Involvement of Herpes Simplex Virus in Cervical Carcinoma

  • Fred Rapp
  • Mary K. Howett
Part of the NATO Advanced Science Institutes Series book series (NSSA, volume 57)


Cancer of the uterine cervix is the most common cancer of the reproductive system. Richart (1975) has stated that cervical intraepithelial neoplasia begins as a single-cell lesion at the squamocolumnar junction, more commonly on the anterior than on the posterior lip of the cervix, and only infrequently at the lateral angles. The progression in growth of lesions exhibiting irreversible malignant cellular changes advances from dysplasia to carcinoma in situ to invasive carcinoma. Massive screening of semi-annual cervical smears via Papanicolaou staining has resulted in increased detection of this cancer prior to invasion, and the cure rate of cancers detected at early stages (dysplasia or carcinoma in situ) is close to 100% (Gellman, 1976). However, women in lower socioeconomic groups and in Third World countries lack access to regular gynecologic examination and present with an increased incidence of invasive tumors. In the United States, the American Cancer Society estimates 16,000 new cases of invasive cervical cancer during 1981 and predicts 7,200 deaths (Table 1).


Cervical Cancer Cervical Carcinoma Cervical Intraepithelial Neoplasia Penile Cancer Verrucous Carcinoma 


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  1. Albrecht, T., and Rapp, F., 1973, Malignant transformation of hamster embryo fibroblasts following exposure to ultraviolet-irradiated human cytomegalovirus, Virology, 55: 53.CrossRefGoogle Scholar
  2. Amstey, M.S., 1975, Genital herpesvirus infection, Clin. Qbstet. Gynecol. 18: 89.CrossRefGoogle Scholar
  3. Aurelian, L., Cornish, J.D., and Smith, M.F., 1975, Herpesvirus type 2-induced tumor specific antigen (AG-4) and specific antibodies in patients with cervical cancer and controls, IARC Sci. Publ. No. 11: 79.Google Scholar
  4. Aurelian, L., Davis, H.J., and Julian, C.G., 1973a, Herpesvirus type 2 induced tumor specific antigen in cervical carcinoma, Am. J. Epidemiol., 98: 1.Google Scholar
  5. Aurelian, L., Schumann, B., Marcus, R.L., and Davis, H.J., 1973b, Antibodies to HSV-2 induced tumor specific antigens in serums from patients with cervical carcinoma, Science, 181: 161.CrossRefGoogle Scholar
  6. Ayre, J.E., 1960, Role of the halo cell in cervical cancerigenesis. A virus manifestation in premalignancy?, Qbstet. Gynecol., 15: 481.Google Scholar
  7. Benson, W.L. and Norris, H.J., 1978, Current problems in gynecologic pathology, in: “Gynecologic Oncology” L. McGowen, ed., Appleton-Century Crofts, New York.Google Scholar
  8. Cabral, G.A., Courtney, R.J., Schaffer, P.A., and Marciano-Cabral, F., 1980, Ultrastructural characterization of an early, nonstructural polypeptide of herpes simplex virus type 1, J. Virol., 33: 1192.Google Scholar
  9. Camacho, A. and Spear, P.G., 1978, Transformation of hamster embryo fibroblasts by a specific fragment of the herpes simplex virus genome, Cell, 15: 993.CrossRefGoogle Scholar
  10. Cancer Facts and Figures, 1980, American Cancer Society.Google Scholar
  11. Collard, W., Thornton, H., and Green, M., 1973, Cells transformed by HSV-2 transcribe virus specific RNA sequences shared by herpes virus types 1 and 2, Nature 243: 264.Google Scholar
  12. Darai, G., and Munk, K., 1973, Human embryonic lung cells abortively infected with herpesvirus hominis type 2 show some properties of cell transformation, Nature 241: 268.Google Scholar
  13. Dawson, D.F., Duckworth, J.K., Bernhardt, H., and Young, J.M., 1965, Giant condyloma and verrucous carcinoma of the genital area. Arch. Pathol., 79: 225.Google Scholar
  14. de-The, G., 1977, Viruses as causes of some human tumors? Results and prospectives of the epidemiologic approach, in: “Origins of Human Cancer,” H.H Hiatt, J.D. Watson, and J.A. Winsten, eds. Cold Spring Harbor Laboratory, New York.Google Scholar
  15. Duff, R., and Rapp, F., 1971a, Oncogenic transformation of hamster cells after exposure to herpes simplex virus type 2, Nature, 233: 48.Google Scholar
  16. Duff, R., and Rapp, F., 1971b, Properties of hamster embryo fibroblasts transformed in vitro after exposure to ultra-violet-irradiated herpes simplex virus type 2, J. Virol., 8: 469.Google Scholar
  17. Duff, R., and Rapp, F., 1973, Oncogenic transformation of hamster embryo cells after exposure to inactivated herpes simplex virus type 1, J. Virol., 12: 209.Google Scholar
  18. Flannery, V.L., Courtney, R.J., and Schaffer, P.A., 1977, Expression of an early, nonstructural antigen of herpes simplex virus in cells transformed in vitro by herpes simplex virus, J. Virol., 21: 284.Google Scholar
  19. Fraumeni, J.F., Lloyd, J.M., Smith, E.M., and Wagoner, J.K., 1969, Cancer mortality among nuns: role of marital status in etiology of neoplastic disease in women, J. Natl. Cancer Inst., 42: 455.Google Scholar
  20. Frenkel, M., Locker, H., Cox, B., Roizman, B., and Rapp, F., 1976, Herpes simplex virus DNA in transformed cells: sequence complexity in five hamster cell lines and one derived hamster tumor, J. Virol., 18: 885.Google Scholar
  21. Frenkel, M., Roizman, B., Cassai, E., and Nahmias, A., 1972, A DNA fragment of herpes simplex 2 and its transcription in human cervical cancer tissue, Proc. Natl. Acad. Sci. USA, 69: 3784.CrossRefGoogle Scholar
  22. Galloway, D.A., and McDougall, J.K., 1981, Transformation of rodent cells by a cloned DNA fragment of herpes simplex virus type 2, J. Virol., 38: 749.Google Scholar
  23. Geder, L., 1980, Oncogenic properties of human cytomegalovirus, in: “Oncogenic Herpesviruses,” F. Rapp, ed., CRC Press, Boca Raton, Florida.Google Scholar
  24. Geder, L., Lausch, R., O’Neill, F., and Rapp, F., 1976, Oncogenic transformation of human embryo lung cells by human cytomegalovirus, Science, 192: 1134.CrossRefGoogle Scholar
  25. Geder, L., Vaczi, L., and Boldough, I., 1973, Development of cell lines after exposure of chicken embryonic fibroblasts to herpes simplex virus type 2 at supraoptimal temperature, Acta Microbiol. Acad. Sci. Hung., 20: 119.Google Scholar
  26. Gellman, D.D., 1976, Cervical cancer screening programs. Can. Med. Assoc. J., 114: 1003.Google Scholar
  27. Gilman, S.C., Docherty, J.J., Clark, A., and Rawls, W.E., 1981, The reaction patterns of HSV type 1 and type 2 proteins with the sera of patients with uterine cervical carcinoma and matched controls, Cancer Res., in press.Google Scholar
  28. Gore, H., and Hertig, A.T., 1964, Definitions, in: “Dysplasia Carcinoma In Situ and Microinvasive Carcinoma of the Cervix Uteri” L.A. Gray, ed., Charles C. Thomas, Springfield.Google Scholar
  29. Hollinshead, A.C., Chretien, P.B., Lee, O., Tarpley, J.L., Kerney, S.E., Silverman, N.A., and Alexander, J.C., 1976, In vivo and in vitro measurements of the relationship of human squamous carcinomas to herpes simplex virus tumor-associated antigens, Cancer Res., 36: 821.Google Scholar
  30. Jariwalla, R.J., Aurelian, L., and Ts’o, P.O.P., 1980, Tumorigenic transformation induced by a specific fragment of DNA from herpes simplex virus type 2, Proc. Natl. Acad. Sci. USA, 77: 2279.CrossRefGoogle Scholar
  31. Jariwalla, R.J., 1981, Neoplastic transforming activity of defined HSV-2 DNA fragments representing 6.5–13% of the Viral Genome, in: “Proceedings of the International Workshop on Herpesviruses,” July 29–31, Bologna, Italy.Google Scholar
  32. Jones, K.W., Fenoglio, C.M., Shevchuk-Chaban, M., Maitland, W.J., and McDougall, J.K., 1978, Detection of herpes simplex virus type 2 mRNA in human cervical biopsies by in situ cytological hybridization, IARC Sci. Publ. No. 24: 917.Google Scholar
  33. Kaufman, R.H., Dreesman, G.R., Burek, J., Korhonen, M.O., Matson, D.O., Melnick, J.L., Powell, K.L., Purifoy, D.J.M., Courtney, R.J., and Adam, E., 1981, Herpesvirus-induced antigens in squamous-cell carcinoma in situ of the vulva, N. Engl. J. Med., 305: 483.CrossRefGoogle Scholar
  34. Kawana, T., Sakamoto, S., Kasamatsu, T., and Aurelian, L., 1978, Frequency of anti-AG-4 antibodies in patients with uterine cervical cancer and controls, Gann, 69: 389.Google Scholar
  35. Keighley, E., 1968, Carcinoma of the cervix among prostitutes in a women’s prison, Br. J. Vener. Pis., 44: 254.Google Scholar
  36. Kessler, I.I., 1974, Perspectives on the epidemiology of cervical cancer with special reference to the herpesvirus hypothesis, Cancer Res., 34: 1091.Google Scholar
  37. Kessler, I., 1976, Human cervical cancer as a venereal disease, Cancer Res., 36: 783.Google Scholar
  38. Kessler, I.I., 1977, Venereal factors in human cervical cancer, Cancer, 39: 1912.CrossRefGoogle Scholar
  39. Lang, P.J., and Kummer, J.F., 1972, Demonstration of cytomegalovirus in semen, N. Engl. J. Med., 287: 756.CrossRefGoogle Scholar
  40. Lang, D.J., Kummer, J.F., and Hartley, D.P., 1974, Cytomegalovirus in semen: persistence and demonstration in extracellular fluids, N. Engl. J. Med., 291: 121.CrossRefGoogle Scholar
  41. Lerch, V., Okagaki, T., Austin, J.H., Kevorkian, A.Y., Youge, P.A., 1963, Cytologic findings in progression of anaplasia (dysplasia) to carcinoma in situ: a progress report. Acta. Cytol., 7: 183.Google Scholar
  42. Macnab, J.C.M., 1974, Transformation of rat embryo cells by temperature-sensitive mutants of herpes simplex virus, J. Gen. Virol,, 24: 143.CrossRefGoogle Scholar
  43. Martinez, I., 1969, Relationship of squamous cell carcinoma of the cervix uteri to squamous cell carcinoma of the penis among Puerto Rican women married to men with penile cancer, Cancer, 24: 777.CrossRefGoogle Scholar
  44. Martzloff, K.H., 1945, Cancer of the cervix. Some fundamental considerations, West. J. Surg., 53: 255.Google Scholar
  45. McDougall, J.K., Crum, C.P., Levine, R.U., Richart, R.M., and Fenoglio, C.M., 1981, Expression of limited regions of the HSV-2 genome in cervical neoplasia, in: “Proceedings of the International Workshop on Herpesviruses,” July 27–31, Bologna, Italy.Google Scholar
  46. Melnick, J.L., Courtney, R.J., Powell, K.L., Schaffer, P.A., Benyesh-Melnick, M., Dreesman, G.R., Anzai, T., and Adam, E., 1976, Studies on herpes simplex virus and cancer, Cancer Res., 36: 845.Google Scholar
  47. Melnick, J.L., Lewis, R., Wimberly, I., Kaufman, R.H., and Adam, E., 1978, Association of cytomegalovirus (CMV) infection with cervical cancer: isolation of CMV from cell cultures derived from cervical biopsy, Intervirology, 10: 115.CrossRefGoogle Scholar
  48. Montgomery, R., Youngblood, L., and Medearis, D.N., Jr., 1972, Recovery of cytomegalovirus from the cervix in pregnancy, Pediatrics, 49: 524.Google Scholar
  49. Munoz, M., 1973, Effect of herpes simplex virus type 2 and hormonal imbalance on the uterine cervix of the mouse, Cancer Res., 33: 1504.Google Scholar
  50. Nahmias, A.J., Del Buono, I., and Ibrahim, I., 1975, Antigenic relationship between herpes simplex viruses, human cervical cancer and HSV-associated hamster tumours, IARC Sci. Publ. No. 11: 309.Google Scholar
  51. Nahmias, A.J., Josey, W.E., Naib, Z.M., Luce, C.F., and Guest, B., 1970. Antibodies to herpesvirus hominis types 1 and 2. II. Women with cervical cancer, Am. J. Epidemiol., 91: 547.Google Scholar
  52. Nahmias, H.J., Naib, Z.M., and Josey, W., 1974, Epidemiological studies relating genital herpes to cervical cancer, Cancer Res., 34: 1111.Google Scholar
  53. Nahmias, A.J., and Norrild, B., 1980, Oncogenic potential of herpes simplex viruses and their association with cervical neoplasia, in: “Oncogenic Herpesviruses,” F. Rapp, ed., CRC Press, Boca Raton, Florida.Google Scholar
  54. Naib, Z.M., Nahmias, A.J., and Josey, W.E., 1966, Cytology and histopathology of cervical herpes simplex infection, Cancer, 19: 1026.CrossRefGoogle Scholar
  55. Naib, Z.M., Nahmias, A.J., Josey, W.E., and Kramer, J.H., 1969, Genital herpetic infection: association with cervical dysplasia and carcinoma, Cancer, 23: 940.CrossRefGoogle Scholar
  56. Notter, M.F.D., and Docherty, J.J., 1976, Comparative diagnostic aspects of herpes simplex virus tumor-associated antigens, J. Natl. Cancer Inst., 57: 483.Google Scholar
  57. Novak, E.R., and Woodruff, J.D., 1979, “Gynecologic and Obstetric Pathology,” W.B. Saunders Co., Philadelphia.Google Scholar
  58. Orth, G., Breitburd, F., Favre, M., and Croissant, O., 1977, Papillomaviruses: possible role in human cancer, in: “Origins of Human Cancer,” H.H. Hiatt, J.D. Watson and J.A. Winston eds., Cold Spring Harbor Laboratory, New York.Google Scholar
  59. Palmer, A.E., London, W.T., Nahmias, A.J., Naib, Z.M., Tunca, J., Fuccillo, D.A., Ellenberg, J.H. and Sever, J.L., 1976, A preliminary report on investigation of oncogenic potential of herpes simplex virus type 2 in Cebus monkeys, Cancer Res., 36: 807.Google Scholar
  60. Pasca, A.S., Kummerlander, L., Pejtsik, B., and Pali, K., 1975, Herpesvirus antibodies and antigens in patients with cervical anaplasia and in controls, J. Natl. Cancer Inst., 55: 775.Google Scholar
  61. Pereyra, A.J,, 1961, The relationship of sexual activity to cervical cancer. Cancer of the cervix in a prison population, Obstet. Gynecol., 17: 154.Google Scholar
  62. Rapp, F., and Falk, L.A., 1964, Study of virulence and tumorigenicity of variants of herpes simplex virus, Proc. Soc. Exp. Biol. Med., 110: 361.Google Scholar
  63. Rapp, F., and Jenkins, F., 1981, Genital cancer and viruses, Gynecol. Oncol., in press.Google Scholar
  64. Rapp, F., Li, J.L.H., and Jerkofsky, M., 1973, Transformation of mammalian cells by DNA-containing viruses following photo-dynamic inactivation, Virology, 55: 339.CrossRefGoogle Scholar
  65. Rapp, F., and Westmoreland, D., 1976, Cell transformation by DNA-containing viruses, Biochim. Biophys. Acta, 458: 167.Google Scholar
  66. Rawls, W.E. and Adam, E., 1977, Herpes Simplex viruses and human malignancies, in: “Origins of Human Cancer,” H.H. Hiatt. J.D. Watson, and J.A. Winston, eds., Cold Spring Harbor Laboratory, New York.Google Scholar
  67. Rawls, W.E., Laurel, D., Melnick, J.L., Glicksman, J.M., and Kaufman, R.H., 1968, A search for viruses in smegma, premalignant and early malignant cervical tissues. The isolation of herpesviruses with distinct antigenic propterties, Am. J. Epidemiol., 87: 647.Google Scholar
  68. Reed, C.L., Cohen, G.H., and Rapp, F., 1975, Detection of a virus specific antigen on the surface of herpes simplex virus transformed cells, Virology, 15: 668.Google Scholar
  69. Reyes, G.R., Lafemina, R., Hayward, S.D. and Hayward, G.S., 1979, Morphological transformation by DNA fragments of human herpes viruses: evidence for two distinct transforming regions in HSV-1 and HSV-2 and lack of correlation with biochemical transfer of the thymidine kinase gene. Cold Spring Harbor Symp. Quant. Biol., 44: 629.CrossRefGoogle Scholar
  70. Richart, R.M., 1963, Cervical neoplasmia in pregnancy. A series of pregnant and postpartum patients followed without biopsy or therapy. Am. J. Obstet. Gynecol., 87: 474.Google Scholar
  71. Richart, R.M., 1975, Cervical intraepithelial neoplasia, in: “Genital and Mammary Pathology, Decennial 1966–1975,” S.C. Sommers, ed., Appleton, New York.Google Scholar
  72. Richart, R.M., and Barron, B.A., 1969, A follow-up of patients with cervical dysplasia, Am. J. Obstet. Gynecol., 105: 386.Google Scholar
  73. Rigoni-Stern, D., 1842, Fatti statistia relativi alle malatie cancerose, Giorn Dervire Progr. Pathol. Terap., 2: 507.Google Scholar
  74. Siegel, A., 1962, Malignant transformation of condyloma acuminatum, Am. J. Surg., 103: 613.CrossRefGoogle Scholar
  75. Sims, C.F., and Garb, J., 1951, Giant condylomata acuminata of the penis associated with metastatic carcinoma of the right inguinal lymph node, Arch. Dermatol. Syphil., 68: 383.Google Scholar
  76. Takahashi, M., and Yamanishi, K., 1974, Transformation of hamster embryo and human embryo cells by temperature sensitive mutants of herpes simplex virus type 2, Virology, 61: 306.CrossRefGoogle Scholar
  77. Thiry, L., Sprecher-Goldberger, S., Hannecart-Pokorni, E., Gould, I., and Bossens, M., 1977, Specific non-immunoglobulin G antibodies and cell mediated responses to herpes simplex virus antigens in women with cervical carcinoma, Cancer Res., 37: 1301.Google Scholar
  78. Towne, J.E., 1955, Carcinoma of the cervix in nulliparous and celibate women, Am. J. Obstet. Gynecol., 69: 606.Google Scholar
  79. Trentin, J.J., Van Hoosier, G.L., Boren, D., Ferguson, P.G., and Kitamuru, T., 1969, Oncogenic evaluation in hamsters of human picornaparamyxo-and herpesviruses, Proc. Soc. Exp. Biol. Med. 132: 912.CrossRefGoogle Scholar
  80. Wentz, W.B., Reagan, J.W., and Heggie, A.D., 1975, Cervical carcinogenesis with herpes simplex virus type 2, Obstet. Gynecol., 46: 117.Google Scholar
  81. Wentz, W.B., Reagan, J.W., Heggie, A.D., Fu, Y., and Anthony, D.D., 1981, Induction of uterine cancer with inactivated herpes simplex virus, types 1 and 2, Cancer, in press.Google Scholar
  82. Willmott, F.E., 1975, Cytomegalovirus in female patients attending a VD clinic, Br. J. Vener. Pis., 51: 278.Google Scholar
  83. Woodruff, J.D., and Peterson, W.F., 1958, Condylomata acuminata of the cervix, Am. J. Obstet. Gynecol., 75: 1359.Google Scholar
  84. zur Hausen, H., 1976, Condylomata acuminata and human genital cancer, Cancer Res., 36: 794.Google Scholar
  85. zur Hausen, H., 1977, Human papillomaviruses and their possible role in squamous cell carcinomas, Curr. Top. Microbial. Immun., 78: 1.Google Scholar

Copyright information

© Springer Science+Business Media New York 1983

Authors and Affiliations

  • Fred Rapp
    • 1
  • Mary K. Howett
    • 1
  1. 1.Department of Microbiology and Specialized Cancer Research CenterThe Pennsylvania State University College of MedicineHersheyUSA

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