are no clear detailed rules for the diagnosis of PMML, and it mainly relies on exclusional diagnosis. Firstly, non-metastatic malignant melanoma should be determined (excluding primary lesions such as the skin and mucosa). Secondly, it should be differentiated from other malignant tumors such as small cell lung cancer, non-small cell lung cancer, and primary pulmonary lymphoma (15). In this case, the patient did not undergo multidisciplinary joint evaluation for differential diagnosis. The diagnosis was made only by combining the imaging results such as PET-CT of the patient, as well as the relevant results of pathology and immunohistochemistry. In addition, there was a “mole” on the patient’s body surface, but no further examination was conducted. The results of biopsy or dermoscopy should include or be processed. These may lead to non-standard diagnosis and treatment. In addition, in this case, although the result of the patient’s cerebrospinal fluid cytology examination was normal, there was an abnormality in the chromosome copy number. The discovery of tumor cells in cerebrospinal fluid cytology is the gold standard for diagnosing meningeal tumors. However, the positive rate of single lumbar puncture cerebrospinal fluid cytology in the diagnosis of meningeal carcinomatosis is limited, which is not conducive to the timely diagnosis of this disease. Recent studies have found that the analysis of chromosomal copy number variations in mNGS of cerebrospinal fluid is helpful for identifying malignant tumors of the central nervous system. In this case, we further combined the imaging manifestations of the patient’s head and diagnosed it as leptomeningeal metastasis of primary malignant melanoma of the lung.

Advances in systemic treatment of local and metastatic melanoma have significantly improved the survival rate of patients. Surgery remains the main treatment method for local and regional diseases (16). Postoperative chemotherapy, radiotherapy, immunotherapy and checkpoint inhibitors, as well as targeted therapy (signal transduction and angiogenesis inhibitors, oncolytic virus therapy) are typically used to treat melanoma. Once distant metastasis occurs, the opportunity for surgery is lost. To date, the most effective treatment for metastatic melanoma is immune checkpoint inhibitors (ICI) (17). The incidence of brain metastasis in advanced melanoma is 10-40% (18). Brain metastasis remains the main complication of metastatic melanoma and causes up to half of melanoma deaths (19). However, patients with untreated brain metastases from primary malignant melanoma of the lung have a shorter survival period (20). It is still unclear how best the existing therapies can be used to prevent or treat brain metastases in patients with melanoma. Multiple studies have found that compared with patients treated with targeted therapy, patients with stage III or IV BRAF mutant melanoma treated with immunotherapy have significantly longer OS (21). Additionally, the addition of immunotherapy to radiotherapy is associated with improved OS (22). In this case, the patient mainly relied on immunotherapy and radiotherapy. Because the patient refused to undergo genetic testing, the opportunity for targeted therapy might have been lost. However, a long-term survival of nearly 30 months was still achieved here. During the follow-up process, we learned that although the brain lesions of the patient did not regress significantly, the symptoms of the central nervous system completely disappeared and the quality of life improved. And the Karnofsky Performance Status (KPS) of the patients remained good. Studies have shown that radiotherapy can increase the permeability of the blood-brain barrier, activate anti-tumor immunity by releasing tumor antigens, and change the pro-inflammatory microenvironment of tumors (23). The response to immunotherapy depends on preexisting tumor infiltrate and may be improved by radiotherapy, which is able to activate an antitumor immune response. Moreover, immunotherapy has proven to synergize with radiation-induced immune activation and to convert the immunosuppressive microenvironment of a tumor into an in situ vaccine (24), boosting the abscopal effect, which is defined as the clinical observation of tumor responses outside the irradiated field (25). In this study, Toripalimab combined with Dacarbazine was given priority treatment based on the economic status of the patients. Later, due to the inability to tolerate the side effects of chemotherapy, immunotherapy was used alone until the disease progressed. Before that, the chest lesions of the patients were well controlled. Treiprilizumab is the first immunosuppressant approved in China for the treatment of advanced melanoma. Studies have shown that the median overall survival time of treiprilizumab in patients with malignant melanoma who have failed systemic treatment has exceeded 22.2 months, and it is beneficial for different subtypes of melanoma (26).