Similar gene expression profiles of sporadic, PGL2-, and SDHD-linked paragangliomas suggest a common pathway to tumorigenesis

Contains fulltext : 81540.pdf (publisher's version ) (Open Access)BACKGROUND: Paragangliomas of the head and neck are highly vascular and usually clinically benign tumors arising in the paraganglia of the autonomic nervous system. A significant number of cases (10-50%) are proven to be familial. Multiple genes encoding subunits of the mitochondrial succinate-dehydrogenase (SDH) complex are associated with hereditary paraganglioma: SDHB, SDHC and SDHD. Furthermore, a hereditary paraganglioma family has been identified with linkage to the PGL2 locus on 11q13. No SDH genes are known to be located in the 11q13 region, and the exact gene defect has not yet been identified in this family. METHODS: We have performed a RNA expression microarray study in sporadic, SDHD- and PGL2-linked head and neck paragangliomas in order to identify potential differences in gene expression leading to tumorigenesis in these genetically defined paraganglioma subgroups. We have focused our analysis on pathways and functional gene-groups that are known to be associated with SDH function and paraganglioma tumorigenesis, i.e. metabolism, hypoxia, and angiogenesis related pathways. We also evaluated gene clusters of interest on chromosome 11 (i.e. the PGL2 locus on 11q13 and the imprinted region 11p15). RESULTS: We found remarkable similarity in overall gene expression profiles of SDHD -linked, PGL2-linked and sporadic paraganglioma. The supervised analysis on pathways implicated in PGL tumor formation also did not reveal significant differences in gene expression between these paraganglioma subgroups. Moreover, we were not able to detect differences in gene-expression of chromosome 11 regions of interest (i.e. 11q23, 11q13, 11p15). CONCLUSION: The similarity in gene-expression profiles suggests that PGL2, like SDHD, is involved in the functionality of the SDH complex, and that tumor formation in these subgroups involves the same pathways as in SDH linked paragangliomas. We were not able to clarify the exact identity of PGL2 on 11q13. The lack of differential gene-expression of chromosome 11 genes might indicate that chromosome 11 loss, as demonstrated in SDHD-linked paragangliomas, is an important feature in the formation of paragangliomas regardless of their genetic background.1 p

The value of ultrasound with ultrasound-guided fine-needle aspiration biopsy compared to computed tomography in the detection of regional metastases in the clinically negative neck

PURPOSE: Head and neck oncologists have not reached consensus regarding the role of contemporary imaging techniques in the evaluation of the clinically negative neck in patients with head and neck squamous cell carcinoma (HNSCC). The purpose of the present study was to compare the accuracy of ultrasound with guided fine-needle aspiration biopsy (UGFNAB) and computed tomography (CT) in detecting lymph node metastasis in the clinically negative neck. METHODS AND MATERIALS: Sixty-four neck sides of patients with HNSCC were examined preoperatively by ultrasound/UGFNAB and CT at one of five participating tertiary care medical centers. The findings were correlated with the results of histopathologic examination of the neck specimen. RESULTS: Ultrasound with guided fine-needle aspiration biopsy was characterized by a sensitivity of 48%, specificity of 100%, and overall accuracy of 79%. Three cases had nondiagnostic aspirations using UGFNAB and were excluded. CT demonstrated a sensitivity of 54%, specificity of 92%, and overall accuracy of 77%. UGFNAB detected two additional metastases not visualized on CT, whereas CT detected no metastases not seen on UGFNAB. The results of UGFNAB were similar between the participating centers. CONCLUSIONS: Approximately one half of the clinically occult nodal metastases in our patient group were identified by both CT and UGFNAB. Overall, UGFNAB and CT demonstrated comparable accuracy. The sensitivity of CT was slightly better than UGFNAB, but the latter remained characterized by a superior specificity. The results of CT and UGFNAB did not appear to be supplementary. The choice of imaging modality for staging of the clinically negative neck depends on tumor site, T-stage, and experience and preference of the head and neck oncologist. If CT is required for staging of the primary tumor, additional staging of the neck by UGFNAB does not provide significant additional value

The Dutch founder mutation SDHD.D92Y shows a reduced penetrance for the development of paragangliomas in a large multigenerational family

Germline mutations in SDHD predispose to the development of head and neck paragangliomas, and phaeochromocytomas. The risk of developing a tumor depends on the sex of the parent who transmits the mutation: paragangliomas only arise upon paternal transmission. In this study, both the risk of paraganglioma and phaeochromocytoma formation, and the risk of developing associated symptoms were investigated in 243 family members with the SDHD.D92Y founder mutation. By using the Kaplan–Meier method, age-specific penetrance was calculated separately for paraganglioma formation as defined by magnetic resonance imaging (MRI) and for paraganglioma-related signs and symptoms. Evaluating clinical signs and symptoms alone, the penetrance reached a maximum of 57% by the age of 47 years. When MRI detection of occult paragangliomas was included, penetrance was estimated to be 54% by the age of 40 years, 68% by the age of 60 years and 87% by the age of 70 years. Multiple tumors were found in 65% and phaeochromocytomas were diagnosed in 8% of paraganglioma patients. Malignant paraganglioma was diagnosed in one patient (3%). Although the majority of carriers of a paternally inherited SDHD mutation will eventually develop head and neck paragangliomas, we find a lower penetrance than previous estimates from studies based on predominantly index cases. The family-based study described here emphasizes the importance of the identification and inclusion of clinically unaffected mutation carriers in all estimates of penetrance. This finding will allow a more accurate genetic counseling and warrants a ‘wait and scan' policy for asymptomatic paragangliomas, combined with biochemical screening for catecholamine excess in SDHD-linked patients