Methylation of the p16INK4A promoter is associated with malignant behavior in abdominal extra-adrenal paragangliomas but not pheochromocytomas.

Pheochromocytomas and abdominal extra-adrenal paragangliomas are related to endocrine tumors of the sympathetic nervous system. Studies in animal models have shown that inactivation of the products of the cyclin dependent kinase inhibitor 2A (CDKN2A) gene locus, p16INK4A and p14ARF, promotes the development of pheochromocytoma, especially in malignant form. The present study evaluated the involvement of CDKN2A in human pheochromocytomas and abdominal extra-adrenal paragangliomas from 55 patients. Promoter methylation was assessed using quantitative Pyrosequencing and methylation-specific PCR, and mRNA expression was measured by quantitative real-time PCR. For p16, western blot analysis and sequencing were also performed. succinate dehydrogenase complex subunit B (SDHB) sequencing analysis included extra-adrenal paragangliomas, all tumors classified as malignant, and cases diagnosed at 30 years or younger. The p16INK4A promoter was heavily methylated in a subset of paragangliomas, and this was significantly associated with malignancy (P<0.0043) and SDHB mutation (P<0.002). p16INK4A mRNA expression showed moderate suppression in malignant cases (P<0.05). In contrast, very little p14ARF promoter methylation was seen and there was no significant difference in p14ARF expression between tumors and normal samples. The p16 protein expression was reduced in 16 tumors, and sequence variations were observed in four tumors including the missense mutation A57V and the single nucleotide polymorphism (SNP) A148T. The results suggest that p16INK4A, and not p14ARF, is a subject of frequent involvement in these tumors. Importantly, hypermethylation of the p16INK4A promoter was significantly associated with malignancy and metastasis, and SDHB gene mutations. This finding suggests an etiological link and could provide a clinical utility for diagnostic purposes.

Laparoscopic approach to fever of unknown origin.

BACKGROUND: Fever of unknown origin (FUO) is difficult to diagnose. Laparotomy is needed to establish the etiologic diagnosis in some patients. The aim of this study was to analyze the feasibility, safety, and success rate of a protocolized laparoscopy in patients with FUO. METHODS: An extensive clinical evaluation was performed before surgery. Laparoscopy included inspection of the abdominal cavity, wedge and tru-cut liver biopsies, lymph node biopsy, splenectomy, and bone marrow biopsy. Histologic analysis, permanent section analysis, and cultures were obtained. RESULTS: The study involved 15 patients with a mean age of 43.6 +/- 14.5 years. The mean operative time was 122 +/- 60 min. Minor complications occurred in 9% of the patients. One patient bled after surgery and underwent reoperation. There was no operative mortality. An etiologic diagnosis was made in 66% of the patients, and laparoscopy helped to rule out intraabdominal pathology in four additional patients, giving a total success rate of 93%. CONCLUSION: Protocolized laparoscopy in patients with FUO is safe, feasible, and accurate.

[Hepatic fine needle aspiration biopsy. Experience in the study of hepatic masses at the Salvador Zubiran National Institute of Nutrition]. / Biopsia de hígado por aspiración con aguja fina. Experiencia del estudio de masas hepáticas en el Instituto Nacional de la Nutrición Salvador Zubirán.

The results of 114 fine-needle aspiration biopsies (FNAB) of the liver performed during six years (1987-1992) at the Departament of Pathology of the Instituto Nacional de la Nutrición Salvador Zubirán are presented. All were done by radiologists under ultrasonographic (three cases) or computerized tomographic guidance (111 cases). In order to determine the diagnostic accuracy, diagnoses made by FNAB were compared with those made by histological examination (coarse biopsies or surgical specimens) and/or by other diagnostic procedures including the clinical follow-up. Six cases were excluded because clinical information was not available. In 92 cases (85.2%) a correct diagnosis was made, in six (5.5%) the sample was inadequate and in 10 (9.3%) the diagnosis made by FNAB was incorrect. The diagnoses made were as follows: hepatocarcinoma 44, metastatic carcinoma 27, inflammatory lesions 12, regeneration 10, normal eight, unclassified carcinoma five, and lymphoma two. The sensitivity was 96.2, specificity 93.1, positive predictive value 97.4, negative predictive value 90.0, accuracy 95.3 and prevalence 73.1. There were three false negative and two false positive for carcinoma. These figures are similar to those found by other authors. No relevant complications were observed. It is concluded that FNAB of the liver is a safe, inexpensive and reliable method in the diagnoses of liver masses.