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.