RESUMEN
CONTEXT: Carney complex is a genetically heterogenous multiple neoplasia syndrome. Adrenal cortical carcinoma is a rare malignancy with a poor prognosis that is not recognized to be associated with this syndrome. OBJECTIVE: We report a 22-yr-old female presenting with Carney complex who developed adrenal carcinoma. The response to adjunctive therapy is also described. METHODS: We performed a detailed pathology review of the adrenal tumor to examine morphologic changes, Ki-67 labeling, and p53 expression. We also performed genetic testing of candidate genes and describe the response to radiation and kinase inhibition therapy. RESULTS: The patient presented with an 8.5-cm adrenal mass with a MIB-1 labeling index of 20% and unequivocal angioinvasion classified as a T3NXM0 carcinoma. The nontumorous adrenal cortex revealed characteristic features of primary pigmented nodular adrenocortical disease. Genetic analysis revealed a novel PRKAR1 frame shift mutation resulting in a premature stop codon and a heterozygous p53 polymorphic substitution previously noted in other solid carcinomas. Disease recurrence in the liver showed partial response to combined stereotactic radiotherapy and sorafenib multikinase inhibition. CONCLUSION: This represents an initial characterization of a malignancy among patients with Carney complex. Our findings have implications for disease surveillance and management of individuals with this genetic syndrome.
Asunto(s)
Neoplasias de la Corteza Suprarrenal/complicaciones , Carcinoma Corticosuprarrenal/complicaciones , Complejo de Carney/complicaciones , Neoplasias de la Corteza Suprarrenal/diagnóstico , Neoplasias de la Corteza Suprarrenal/patología , Carcinoma Corticosuprarrenal/diagnóstico , Carcinoma Corticosuprarrenal/patología , Complejo de Carney/diagnóstico , Complejo de Carney/patología , Femenino , Humanos , Neoplasias Hepáticas/secundario , Invasividad Neoplásica , Carga Tumoral , Adulto JovenRESUMEN
It is now almost 70 years since Charles Huggins described the relationship between testosterone and the prostate gland. Arguably defining one of the first targeted therapies, the reduction of testosterone to castrate levels remains unaltered as the standard of care for men with metastatic prostate cancer. The failure of castration to permanently control the growth of prostate cancer leads to a state called castration-resistant prostate cancer (CRPC). Whilst numerous mechanisms have been suggested for the emergence of castration resistance [Scher and Sawyers (J Clin Oncol 23(32):8253-8261, 2005); Chen et al. (Curr Opin Pharmacol 8(4):440-448, 2008), Pienta and Bradley (Clin Cancer Res 12(6):1665-1671, 2006); Feldman and Feldman (Nat Rev Cancer 1(1):34-45, 2001); Mostaghel and Nelson (Best Pract Res Clin Endocrinol Metab 22(2):243-258, 2008)], a greater understanding of prostate cancer biology suggests that many such cancers retain a dependency on androgens and endeavour to increase bioavailable androgens through mechanisms such as AR amplification and intracrine androgen synthesis [Mohler et al. (Clin Cancer Res 10(2):440-448, 2004); Attard et al. (Clin Cancer Res 17(7):1649-1657, 2011); Hu et al. (Expert Rev Endocrinol Metab 5(5):753-764, 2010)]. With the recent approval of abiraterone acetate (Zytiga) and the pending approval of MDV3100, this article previews the future directions in clinical development and issues that will arise with the next generation of androgen-targeted agents.
Asunto(s)
Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/cirugía , Receptores Androgénicos/metabolismo , Acetato de Abiraterona , Androstadienos/uso terapéutico , Benzamidas , Resistencia a Antineoplásicos , Inhibidores Enzimáticos/farmacología , Humanos , Masculino , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Neoplasias Hormono-Dependientes/cirugía , Nitrilos , Orquiectomía , Feniltiohidantoína/análogos & derivados , Feniltiohidantoína/farmacología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Esteroide 17-alfa-Hidroxilasa/antagonistas & inhibidoresRESUMEN
The causes of early genomic events underlying the development of prostate cancer (CaP) remain unclear. The onset of chromosomal instability is likely to facilitate the formation of crucial genomic aberrations both in the precursor lesion high-grade prostatic intraepithelial neoplasia (HPIN) and in CaP. Instability generated by telomere attrition is one potential mechanism that could initiate chromosomal rearrangements. In this study, normalized telomere length variation was examined in a cohort of 68 men without CaP who had HPIN only on prostatic biopsies. Multiple significant associations between telomere attrition and eventual diagnosis of CaP in the HPIN and in the surrounding stroma were found. Kaplan-Meier analysis of telomere length demonstrated a significantly increased risk for the development of cancer with short telomeres in the surrounding stroma [P = .035; hazard ratio (HR) = 2.12; 95% confidence interval (95% CI) = 0.231-0.956], and a trend for HPIN itself (P = .126; HR = 1.72; 95% CI = 0.287-1.168). Cox regression analysis also demonstrated significance between the time from the original biopsy to the diagnosis of cancer and telomere length in HPIN and in the surrounding stroma. These analyses showed significance, both alone and in combination with baseline prostate-specific antigen, and lend support to the hypothesis that telomere attrition in prostatic preneoplasia may be fundamental to the generation of chromosomal instability and to the emergence of CaP.