THE CIRCUMCISION REFERENCE LIBRARY
Joseph Menczer MD
Gynecologic Oncology Unit, Department of Obstetrics and Gynecology, Wolfson Medical Center, Holon, Israel Affilated to Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel
Key words: cervical cancer, Jewish women, origin, circumcision, sexual habits, papillomavirus, genetics
IMAJ 2003;5:120–123
Cervical carcinoma is one of the most common gynecologic malignant tumors worldwide and a leading cause of death from genital malignancies in women. One of the most important epidemiologic observations concerning this neoplasm is that the disease is practically non-existent in celibate populations. This was first noticed in the 19th century by Rigonni-Stern [1] of Verona, Italy, regarding Catholic nuns, who are sexually inactive. Gagnon of Quebec [2] subsequently confirmed this observation. He served as a gynecologist in a few Quebec nunneries for several years, and it occurred to him that he had never seen a case of cancer of the cervix in a nun. Among 13,000 deaths of nuns, 12 were recorded as due to corpus cancer. If the same ratio of cervix to corpus cancer exists among nuns as among the general population, there should have been 5 to 8 times as many cervical cancers. Instead there was none. These observations and the subsequent identification of risk factors led to the conclusion that cervical cancer is associated with coitus, and that it shares many characteristics with communicable diseases which follow a venereal mode of transmission. These findings led eventually to the identification towards the end of the 20th century of the human papillomavirus and its major etiologic role in this neoplasm [3–5].
A potentially similarly important observation was published by Braithwaite [6] in The Lancet in 1901. Referring to the experience with cancer of the cervix at the Leeds General Infirmary and at the London Hospital, he stated that it ``was seldom or never met with amongst the numerous Jewesses'' attending these institutions. Although the low incidence among Jewish women has been repeatedly confirmed since then, the reason for it has intrigued and eluded many investigators.
The purpose of the present review is to survey investigations concerning cervical cancer in Jewish women, with special emphasis on attempts made to elucidate the reason for the infrequency of this neoplasm among this population, including the most recent genetic study.
Since the report by Braithwaite [6], numerous publications have verified his observation. Hochman et al. [7] cite 14 individual studies published from 1902 to 1947, all indicating the low frequency of cervical carcinoma in Jewish women. Kennaway, in 1948 [8], published an extensive summary including reports from various cities in the United States and many countries in Europe, all pointing to the infrequency of cervical carcinoma in Jewish women. Many additional reports on the low occurrence of cancer of the cervix in Jewish women were published in the U.S. in the 1950s and 1960s [9,10]. The ratio between Jewish and non-Jewish patients with cancer of the cervix was variously calculated at between 1/9 and 1/5.
After the State of Israel was established in 1948, even more studies were published indicating the low occurrence of cervical cancer in Israeli Jewish women [7,11]. Hochman et al. [7] reviewed all the cervical carcinoma cases registered between 1933 and 1951 at the Hadassah University Hospital in Jerusalem. Since radical operations were not performed in the country at that time, and this was the only hospital that could administer radium therapy, they assumed that the 125 cases they located (only 67 of which were histologically confirmed) represent all the cases diagnosed in Jewish women. They were the first to consider ethnic differences within the Israeli Jewish population. Their study compared three ethnic groups: the Mizrahi (Oriental) – i.e., descendants of those born in Iraq, Syria, Persia, Yemen and North Africa; the Sephardic (Spanish) – descendants of those born in Spain, Portugal and some Mediterranean countries; and the Ashkenazi – descendants of those born in Eastern Europe. But they found no incidence difference between the Ashkenazi and non-Ashkenazi groups. Stewart et al. [12], in the early 1950s, conducted an extensive interview and incidence study of cervical cancer, comparing Israeli Jewish women with Jewish and non-Jewish white women in New York City. In Israel, the interviewers were located in three medical centers in the major cities and were notified of new patients by staff members of hospitals in and around these cities. In addition, cases were located from records of hospital discharges and death certificates. The Central Bureau of Statistics provided an estimate of the female population of Israel, classified by age and country of birth. The incidence rates of cervical cancer in Israeli Jewish women and Jewish women in New York City were virtually identical (4.8 and 4.1 respectively), and strikingly lower than the rate in non-Jewish white women (15.0). Similar to the findings of Hochman's study [7], the rates in the Ashkenazi and Sephardi-Oriental subgroups were also virtually identical (4.7 and 4.9 respectively). In 1960 the Israel Cancer Registry was established. This registry is notified by law of all new cancer patients and obtains its information from three sources: hospital records, pathologic reports, and death certificates. Steinitz and Costin [13] published the first population-based incidence rates of cervical cancer, again showing that they are markedly low in Israeli Jewish women. Between 1960 and 1967, only about 60 new cases were diagnosed annually throughout Israel, and the incidence rate was about 5.8. Subsequently, when differences between ethnic groups were analyzed by continent of birth and not by allocation to Ashkenazi and Sephardi-Oriental subgroups, appreciable differences were noted. Modan et al. [14], and later Sharon et al. [15], reported that the incidence of cervical carcinoma among Jewish women born in North Africa was considerably higher than in those born in the other continents, mainly due to the high incidence in women born in Morocco. This observation was subsequently confirmed by Menczer and colleagues [16]. Their study included all cases of cervical cancer diagnosed in Israel during the 11 year period 1961–71. They found that the mean age-adjusted incidence rate in North African-born Jewish women was statistically significantly higher than in women born in Europe, Asia and Israel (8.3 vs. 3.6, 2.8, 2.5 respectively; P < 0.01). The lowest rates (1.54) were observed in Jewish women born in Yemen [17]. It seems, therefore, that there are not only marked differences in incidence between Jewish and non-Jewish women, but also considerable differences between various Jewish ethnic groups. The reason for these inter-ethnic differences has not yet been clarified. Many attempts have been made to identify the cause of the remarkable infrequency of carcinoma of the cervix among Jewish women. This quest is of great general importance, since an explanation for this phenomenon might contribute to a better understanding of the process of carcinogenesis and possibly assist in the prevention of the neoplasm. The low occurrence of cervical cancer in Jewish women has been variously attributed to traditional habits, to different risk factors, or to genetic factors that provide some degree of resistance or immunity.
Traditional
habits
Jews around the world practice two distinct traditional
habits: the ritual circumcision of males 8 days after birth,
and the prohibition by the family purity laws (Niddah) against sexual intercourse
both during menses and 7 days after its complete
cessation.
Circumcision
The low incidence of cervical cancer in Jewish women has
been ascribed to maximal circumcision of Jewish male infants
[18]. However, others subsequently
concluded that non-circumcision does not increase the risk of
cervical cancer [19]. It is beyond the
scope of the present survey to review the innumerable studies
dealing with the association between circumcision and
cervical cancer. Many of the studies were performed in
non-Jewish women, or compared non-circumcised Christian
populations with circumcised Moslem populations, or
non-circumcised Hindu populations with Moslem populations.
The findings of these epidemiologic studies are often
conflicting. The reason for the inconsistent results is that
attempts to assess the association between the circumcision
status of the male partner and cervical cancer encountered
several difficulties [20]. Many
confounding factors were not accounted for, and when multiple
partners were involved the issue became even more
complicated. Many women did not know the circumcision status
of their sexual partner. In addition, there may have been
discrepancies between men's reports of their circumcision
status and the results of examinations. Finally, the degree
of circumcision was not uniform. It has therefore been
suggested that circumcision studies should be based on actual
examination of the male partners. Such a study was conducted
by Terris et al. [20], who found no
significant differences in the circumcision status of the
first marital partners of women with invasive and
pre-invasive cervical lesions and controls matched by age and
ethnic group. The circumcision status of the partners of the
few Jewish women included in the study was not specified.
Another example of a study negating the association was
performed in Lebanon [21]. This
population- based study found that notwithstanding the
circumcision status of men, cervical carcinoma was as
frequent in Moslems as in Christians. There was also no
difference between cases and controls in circumcision status
of the husband as determined by physical examination. The
data by Stewart et al. [12] also yielded
no support for a relationship between lack of circumcision
and cancer of the cervix in non-Jewish white women. They
found that among Jewish women in Israel, only 1 of the 48
with cancer of the cervix stated that she had had intercourse
with an uncircumcised male. Of the Jewish women in New York
City, 7 of 46 cases (15.2%) and 1.7% of controls gave a
history of intercourse with one or more uncircumcised
partners. This difference was significant (P < 0.01).
However, the higher rate of intercourse with uncircumcised
males in the cases may be a reflection of the liberal sexual
habits in this group and not of the circumcision status of
their partners. It should also be mentioned that the
incidence of cervical cancer among Israeli Jewish female
immigrants from the former Soviet Union, some of whom are
married to uncircumcised men, is not different to that in the
general population [22].
Although the dispute over the association of circumcision and cervical cancer in various populations is still ongoing [23,24], there seems to be no hard evidence that circumcision prevents its occurrence in Jewish women, and it is no longer considered to play a protective role.
Abstinence from
intercourse
Among orthodox Jewish women who observe the laws of Niddah, cervical cancer is even less
common than in the rest of Israeli Jewish women. This
observation seems to support the notion that abstinence from
intercourse during and for several days after menses is a
protective factor. However, it is extremely difficult to
isolate this ritual from other risk factors that are absent
in the orthodox group, such as early coitarche, multiple
partners, and smoking. A similar low occurrence has been
found in other communities with strict sexual conduct that
practice endogamy – i.e., marrying within their faith
[25], but do not practice circumcision.
The data by Stewart and co-workers [12]
also failed to show any significant association between
cancer of the cervix and abstinence from intercourse during
or after menses in Israeli Jewish women and Jewish women in
New York City, as well as in non-Jewish white women. It
should also be mentioned that the great majority of Israeli
Jewish women no longer practice the laws of Niddah, yet the incidence of cervical
cancer among them remains persistently low.
Risk factors
General risk factors
No difference between Jewish and non-Jewish women has been
found with regard to general risk factors for cervical
carcinoma. Comprehensive epidemiologic studies by Martin in
the U.S. [25] and by Pridan and Lilienfeld
in Israel [26] indicated that like other
populations, cervical cancer in Jewish women is associated
with younger age at first coitus and first marriage, a higher
number of sexual partners, and lower socioeconomic
status.
Herpes simplex virus type 2 infection
For almost a decade the sexually transmitted HSV-2 was
implicated in the etiology of cervical carcinoma and has been
the subject of detailed investigations [27,28]. The association between HSV-2 and
cervical cancer was also assessed in Israeli Jewish women.
Menczer et al. [29] examined HSV-2 titers
in sera from 39 Jewish women with cervical cancer, in sera
from controls hospitalized for benign gynecologic diseases,
matched by age and country of origin, and in sera from the
general population of healthy female subjects. The HSV-2
titers were significantly higher in patients than in
controls, and in the range of reported rates in cervical
carcinoma patients in other populations. On the other hand,
the HSV-2 titers in the general female population were low
compared to many other demographic areas. The authors
suggested that the low incidence of cervical cancer among
Jewish women may be related to the low reservoir of the HSV-2
virus in the general population. These findings contradicted
another study in Israeli Jewish women in which the percentage
of HSV-2-positive controls resembled that in the cervical
cancer cases [26].
It is now generally accepted that HSV-2 plays no major role in the etiology of cervical cancer, except perhaps as a co-factor in a limited number of patients [30], or as an initiating agent [31]. The low reservoir of HSV-2 therefore does not explain the infrequency of cervical cancer in Jewish women.
Human papillomavirus
infection
Currently, it is widely accepted that degradation of the
p53 suppressor gene by oncogenic HPV E6 early protein
plays a crucial role in the etiology of cervical cancer
[3–5]. Oncogenic HPV was found in about 90% of cervical
carcinoma tissue samples in many demographic areas [31]. Previously, using the Southern blot
hybridization technique, a low (36%) prevalence rate among 22
Israeli cervical carcinoma patients had been reported [32]. However, another recent study, using a
sensitive polymerase chain reaction technique, found that, as
in other populations, the prevalence of HPV in cervical
cancer cases is very high [33]. In the
general Israeli population the prevalence of HPV, as assessed
by filter in situ hybridization of cervical smears,
was found to be low [34]. Whether this
affects the frequency of cervical cancer in Israeli Jewish
women is not clear.
Genetic factors
Hochman et al. [7] contend that the equal
incidence of cervical cancer in the Ashkenazi and
non-Ashkenazi ethnic groups is clear evidence that the low
cervical cancer incidence in Jewish women is not a genetic or
racial phenomenon. On the other hand, Stewart et al. [12] proposed that the similar incidence rate
in the various groups of Jewish women studied in New York and
Israel support the assumption that the disease is infrequent
because of a genetically determined lack of
susceptibility.
p53
polymorphism
In 1998, Storey and associates [35]
reported that the presence of homozygous arginine
polymorphism at codon 72 of p53 represents a
significant risk factor in the development of HPV-associated
cervical carcinoma. If this observation is valid, then a low
prevalence of this polymorphism in Jewish women might
constitute the genetic basis for the low incidence among
them. Thus, it was of tremendous interest to assess the
prevalence of the homozygous arginine polymorphism in healthy
Israel Jewish women, and the association between the presence
of this polymorphism and cervical cancer in Jewish women. We
recently performed such an investigation [36]. Our study group included 23 Israeli
Jewish patients with histologically confirmed squamous cell
carcinoma of the cervix. The control group comprised 162
randomly chosen Israeli Jewish healthy women, considered to
represent the general population. The germline p53
polymorphism at codon 72 was determined by PCR in DNA
obtained from a blood sample taken from each subject. In this
study, Arbel-Alon et al. [36] showed that
among healthy Israeli Jewish women, the prevalence of the
arginine homozygous p53 polymorphism paralleled the
pattern of cervical carcinoma in the Israeli population.
While lower than in other populations, it was significantly
higher in women of North Africa origin than in the other
ethnic groups (30.3 vs. 10.8%, P < 0.01). Furthermore, the
association between the homozygous arginine polymorphism and
cervical cancer, as reported by Sorey et al. [35], was also found in Israeli Jewish
women.
These findings support the possibility that the low prevalence of the homozygous arginine polymorphism may play a role in determining the low incidence of cervical cancer in Jewish women and may also explain the differences between the ethnic groups. If these observations are confirmed, then the low incidence of cervical cancer in Jewish women is genetically determined, and an explanation for the ethnic incidence pattern of cervical cancer in Jewish women has also finally been found.
Conclusions
For many years it was predicted, on the basis of
observations in selected cohorts or individual institutions,
that the incidence of invasive cervical carcinoma in Israeli
Jewish women will increase [37-39]. While
ritual circumcision is still practiced widely, today only a
minority of Jewish women observes the laws of Niddah. Sexual habits have also
changed considerably, becoming far less stringent. In spite
of these trends of the last four to five decades, the
population-based incidence of cervical cancer in Israeli
Jewish women has not increased and remains very low [22,40].
Braithwaite [6], who first noted the low incidence in Jewish women in 1901, suggested two explanations for this ``immunity.'' The first was the difference of race, and the second the difference in diet, namely the ``absence of bacon and ham in the diet of Jews.'' He then added: ``The latter is far more probable than the former, although there may be something in race.'' Now, a century after Braithwaite's original observation, it seems that there may indeed be something in ``race.''
References
Correspondence: Dr. J. Menczer, Gynecologic
Oncology Unit, Dept. of Obstetrics and Gynecology,
Wolfson Medical Center, Holon 58100, Israel.
Phone: (972-3) 502-8490
Fax: (972-3) 502-8107
email: joseph12@internet-zahav.net
[CIRP Note: This article is also available in PDF format from http://www.ima.org.il/imaj/ar03feb-11.pdf.]
http://www.cirp.org/library/disease/cancer/menczer1/