RESUMO
OBJECTIVE: We investigated the mutational landscape of mammalian target of rapamycin (mTOR) signalling cascade in hepatocellular carcinomas (HCCs) with chronic HBV background, aiming to evaluate and delineate mutation-dependent mechanism of mTOR hyperactivation in hepatocarcinogenesis. DESIGN: We performed next-generation sequencing on human HCC samples and cell line panel. Systematic mutational screening of mTOR pathway-related genes was undertaken and mutant genes were evaluated based on their recurrence. Protein expressions of tuberous sclerosis complex (TSC)1, TSC2 and pRPS6 were assessed by immunohistochemistry in human HCC samples. Rapamycin sensitivity was estimated by colony-formation assay in HCC cell lines and the treatment was further tested using our patient-derived tumour xenograft (PDTX) models. RESULTS: We identified and confirmed multiple mTOR components as recurrently mutated in HBV-associated HCCs. Of significance, we detected frequent (16.2%, n=18/111) mutations of TSC1 and TSC2 genes in the HCC samples. The spectrum of TSC1/2 mutations likely disrupts the endogenous gene functions in suppressing the downstream mTOR activity through different mechanisms and leads to more aggressive tumour behaviour. Mutational disruption of TSC1 and TSC2 was also observed in HCC cell lines and our PDTX models. TSC-mutant cells exhibited reduced colony-forming ability on rapamycin treatment. With the use of biologically relevant TSC2-mutant PDTXs, we demonstrated the therapeutic benefits of the hypersensitivity towards rapamycin treatment. CONCLUSIONS: Taken together, our findings suggest the significance of previously undocumented mutation-dependent mTOR hyperactivation and frequent TSC1/2 mutations in HBV-associated HCCs. They define a molecular subset of HCC having genetic aberrations in mTOR signalling, with potential significance of effective specific drug therapy.
Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/metabolismo , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Animais , Antibióticos Antineoplásicos/farmacologia , Proteína Axina/genética , Carcinoma Hepatocelular/química , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Análise Mutacional de DNA , Proteínas de Ligação a DNA , Feminino , Humanos , Neoplasias Hepáticas/química , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Taxa de Mutação , Transplante de Neoplasias , Proteínas Nucleares/genética , Transdução de Sinais , Sirolimo/farmacologia , Fatores de Transcrição/genética , Proteína 1 do Complexo Esclerose Tuberosa , Proteína 2 do Complexo Esclerose Tuberosa , Ensaio Tumoral de Célula-Tronco , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor/análise , Adulto Jovem , beta Catenina/genéticaRESUMO
OBJECTIVE: We conducted a 12-year retrospective review of vulvar basal cell carcinoma (BCC) in a Chinese population. STUDY DESIGN: Medical records and histopathologic reports were examined from 5 major Hospitals in Hong Kong to list all patients diagnosed with vulvar BCC. Clinical data and histologic materials were reviewed. RESULTS: Sixteen vulvar BCCs were diagnosed. Most of them were pigmented. They were removed by simple excision or wide local excision. All the carcinomas were identified in the reticular dermis. The predominant histologic pattern was nodular, which may be mistaken as adenoid cystic carcinoma. CONCLUSION: The high proportion of pigmented vulvar BCCs suggested that biopsy should be performed for any pigmented lesion in a Chinese patient. The BCCs are superficial and tissue-preserving treatment approach is recommended. The tumor depth estimation is difficult and intraoperative frozen section consultation may be helpful. Formal histopathologic assessment should be used to reach an objective diagnosis.
Assuntos
Carcinoma Basocelular/etnologia , Carcinoma Basocelular/patologia , Neoplasias Vulvares/etnologia , Neoplasias Vulvares/patologia , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/estatística & dados numéricos , Biópsia , Feminino , Secções Congeladas , Hong Kong/epidemiologia , Humanos , Incidência , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias Cutâneas/etnologia , Neoplasias Cutâneas/patologia , Pigmentação da PeleRESUMO
AIM: To determine the pathognomonic diagnostic cytological features of invasive micropapillary carcinoma of the breast which is a poor prognostic subtype of infiltrating ductal carcinoma. METHODS: A series of 20 histologically proven tumours were reviewed retrospectively to evaluate the various cytological features, including tumour morules, isolated malignant cells, staghorn epithelial structures, mucinous background and apocrine metaplasia. RESULTS: Tumour morules formation and isolated malignant cells were the two most reliable and constant cytological features, being present in 75% (15/20 cases) of cases. Staghorn epithelial structures were present in 35% (7 cases). Mucinous background (2 cases, 10%) and apocrine metaplasia (4 cases, 20%) of the tumour cells were seen in a few cases only and did not appear very helpful. CONCLUSION: Tumour morules formation, isolated malignant cells and staghorn epithelial structures are the most reliable cytological features, and the presence of these should raise suspicion of invasive micropapillary carcinoma.
