Basic fibroblast growth factor and fibroblastic growth factor receptor-1 may contribute to head and neck paraganglioma development by an autocrine or paracrine mechanism.

Paragangliomas are hypervascular tumors arising from neural crest-derived paraganglia that are associated with the autonomic nerve system. Mutations in genes coding for subunits of mitochondrial complex II are associated with hereditary paragangliomas, and it has been suggested that these mutations result in a pseudohypoxic signal triggering tumorigenesis. Fibroblastic growth factors are hypoxia-inducible angiogenic stimuli that are involved in the angiogenesis and tumorigenesis of several neoplasms. It has been demonstrated that basic fibroblastic growth factor (bFGF) is a survival factor for cultured chief cells of the carotid body, capable of inducing proliferation. To examine the role of this growth factor in paragangliomas, we studied the immunohistochemical expression of bFGF and its high affinity receptor fibroblastic growth factor receptor 1 (FGFR1) in 7 normal carotid bodies and in 33 head and neck paragangliomas, including 2 malignant cases and their metastases. Immunohistochemical expression of bFGF and FGFR1 in tumors was confirmed by real-time polymerase chain reaction. FGFR1 was moderately present in carotid bodies, and there was strong and significantly enhanced cytoplasmatic staining of FGFR1 in all paragangliomas. Chief cells in carotid bodies and tumors showed strong cytoplasmatic staining for bFGF. The results indicate that FGFR1 and bFGF may contribute to the development of head and neck paragangliomas.

G2M arrest, blocked apoptosis, and low growth fraction may explain indolent behavior of head and neck paragangliomas.

Head and neck paragangliomas are characterized by unusually slow growth and a strong hereditary component, which is associated with inactivating mutations in subunits of complex II of the mitochondrial respiratory chain. It is unclear how mutations induce tumorigenesis and lead to the indolent clinical behavior that often plays a prominent role in treatment strategies. To better understand the natural course of the tumors, we studied a number of growth-related parameters in 42 hereditary and sporadic paragangliomas. Computerized image analysis showed that the fraction of Ki-67-positive cells was generally below 1%, in accordance with the slow growth. Weak or negative immunohistochemical staining indicated wild-type TP53 status, whereas p-21(waf) expression was heterogeneous. Most tumors showed strong expression of Bcl-x(L), and no apoptotic cells could be detected with the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay. Flow cytometry showed abnormal DNA content profiles in 52% of the tumors, including overt aneuploidy as well as G(2)/M arrest or tetraploidization. These results fit into a model in which a stress-activated cell cycle checkpoint at the G(2) to M transition and inhibition of apoptosis permit the expansion of only a minor fraction of cycling cells with high likelihood of polyploidization.