SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma.

BACKGROUND: Paragangliomas and phaeochromocytomas are neuroendocrine tumours associated frequently with germline mutations of SDHD, SDHC, and SDHB. Previous studies have shown the imprinted SDHAF2 gene to be mutated in a large Dutch kindred with paragangliomas. We aimed to identify SDHAF2 mutation carriers, assess the clinical genetic significance of SDHAF2, and describe the associated clinical phenotype. METHODS: We undertook a multicentre study in Spain and The Netherlands in 443 apparently sporadic patients with paragangliomas and phaeochromocytomas who did not have mutations in SDHD, SDHC, or SDHB. We analysed DNA of 315 patients for germline mutations of SDHAF2; a subset (n=200) was investigated for gross gene deletions. DNA from a group of 128 tumours was studied for somatic mutations. We also examined a Spanish family with head and neck paragangliomas with a young age of onset for the presence of SDHAF2 mutations, undertook haplotype analysis in this kindred, and assessed their clinical phenotype. FINDINGS: We did not identify any germline or somatic mutations of SDHAF2, and no gross gene deletions were noted in the subset of apparently sporadic patients analysed. Investigation of the Spanish family identified a pathogenic germline DNA mutation of SDHAF2, 232G-->A (Gly78Arg), identical to the Dutch kindred. INTERPRETATION: SDHAF2 mutations do not have an important role in phaeochromocytoma and are rare in head and neck paraganglioma. Identification of a second family with the Gly78Arg mutation suggests that this is a crucial residue for the function of SDHAF2. We conclude that SDHAF2 mutation analysis is justified in very young patients with isolated head and neck paraganglioma without mutations in SDHD, SDHC, or SDHB, and in individuals with familial antecedents who are negative for mutations in all other risk genes. FUNDING: Dutch Cancer Society, European Union 6th Framework Program, Fondo Investigaciones Sanitarias, Fundación Mutua Madrileña, and Red Temática de Investigación Cooperativa en Cáncer.

[Primary systemic amyloidosis with exclusive involvement of the tongue as an exceptional cause of dysphagia]. / Amiloidosis primaria AL con afección exclusiva de la lengua como causa excepcional de disfagia.

We present a 73-year-old woman with progressive dysphagia and dysarthria over two years associated with systemic symptoms including weight loss, asthenia and dyspnoea. Biopsy of the tongue demonstrated amyloid AL deposits. The immunohistochemical study showed a notable positiveness to antibodies for L-kappa chains. The patient died 6 months after diagnosis.

Role of intratumoral lymphatic vessels in the lymph node dissemination of laryngopharyngeal squamous cell carcinoma.

BACKGROUND: The development of new markers for lymphatic endothelium allowed the study of intratumoral lymphatic microcirculation, as well as its association with lymph node metastasis. METHODS: In all, 120 patients with laryngopharyngeal squamous cell carcinoma (LPSCC) without previous treatment were retrospectively studied. The immunohistochemical determination of PA2.26 antigen/podoplanin was used to assess intratumoral lymphatic vessels (ILVs) in the primary tumor. RESULTS: Multivariate analysis revealed that lymph node metastasis was associated with tumor location (p = .001), differentiation grade (p = .02), and ILV (p = .013). Hypopharyngeal and supraglottic locations, poor grade of differentiation, and ILV, respectively, increased the risk of developing lymph node metastasis 13.5-, 4.7-, 5.2-, and 3.2-fold. CONCLUSIONS: In our series, the presence of ILV in the primary tumor was an independent risk factor for the development of lymph node metastasis. The incorporation of ILV assessment into routine clinicopathological study might improve the evaluation of patients with LPSCC.

Influence of thymidylate synthase DNA polymorphisms and gender on the clinical evolution of patients with advanced colorectal cancer.

Experimental evidence has revealed that several thymidylate synthase (TS) DNA polymorphisms modulate gene expression, which, in turn is known to be down-regulated by oestrogen receptor subtypes. Consequently, this process might be influenced by female hormones. Based on these data, we investigated whether patient's gender and TS polymorphism exert an interactive effect on the clinical evolution of patients with advanced colorectal cancer (CRC) subjected to 5 fluorouracil (5FU)-based adjuvant chemotherapy. A retrospective study was carried out on paraffin-embedded sections from 81 CRC patients. A variable tandem repeat (VNTR) of 28 bp, a G/C single nucleotide polymorphism (SNP), and a deletion of 6 bp (ins1494del 6 bp) were studied. Genotyping methods were polymerase chain reaction (PCR) for VNTR, and PCR followed by restriction length fragment polymorphism (PCR-RFLP) for SNP and ins1494del 6 bp. The effect of TS genotype and gender on overall and progression-free survival was assessed in univariate and multivariate (Cox regression model) tests. In male patients, the study of combined TS genotypes showed that G&6+/6+ was an adverse marker for overall (P=0.04; median: not reached) and progression-free survival (P=0.03; median: 12 months, 95% CI: 0-32.4). In the multivariate analysis, the concurrence of G&6+/6+ combination and male patients resulted in a 5.5-fold increased risk of relapse or disease progression (95% CI: 1-32.1; likelihood test P=0.004; interaction P=0.06). TS genotype did not affect survival among women. The present study supports that the effect of TS polymorphisms on the clinical evolution of advanced CRC patients is significantly influenced by gender.

Intratumoral lymphatic vessels and VEGF-C expression are predictive factors of lymph node relapse in T1-T4 N0 laryngopharyngeal squamous cell carcinoma.

BACKGROUND: The presence of intratumoral lymphatic vessels (ILVs) and the expression of vascular endothelial growth factor-C (VEGF-C) in tumour cells have been studied as markers of lymphangiogenesis in order to evaluate their role in metastatic dissemination in laryngopharyngeal squamous cell carcinoma. METHODS: A retrospective study was performed in 76 patients of N0 laryngopharyngeal carcinoma. with variable tumour size (T1-T4), histological grade, and location (supraglottic, glottic and hypopharyngeal). The presence of ILVs, as revealed by the expression of PA2.26 antigen and VEGF-C expression, were determined by immunohistochemistry (IHC). Low-grade and high-grade lymphangiogenesis were defined by qualitative and quantitative criteria. RESULTS: Multivariate analysis revealed low-grade ILV and VEGF-C expression to be associated respectively with 30.3- and 16.2-fold higher probabilities of cervical lymph node relapse (P = 0.005 and P = 0.032) and with 16.2- and 8.44-fold shorter disease-free survival (P = 0.009 and P = 0.045). CONCLUSIONS: Low-grade ILV and VEGF-C expression are independent predictive factors of cervical lymph node relapse and shortening of time to relapse in N0 laryngopharyngeal carcinoma.