Molecular characterization of a selected cohort of patients affected by pulmonary metastases of malignant melanoma: Hints from BRAF, NRAS and EGFR evaluation.

BACKGROUND: Melanoma is highly curable in early stages but holds devastating consequences in advanced phases with a median survival of 6-10 months. Lungs are a common metastasis target, but despite this, limited data are available on the molecular status of pulmonary lesions. MATERIALS AND METHODS: 25 patients with surgically resected melanoma lung metastases were screened for BRAF, NRAS, CKIT and EGFR alterations. The results were correlated with time to lung metastasis (TLM), relapse-free survival after metastasectomy (RFS) and overall survival (OS). RESULTS: BRAF or NRAS were mutated in 52% and 20% of cases while CKIT was unaffected. Chromosome 7 polysomy was detected in 47% of cases with 17.5% showing EGFR amplification and concomitant BRAF mutation. NRAS mutated patients developed LM within 5 yrs from primary melanoma with larger lesions compared with BRAF (mean diameter 3.3 ± 2.2cm vs 1.9 ± 1.1cm, p = 0.2). NRAS was also associated with a shorter median RFS and OS after metastasectomy. Moreover, Cox regression analysis revealed that NRAS mutation was the only predictive factor of shorter survival from primary melanoma (p = 0.039, OR = 5.5 (1.1-27.6)). CONCLUSIONS: Molecular characterization identifies advanced melanoma subgroups with distinct prognosis and therapeutic options. The presence of NRAS mutation was associated to a worse disease evolution.

Morphological and molecular characteristics of nested melanoma of the elderly (evolved lentiginous melanoma).

We identified a group of melanocytic lesions with an architectural pattern very similar to that of a junctional nevus: cells mostly grouped in distinct nests, more or less of the same size and shape, and regularly distributed along the dermoepidermal junction. In contrast with these nevus-like features, these neoplasms display additional details which are incompatible with a diagnosis of junctional nevus. These include areas of lentiginous array with focal pagetoid spread of melanocytes above the junction; marked cytological atypia, such as nuclear enlargement, hyperchromasia, nuclear membrane thickening and with a mild degree of cellular pleomorphism. Moreover, these lesions mostly developed on severely sun-damaged skin of old patients. Using a four-probe fluorescence in situ hybridization (FISH) assay targeting RREB1, MYB, Cep6, and CCND1, we found that seven of the eight propositus cases showed chromosomal aberrations consistent with the standardized FISH diagnostic criteria for melanoma. Instead, the five junctional nevi that served as controls were negative in this test. These findings underline the utility of correlating clinical-pathological observations with FISH analysis for diagnosing correctly as melanoma these malignant neoplasms, which closely simulate a junctional nevus.

Long-term disease-free survival of a patient with synchronous bilateral lung adenocarcinoma displaying different EGFR and C-MYC molecular characteristics.

The main difficulty with multiple lung tumors is distinguishing synchronous and metachronous lesions from second independent primary tumors, particularly when dealing with the same histologic type. Challenging diagnostic hurdles may explain, at least in part, the extremely variable (0%-79%) 5-year survival rate. We present a case report of a patient with synchronous primary adenocarcinoma treated with surgery that exhibited different EGFR gene status, with an exon 19 mutation in the adenocarcinoma of the left upper lobe that was absent in the right upper lobe. Further, specific EGFR and C-MYC amplification events were associated only with the EGFR-mutated lesion. According to an independent evolution theory, these events were classified as early stage, and the patient is still alive and free of disease 70 months after surgery. Molecular evaluation was an important tool to support the diagnosis of synchronous primary adenocarcinoma, which had not been possible with the application of Martini-Melamed criteria.

Polypoid Spitz nevus: two cases evaluated with genetic technique, prolonged follow up, and sentinel lymph node biopsy.

Polypoid Spitz nevus represents a spitzoid melanocytic neoplasm that frequently has worrying and challenging histopathological details. Distinction from polypoid melanoma may not be straightforward. Two cases of polypoid Spitz nevus with striking histopathological features were studied. One case had prolonged follow up (Case 1) and one patient had undergone sentinel lymph node biopsy (Case 2), and fluorescence in situ hybridization (FISH) analysis was also completed (both cases). Follow up and genetic analysis of three control cases of polypoid melanoma is also presented. Our clinical and genetic results suggest that both the polypoid Spitz nevi were benign. The patients are alive with no evidence of disease. FISH analysis did not show abnormalities with probes tested. This is in sharp contrast with the control cases of polypoid melanoma, wherein genomic alterations were detectable. Our data indicate that the two polypoid lesions presented here are most probably benign, despite their worrying histopathological features. More cases with long-term follow up and greater numbers of DNA probes are necessary to extend this conclusion to other ambiguous melanocytic tumors.