Human Cervical Cancer As a Venereal Disease

[CANCER RESEARCH 36, 783-791, February 1976]

Human Cervical Cancer as a Venereal Disease

Irving I. Kessler

Department of Epidemiology, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland 21205

Summary In this paper, evidence on the venereal nature of HSV-2 infections in man will be reviewed in the light of existing The operation of venereal factors in human cervical can- knowledge on other, more established, venereal diseases. cer is suggested by demographic and epidemiological data. Demographic and epidemiological data consistent with the Recent evidence supporting the genital herpesvirus hypoth- notion that human cervical cancer behaves like a venereal esis is consistent with this notion. A controlled epidemiolog- disease will be cited. Published data on the possible role of ical investigation has been undertaken on the role of the the male in cervical carcinogenesis will be evaluated, with male coital partner in cervical carcinogenesis. An answer is special reference to the herpesvirus hypothesis. Finally, sought to the question, "Is the risk of developing cervical preliminary findings from an ongoing investigation will be cancer increased among the wives of men who at some presented in support of a model of human cervical cancer other time were married to other women who developed as a venereal disease. cervical cancer?" With one-quarter of the study completed, a total of 14 marital clusters have been identified in which 2 HSV-2 as a Venereal Disease or more wives of the same men developed cervical carci- A wide variety of diseases are now regarded as venereal, noma. The expected number of such clusters is estimated i.e., "due to or propagated by sexual intercourse" (16). to be 4. These include not only spirochetal and bacterial diseases (syphilis, gonorrhea, chancroid, and granuloma inguinale) Introduction but also a number of viral, protozoal, fungal, and parasitic conditions. The latter consist of herpes simplex, lympho- Prevention or control of a disease such as human cervical granuloma venereum, condylomata acuminata, trichomo- cancer requires intervention at the level of 1 or more ele- niasis, moniliasis, tinea cruris, scabies, and pediculosis, ments in its natural history: (a) the etiological agent; (b) the among others (102). host at risk; (c) the disease itself; and (d) the environment in The relatively more serious venereal diseases, such as which these elements interact. syphilis and gonorrhea, share a number of attributes. They At the present time, cervical cancer control activities are usually occur among sexually active young adults who com- directed primarily at the human host and at the disease. prise the principal reservoir of infection through a venereal Women, especially those at increased risk, are encouraged mode of transmission. The agent has a relatively short incu- to undergo periodic cytological screening for the detection bation period, and immunity to reinfection is absent or of the neoplasm or one of its precursors. In addition, effec- insubstantial. The considerable individual variation in sus- tive therapeutic modalities are now available for the treat- ceptibility to infection may be related to characteristics of ment of both invasive and intraepithelial carcinoma of the the agent, such as virulence, or to characteristics of the cervix. On the other hand, relatively less has been accom- host, including genetic, constitutional, hormonal, or other plished thus far in identifying the specific etiological agent factors. or agents of the disease and in developing effective meth- The true incidence and prevalence of these diseases are ods for modifying those environmental factors that operate unknown because of the difficulties in case ascertainment to the advantage of the neoplasm. and because of the relatively high proportions of asympto- In recent years, a consistent body of evidence has accu- matic cases. Despite this, the numbers and rates at which mulated that suggests a possible etiological role for the both these diseases have been reported in recent years genital herpesvirus, HSV-2, 2 in human cervical cancer. In indicate a marked increase in their relative frequency (7, 26, view of this, it may be useful to review the known or sus- 31, 42, 97). As will become evident below, genital herpetic pected mechanisms of HSV-2 transmission in man and to infections share many of these characteristics. speculate about cervical cancer prevention in terms of the Early Studies. It is not possible to identify with certainty environment in which the agent, host, and disease interact. the study that first demonstrated the venereal nature of HSV-2 infections in man. In his classical description of ' Presented at the symposium "Immunological Control of Virus-associated genital herpes, published in 1736, Jean Astruc not only Tumors in Man: Prospects and Problems," April 7 to 9, 1975, Bethesda, Md. classified the condition as a venereal disease but also noted These studies were supported in part by Grant CA 11489 from the National its increased frequency among practicing homosexuals Cancer Institute and by Faculty Research Award PRA-112 of the American Cancer Society. (36). Roller, in 1869, was probably the first investigator to 2 The abbreviation used is: HSV-2, herpes simplex virus type 2. describe a specific venereal infection of the uterine cervix

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Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1976 American Association for Cancer Research. I. I. Kessler termed "blennorrhagie," which was regarded by some con- lesions seen aboard a troopship shortly after exposure to temporaries as herpetic in origin (84). Oriental prostitutes. Although the diagnosis of herpes geni- In a paper delivered at a meeting of the American Derma- talis was arrived at by exclusion, the author concluded that tological Association in Newport, R. I., in 1880, Greenough "nearly all of these diseases must result from sexual inter- (29) noted that "the influence of the venereal act as the course." immediate cause of herpes progenitalis has [not] been Inferential Problems. The studies just described, while given the importance that it deserves," although he credited far from conclusive, are not different in kind from most of the French physician Doyon with having previously called the earlier clinical efforts to demonstrate the venereal trans- attention to this problem. He emphasized that, in his prac- mission of such diseases as syphilis and gonorrhea. Even tice, genital herpes was seen only in males, particularly the controlled experimental studies, primarily of gonococ- young adults with histories of other venereal diseases. This cal infections, which have been conducted in human popu- conclusion was challenged in a subsequent paper by the lations are not entirely free of inferential problems, if only German physician, P. G. Unna, who had also attended the because the infections were artificially induced by inocula- Newport meeting. After reviewing earlier inferential evi- tion rather than by sexual intercourse (9, 57). dence from the French literature, Unna assembled the rec- There is an analog in the studies of gonorrhea to the ords of genital herpes infections among patients seen at the previously cited military investigation of herpes by Tylerl Hamburg General Hospital (99). Over a recent 4-year period Holmes et al. (34) observed the occurrence of gonorrhea he was able to identify a total of only 17 males as compared among a large group of naval personnel who admitted to with 423 females who were treated for herpes genitalis in sexual intercourse with a group of women whose preva- the venereal diseases department. He concluded that lence of neisserial infection could be estimated. To account "women are just as susceptible to herpes as men are; there for the relatively low rate of venereal transmission observed is no immunity from herpes for the female sex." (22%), these investigators suggested the possible effects of Clinical Studies. Direct evidence concerning the venereal variations in such parameters as virulence of the agent, transmissibility of genital herpes infections derives from a immunity of the exposed male, sensitivity of the serological number of observational studies on the sexual contacts of tests used, and degree of mechanical exposure, among infected consorts. In many of these studies, clinical diag- others. A quite similar situation may apply to the question of noses of herpetic infections were made in the contacts and, the venereal transmission of HSV-2. sometimes, in the consorts, but serological measurements There are several unique features of HSV-2 that probably or virus isolations were not undertaken (35, 88). In other influence its venereal spread and, in addition, confound investigations, laboratory tests were performed on the con- studies of the same phenomenon. In view of latency, which tacts, the consorts, or both. Measurement of herpes anti- is characteristic of herpetic infections, "it would be of inter- bodies, virus isolations, or cytological diagnosis through est to know whether secondary genital herpes follows the visualization of characteristic multinucleated giant cells in stimulation of a dormant virus left in the tissues after a exfoliate smears were variously used (10, 14, 15, 19, 41, 51, primary infection of the area, or if new infectious herpetic 69, 75, 79, 91, 101). Special attention was usually given to material is introduced via sexual intercourse" (51). In very the temporal relationships between the reported coital expe- few of the clinical studies on the venereal transmission of riences and the subsequent manifestations of genital dis- HSV-2 is there an adequate differentiation between primary ease in contacts and consorts. and secondary (or recurrent) herpetic infections. Thus, the The most impressive clinical evidence on the venereal postcoital manifestations of HSV-2 infections may, in fact, transmission of HSV-2, to date, is to be found in the investi- be venereal (i.e., due directly to the transmission of herpetic gations of Nahmias and Rawls and their respective col- virions) or nonvenereal. The latter, in turn, may be either leagues. Eight female sex contacts of 7 male patients with coitus related (i.e., due to the triggering of a clinical recru- virologically confirmed HSV-2 penile infections were exam- descence by, or associated with, the coital act) or not coitus ined within 1 week of the initial detection of the herpetic related (i.e., triggered by menstruation, hormone imbal- lesions in their consorts (69). Seven of the 8 contacts gave ance, fever, or other stresses unrelated to sexual inter- evidence of a current genital HSV-2 infection of either the course) (73). All such recurrences, both endogenous and vulva or the cervix. Genital herpesvirus was isolated from exogenous, cannot presently be differentiated from one each of these 7 women. another on serological or other grounds. Confounding the Rawsl et al. (79) examined 30 female contacts of 30 males problem is the possibility that other venereal diseases such with clinically diagnosed genital herpes infections from a as gonorrhea may activate latent cervical herpes (6). public venereal disease clinic. HSV-2 was successfully iso- Another consideration, of possible relevance to the her- lated from the penile lesions of 53% of the male patients and pesvirus hypothesis in cervical cancer, stems from the fact from the genital secretions of 33% of their female contacts. that herpetic cervicitis is usually asymptomatic whereas These rates were markedly in excess of the prevalence of penile herpes is an extremely painful and incapacitating, HSV-2 infections in a control group of women from the although self-limited, condition (14). Therefore, while in- same clinic. fected males are extremely unlikely to engage in sexual Another approach to studying the venereal transmission intercourse during a productive herpetic infection, females of genital herpesvirus infections is exemplified by the obser- with active cervical lesions may continue to do so. The vations of Tyler (98) on 200 military patients with penile relevance to cervical cancer risk of sexual intercourse or

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Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1976 American Association for Cancer Research. Cervical Cancer as a Venereal Disease abstention at a time when the cervical epithelium has been in the serum. However, venereal transmission of such infec- compromised by active herpetic lesions is presently un- tions to male monkeys mated with infected females has not known. yet been achieved. The latter, of course, would constitute In their investigation of patients with clinically diagnosed evidence of the highest quality on the venereal transmission primary and recurrent HSV-2 infections, Rawls et al. (79) of HSV-2. successfully isolated virus 1 week or more after the infec- Nonvenereal Herpes. While there seems little doubt that tion from 75% of patients with primary lesions but from only HSV-2 infections are relatively prevalentamong the sexually 15% of those with recurrences. These observations suggest promiscuous, not much has yet been documented on her- that the venereal transmission of HSV-2 is more likely to petic infections among virgins or other sexually inactive occur after an individual's primary infection than during the persons. We are aware of only 1 specific citation in the relatively brief periods of infectiousness following second- literature, namely, the statement by Nahmias et al. (70) to ary recurrences. In other words, the principal reservoir may the effect that they "have found that only one (3%) of 35 consist disproportionately of sexually active (and recently nuns had type 2 antibodies." No additional details concern- infected) teenagers. ing this interesting observation have been published by The effect of changing sexual mores on the patterns of these authors, to our knowledge. venereal transmission of HSV-2 is only now becoming evi- During the past 2 years, we have been conducting a dent. An example is afforded by the apparently increased survey of health and disease among several orders of reli- prevalences of cunnilingus and fellatio which have been gious nuns and their married female siblings. Data sources reported (102). Such practices also open up possibilities of include personal interviews, medical record reviews, exfolia- the venereal transmission of oral herpesviruses which can- tive cytology, and bleeding for serological analysis. A pre- not be distinguished from HSV-2 on clinical or cytological liminary and quite incomplete review of the initial findings grounds alone and which are differentiated imperfectly by some months ago revealed the following prevalence rates of most serological techniques in current use (45, 100). neutralizing antibodies to HSV-2: 58.6% among the nuns That genital herpes is a venereal disease is also sug- and 57.4% among their blood sisters. These findings must gested by clinical studies of prostitutes (18, 29, 63, 99) and be interpreted very cautiously in view of the incomplete data patients seen in venereal disease clinics (6, 37, 38, 48, 69). It upon which they are based. However, they do suggest the is clear from such investigations that the prevalences both possibility of nonvenereal modes of HSV-2 transmission. of clinically manifest disease and of serologically diagnosed This is further substantiated by the complete absence of infection are increased among the sexually promiscuous as trichomonads from the cervical smears of the nuns but not compared with control population groups. from those of their siblings. Animal Models. Evidence from animal models on the That not all genital herpetic lesions should be attributed venereal transmission of HSV-2 is relatively meager. In to venereally transmitted herpesvirus was succinctly put by 1923, Levaditi and Nicolau (52) mated 5 normal mature male Sharlit (88), namely, "1 profoundly trust that none will be so rabbits with 1 female in whom herpetic vaginitis had been ~rash as to challenge the claim of celibacy or to impugn the induced by intravaginal inoculation of herpesvirus re- professions of chastity or fidelity on the prima facie evi- covered from human sources. On the 5th postcoital day, 1 dence of herpes progenitalis." There is, of course, the fact of the 5 males developed a typical herpetic penile lesion. of herpetic genital infections among infants and young chil- Inferences from these results to man are tenuous because dren (49, 68, 89,105). To some extent this is complicated by of the small size of the experiment and, more importantly, the question of transplacental transmission of HSV-2 in the because of the likelihood that the virus was, in fact, an oral newborn (24, 65, 103). Middelkamp et al. (64) reported on type. In 1967, Nahmias et al. (72) mated uninfected male the successful transplacental transmission of herpes sim- mice with females in whom vaginal HSV-2 infection had plex virus in female rabbits given i.v. injections with high been produced by direct inoculation of undiluted virus with concentrations of the virus. While this work antedated the cotton pellets. They reported that "sexual transmission of development of techniques for distinguishing between oral genital infection was demonstrated when uninfected male and genital herpesvirus types, it is likely that an oral virus mice placed in contact with infected females developed type was used by these workers. herpetic penile lesions." Unfortunately, no details on this In any event, the weight of evidence to date suggests that interesting experiment were offered by the authors in the most newborns are infected from active lesions in the mater- cited abstract and, to our knowledge, the details have not nal birth canal rather than hematogenously. Furthermore, been elaborated in published papers. the isolation of HSV-2 from the genital lesions of a 15-year- Nahmias et al. (71) have also reported on the successful old girl with a virginal introitus (1) is instructive. The situa- establishment of an HSV-2 genital infection in female Cebus tion may be analogous with syphilis which generally follows monkeys. Although efforts at infecting rhesus and squirrel a venereal mode of transmission, but which manifests itself monkeys fai led, 10 female Cebus monkeys did develop geni- in endemic nonvenereal forms as well (30). tal infections with a HSV-2 strain recovered from a human female patient. Intravaginal inoculations as performed in Analogy of Cervical Cancer with Venereal Disease their earlier mouse study were followed by the appearance of typical herpetic lesions, successful isolation of the virus, In 1842, Rigoni-Stern (81) speculated that the susceptibil- and demonstration of rising titers of herpesvirus antibodies ity of the uterus to cancer in cloistered sisters and married

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Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1976 American Association for Cancer Research. I. I. Kessler women differed according to "the natural exercise of its against "mixed bacterial infections" of the cervix during functions." His findings on the rarity of cervical cancer coitus. A more direct approach to the relationship between among nuns have since been confirmed by other investiga- cervical and penile cancer was undertaken by Martinez. tors (21-23, 87, 95). Explanations offered for the unusually Utilizing data from the Central Cancer Registry of Puerto low risk of cervical cancer among Jewish women include Rico, this investigator noted an unusually high rate of cervi- their traditional sexual abstinence during the menses, cir- cal cancer among the wives of 889 men diagnosed as hav- cumcision of the male, undefined genetic factors, and re- ing penis cancer (59). A significant correlation between the duced sexual promiscuity (46). death rates from cervical and penile cancer has been re- These populations at low risk stand in marked contrast to ported in Japan (50). Additional evidence on the possible prostitutes and incarcerated women who may experience a role of the male coital partner in cervical carcinogenesis will 4- to 6-fold higher rate of cervical cancer than do other be discussed subsequently. females (2, 43, 66, 76). In general, cervical cancer risk Associated Venereal Diseases. That women with cervi- appears to vary inversely with socioeconomic class, how- cal cancer are more likely than expected to have syphilis ever defined (17, 56). has been known for many years (53). During the 1950's at Coital and Marital Factors. The data just cited on popula- least 5 epidemiological studies yielded information on the tion groups at high and low risk of cervical cancer are prevalence of syphilis among cervical cancer patients (40, consistent with a fundamental relationship of the disease 55, 60, 83, 104). A positive association between the 2 dis- with coital or venereal factors. Over the past 2 decades a eases was consistently noted, but a more detailed examina- number of epidemiological studies have been directed at tion of the data compelled one of the investigators "to the possible etiological roles of coitus, marriage, and preg- assume the existence of a particularly potent carcinogenic nancy in cervical neoplasia. The findings are consistent factor among prostitutes--a factor which has no relation to with the operation of coital determinants in this disease. syphilis" (83). Unfortunately, this work antedated the her- Mortality from cervical cancer is increased among the mar- pesvirus hypothesis, and one may only speculate on the ried and decreased among the never married of all ages extent to which HSV-2 might have constituted the hypothe- (54). More importantly, cervical cancer incidence conforms sized carcinogen. to the same pattern (17, 32, 44). Further evidence on the venereal nature of cervical can- In addition to mortality and incidence surveys, a number cer comes from the analysis of Beral (8) who compared of controlled epidemiological investigations have been de- mortality patterns for cancer of the uterine cervix with signed specifically to explore coital, marital, and parity fac- trends in incidence of syphilis and gonorrhea in the United tors in cervical cancer by means of personal interviews with Kingdom. She noted "striking associations between the cases and controls. Despite differences in definitions and temporal, social class, occupational and geographic distri- specific parameters used, a positive association of cervical butions of these diseases." These data suggest that expo- cancer with coitus and marriage has been repeatedly dem- sure to sexually transmitted factors is an important determi- onstrated. Mean age at 1st coitus is younger and the propor- nant of cervical cancer. tion initiating coitus early is greater among cervical cancer Cytologists are also in agreement that trichomoniasis is cases than among controls. These cases also tend to have relatively more prevalent among women with cervical dys- had more coital partners on the average than other women. plasia and carcinoma (13, 62). However, it is rather gener- Furthermore, the proportion of cervical cancer cases deny- ally accepted today that the associations of both trichomo- ing coitus is essentially zero, while among controls it is niasis and syphilis with cervical cancer are secondary, re- small but definite. sulting from the relationship of each to sexual behavior. The relationships of marital variables with cervical cancer The observed relationships of cervical cancer to coital are equally consistent. Women who develop cervical cancer practice, circumcision, syphilis, prostitution, and low socio- are less likely to remain unmarried, they tend to marry for economic class led a number of investigators to suggest the the 1st time at a younger age, and they are more likely to possibility of a venereally transmitted viral etiology for this have had several marital partners than other women do. Age neoplasm (5, 76, 85). Rawls eta/. (80) succeeded in isolating at 1st coitus appears to be more important than age at 1st HSV-2 from 4 smegma specimens of young male venereal marriage in differentiating between cervical cancer patients disease clinic patients. Naib eta/. (74) observed the develop- and controls. Another risk factor that implicates venereal ment of cervical anaplasia (carcinoma or squamous atypia) elements in the disease is extramarital sexual practice by in 23.7% of biopsied cervices giving cytological evidence of either the patient or her spouse (58, 78). Associations of active herpetic infection. cervical cancer with pregnancy, in large measure, appear to At about the same time, a series of seroepidemiological be secondary to the marital or coital determinants. These studies involving the determination of neutralizing antibod- relationships have been discussed more fully elsewhere ies to HSV-2 in groups of women with and without cervical (45, 46, 58, 85, 86, 94). neoplasia were undertaken. In spite of the diversity of these Penile Factors. Inferences on cervical cancer as a vene- studies, a positive association between cervical cancer and real disease are strengthened by considerations of penile HSV-2 antibodies was evident (45). In more recent years, factors. In 1936, Handley (33) sought to relate the immunity Aurelian eta/. (4) have identified a tumor-specific antigen, of Jewish males to penile carcinoma to the decreased risk of AG-4, which is present in nearly all patients with cervical cervical cancer among Jewish females. He attributed this to cancer, disappears following effective therapy, and reap- the practice of circumcision and the resulting protection pears if the cancer recurs. It is also absent in most controls

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Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1976 American Association for Cancer Research. Cervical Cancer as a Venereal Disease and in two-thirds of patients with dysplasia. Data associat- HSV-2, an alternative theory consistent with a male role may ing HSV-2 with cervical cancer have been summarized in a also be cited. Coppleson and Reid (12) have postulated that recent paper and need not be further elaborated here (3). malignant transformations of the cervix are most likely to Additional findings concerning the specific role of the male occur when the epithelium is actively undergoing squa- coital partner will be discussed below. mous metaplasia, such as in early adolescence and at 1st pregnancy. They suggest that DNA viruses might be involved but also that the spermatozoa themselves may be Male Role in Cervical Carcinogenesis mutagenic in particular circumstances. Elaborating on their argument, Singer (90) hypothesizes that "the presence of As noted above, smegmal specimens of 4 young males in an oestral-type mucus for long periods during the immedi- a venereal disease clinic yielded HSV-2. All 4 had penile ate post menarchial era--a period associated predomi- herpetic lesions. This suggests a male role, although the nantly with anovulation--provides an avenue for the facili- virus could not be isolated from the smegma of the hus- tated entry of a potential mutagen by virtue of its open bands of 22 women with cervical cancer (80). That males channel configuration." The likeliest candidate for such a may serve as reservoir of HSV-2 is also suggested by the mutagen, according to Singer, is the spermatozoon, which data of Centifanto et al. (11) who isolated the virus from the has far more DNA than the genital herpesvirus does. genitourinary specimens of 15% of 190 male patients seen at a urology clinic. None of the subjects had a previous known history of genital herpes (11). Successful isolations Ongoing Study of the Male Role in Cervical Cancer were obtained from the prostate, the vas deferens, and the urethra. Others have also reported on successful HSV-2 Since 1973, we have been conducting an epidemiological isolations from urethral discharges of men with nonspecific study of the role of the male in cervical carcinogenesis. The urethritis attending venereal disease clinics (27, 39). On the method involves direct observations on 2 large groups of other hand, Traub et al. (96) were unable to isolate any virus women: 1 group married to men who, at some other time, from 144 cultured vas deferens specimens of patients un- had wives who developed cervical cancer, and a 2nd group dergoing vasectomy. These findings suggest that, if the married to men without such histories. The study seeks to male is the reservoir of herpetic infections, only certain answer the basic question, "Is the risk of developing cervi- regions of the genitourinary tract are involved. cal cancer increased among the wives of men who, at some For selected males to serve as asymptomatic carriers of other time in their lives, were married to other women who HSV-2, they would most likely have to experience chronic developed cervical cancer?" infections rather than latent infections of the genitourinary The study begins with the identification of a large cohort tract. The reason is that, in latent herpetic infections, viral of women who had pathologically confirmed epidermoid replication (and, therefore, viral isolation) does not occur carcinoma of the uterine cervix during the past 20 years. except during the relatively brief periods of clinical recru- The husbands of these women are investigated to the extent descence. However, because clinically symptomatic her- of identifying their previous and subsequent wives ("case" petic lesions of the penis are extremely painful, venereal wives). A random sample of "control" wives, similar to the transmission of the agent through sexual intercourse would "case" wives in demographic and marital characteristics is rarely, if ever, take place. Therefore, it is the asymptomatic then selected. males with chronic low-grade herpetic infections of the The cohorts of "case" and "control" wives are traced genitourinary tract who are the more likely carriers and prospectively to death or survival as of a recent point in transmitters of the putative carcinogen. time. The ultimate risk of cervical neoplasia among the 2 Proceeding with this line of reasoning, one might specu- cohorts is ascertained by interview, medical record review, late that the coital partners of women destined to develop and exfoliative cytological screening by means of a self- cervical cancer would characteristically suffer from low- administered irrigation pipet. Cervical scrapings under di- grade chronic herpetic genitourinary tract infections, rect visualization are obtained from all women with nonnor- whereas their consorts would undergo primary infection mal irrigation findings. This approach affords a direct epide- leading to the latent state which, on biochemical grounds, miological test of the role of any venereally transmitted male is potentially oncogenic (82). In turn, the male partners factor in cervical cancer, whether viral, chemical, or other- themselves would most likely have been infected by females wise. with chronic herpetic infections, because the proportion of To date, 4178 probands with cervical cancer have been women at any given time with active primary infections is identified, and their histopathological diagnoses have been probably negligible. confirmed. A total of 726 husbands of these probands have Mention should also be made of 2 studies in which HSV-2 been studied and 858 "other" wives ascertained, of which was isolated from the urinary sediment of women with 625 have been fully traced, cytologically screened (if alive), known herpetic infections (61,77). Virus recovery was more and their histories of cervical cancer elucidated. Among the frequent among the patients with dysuria than among those latter, 14 "other" wives with cervical cancer have thus far without, suggesting that dysuria associated with genital been detected. This compares with a total of 4 cancers HSV-2 infections may be caused by herpetic cystitis. among the "control" wives. A flow diagram of the prelimi- While, in the main, this discussion of the male role in nary results of the study is presented in Chart 1. It may be cervical carcinogenesis has been oriented primarily toward seen that the prospective approach of this study had made it

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Cervical Cancer as a Venereal Disease - Kessler

Chart 1 Case Probands Treated and Cervix Cancers Found

4,178 I Ptobands Identified

f I~541 I Probands whose Probands whose Probands whose husbands married husbands had 1 husbands ' marital only once and or more "other histories are still single probands wives" unknown. !

Number of "other wives" 1 I 233 I Traced Not yet traced

l -i 1,441 I 72 J Deceased Interviewed Not Yet Refused Interviewed

14 cervical cancers in "other wives": observed

4 cervical cancers in "other wives": e_~_~poctcd possible to ascertain the development of cervical neoplasia putative venereal carcinogen; (d) data from our Yugoslavian among the deceased, the nonrespondents, and the other study suggest that an essential female host characteristic uninterviewed women as well as among those who have for effective venereal transmission is related to steroid hor- been interviewed and examined. mone balance. Among the 350 cervical cancer cases stud- Some characteristics of the 14 marital clusters with cervi- ied, the proportion with any menstrual abnormality (in fre- cal cancer that have been identified to data are presented in quency, duration, quantity, or pain) was significantly less Table 1. Three of the husbands have each been married to 3 than among the 350 demographically similar controls (47). women. While these data are suggestive, their incom- The possible role of estrogenic hormones in cervical neopla- pleteness must be emphasized. They are based on approxi- sia is also suggested from the results of a number of clinical mately one-quarter of the total probands that are to be (20, 92) and laboratory animal (25, 28, 67, 93) studies; (e) a followed. probable condition for this model is that the male role Among the tentative implications of the present findings involve more than a 1-time transmission of the carcinogenic are the following: (a) certain males may venereally transmit factor (e.g., primary HSV-2 infection).'lt is more likely an a risk factor for cervical cancer in women; (b) HSV-2 ap- effect resulting from or exacerbated by multiple coital pears to be the likeliest candidate for such a risk factor; (c) events at periods of life when conditions for donor transmis- because HSV-2 prevalence greatly exceeds cervical cancer sion and host response are optimal; (f) the alternative hy- prevalence, a necessary condition for the herpesvirus hypothesis to explain our present findings, namely, that the pothesis is that certain females be receptive hosts for the male partners in these marital clusters somehow tend to

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Table 1 Details on marital clusters of cervical cancer

Age at marriage Yr of marriage prior to cervical cancer

Wife's age at Married to Married to an- Cluster Wife Husband Wife cervical cancer Pathological diagnosis this husband other Other a

1st 19 18 39 In situ carcinoma 10 3 8 2nd 32 32 38 In situ carcinoma 6

1st 19 19 34 Squamous cell carcinoma 4 9 1 2nd 24 22 3rd 29 24 29 Microinvasive carcinoma 5 DK b DK

I st 20 20 34 Squamous cell carcinoma 14 2nd 42 25 27 In situ carcinoma 2

1 st 22 18 47 Transitional cell carcinoma 28 1 2nd 56 41 43 Squamous cell carcinoma 3 12

I st 18 15 35 In situ carcinoma 2 18 1 2nd 32 26 34 In situ carcinoma 9 7

1 st 25 26 38 Microinvasive carcinoma 12 2nd 40 41 44 In situ carcinoma 3 6

I st DK 15 41 Papillary adenocarcinoma 15 11 2nd DK 39 40 Squamous cell carcinoma 1 DK DK

I st 18 19 35 In situ carcinoma 3 11 DK 2nd 21 36 40 Adenocarcinoma 4 3rd 32 45

I st DK DK 48 Microinvasive carcinoma DK 24 5 2nd 34 31 33 In situ carcinoma 1

10 1st 21 16 25 In situ carcinoma 6 3 2nd 27 19 25 Microinvasive carcinoma 6 3 2

I st 17 16 26 Microinvasive carcinoma 10 2nd 29 35 36 In situ carcinoma 1 11 5

12 1st 24 19 46 In situ carcinoma 4 18 5 2nd 29 30 43 In situ carcinoma 13

13 1st DK DK 49 In situ carcinoma DK DK DK 2nd 60 59 67 In situ carcinoma 9 23 13

14 1st DK DK 2nd 30 32 36 In situ carcinoma 4 3rd 50 50 59 In situ carcinoma 9

" Years lived while unmarried, divorced, or widowed, between the 1st marriage indicated and diagnosis of cervical cancer. b DK, data unavailable at the time of this report.

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