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Etiological Involvement of Oncogenic Human Papillomavirus in Tonsillar Squamous Cell Carcinomas Lacking Retinoblastoma Cell Cycle Control¹

Molekularbiologisches Labor, Hals-Nasen-Ohren-Klinik [T. A., A. P., R. E., W. K., M. H., A. D., H. W., F. X. B.], Institut für Medizinische Biometrie [C. C.], Universität Heidelberg, Angewandte Tumor Virologie, Deutsches Krebsforschungszentrum [T. K., T. N.], 69120 Heidelberg, Germany

Two hundred eight primary squamous cell carcinomas of the head and neck have been analyzed with respect to the presence of the retinoblastoma tumor suppressor protein, pRb. Of these, 23 tumors (11%) that preferentially localized to the tonsils revealed complete absence or dramatic reduction in the amount of pRb. Other cell cycle components, cyclin D1 and p16^INK4A, which are intimately related to pRb through an autoregulatory loop, were also dramatically decreased or overexpressed, respectively, in these pRb-defective tumors. On the other hand, the majority of the pRb-defective tumors contained the wild-type p53 gene. No evidence was found for genetic defects at the Rb locus in these tumors. Very significantly, in 11 of 12 pRb-defective tonsillar tumors, but in none of 9 pRb-positive tonsillar tumors (P < 10^-7), DNA of oncogenic human papillomavirus types was identified, providing a strong indication for a human papillomavirus-associated etiology of these tumors and suggesting the functional inactivation of the pRb protein by the viral E7 gene product. In comparison to all head and neck squamous cell carcinomas studied, the pRb-defective tonsillar tumors were in general more poorly differentiated (P = 0.0059), and they were all metastatic at the time of resection. Of particular clinical interest, despite these adverse histopathological factors, the clinical outcome for these patients was relatively favorable, strongly implying that the pRb-defective tumors responded uniformly well toward postoperative radiation therapy.

¹ The work was supported by grants from the Verein zur Förderung der Krebsforschung in Deutschland e.V. and the Tumorzentrum Heidelberg/Mannheim.

² To whom requests for reprints should be addressed, at Molekularbiologisches Labor, Universitaet-HNO-Klinik, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany. Phone: 06221/566751; Fax: 06221/564604; E-mail: Franz_Bosch@krzmail.krz.uniheidelberg.de.

Received 9/ 3/97. Accepted 11/19/97.

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