RESUMO
Mucoepidermoid carcinoma (MEC) of the breast is an extremely rare salivary gland-type tumor characterized by epidermoid, basaloid, intermediate, and/or mucinous cells arranged in solid and cystic patterns. Despite their triple-negative phenotype, breast MECs are generally considered low-risk malignancies but their biology is largely unexplored; therefore, guidelines for clinical management are lacking. Here, we sought to characterize the molecular landscape of breast MECs. Thirteen cases were histologically reviewed, characterized for tumor-infiltrating lymphocytes (TILs), and were subjected to immunohistochemistry for programmed death-ligand 1 (PD-L1, clone 22C3), EGFR, and amphiregulin (AREG). Rearrangements in MAML2 and EWSR1 were investigated by fluorescent in situ hybridization. Targeted next-generation sequencing of 161 genes was performed on eight cases. Most MECs had low histological grade (n = 10, 77%), with the presence of TILs (n = 9/12; 75%) and PD-L1 combined positive score ranging from 10 to 20 (n = 4/6; 67%). All cases showed EGFR and AREG overexpression and were fusion negative. Enrichment of genetic alterations was observed in PI3K/AKT/mTOR and cell cycle regulation pathways, while only one case harbored TP53 mutations. This is the first study providing extensive molecular data on breast MECs and the largest collection of cases available to date in the literature. Breast MECs lack TP53 mutations found in high-grade forms of triple-negative breast cancers and MAML2 or EWSR1 rearrangements pathognomonic of salivary MECs. Triple-negativity and PD-L1 positivity suggest a window of opportunity for immunotherapy in these patients. The EGFR/AREG axis activation, coupled with the mutational patterns in PI3K/AKT/mTOR and cell cycle pathways warrants caution in considering MECs as low-risk neoplasms.
Assuntos
Carcinoma Mucoepidermoide , Neoplasias das Glândulas Salivares , Humanos , Proteínas de Ligação a DNA/genética , Transativadores/genética , Antígeno B7-H1/genética , Hibridização in Situ Fluorescente , Carcinoma Mucoepidermoide/genética , Carcinoma Mucoepidermoide/química , Carcinoma Mucoepidermoide/patologia , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Neoplasias das Glândulas Salivares/genética , Neoplasias das Glândulas Salivares/patologia , Receptores ErbB/genética , Receptores ErbB/metabolismo , Serina-Treonina Quinases TOR/genética , Biomarcadores Tumorais/genéticaRESUMO
BACKGROUND: Very little is currently known about molecular alteration of matrix-producing carcinoma of the breast. However, the morphological similarity with other neoplasm with a myxo-chondroid component is remarkable. In this pilot study we evaluated the molecular alterations involving PLAG1 and MYC genes in 12 cases of matrix producing carcinoma. METHODS: We evaluated PLAG1 rearrangements as Break-Apart and Gene Copy Gain, and MYC as amplification and polysomy in 12 cases of matrix producing carcinoma using a FISH method. RESULTS: Among the 12 cases of matrix producing carcinomas we found that the three cases harboring MYC amplification were all negative for PLAG1 break-apart; four cases with MYC polysomy were associated to PLAG1 break-apart and high Gene Copy Number; among four cases wild type for MYC, three showed a PLAG1- break-apart signal and of them two died with disease. One of the deceased patients showed an amplification of MYC with PLAG1- wild-type and the other showed a PLAG1 break-apart (6%) and a MYC wild-type. CONCLUSION: This is the first report to the best of our knowledge that shows a possible correlation between a matrix producing carcinoma with PLAG1 and MYC involvement in the development and progression of this kind of tumor. We can suppose that MYC amplification behaves in an aggressive way together with PLAG1- break-apart in the cases of matrix producing carcinoma presented here. The gene copy gain is a useful diagnostic tool in the case of difficult diagnosis because an increase was observed in more than 50% of cases.
Assuntos
Adenoma Pleomorfo , Carcinoma , Neoplasias das Glândulas Salivares , Humanos , Adenoma Pleomorfo/diagnóstico , Adenoma Pleomorfo/genética , Adenoma Pleomorfo/patologia , Carcinoma/genética , Proteínas de Ligação a DNA/genética , Imuno-Histoquímica , Projetos Piloto , Neoplasias das Glândulas Salivares/diagnóstico , Neoplasias das Glândulas Salivares/genética , Neoplasias das Glândulas Salivares/patologia , Fatores de Transcrição , Proteínas Proto-Oncogênicas c-myc/metabolismoRESUMO
Accurate detection of altered anaplastic lymphoma kinase (ALK) expression is critical for the selection of lung cancer patients eligible for ALK-targeted therapies. To overcome intrinsic limitations and discrepancies of currently available companion diagnostics for ALK, we developed a simple, affordable and objective PCR-based predictive model for the quantitative measurement of any ALK fusion as well as wild-type ALK upregulation. This method, optimized for low-quantity/-quality RNA from FFPE samples, combines cDNA pre-amplification with ad hoc generated calibration curves. All the models we derived yielded concordant predictions when applied to a cohort of 51 lung tumors, and correctly identified all 17 ALK FISH-positive and 33 of the 34 ALK FISH-negative samples. The one discrepant case was confirmed as positive by IHC, thus raising the accuracy of our test to 100%. Importantly, our method was accurate when using low amounts of input RNA (10 ng), also in FFPE samples with limited tumor cellularity (5-10%) and in FFPE cytology specimens. Thus, our test is an easily implementable diagnostic tool for the rapid, efficacious and cost-effective screening of ALK status in patients with lung cancer.