Clinical And Biological Studies On Head And Neck Paragangliomas

Head and neck paragangliomas(HNPs)are mainly composed of glomus jugular tumor(GJT)and carotid body tumor(CBT).They are rare and highly vascularised tumours,originating from neural crest derived chief cells of paraganglia and comprising about 0.6%of head and neck tumors and about 0.03% of all tumors.HNPs usually are benign and slow-growing tumours.The frequent locations of GJT are in the adventitia of the jugular bulb,on the promontory and along Jacobson's nerve in the hypotympanum According to the topography of their origin they are referred to as glomus jugulare tumours and tympanic body tumor.In the process of their slow growth,they often compress the adjacent structures,infiltrate the regional cranial nerves,erode the bony skull base,and even threat to life.Controversy exists about the choice of treatment modalities of GJT.The ideal primary treatment of these tumors is total surgical extirpation. Meanwhile,it is important to avoid severe complications such as cerebrospinal fluid leak and meningitis.Currently there are some limitations for selecting and administering the therapeutic regimens of HNPs.So it is necessary to get thoroughly understood about the characteristic of these tumors.In this study,surgical practices of GJT were retrospectively analyzed and the factors influencing post-operative complications were discussed in the past 19 years.Additionally,the expressions of VEGF,IGF-1,ERK1,ERK2,HIF-1αand HIF-2αwere examined and the correlations among these values in HNPs were investigated.Furthermore, peripheral blood and tumor DNA of patients with sporadic HNPs were analysed by sequencing(SDHD,SDHB and SDHC genes)and succinate dehydrogenase (SDH)enzyme activity assays were performed.The aim of this study is to explore the pathogenesis of HNPs,and find the markers to predict the genesis,biological behavior and genetic predisposition of this tumor.Part one:clinical research of surgical treatment for glomus jugulare tumors47 consecutive patients of glomus jugulare tumors surgically treated from July 1987 to October 2006 were analyzed retrospectively.Among them,4 cases recurred and had operation once more.38 cases had complete follow-up information.In the 51 operations,4 cases were treated via trans external auditory canal approach,8 cases via retroauricular approach,and 39 cases via auriculocervical or craniocervical combination approach.There were 44 cases with complete excision (86.3%),while 5 cases with subtotal excision and 2 cases with partial excision. There was no perioperative mortality.The most frequent complication was total conductive hearing loss,which occurred in 21 cases(41.2%,21/51).The facial paralysis was in 29.4%(15/51)and lower cranial nerve palsies 27.5%(14/51). Other complications were cerebrospinal fluid leak(5.9%,3/51),hearing disability (5.9%,3/51),vertigo(5.9%,3/51),cerebral infarction(2.0%,1/51),partial auricle necrosis(2.0%,1/51),and parotid gland fistula(2.0%,1/51).Factors found to be relevant to post-operative complications are tumor type,tumor size and structures involved.Of the 38 patients followed up with a mean follow-up time of 5.3 years (1.5-16.4 years),2 cases died of neuroblastoma or extensive involvement of GJT respectively,30 survived without tumor,and 6 survived with the tumor.This study shows that there is no perioperative mortality,high surgical control and low level of serious post-operative complications in our series.Surgery is the treatment of choice for most patients.Part two:biological studies of head and neck paragangliomas1.Immunohistochemical techniques were used to detect the expression of VEGF,and its relation with PCNA labelling index(PCNA LI)and MVD in 33 cases of human glomus jugulare tumor with complete clinical information.Results:The MVD and PCNA LI in VEGF positive tumors were significantly higher than those in VEGF negative tumors.The expression of VEGF was significantly correlated with MVD,PCNA LI and tumor clinical growth rate(P＜0.05).Conclusion:The expression of VEGF in human glomus jugulare tumors has correlation to MVD and PCNA LI,and VEGF may play an important role in tumor angiogenesis and proliferation through a paracrine or autocrine manner.2.The expression of IGF-1,ERK1 and ERK2 were examined in 33 cases of glomus jugulare tumor and 9 cases of adrea medulla by immunocytochemistry.Results:The expression of IGF-1,ERK1 and ERK2 in GJT were higher than those in normal adrenal medulla(P＜0.05).Furthermore,the expression of IGF-1 correlated significantly with those of ERK1/2(P＜0.05).Conclusion: Over-expression of IGF-1 and ERK1/2 may contribute to the tumorigenesis and growth.IGF-1 may play its biological effect through ERK1/2 signaling pathway.3.We studied the expression of HIF-1α,HIF-2αand VEGF in 33 cases of GJT,17 cases of CBT and 9 cases of adrea medulla by immunocytochemistry.Results:In GJT,the expression of HIF-1α,HIF-2αand VEGF was noted in 69.7%(23/33),60.6%(20/33),and 81.8%(27/33),respectively.In CBT,the expression of the HIF-1α,HIF-2αand VEGF was noted in 70.6%(12/17),64.7% (11/17),and 76.5%(13/17),respectively.Whereas in normal adrenal medulla, they were of negative expression.There were significant correlations between the expression of HIF-1α,HIF-2αand that of VEGF(P＜0.05).There were no obvious differences in expressions of the above values between GJT and CBT.Conclusion: HIF-1αand HIF-2αmay promote tumorigenesis and growth of GJT and CBT through induction of VEGF.GJT and CBT possess similar biological characteristics.4.Peripheral blood and tumor DNA extracted from 13 cases of sporadic HNPs were analysed by sequencing(SDHD,SDHB and SDHC genes)and SDH enzyme activi.ty assays were performed.Results:Only one patient from our patient cohort showed SDH gene mutation,a G-to-C substitution in SDHD exon 1, resulting in the substitution of the lie for Met-1.The MⅡmissense mutation may affect the function of translated protein.SDH activity was detected in 2/7 patients.Conclusion:SDH mutation may promote tumorigenesis of sporadic HNPs and that SDH inactivation maybe general phenomenon in sporadic HNPs.