Primary malignant melanoma of the lung in the elderly: case report and literature review

Abstract

Malignant melanoma involving the respiratory tract, which is predominantly found in the skin, is nearly metastatic and true primary tumours are very rare.1 To date, only 32 cases have been reported in English literature and 22 cases of primary malignant melanoma of the lung have been reported in Chinese literature.2–6 In this article we present a case of primary malignant melanoma of the lung in an elderly man, who was finally diagnosed by a whole body 18F fluoro-2-deoxy-glucose positron emission tomography with computed tomography (18F-FDG PET-CT) and pathological examination. CASE REPORT Clinical presentation An 81-year-old man with history of hypertension and coronary heart disease was admitted with a four-month history of hemoptysis, and disease conditions were aggravated progressively during last week, about 50 ml per day. He was an ex-smoker, having smoked 15 cigarettes per day between the ages of 31 and 60. The patient, who had no relevant past medical history and family heredity history, was of stable vital signs, and physical examination revealed no positive signs on admission. There were no suspicious pigmented lesions of the skin or eyes and was unremarkable otherwise. Routine biochemical and hematological profiles were normal. Arterial blood gas analysis with the patient breathing room air revealed a PaO2 of 79 mmHg and a PaCO2 of 41 mmHg. A thoracic computed tomography (CT) showed a pulmonary mass measuring 6 cm × 4 cm (Figure 1) in the right lower lobe. The level of tumor marker cytokeratin fragment antigen 21–1 (CYFRA21–1) was 4.77 ng/ml (normal: 0–3.30 ng/ml) and a cranial magnetic resonance imaging (MRI) revealed no abnormality. A whole body 18F-FDG PET-CT revealed density anomaly of mass in pulmones dexter complicated by an increase of glucose metabolism with 11.66 in maximum of standardized uptake value (SUVmax), and an increase of glucose metabolism of both hilar lymph nodes in which SUVmax was 3.67 (Figure 2). Fiberoptic bronchoscopy revealed obsolete bloodstain in airway, a bit of black-colored pigmentation on mucosa of bronchus lobaris superior dexter, slight pachymucosa of bronchus lobaris inferior sinister, and lumens with mild stenosis of right segmentum basale mediale. Bronchial mucosal biopsy was performed and chronic inflammation complicated with lipid granuloma was seen. Alveolar lavage fluid was examined in which erythrocytes, columnar epithelial cell and alveolar macrophage were seen.Figure 1: . CT scan of the chest demonstrates an ill-defined mass in the right lower lobe.Figure 2: . Demonstrations on 18F-FDG PET-CT. A: A whole body 18F-FDG PET-CT revealed density anomaly of mass in pulmones dexter with an increase of glucose metabolism (SUVmax was 11.66). B: An increase of glucose metabolism of both hilar lymph nodes was seen, obvious in the left (SUVmax was 3.67).Pathological findings Right lower lobe lobectomy and lymph node dissection were performed. The hard beige tumor in size of 7.5 cm × 7 cm × 4 cm was located in the segmentum basale anterius of right lower lobe. Several melanin pigmentation on pleura was cauterized by electric scalpel. Histopathologically, the tumor was comprised of malignant epithelial tumor cells and spindle cells with large amounts of acidophilic cytoplasm and prominent nucleoli, and the surrounding stroma demonstrated variable mononuclear cell infiltrates, fibroplasias, telangiectasia, and melanophages (Figure 3A). A dark brown pigment was observed in the viable tumor cells. Invasion of the bronchial epithelium and lymph nodes in group 11 (4/4) by melanoma cells were also observed. Immunohistochemical staining was positive for S-100 protein (Figure 3B), Ki-67 (40%) and HMB45 (Figure 3C); staining for vimentin, desmin, somatomedin A (SM-A), CD34, CD68 (KP-1), cytokeratin (CK), CK18, leucocyte common antigen (LCA) was negative. The final diagnosis was malignant melanoma of the lung.Figure 3: . Histopathological findings. A: Tumor consisted of malignant epithelial tumor cells and spindle cells with large amounts of acidophilic cytoplasm and prominent nucleoli (HE, original magnification ×10). B: Immunohistochemical staining for S-100 is positive (Original magnification ×10). C: Immunohistochemical staining for HMB45 is positive (Original magnification ×10).More than 6 months after discharge, the patient received the treatment of Zadaxin (Tα1) (Patheon Italia S.P.A, Italy) and Lentinan for Injection (Nanking Kanghai Pharmaceutical Industrial Co., Ltd, China) regularly, and he is alive at the recent follow-up without any chief complaint. DISCUSSION Malignant melanoma, a serious type of skin tumor, results from the uncontrolled growth of pigment cells called melanocytes. Malignant melanoma most commonly presents as a primary neoplasm of the skin, but it has also been identified in other sites, such as the oral cavity, esophagus, liver, and vagina.7–9 As a primary tumor, primary malignant melanoma of the lung (PMML) is an uncommon neoplasm that accounts for only 0.01% of all primary lung tumors,10 and metastasis from the more common primary sources must be convincingly ruled out before considering this diagnosis. Based on documented references, there was no significant statistical difference of PMML incidence in sex,6 and the mean age at diagnosis was 51 years (range 45–71).10 Moreover, the precise etiology of PMML has not yet been elucidated, the possible mechanism is discussed. One speculation is that such a tumor may arise from areas of squamous metaplasia in which a certain number of epithelial cells have undergone differentiation towards melanocytes, a phenomenon which also explains the occurrence of pigmented squamous and basal cell tumors in the skin.1 Squamous metaplasia might occur in bronchi irritated by cigarette smoke. Our patient had smoked for 30 years, making his lung a potential site for primary malignant melanoma. The clinical diagnostic criteria have therefore been established before making a diagnosis of PMML: (1) no previously resected pigmented skin lesion; (2) no ocular tumor removed or evidence of a current or previous primary melanoma in any organ; (3) solitary tumor in the surgical specimen from the lung; (4) tumor morphology consistent with malignant melanoma involving the respiratory epithelium; and (5) junctional change, with invasion of intact bronchial mucosa by malignant melanoma cells.10 The present case fulfilled all of these criteria, meanwhile, a whole body 18F-FDG PET-CT also proved that the pulmonary mass was malignant. Histologically, PMML has a solid growth pattern with organoid and fascicular areas. Loosely cohesive epithelioid cells with large, round hyperchromatic to vesicular nuclei and prominent eosinophilic nucleoli are the predominant characteristics. A dark brown pigment is observed in tumor cells.5 Atypical melanocytes often have large nuclei and nucleoli and abundant pale cytoplasm. The tumor cells most frequently are epithelioid, but other cell types, including spindle cells, small epithelioid cells resembling naevus cells, and giant mononuclear or multinucleate forms. The cell population usually appears monomorphous but closer examination reveals enlargement, nuclear enlargement, variation in nuclear size and shape, hyperchromatism, and prominent nucleoli. High nuclear-to-cytoplasmic ratios are often noted. The cytoplasm of tumor cells often has eosinophilic granular qualities. It may contain melanin granules that vary in size, or appear fine and “dusty”. The differential diagnosis of primary malignant melanoma of the lung includes carcinoid tumor, especially melanocytic carcinoid tumor, and large-cell carcinoma. Immunohistochemical staining can be used to distinguish between primary malignant melanoma of the lung and others. Malignant melanoma of the lung rarely stains for cytokeratin or neuroendocrine markers, such as chromogranin, and it usually stains positively for S-100 and HMB45.10 The optimal treatment for patients with PMML remains to be determined. To date, 32 cases of PMML have been reported in the English literature. Five patients did not undergo surgery, two patients were diagnosed at autopsy, and the tumors were unresectable in three patients, all of whom died within 4 months of their diagnoses. In 22 of the 27 patients who underwent surgical resection, only 8 patients were free of disease; and the disease-free survival durations ranged from 6 months to 11 years. All of the eight patients who were free of disease had undergone lobectomy or pneumonectomy. Therefore, an aggressive surgical approach is considered warranted.2–5,10 As mentioned above, surgery may be insufficient because of the tumor's aggressive behavior. Recently, various chemotherapeutic agents have been used, including dacarbazine and immunotherapy with interleukin-2 (IL-2) or interferon (IFN). These measures occasionally show dramatic success for malignant melanoma of the skin, but the overall success for metastatic melanoma is quite limited.11 IL-2 is the first new approved therapy for the treatment of metastatic melanoma for 20 years. Studies have demonstrated that IL-2 offers the possibility for a complete, long-lasting remission of this disease, although only for a small percentage of patients.12 Moreover, thymosin alpha 1 (Tα1) as an immune stimulant and adjuvant, combined with either IFN or IL-2 plus chemotherapy, was efficient in preclinical model with melanoma,13 and it is also in late-stage clinical testing in the United States and Europe for stage IV melanoma.14 Our patient, to whom Zadaxin (Tα1) was given after operation, is alive more than 6 months after surgery at last follow-up. Radiation therapy is often used after a surgical resection for patients with locally or regionally advanced melanoma of the skin or for patients with unresectable distant metastases. This may reduce the rate of local recurrence, but it does not prolong survival.15 The prognosis of malignant melanoma is unknown, and the long term survival of patients with primary malignant melanoma is unpredictable but is usually poor. Effective therapeutic modalities combined with surgery should be evaluated to improve outcomes, even when the tumor is in an early stage. Further accumulation of knowledge and experience is needed to formulate the optimal therapy for this rare, virulent tumor of the lung.