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Viruses in the pathogenesis of cervical neoplasia: An update
HUMAN PATHOLOGY
V O L U M E 13 NUMBER 9
September 1982
Current Topics VIRUSES IN-THE PATHOGENESIS OF C E R V I C A L N E O P L A S I A : AN UPDATE Cecilia M. Fenoglio, MD* For decades the epidemiologic factors associated with cervical neoplasia have been extensively studied, leading to the identification of clearly delineated risk factors? The weight of scientific evidence suggests that the oncogenic agents, whatever they are, are venereally transmitted and that a young age at first intercourse is the single most important epidemiologic variable in its development. The importance o f sexual factors in the genesis of cervical neoplasia is not a new concept; it was most dramatically brought out in the now classic research o f Gagnon, who studied 13,000 Canadian nuns and found no cases of cervical cancer among them. These findings have been confirmed by other studies of religious and nonreligious populations, t A m o n g the postulated agents are chemicals, hormones, sperm, radiation, and infectious agents. Any of these could, potentially, affect the cervix oncogenically by interacting with the immature squamous epithelium in the cervical transformation zone. However, since the epidemiologic observations clearly indicate that cervical neoplasia has many o f the attributes of a communicable disease, leading contenders for an etiologic agent fall into the category o f infectious diseases. Numerous viruses, bacteria, chlamydiae, mycoplasmas, parasites, and fungi are known to be venereally transmitted. O f these, certain organisms have had their period in the investigational limelight. Currently, viruses occupy this spot, since they have a documented ability to cause tumors in animals. They not only are capable o f initiating the neoplastic alterAccepted for publicationJanuary 3, 1982. * Professor of Pathology,Collegeof Physiciansand Surgeons, Columbia University,New York, NY 10032. Addresscorrespondenceand reprint requeststo Dr. Fenoglio.
ations but also are responsible for transmitting new genetic information to the infected cells, which provides for the maintenance of the neoplastic state. With respect to cervical neoplasia, only two viruses are seriously considered potential cervical carcinogens. These are herpes simplex virus type 2 (HSV-2) and the human papillomavirus (HPV). Both viruses are known to produce tumors in animal systems, and both are known to be venereally transmitted. HERPES SIMPLEX VIRUS
When herpesviruses infect cells, they attach themselves to the cell surface and insert their genetic material into the host cell. Once inside, they may rep: licate to produce whole viral particles in a process known as an acute productive infection. Such infections are frequently cytolytic and may cause the death o f the infected cell. If only a part of the genetic material is replicated in nonproductive infections, whole virus is not produced. The cell does not die, enabling each daughter cell to carry its own genetic material plus that of the infecting virus each time it divides. HSV-2 infections primarily involve persons beyond the age of puberty, predominate in sexually active adults of both sexes, and are among the venereally transmitted disorders. In the 1960s Naib et al. 2 noted that there was an increased incidence of cervical neoplasia in patients with cytologically detectable herpetic cervicitis. This observation provided the stimulus for n u m e r o u s seroepidemiologic studies, which have validated this association. Nearly all these investigations have taken the form of case-controlled studies in which the prevalence of HSV-2 antibodies and/or antigens among women with cervical neoplasia
0046-8177182/0900/0785 $00.60 9 W. B. Saunders Co.
785
HUMAN PATHOLOGY--VOLUME 13, NUMBER 9 September1982 were compared with that among women without neoplastic lesions, in a control group. Because marital status and coital practices often were not considered in the selection of the control groups, it has been stated that cervical neoplasia and herpes infections are merely covariables o f sexual activity. An argument against the hypothesis that carcinoma of the cervix and herpesvirus infections are merely covariables o f sexual promiscuity was reviewed by Adam et al, 3 who found that the incidence of antibodies and the titers to the virus were higher in nonpromiscuous cancer patients than in nonpromiscuous controls. Further evidence against the covariability hypothesis was presented by Kessler and AurelianJ who reported a similar incidence rate for syphilis and trichomonas vaginitis among patients with cervical cancer and among controls. They reasoned that if cervical cancer were directly related to sexual promiscuity, one would expect a higher rate of all venereal infections among patients with cervical neoplasia. It is possible that neoplastic changes alter the susceptibility of the epithelium to subsequent viral infections and that HSV infections may follow, rather than precede, the neoplastic state. However, the data o f Rawls et al. 5 suggest that this does not occur. T h e prevalence of HSV antibodies among women with carcinoma in situ did not increase with age as would have been expected if an increased susceptibility for HSV infection did occur. 5 The first clue that cells transformed by herpesviruses contain viral DNA sequences came from the identification of virus-specific antigens on experimentally derived neoplastic cells. Herpes simplex virus antigens have also been identified on cells from cervical neoplasms. 6 More direct evidence that HSVtransformed cells retain viral information comes from the identification o f viral-specific nucleic acids, utilizing the techniques of molecular hybridization. This technology can be applied to histologic specimens in the technique known as in-situ molecular hybridization. By means o f this technique and a probe to whole HSV-2, sequences complementary to the HSV genome have been found in cervical neoplasms. A battery o f restriction endonuclease-derived subgenomic fragments can be generated from the HSV genome to distinguish between productive and nonproductive infections. Since a productive infection is associated with the formation o f complete viral particles, expression of the entire battery of subgenomic probes, i.e., the total genomic expression, Would be expected. In contrast, nonproductively infected cells should not be associated with the expression of all the subgenomic fragments. When the expression of these s u b g e n o m i c f r a g m e n t s in e x p e r i m e n t a l l y HSVtransformed cells was mapped, it was found that only certain restriction endonuclease-derived subgenomic fragments were consistently expressed in each o f the experimentally transformed cell lines. This suggests that a certain portion o f the herpesvirus genome may be responsible for the induction and/or maintenance o f the neoplastic state. Further evidence to support this observation comes from the fact that it is possible
786
to transform cells and induce tumors in nude mice, using these same subgenomic fragments. O f particular relevance to this discussion is the fact that these same subgenomic fragments (the putative transforming fragments o f the HSV genome) are found in approximately 40 per cent of cervical neoplasms, e H U M A N PAPILLOMAVIRUS
The papillomaviruses, like the herpesviruses, contain DNA. They produce local infections o f the epithelium lining skin and mucous membranes. These infections are usually not systemic, but they usually manifest as warty, papillary, condyloma-like lesions. Recently, colposcopic and cytologic studies have focused attention on the high incidence of condylomatous lesions (both warty and flat) of the cervix in sexually active women, necessitating re-evaluation of many cervical lesions. Most investigators who have restudied their material have reinterpreted many lesions previously interpreted as cervical intraepithelial neoplasias g r a d e s 1 a n d 2 (mild to m o d e r a t e dysplasia) as flat condylomas. 7's A flat condyloma (koilocytotic atypia) cannot be seen with the naked eye but is usually detected by standard cytologic, histologic, or colposcopic techniques. Cytologically and histologically, koilocytotic cells with their characteristic cytoplasmic perinuclear cavitation and pyknotic, d e g e n e r a t e d nuclei are pathognomonic o f cervical condylomas. Approximately one half of these condylomas contain papilloma viral antigens demonstrable by the immunoperoxidase technique, and the virus can be identified by electron microscopy in the superficial cells of a high percentage of the lesionsY ''~ Approximately 10 to 25 per cent of fiat condylomas contain enough atypia to have been classified in the past as cervical intraepitheliaI neoplasia grade 1 or 2?' The distribution of these lesions is associated with age, and they have morphologic features and p o l y p l o i d - a n e u p l o i d n u c l e a r DNA values intermediate between those o f condylomas and cervical intraepithelial neoplasia grade 3. T h e fact that m a n y a u t h o r s who have reevaluated their material have reclassified their CIN-I lesions as fiat condylomas with atypia suggests that this lesion is significant and may be the earliest precursor of cervical cancer. The literature contains well-documented cases of transformation o f genital warts into intraepithelial or invasive squamous cell carcinomas, further suggesting that HPV may be a significant carcinogen. Finally, supporting the concept that HPV may be important in the induction of some human cancers is the observation that 34 per cent of patients with epidermodysplasia verruciformis, a disease believed to be related to HPV infections, develop carcinoma in situ and occasionally squamous cell cancers from flat warts. 12 T h e average progression time is approximately 24 years. At present, many laboratories are trying to apply the technique o f in-situ molecular hybridization
VIRUSES IN CERVICAL NEOPLASIA--FENoGL:O utilizing the papillomavirus D N A as a p r o b e to determine whether HPV may assume a nonproductive infectious f o r m in which only certain s u b g e n o m i c f r a g m e n t s o f the viral D N A are e x p r e s s e d in the replicating portion o f the cervical epithelium. P r e s u m ably, as with H S V , partial H P V D N A f r a g m e n t s , which m i g h t i n d u c e m a l i g n a n t t r a n s f o r m a t i o n o f cells, will be detectable. CERVICAL CARCINOGENESIS It is clear that cervical n e o p l a s m s arise in a welld e f i n e d n a r r o w a r e a o f the cervix, the susceptible epit h e l i u m b e i n g located in the t r a n s f o r m a t i o n zone. T h i s t r a n s f o r m a t i o n zone actively proliferates d u r i n g fetal d e v e l o p m e n t , at the time o f the m e n a r c h e , a n d immediately following the first p r e g n a n c y . T h e proliferating i m m a t u r e s q u a m o u s epithelium a p p e a r s to be t h e m o s t s u s c e p t i b l e cell p o p u l a t i o n f o r c a r cinogenic influences. At present, we have the m e t h odology to a d d r e s s several issues raised by these observations in q u a n t i f i a b l e b i o c h e m i c a l t e r m s . T h e unique sensitivity o f the i m m a t u r e s q u a m o u s e p i t h e lium in the f o r m i n g o r r e m o d e l i n g t r a n s f o r m a t i o n zone is subject to analysis. S o m e answers m a y c o m e f r o m studies o f the s t r u c t u r e o f the cell m e m b r a n e s , l o o k i n g f o r b i n d i n g sites ( r e c e p t o r s ) f o r v i r u s e s , chemicals, a n d o t h e r p o t e n t i a l o n c o g e n i c a g e n t s . S i m i l a r l y , with t h e t e c h n i q u e s o f m o l e c u l a r hybridization a n d genetic e n g i n e e r i n g , one can begin to dissect the g e n o m e s o f viruses i m p l i c a t e d in the genesis o f cervical c a r c i n o m a to identify those portions o f the virus that a p p e a r to be responsible for the induction a n d m a i n t e n a n c e o f the neoplastic state a n d to assess w h e t h e r these are, in fact, present in cervical neoplasia o r its p r e c u r s e r s . At present, t h e r e are s t r o n g associations b e t w e e n cervical neoplasia and H P V a n d HSV-2, but t h e r e is no conclusive p r o o f that these viruses, either alone or in c o m b i n a t i o n , cause cervical c a r c i n o m a . Both have d e m o n s t r a b l e o n c o g e n i c p r o p e r t i e s in e x p e r i m e n t a l systems, but that they definitely t r a n s f o r m cervical epithelial cells into c a r c i n o m a is u n p r o v e d . T h e m e c h a n i s m s by which they act are unclear but are b e i n g extensively evaluated at the p r e s e n t time. Certainly, ill-defined genetic factors m a y m o d i f y whate v e r oncogenic p r o p e r t i e s these two wruses have. Similarly, i m p a i r e d i m m u n e defenses m a y have an
i m p o r t a n t role in potentially virally i n d u c e d cervical neoplasms. In assessing the p a t h o g e n e s i s o f cervical neoplasia, it is not necessary to view any single a g e n t as the sole factor responsible for the induction a n d maintenance o f the neoplastic state. N o r is it necessary that the same factors be o p e r a t i v e in each patient. Und o u b t e d l y , m a n y f a c t o r s a r e i n v o l v e d in t h e pathogenesis o f b o t h cervical intraepithelial neoplasia a n d invasive cervical cancer. S o m e factors m a y be imp o r t a n t in the i n i t i a t i o n o f the n e o p l a s t i c state, whereas others m a y be i m p o r t a n t in its p r o g r e s s i o n to invasive cancer.
REFERENCES 1. Fenoglio CM, Ferenczy A: Etiologic factors in cervical neoplasia. Semin Oncol, in press 2. Naib ZM, Nahmias AJ,Josey WE: Cytology and histopathology of cervical herpes simplex infection. Cancer 19:1206, 1966 3. Adam E, Kaufman RH, Melnick JL, et al: Seroepidemiologic studies of herpesvirus type 2 and carcinoma of the cervix. IV. Dysplasia and carcinoma in situ, Am J Epidemiol 98:77, 1973 4. Kessler OI, Aurelian I: Uterine cervix. In Schottenfeld D (ed): Cancer Epidemiotogy and Prevention. Springfield, 111., Charles C Thomas, 1975, p 263 5. Rawls WE, Gardner HL, Kaufman RL: Antibodies to genital herpesvirus in patients with carcinoma of the cervix. Am J Obstet Gynecol 107:710, 1970 6. Fenoglio CM, Galloway DA, Crum CP, et al: Herpes simplex virus and cervical neoplasia. In Fenoglio CM, Wolff M (eds): Progress in Surgical Pathology, vol 4. New York, Masson Publishing USA, 1981, p 45 7. Meisels A, Roy M, Fortier M, et al: Human papilloma virus (HPV) infection of the cervix: tile atypical condyloma. Acta Cytol 25:7, 1981 8. Ferenczy A, Braun L, Shah KV: Human papilloma virus (HPV) in condylomatous lesions of cervix: a comparative ultrastructural and immunohistochemical study. Am J Surg Pathol 5:661, 1981 9. Della Torre G, Pilotti S, de Palo G, et al: Viral particles in cervical condylomatous lesions. Tnmori 64:549, 1978 10. zur Hausen H, Meinhof W, Schreiber W, et al: Attempts to detect virus-specific DNA sequences in human tumors. I. Nucleic acid hybridizations with complementary RNA of human wart virus. IntJ Cancer 13:650, 1974 11. Pilotti S, Rilke F, De Palo G, et ah Condylomata of the uterine cervix and koilocytosisof cervical intraepithelial neoplasia. J Clin Pathol 34:532, 1981 12. Pfister H, Nurnberger F, Gissmann L, et al: Characterization of a human papillomavirus from epidermodysplasia verruciformis lesions of a patient from Upper Volta. Int J Cancer 27:645, 1981
787
V O L U M E 13 NUMBER 9
September 1982
Current Topics VIRUSES IN-THE PATHOGENESIS OF C E R V I C A L N E O P L A S I A : AN UPDATE Cecilia M. Fenoglio, MD* For decades the epidemiologic factors associated with cervical neoplasia have been extensively studied, leading to the identification of clearly delineated risk factors? The weight of scientific evidence suggests that the oncogenic agents, whatever they are, are venereally transmitted and that a young age at first intercourse is the single most important epidemiologic variable in its development. The importance o f sexual factors in the genesis of cervical neoplasia is not a new concept; it was most dramatically brought out in the now classic research o f Gagnon, who studied 13,000 Canadian nuns and found no cases of cervical cancer among them. These findings have been confirmed by other studies of religious and nonreligious populations, t A m o n g the postulated agents are chemicals, hormones, sperm, radiation, and infectious agents. Any of these could, potentially, affect the cervix oncogenically by interacting with the immature squamous epithelium in the cervical transformation zone. However, since the epidemiologic observations clearly indicate that cervical neoplasia has many o f the attributes of a communicable disease, leading contenders for an etiologic agent fall into the category o f infectious diseases. Numerous viruses, bacteria, chlamydiae, mycoplasmas, parasites, and fungi are known to be venereally transmitted. O f these, certain organisms have had their period in the investigational limelight. Currently, viruses occupy this spot, since they have a documented ability to cause tumors in animals. They not only are capable o f initiating the neoplastic alterAccepted for publicationJanuary 3, 1982. * Professor of Pathology,Collegeof Physiciansand Surgeons, Columbia University,New York, NY 10032. Addresscorrespondenceand reprint requeststo Dr. Fenoglio.
ations but also are responsible for transmitting new genetic information to the infected cells, which provides for the maintenance of the neoplastic state. With respect to cervical neoplasia, only two viruses are seriously considered potential cervical carcinogens. These are herpes simplex virus type 2 (HSV-2) and the human papillomavirus (HPV). Both viruses are known to produce tumors in animal systems, and both are known to be venereally transmitted. HERPES SIMPLEX VIRUS
When herpesviruses infect cells, they attach themselves to the cell surface and insert their genetic material into the host cell. Once inside, they may rep: licate to produce whole viral particles in a process known as an acute productive infection. Such infections are frequently cytolytic and may cause the death o f the infected cell. If only a part of the genetic material is replicated in nonproductive infections, whole virus is not produced. The cell does not die, enabling each daughter cell to carry its own genetic material plus that of the infecting virus each time it divides. HSV-2 infections primarily involve persons beyond the age of puberty, predominate in sexually active adults of both sexes, and are among the venereally transmitted disorders. In the 1960s Naib et al. 2 noted that there was an increased incidence of cervical neoplasia in patients with cytologically detectable herpetic cervicitis. This observation provided the stimulus for n u m e r o u s seroepidemiologic studies, which have validated this association. Nearly all these investigations have taken the form of case-controlled studies in which the prevalence of HSV-2 antibodies and/or antigens among women with cervical neoplasia
0046-8177182/0900/0785 $00.60 9 W. B. Saunders Co.
785
HUMAN PATHOLOGY--VOLUME 13, NUMBER 9 September1982 were compared with that among women without neoplastic lesions, in a control group. Because marital status and coital practices often were not considered in the selection of the control groups, it has been stated that cervical neoplasia and herpes infections are merely covariables o f sexual activity. An argument against the hypothesis that carcinoma of the cervix and herpesvirus infections are merely covariables o f sexual promiscuity was reviewed by Adam et al, 3 who found that the incidence of antibodies and the titers to the virus were higher in nonpromiscuous cancer patients than in nonpromiscuous controls. Further evidence against the covariability hypothesis was presented by Kessler and AurelianJ who reported a similar incidence rate for syphilis and trichomonas vaginitis among patients with cervical cancer and among controls. They reasoned that if cervical cancer were directly related to sexual promiscuity, one would expect a higher rate of all venereal infections among patients with cervical neoplasia. It is possible that neoplastic changes alter the susceptibility of the epithelium to subsequent viral infections and that HSV infections may follow, rather than precede, the neoplastic state. However, the data o f Rawls et al. 5 suggest that this does not occur. T h e prevalence of HSV antibodies among women with carcinoma in situ did not increase with age as would have been expected if an increased susceptibility for HSV infection did occur. 5 The first clue that cells transformed by herpesviruses contain viral DNA sequences came from the identification of virus-specific antigens on experimentally derived neoplastic cells. Herpes simplex virus antigens have also been identified on cells from cervical neoplasms. 6 More direct evidence that HSVtransformed cells retain viral information comes from the identification o f viral-specific nucleic acids, utilizing the techniques of molecular hybridization. This technology can be applied to histologic specimens in the technique known as in-situ molecular hybridization. By means o f this technique and a probe to whole HSV-2, sequences complementary to the HSV genome have been found in cervical neoplasms. A battery o f restriction endonuclease-derived subgenomic fragments can be generated from the HSV genome to distinguish between productive and nonproductive infections. Since a productive infection is associated with the formation o f complete viral particles, expression of the entire battery of subgenomic probes, i.e., the total genomic expression, Would be expected. In contrast, nonproductively infected cells should not be associated with the expression of all the subgenomic fragments. When the expression of these s u b g e n o m i c f r a g m e n t s in e x p e r i m e n t a l l y HSVtransformed cells was mapped, it was found that only certain restriction endonuclease-derived subgenomic fragments were consistently expressed in each o f the experimentally transformed cell lines. This suggests that a certain portion o f the herpesvirus genome may be responsible for the induction and/or maintenance o f the neoplastic state. Further evidence to support this observation comes from the fact that it is possible
786
to transform cells and induce tumors in nude mice, using these same subgenomic fragments. O f particular relevance to this discussion is the fact that these same subgenomic fragments (the putative transforming fragments o f the HSV genome) are found in approximately 40 per cent of cervical neoplasms, e H U M A N PAPILLOMAVIRUS
The papillomaviruses, like the herpesviruses, contain DNA. They produce local infections o f the epithelium lining skin and mucous membranes. These infections are usually not systemic, but they usually manifest as warty, papillary, condyloma-like lesions. Recently, colposcopic and cytologic studies have focused attention on the high incidence of condylomatous lesions (both warty and flat) of the cervix in sexually active women, necessitating re-evaluation of many cervical lesions. Most investigators who have restudied their material have reinterpreted many lesions previously interpreted as cervical intraepithelial neoplasias g r a d e s 1 a n d 2 (mild to m o d e r a t e dysplasia) as flat condylomas. 7's A flat condyloma (koilocytotic atypia) cannot be seen with the naked eye but is usually detected by standard cytologic, histologic, or colposcopic techniques. Cytologically and histologically, koilocytotic cells with their characteristic cytoplasmic perinuclear cavitation and pyknotic, d e g e n e r a t e d nuclei are pathognomonic o f cervical condylomas. Approximately one half of these condylomas contain papilloma viral antigens demonstrable by the immunoperoxidase technique, and the virus can be identified by electron microscopy in the superficial cells of a high percentage of the lesionsY ''~ Approximately 10 to 25 per cent of fiat condylomas contain enough atypia to have been classified in the past as cervical intraepitheliaI neoplasia grade 1 or 2?' The distribution of these lesions is associated with age, and they have morphologic features and p o l y p l o i d - a n e u p l o i d n u c l e a r DNA values intermediate between those o f condylomas and cervical intraepithelial neoplasia grade 3. T h e fact that m a n y a u t h o r s who have reevaluated their material have reclassified their CIN-I lesions as fiat condylomas with atypia suggests that this lesion is significant and may be the earliest precursor of cervical cancer. The literature contains well-documented cases of transformation o f genital warts into intraepithelial or invasive squamous cell carcinomas, further suggesting that HPV may be a significant carcinogen. Finally, supporting the concept that HPV may be important in the induction of some human cancers is the observation that 34 per cent of patients with epidermodysplasia verruciformis, a disease believed to be related to HPV infections, develop carcinoma in situ and occasionally squamous cell cancers from flat warts. 12 T h e average progression time is approximately 24 years. At present, many laboratories are trying to apply the technique o f in-situ molecular hybridization
VIRUSES IN CERVICAL NEOPLASIA--FENoGL:O utilizing the papillomavirus D N A as a p r o b e to determine whether HPV may assume a nonproductive infectious f o r m in which only certain s u b g e n o m i c f r a g m e n t s o f the viral D N A are e x p r e s s e d in the replicating portion o f the cervical epithelium. P r e s u m ably, as with H S V , partial H P V D N A f r a g m e n t s , which m i g h t i n d u c e m a l i g n a n t t r a n s f o r m a t i o n o f cells, will be detectable. CERVICAL CARCINOGENESIS It is clear that cervical n e o p l a s m s arise in a welld e f i n e d n a r r o w a r e a o f the cervix, the susceptible epit h e l i u m b e i n g located in the t r a n s f o r m a t i o n zone. T h i s t r a n s f o r m a t i o n zone actively proliferates d u r i n g fetal d e v e l o p m e n t , at the time o f the m e n a r c h e , a n d immediately following the first p r e g n a n c y . T h e proliferating i m m a t u r e s q u a m o u s epithelium a p p e a r s to be t h e m o s t s u s c e p t i b l e cell p o p u l a t i o n f o r c a r cinogenic influences. At present, we have the m e t h odology to a d d r e s s several issues raised by these observations in q u a n t i f i a b l e b i o c h e m i c a l t e r m s . T h e unique sensitivity o f the i m m a t u r e s q u a m o u s e p i t h e lium in the f o r m i n g o r r e m o d e l i n g t r a n s f o r m a t i o n zone is subject to analysis. S o m e answers m a y c o m e f r o m studies o f the s t r u c t u r e o f the cell m e m b r a n e s , l o o k i n g f o r b i n d i n g sites ( r e c e p t o r s ) f o r v i r u s e s , chemicals, a n d o t h e r p o t e n t i a l o n c o g e n i c a g e n t s . S i m i l a r l y , with t h e t e c h n i q u e s o f m o l e c u l a r hybridization a n d genetic e n g i n e e r i n g , one can begin to dissect the g e n o m e s o f viruses i m p l i c a t e d in the genesis o f cervical c a r c i n o m a to identify those portions o f the virus that a p p e a r to be responsible for the induction a n d m a i n t e n a n c e o f the neoplastic state a n d to assess w h e t h e r these are, in fact, present in cervical neoplasia o r its p r e c u r s e r s . At present, t h e r e are s t r o n g associations b e t w e e n cervical neoplasia and H P V a n d HSV-2, but t h e r e is no conclusive p r o o f that these viruses, either alone or in c o m b i n a t i o n , cause cervical c a r c i n o m a . Both have d e m o n s t r a b l e o n c o g e n i c p r o p e r t i e s in e x p e r i m e n t a l systems, but that they definitely t r a n s f o r m cervical epithelial cells into c a r c i n o m a is u n p r o v e d . T h e m e c h a n i s m s by which they act are unclear but are b e i n g extensively evaluated at the p r e s e n t time. Certainly, ill-defined genetic factors m a y m o d i f y whate v e r oncogenic p r o p e r t i e s these two wruses have. Similarly, i m p a i r e d i m m u n e defenses m a y have an
i m p o r t a n t role in potentially virally i n d u c e d cervical neoplasms. In assessing the p a t h o g e n e s i s o f cervical neoplasia, it is not necessary to view any single a g e n t as the sole factor responsible for the induction a n d maintenance o f the neoplastic state. N o r is it necessary that the same factors be o p e r a t i v e in each patient. Und o u b t e d l y , m a n y f a c t o r s a r e i n v o l v e d in t h e pathogenesis o f b o t h cervical intraepithelial neoplasia a n d invasive cervical cancer. S o m e factors m a y be imp o r t a n t in the i n i t i a t i o n o f the n e o p l a s t i c state, whereas others m a y be i m p o r t a n t in its p r o g r e s s i o n to invasive cancer.
REFERENCES 1. Fenoglio CM, Ferenczy A: Etiologic factors in cervical neoplasia. Semin Oncol, in press 2. Naib ZM, Nahmias AJ,Josey WE: Cytology and histopathology of cervical herpes simplex infection. Cancer 19:1206, 1966 3. Adam E, Kaufman RH, Melnick JL, et al: Seroepidemiologic studies of herpesvirus type 2 and carcinoma of the cervix. IV. Dysplasia and carcinoma in situ, Am J Epidemiol 98:77, 1973 4. Kessler OI, Aurelian I: Uterine cervix. In Schottenfeld D (ed): Cancer Epidemiotogy and Prevention. Springfield, 111., Charles C Thomas, 1975, p 263 5. Rawls WE, Gardner HL, Kaufman RL: Antibodies to genital herpesvirus in patients with carcinoma of the cervix. Am J Obstet Gynecol 107:710, 1970 6. Fenoglio CM, Galloway DA, Crum CP, et al: Herpes simplex virus and cervical neoplasia. In Fenoglio CM, Wolff M (eds): Progress in Surgical Pathology, vol 4. New York, Masson Publishing USA, 1981, p 45 7. Meisels A, Roy M, Fortier M, et al: Human papilloma virus (HPV) infection of the cervix: tile atypical condyloma. Acta Cytol 25:7, 1981 8. Ferenczy A, Braun L, Shah KV: Human papilloma virus (HPV) in condylomatous lesions of cervix: a comparative ultrastructural and immunohistochemical study. Am J Surg Pathol 5:661, 1981 9. Della Torre G, Pilotti S, de Palo G, et al: Viral particles in cervical condylomatous lesions. Tnmori 64:549, 1978 10. zur Hausen H, Meinhof W, Schreiber W, et al: Attempts to detect virus-specific DNA sequences in human tumors. I. Nucleic acid hybridizations with complementary RNA of human wart virus. IntJ Cancer 13:650, 1974 11. Pilotti S, Rilke F, De Palo G, et ah Condylomata of the uterine cervix and koilocytosisof cervical intraepithelial neoplasia. J Clin Pathol 34:532, 1981 12. Pfister H, Nurnberger F, Gissmann L, et al: Characterization of a human papillomavirus from epidermodysplasia verruciformis lesions of a patient from Upper Volta. Int J Cancer 27:645, 1981
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