Cervical cancer screening programs* I. Epidemiology and natural history of carcinoma of the cervix Terms used in this report: The International Classification of

(ICD), 8th revision, contains

Diseases

number of rubrics under which car¬ cinoma of the uterus may be classified. These are: 180 malignant neoplasm of cervix uteri 181 chorionepitheiioma 182 other malignant neoplasm of a

synonyms are used for the sake of

style. Thus, 180 malfgaant neoplasm of cer¬ vix uteri, also referred to as .

.

182.0

.

182.9

.

.

.

182.0 182.9 234.

.

.

corpus uteri

uterus

of unspecifled nature of uterus 234.0 carcinoma in situ of cervix uteri 234.1 .cervix uteri, other 234.9 other and unspecifled

-neoplasm .

.

part

This report is primarily concerned with squamous carcinoma of the cervix uteri and its precursor, carcinoma in situ of the uterine cervix. These cor¬ respond respectively to ICD rubrics 180 and 234.0, although the former in¬ cludes adenocarcinoma of tbe cervix* Because of problems with certification, which are discussed in part I, the re» port also has to concern itself with rubrics 182.0 and 182.9. Since the official designations of all these rubrics are somewhat cumbersome and would be tedious to repeat, a number of ?Report of the task force appointed by the Conference of Deputy Ministers of Health in December 1973 and submitted to the conference Mar. 16 and 17, 1976. Members of the task force were selected by officers of the Department of National Health and Welfare from a group of 30 proposed in response to invitations issued by DNH&W to the Canadian Association of Pathologists, the Canadian Medical Association, the Society of Obstetricians and Gynaecologists of Canada, I'Association des medecins de langue francaise du Canada, the Canadian Public Health Association, the Canadian Nurses' Association and the provincial deputy ministers of health. Chairman was Dr. R.J. Walton, professor of radiology, University of Manitoba and vice-president, medical, Health Sciences Centre, Winnipeg. Members included Dr. M. Blanchet, chief, epidemiologicofservices, planning directorate, Social Affairs, Quebec; Department Dr. D.A. Boyes, associate professor of obstetrics and gynecology, University of British Columbia and director, cytology laboratory, British

of tbe cervix and invasive carcinoma of the cervix* malignant neoplasm of cor¬ pus uteri, also referred to as carcinoma of the corpus! or carchioma of me body of the uterus or carcinoma of the endometrium. malignant neoplasm of uter¬ us, unspecifled, also referred t© as carcinoma of the carcmoma

uterus, unspecifled.

Tbe words carcinoma and cancer are used interchangeably. Unless other¬ wise specified, tbe report Is concerned with squamous carcinoma of tbe cervix uteri, not other types of carcinoma. It should be noted that two condi¬ tions, previously seldom recognized, are being seen as a result of screening programs. These are occult (Le., asymp¬ tomatic) invasive carcinoma and microinvastve carcinoma, which is also usually asymptomatic. ln a sense, these are "new" diseases for which specific ICD rubrics do not exist, though they are almost invariably coded within ICD rubric 180, malignant neoplasm of cervix uteri. Columbia Cancer Institute, Vancouver; Dr. J.A. Carmichael, associate professor, department of obstetrics and gynecology and head, division of gynecologic oncology, Queen's University and chairman, department of gynecology, Hotel-Dieu Hospital, Kingston; Dr. K.G. Marshall, associate professor of pathology, associate dean, faculty of medicine and past director, Macdonald Stewart division of cytopathology, pathology institute, McGill University, Montreal; Dr. A.B. Miller, director, epidemiology unit, National Cancer Institute of Canada, Toronto; and Dr. D.W. Thompson, associate professor of pathology, University of Toronto and director of cytopathology, Toronto General Hospital, Toronto. A valued resource person was Dr. G.B. Hill, planning consultant (epidemiology) and former director, health division, Statistics Canada. The task force report, presented in its entirety, has been subjected to editing for Journal format and style only.

Epidemiology One of the earliest studies of this condition, using epidemiologic tech¬ niques, was conducted in the middle of the 19th century by Rigoni-Stern,1 the chief physician of a Verona hospital and an instructor at the University of Padua. He investigated the frequency of marriage in relation to risk of both uterine and breast cancers. He con¬ cluded, on the basis of studies of mor¬ tality records, that more uterine cancers were found in married than in unmar¬ ried women, that cancer of the uterus became prevalent in women between 30 and 40, that the frequency of this cancer doubled in the following two age decades and then declined, and that it was rare among unmarried women and almost absent in certain orders of nuns. He observed an inverse relation¬ ship between cancer of the breast and cancer of the uterus, in that breast cancer was frequently a cause of death in nuns and in unmarried women. Nearly a century later Gagnon,2 a Canadian investigator, substantiated this work in studies on nuns. These studies were commenced in the 1930s and involved a 20-year follow-up of a well documented cohort. It is startling and somewhat sobering to realize that although we have refined these observations we have not yet es¬ tablished the etiology of either of the conditions Rigoni-Stern investigated. Nevertheless, in a document concerned with secondary prevention namely, screening for carcinoma of the cervix it is well to review what knowledge we do have of the epidemiology of the condition.

Reprint requests to: Dr. D.D. Gellman, Director general, health standards, Health programs branch, Health and Welfare Canada, Ottawa, ON K1A 1B4

CMA JOURNAL/JUNE 5, 1976/VOL. 114 1003

International data Studies of the incidence of cancer of the cervix, based on the data collected by cancer registries throughout the world and published in the two volumes "Cancer Incidence in Five Continents",8 show a striking variation in rates. As shown in Fig. 1, the highest rate is recorded in the Cali, Colombia regis¬ try and the lowest in the Israel registry. The ratio between these, using agestandardized truncated rates per 100000, based on women aged 35 to 64, is approximately 180 in Colombia to 12 in Israel. Canadian registries' rates per 100 000 ranged from 70 in Quebec to 40 in Saskatchewan. Within the United States the range is from 90 in El Paso Latins to 23 in Connecticut. Differ¬ ences in rates are also noted by race for example, in Alameda County the rate for whites was 40 and for Negroes, 75. Within these data there are also variations in age-specific rates, as shown in Fig. 2. Colombia has a peak incidence at the age of 60, with a steep rise to this point and a steep fail there¬ after. In Denmark, one of the Euro¬ pean countries with highest incidence, the incidence has a relatively flat peak at the ages of 40 to 45, with a fairly rapid rise before this and a slow fail thereafter. In Saskatchewan the inci¬ dence rises to age 40 and is almost .

stable thereafter but at a lower level than the rates for Denmark and Colom¬ bia. Israel has the lowest rates of all, with a very slow rise and a small peak at the age of 70. In interpreting these figures, one must be constantly aware of differences in reporting practices and of the prob¬ lem of accurate identification of cancer of the cervix as a segment of all can¬ cers of the uterus. What is more, a registry that regards in situ carcinoma or other preclinical conditions as justifying registration as invasive cancer will record artificially inflated figures if it is based on a jurisdiction that has a screening program. For example, the Quebec tumour registry included carci¬ noma in situ in the time period covered in Fig. 1 but subsequently this was cor¬ rected (see discussion in part II). The impact of these problems in re¬ lation to Canadian data will be pre¬ sented later in this section. The interna¬ tional differences are enormous. They do not seem to be explicable on the basis of the existence or possible effect of screening programs alone and it seems difficult to avoid the conclusion that, as for other cancers, there must be substantial environmental or lifestyle components contributing to the etiology of carcinoma of the cervix that may be operating differently in different coun¬ tries.

125

160

176

;

ences observed are due to screening occurring in some countries but not in others. Eliminating the contribution of deaths at age 65 or more removes some of the uncertainty in certification of

death of older women. It is apparent that the international variation in death rates is substantial, ranging from 45.5/100 000 in Romania to 9.5/100 000 in Israel. Once again it is difficult to avoid the conclusion that there are real and substantial differ¬ ences between countries, based on en¬ vironmental factors.

200

FIG. 1.Incidence of carcinoma of the cervix (age-standardized rates per 100 000 women aged 35 to 64 from selected registries,3 some of which may include carcinoma in situ).

1004 CMA JOURNAL/JUNE 5, 1976/VOL. 114

This conclusion is strengthened when studies mortality data. The most recent study of international mortality is based on data collected by the World Health Organization for a number of years.4 Although, in this study, rates are presented for cancer of the cervix, confidence cannot be placed in these because of the different and changing extent to which deaths from cancer of the cervix are correctly certified to "cervix" or actually certified to "uterus, unspecified". Therefore, only the rates for "cancer of the uterus" will be dis¬ cussed here. The rates for 1965 to 1969 are set out in Table I, using age-standardized rates restricted to ages 35 to 64. The rates for 1965 to 1969, rather than for a more recent period, are used in order to reduce the possibility that the differ¬ one

20-24 26-29 30-34 36-39 40-44 46-49 60-54 55-59 60-64 66-69 70-74 75-79 80+

FIG. 2.Incidence of carcinoma of the cervix (age-specific rates per 100 000 women from selected registries3).

Canadian data

are

included because Ontario data are national system at

not included in the

Since 1969, incidence data collected

present.

It is apparent that the incidence of by the provincial cancer registries have been reported to Statistics Canada as invasive carcinoma is higher in the At¬ part of the National Cancer Reporting lantic provinces of Canada than in the System.5 Table II sets out incidence West, with the lowest incidence being rates for invasive carcinoma of the reported from the province of Saskat¬ cervix, for the 4-year period for which chewan. The Ontario rate may well be data are available, calculated as age- inflated because it is derived from an standardized rates per 100 000 for fe¬ earlier year. Patients with invasive but preclinical males aged 35 to 64. For comparative cancer discovered as a result of screen¬ from the data purposes unpublished 1966 Ontario cancer incidence survey6 ing can be included in the registry data on the incidence of invasive carcinoma only in the ICD rubric 180 for invasive cancer. Thus it might be expected that the rates of invasive cancer reported by Table I.Mortality from carcinoma of a province with an active screening the uterus, 1965-69 program would be inflated by the pres¬ ence of patients who are registered purely by virtue of their discovery as a result of screening. This inflation of rates is most clearly seen in the data from the Saskatchewan Cancer Com¬ mission, which are described in con¬ sidering trends of incidence data in

part II.

*Age-standardized rates per 100 000 women aged 35

to64.4

Table II.Incidence of invasive carcinoma of the cervix (ICD 180), Canada, 1969-72

^Age-standardized rates per 100 000 women aged 35 to64.fi tData from 1966 Ontario cancer incidence survey.6

One further factor must be borne in mind in interpreting incidence rates for invasive carcinoma derived from can¬ cer registry data. Currently, few cancer registries are in a position to publish rates on the basis of histologic type. Careful distinction between "squamjous" and "adeno-" carcinoma of the cervix is important when considering the conditions likely to be influenced by screening. Although most of the dis¬ cussion in this report is directed to¬ wards squamous carcinoma of the cervix, adenocarcinoma is, almost in¬ variably, also included in cancer regis¬ try data. Great caution, therefore, has to be exercised in interpreting rates for in¬ cidence of invasive cancer published in cancer registries. Only when particular care is taken to exclude cases diagnosed on screening is the true rate of clinical invasive carcinoma consistently re¬ corded. Currently this only occurs in British Columbia, where such data are

unspecified. This is not a problem with the data from Canadian registries: in nearly all such registries the proportion of "uterus, unspecified" is low, and this category has been eliminated from the registered data in at least three prov¬ inces namely, Alberta, New Brun¬ swick and Prince Edward Island. How¬ ever, the problem has not yet been solved for mortality data, which, in view of the absence of incidence data from most countries over a long time period, may have to be used to de¬ termine changes brought about by screening and other factors. The Canadian mortality data for the years 1969 to 1972 are set out in Table III.7 Considering first carcinoma of the cervix, it is apparent that, as for the incidence data, the rates are higher to the east of the country and lower to the west, with Ontario and Quebec in between. However, the rates for Que¬ bec may be artificially low, as will be seen by perusing the columns for rates for carcinoma of the corpus uteri and for uterus, unspecified. Rates for uter¬ us, unspecified, which could include both carcinoma of the cervix and carci¬ noma of the corpus, range from 0.1 in British Columbia to 9.0 in Prince Edward Island, with Quebec second highest at 5.9. The highest rates for carcinoma of the corpus appear in provinces where a low proportion is certified as uterus, unspecified. The low rate for British Columbia for mortality from carcinoma of "uter¬ us, unspecified" is due to a procedure, introduced in 1965, to question death registrations from this cause and from other causes that might be related to cancer of the cervix or corpus uteri (R. Gallagher: personal communica¬ tion, 1975). The effect of this proce¬ dure on rates for cancer of the cervix was relatively minor. During the time period 1965-72, 442 deaths had been certified due to carcinoma of the cer¬ vix: this was increased, as a result of .

kept by the central cytology registry Table lll.Mortality from carcinoma of maintained by the Cancer Control the cervix uteri (ICD 180), corpus uteri Agency of British Columbia. Their pub¬ (ICD 182.0) and uterus, unspecified

lished rates, based on females over the age of 20, restricted to squamous car¬ cinoma, have fallen from 28.5/100 000 women in 1955 to 8.6/100 000 in 1974. In contrast, the British Columbia provincial cancer registry, maintained by the Division of Vital Statistics of British Columbia, does not make this distinction. Another cause for concern in pub¬ lished data arises from the possibility that patients with carcinoma of the cervix may be wrongly regarded as having cancer of the corpus uteri or, more likely, be included under uterus,

(ICD 182.9), Canada, 1969-72

?Age-standardized rates per 100 000 women aged 35

to64.7

CMA JOURNAL/JUNE 5, 1976/VOL. 114 1007

Some of these variables are highly reconsideration, to a final total of 491. By contrast there was substantial effect correlated. Thus, the effect of age at first marriage and age at first preg¬ on the number of deaths certified as due to cancer of the corpus uteri, which nancy disappear when the data are con¬ trolled for age at first intercourse. rose from 92 to 244. If the certification practices in other provinces were simi¬ Rotkin9 has summarized a number of lar to those in British Columbia, these studies that show that first marriage data would suggest that most deaths under age 20 or 21, two or more marreported due to "uterus, unspecified" riages, first coitus before age 20, two should be regarded as due to carcinoma or more sexual partners in life, broken of the corpus rather than of the cervix marriages and unstable sexual relation¬ uteri. However, this assumption seems ships are all significant. As before, untenable for Quebec and probably some of these are interrelated. The also for Prince Edward Island and strength of the association with age at Newfoundland. If it were applicable, first coitus is even higher if the division the death rates from cancer of the is taken before and after age 17. For some variables, such as unfaithcorpus uteri would be unreasonably high in comparison with the rest of the ful husbands, current data are sugges¬ tive but not conclusive. Others, which country. These considerations suggest that the were suspected in the past as being true mortality rate for carcinoma of associated, clearly are not when a num¬ the cervix is lowest in the West, a little ber of studies are considered. These higher in Ontario, higher still in Que¬ include coital frequency, mean age at bec, and highest in the east of the menarche and noncircumcision of part¬ ners. The studies reviewed by Rotkin9 country. However, assumptions of this sort suggested that a protective barrier may are unsatisfactory, particularly when prevent an agent from reaching the trends of mortality are being consid¬ cervix, and other studies also appear ered. It is known that the precision of to be producing evidence that the risk certification has improved across the of cervical cancer is less in women who country and in the past the proportion use barrier contraceptives than in those certified to "uterus, unspecified" was who use oral contraceptives.10 Whether substantially larger than it is now. this is a protective physical effect or Thus, in considering trends of mortality a difference because of confounding in a period of increasing precision in variables associated with other aspects death certification, it is preferable of sexual activity it is not yet possible to consider "total uterus", including to determine. However, so far no evid¬ deaths certified as due to cancer of ence has been produced to indicate that the cervix, corpus and unspecified. oral contraceptives have a direct car¬ cinogenic effect on the cervix.11 Special studies Studies by Beral12 in Great Britain There have been a number of studies have recently shown that, although of the epidemiology of carcinoma of standardized mortality ratios for cervi¬ the cervix and the interested reader is cal cancer in married women rise from referred to reviews by Clemmesen8 34 in the highest social class (class I) and Rotkin9 for summaries of most of to 181 in the lowest social class (class these. Carcinoma of the cervix has V), within each social class there is a been shown to occur in high incidence substantial gradient related to the hus¬ in urban residents, compared with band's occupation. It seems that occu¬ rural; in people of low social class, pations that entail mobility of the hus¬ compared with those of high; in Ne- band and periods away from home are groes in the United States, compared associated with higher mortality from with whites; in married women, com¬ cancer of the cervix in the wife. Beral pared with single; in widowed or also found a close association between divorced women, compared with mar¬ mortality ratios for cervical cancer and ried; in women with many pregnancies, the incidence of gonorrhea 20 years compared with those with few or none; after the year of birth of the cohort, in women with young age at first in cohorts born in the years 1902 to marriage, compared with those who 1947. These studies appear to suggest that marry older; in women with young age at first pregnancy, compared with those the important covariable with incidence whose first pregnancy is later; in those of and mortality from carcinoma of the who have first intercourse in adoles- cervix is early onset of sexual activity cence, compared with those whose first in the female, particularly with multiple intercourse is after adolescence; in peo¬ male partners. Other effects disappear ple with a history of syphilis or gonor¬ once full account is taken of these rhea, compared with those without such factors. Consequently, many people history; and in those with a number now regard cancer of the cervix as a of sexual partners, compared with those venereal disease. This has led to the search for appropriate transmittable with only one partner. 1008 CMA JOURNAL/JUNE 5, 1976/VOL. 114

agents.

Over the past several years there has been an increased effort to evaluate the role of viruses in malignant disease. These efforts, based on observations made in experimental animal models, have three possible goals: 1. The understanding of malignant transformation of cells by viruses at the biochemical level might lead to the de¬ velopment of specific therapeutic agents that can be used to treat patients with cancer.

2. If cancer induction by viruses is similar to the classic patterns of in¬ fectious diseases, with an extended in¬ cubation period, it may be feasible to prevent cancer by developing vaccines. 3. Knowledge related to virus-induced cancer might be used to develop tests that may be of prognostic or diag¬

nostic value, or both. There is a body of evidence suggest¬ ing that herpesvirus type 2 may be etiologically related to carcinoma of the cervix. The epidemiologic features of cervical cancer and infection with this virus are similar.13 An excess of neutralizing antibodies to the virus has been found among women with cervical cancer when compared with control women.14 There are unconfirmed re¬ ports of the presence of herpesvirus genetic information in cervical cancer cells.15'16 Finally, the virus has been shown in the laboratory to have onco-

genic potential.17

Evaluation of the applicability of the information available is hampered somewhat by the noncomparability of the assay systems used to measure anti¬ bodies to herpesvirus type 2. Herpes¬ virus type 1 and type 2 share antigens, and, hence, share antibodies that will cross-neutralize following an infection with either type of virus. Presently available assay methods are not highly specific. However, in 1973 three sep¬ arate groups reported the presence of antibodies to a herpesvirus-induced "nonvirion" antigen in the sera of cer¬ vical cancer patients but in few patients without malignant disease.18 It has been suspected that it is not the virus as such that is responsible for the occurrence of cancer of the cervix, but some other covariable associated with sexual behaviour. Nevertheless, de¬ tailed studies by Rawls, Adam and Melnick14 appear to support herpesvirus as a factor, rather than something else associated with sexual activity. Earlier studies have been reviewed by Kessler.19 It seems likely that further work in this field will be dependent on refining the methodology and then per¬ forming long-term studies on appro¬ priately documented cohorts. For the time being it cannot be certain that herpesvirus type 2 is either necessary

or sufficient to cause carcinoma of the cervix. If necessary, it should be dem¬ onstrable in all cases; if sufficient, it may be one of a number of different causes, each one of which might result in the condition if applied alone. It is possible to visualize circumstances where the virus would be both neces¬ sary and sufficient, or necessary but not sufficient because of the need for another covariable, or not necessary but sufficient in some instances, or neither necessary nor sufficient. In the latter event, the virus would cause the cancer, together with another variable in some cases, but other women might get cancer of the cervix for completely different reasons. It is obvious that a great deal more work will have to be done to sort out these various possibil¬ ities. There are other hypotheses that must be considered. Coppleson and Reid20 proposed that the carcinogenic agent for the cervical epithelium is a sperm factor that sensitizes cells and initiates the neoplastic process.21 The very na¬ ture of the hypothesis makes it difficult to prove or disprove. This concept of the high-risk male could explain some of the findings of Beral12 referred to above. Other studies9 in the past have pro¬ duced suggestive evidence that a carci¬ nogenic factor in smegma or other factors associated with penile hygiene might be relevant. Very few firm data are

being produced, however, though

such associations are not incompatible with a venereally transmitted infectious agent, such as herpesvirus type 2. Finally, especially in a document pri¬ marily concerned with screening, it is necessary to consider the recent identi¬ fication of diethylstilbestrol and other synthetic estrogens in the etiology of clear-cell adenocarcinoma of the cervix and vagina. The original demonstration by Herbst, Ulfelder and Poskanzer22 in Boston of the association of stilbestrol with these relatively uncommon tu¬ mours in young women was rapidly confirmed by others,23 and by an inter¬ national registry.24 Although women who received the estrogens for threatened abortion did not seem to be at risk, the daughters of women treated for threat¬ ened abortion with stilbestrol during the first 17 weeks of pregnancy have a small but demonstrably increased risk of clear-cell adenocarcinoma of the cervix and vagina at puberty or later. The incidence is estimated to be no greater than 3 to 4 per 1000 daughters, though the incidence may increase as the daughters grow older. A predisposing or linked condition is vaginal adenosis, and this (and the invasive cancer) can be identified by examination.25 More recent unpublished observations show

that a significant and increasing propor¬ tion of these girls are at risk of dys¬ plastic changes in both cervical and vaginal epithelium. This is because the "transformation zone" is abnormal and extends over a wide area of the cervix and upper vagina. Hence, in the longer term there may be a substantial risk of squamous carcinoma of the cervix and vagina. Those daughters known to be at risk should therefore be examined regularly after the age of 16.

Natural

history

Carcinoma of the cervix affords a unique opportunity for study of its natural history because of two factors: (a) the small localized area of the squamocolumnar junction has a high rate of neoplasia; and (b) despite the encumbrance of the vaginal canal, the cervix is a surface area requiring only a simple maneuver for visualization and continuing study. This easy accessibility and high neoplastic rate has permitted

investigators

identify a sequential to invasive dis¬ ease, which has been generally accepted in principle although details are still to

pattern of preinvasive debated.

Traditional concept The general concept of the progres¬ sion from preinvasive to invasive dis¬ ease has been traditionally depicted as is shown in Fig. 3.26 This figure suggests that carcinoma of the cervix is a progressive disease beginning with in situ changes and ending 2 or 3 decades later with clinical invasive cancer, and that there is a period of time of some 1 or 2 decades within this natural history when the disease may be identified, removed, or reversed prior to the onset of invasive cancer.

Dysplasia does not appear in the figure but, as is discussed below, there is some evidence to place this change

a decade or so younger than in situ disease. Re-evaluation of previously available information and data recently collected for the task force has cast some doubt on this duration of natural history and

the

timing of some of its component parts. The previously reported informa¬ tion will therefore be reviewed first, and then the revised concept presented.

Dysplasia The concept that progressive degrees of cervical dysplasia are part of the natural history of neoplastic disease of the cervix now seems firm. The ques¬ tions that need to be answered are: Does cervical dysplasia always progress to in situ cancer (and, hence, presum¬ ably, to invasive cancer)? Can invasive disease develop directly from cervical dysplasia? Does cervical dysplasia sometimes revert to normal? and If dys¬ plasia is a phase in the natural his¬ tory of carcinoma of the cervix, how long does this phase last? These ques¬ tions will now be considered. 1. Does dysplasia always progress to in situ cancer? Two prospective studies have shown an annual progression rate from dysplasia to cancer of 5 and 6.4% ,27 The incidence of preinvasive cancer in a population previously dem¬ onstrating dysplastic change has been reported as 49/1000, in contrast to 0.04/1000 in a dysplasia-free popula¬ tion. The problem of underdiagnosis at the time of original assessment by biop¬ sy or cytology is recognized. Neverthe¬ less, the difference is too striking to be dismissed on the basis of diagnostic inaccuracies. 2. Can invasive disease develop di-

rectly from dysplasia? Microscopically, early invasive disease originating in an area of "dysplastic change" has been demonstrated, with and without in situ change in adjacent areas.28 It must be remembered that the distinction be¬ tween severe dysplasia and in situ car¬ cinoma is sometimes arbitrary. This suggests the possibility that, in some patients, the in situ phase of the natural history might be skipped or not be detectable. 3. Does dysplasia sometimes regress? Regression rates (with biopsy control) of 30 to 40% have been reported. One must acknowledge the apparent therapeutic effect of cervical biopsy, but the same figures have been obtained by cytologic follow-up. The regression

Mean age at diagnosis of carcinoma in situ

34 yr

Mean age at diagnosis of occult carcinoma of cervix

43.7 yr Mean age at diagnosis of carcinoma in situ with microinvasion

48.6 yr

52 yr Mean age at diagnosis of

clinical

carcinoma of cervix

FIG. 3.Natural

history of carcinoma of the cervix, based on mean ages at diagnosis. CMA JOURNAL/JUNE 5, 1976/VOL. 114 1009

rate is similar for dysplasia diagnosed during and immediately following preg¬ nancy. However, a high rate of recur¬ rence of dysplasia following spontane¬ ous regression has been reported.29 The greater the degree of dysplasia, the greater the probability of progression to in situ and invasive disease. Conversely, the less the degree of dysplasia, the greater the likelihood of regression. 4. How long does dysplasia last? The wide range of degrees of dysplasia and the differences of individual interpreta¬ tion, as well as the problem of identi¬ fying the beginning and end-point of the dysplastic phase make such figures as are available almost meaningless. It has been noted, however, that the pre¬ valence of dysplasia is highest in the 20- to 29-year-old age group, a decade or more before the peak prevalence

yield estimates varying from 1 to 20 years.36 The problem of accurately identifying the time of onset of the in situ change as well as the date of pro¬ gression, is obvious. Peterson87 gives an average of 3.6 years. Previous British Columbia figures showed a mean age at diagnosis of in situ carcinoma of 34.0 years and mean age at diagnosis of clinical invasive disease of 52 years.88 2. Does carcinoma in situ regress? As in the case of dysplasia, this is un¬ certain because of the destructive na¬ ture of most diagnostic procedures. Re¬ ported series are small and the figures must be accepted with caution. Over follow-up periods of 1 to several years the regression rate has been estimated at from 0 to 25%.87'M The reported regression rates are lowest in those pa¬ tients followed up by cytology rather of carcinoma in situ.27 than by biopsy, suggesting a therapeutic effect of the latter. A current study in Carcinoma in situ British Columbia is attempting to an¬ question more accurately by The significance of carcinoma in swer this two of women. How¬ studying situ as a precursor of invasive disease ever, even if cohorts the rate were regression has been recognized for more than 3 to be as high as 50% this, in opera¬ decades.30 Several series of patients, tional terms, would not invalidate the followed for months or years, have of demonstrated progression from carci¬ concept screening. noma

3. Is invasive disease always pre¬ ceded by carcinoma in situ? Individual instances of the development of in¬ vasive disease in a patient with a long history of regular and negative screen¬ ing can be identified. While one can always say that a preinvasive lesion has been missed, it cannot be excluded that the natural variants of this disease must allow for occasional invasive cancers to arise de novo or to be preceded by an in situ change so brief as to be missed by the usual screening program. Nevertheless, experience suggests that such cases, if they occur, are very rare. New data and reinterpretation of old In this section previously available data as well as some new data based on age-specific rates of diagnosis, as distinct from calculations of mean ages of diagnosis, are considered. Fig. 4 illustrates some old and some recent unpublished data from the Brit¬ ish Columbia screening program that throw further light on the natural his¬ tory of carcinoma of the cervix. The figure shows the age-specific rates of diagnosis of in situ carcinoma in women previously screened (true in-

in situ to invasive disease at rates

ranging from 25 to 70% .31 Individual series are small but the aggregate is significant. The arguments that cervical biopsies (a) have a therapeutic effect (induce regression)32 or simply remove the disease, thus giving a falsely high regression rate, or (b) miss a juxtaposed invasive lesion, thus giving a falsely high progression rate, are acknowledged, but do not dissuade from the general conclusion. Cytologic followup, eliminating the criticism of biopsy

assessment, has resulted in similar con¬ clusions. Inferential observations tend to sup¬ port the concept of progression from in situ to invasive disease. As early as 1957 the average age at onset of carci¬ noma in situ had been reported to be significantly younger than the average age at diagnosis of invasive cancer.83 As discussed previously, both in situ and invasive disease have a higher in¬ cidence in the lower socioeconomic groups, in women who marry early, in women who have multiple sex partners,

ete.84-35

If one accepts the postulate that, in general, carcinoma of the cervix is pre¬ ceded by a period of in situ change, then from the point of view of a screen¬ ing program, the following questions need be asked: How long does the in situ phase last? Does carcinoma in situ regress? and Is invasive disease always preceded by carcinoma in situ? The an¬ swers, as reported, are as follows: 1. How long does the in situ phase

20-24 26-20 30-34 36-30 40-44 46-40 60-64 66-60 00-04 06-60 70-74

4.Age at diagnosis of preclinical and clinical carcinoma of the cervix age-specific rates per 1000 women; source, British Columbia screening program). 1010 CMA JOURNAL/JUNE 5, 1976/VOL. 114

last? Individual series

are

small and

FIG.

cidence) for the years 1966 to 1970, the age-specific rates of occult invasive carcinoma and microinvasive carcino¬ ma in all women screened (a mixture of incidence and prevalence) for 1964 to 1968, and age-specific rates for clin¬ ical invasive carcinoma (rates derived from the total population, which must be regarded as true incidence) for the years 1959 to 1963. Note that the scale for in situ carcinoma, which appears on the left-hand side of the figure, is different from the scale for all other conditions, which appears on the righthand side. Different time periods were chosen for the following reasons: 1966-70 is the most recent period for which in situ incidence data are available; 1964-68 was a period when a screening program had been operating for some time (so that many cases were found in women who had previously been screened) but before extensive screening had re¬ moved most cases of microinvasive and occult invasive from the population; 1959-63 is the most recent period in which clinical invasive carcinoma was occurring in a largely unscreened popu¬ lation in British Columbia. The incidence of in situ carcinoma peaks in the age group 25 to 29 and gradually declines to nearly zero at older ages. In the youngest age group studied, 20 to 24, there is already an appreciable incidence. This is an earlier peak in incidence than had been noted previously and is an expression not only of the use of incidence rates as distinct from prevalence rates but also of the changing characteristics of the disease in the population that is, a cohort or generation effect. Microinvasive carcinoma is bimodal. The first peak occurs at ages 35 to 44, and the second and broader peak at ages 55 to 74. Because this curve re¬ presents a mixture of prevalence and incidence, it is not really comparable with the curve for in situ cancer. If a true incidence curve for a similar time period were available, the first mode might more nearly correspond with that for in situ carcinoma and the second mode might be depressed. To help ex¬ clude the possibility that either mode might be an artefact of a particular cohort, available data for three time periods have been plotted in Fig. 5. In each time period two modes at simi¬ lar ages are seen, though in the most recent period (1969-73) the rates are much lower. It is important to appre¬ ciate that these data are derived from one program with review of all histology by one team of cytopathologists, so that consistent diagnostic criteria have been applied. During the 1960s many young women entered the British Columbia

arrow, but most patients who fail to respond to treatment will die approxi¬ mately 3 years after the diagnosis of invasive disease. This concept of the natural history is derived from cross-sectional data. Lon¬ gitudinal data derived from an unpublished study of two cohorts from the British Columbia population tend to confirm the concepts envisaged here. The natural history seems to be longer Occult invasive carcinoma and clin¬ than had previously been thought to be ical invasive carcinoma are both uni- the case, and progression appears to modaL'(Fig. 4), with identical peaks at occur in the majority of patients if they ages JoO to 64. This suggests that they are left untreated. The British Colum¬ bia cohort study does not yet encomare essentially similar conditions, the of not serving pass the modal age at onset of clinical symptoms development to distinguish different points in the invasive carcinoma, but suggests that natural history. It will be noted that the mode of onset of in situ carcinoma the older mode for microinvasive carci¬ is at ages 30 to 34. This, as previously noma approximates to the mode for indicated, is an expression of the parti¬ the other invasive states and suggests cular birth cohorts studied and suggests that at these ages it may be a similar that the peak incidence of in situ carci¬ noma is becoming earlier. Therefore, condition. These modes may be summarized in some caution is necessary in interpreta¬ the form of an arrow similar to that tion of the data in Fig. 6. If the modal in Fig. 1, suggesting the progressive age at onset of in situ carcinoma has nature of the condition (Fig. 6). recently become 5 years earlier, it is This new interpretation suggests a possible that when the same cohort of somewhat longer natural history than women reach the modal age at onset of invasive carcinoma, it too will be was suspected previously, with a 35year period between the modes for in 5 years earlier. If this is the case, the situ carcinoma and for clinical or oc¬ natural history at present might include cult invasive carcinoma. For simplicity, a modal age at onset of in situ carci¬ death has not been shown on either noma of 25 to 29 years and a 30-year

phy¬ requested to screen all women using contraceptive pills or intrauterine devices. Thus, a high-risk group was brought to the attention of the program for the first time. The double peak then could bean expres¬ sion of earlier onset of microinvasive disease in a group that has already shown an increased number of invasive lesions clinically. program for the first time because

sicians

were

.

5.Age at diagnosis of microinvasive carcinoma of the cervix in three periods (age-specific rates per 1000 women screened; source, British Columbia screening program). FIG.

Clinical invasive

25-29 yr FIG. 6.Natural

60-6*4

yr

history of carcinoma of the cervix, based on modal age of incidence. CMA JOURNAL/JUNE 5, 1976/VOL. 114 1011

period for progression to occult or clinical invasive carcinoma. It will be noted that dysplastic change does not appear in any of the figures. As has already been discussed, there is evidence to suggest that this commences a decade or so earlier than in situ disease. It may be objected that the modal ages depicted in Fig. 6 do not coincide with clinical experience. Because there are more young women than old women in the population, the peak occurrence of cases is seen at an earlier age than the peak rates. This discrepancy, which leads to the misconceptions that arose when mean ages were used as the basis of previous attempts to illustrate the natural history, but which are nevertheless important in operational terms, is illustrated in Table IV, which is derived from the most recently available British Columbia data and extrapolated to the total Canadian population. This indicates the modal age for cases is 25 to 29 for in situ carcinoma, 35 to 39 for microinvasive carcinoma and 50 to 54 for invasive carcinoma (comprising both occult and clinical invasive disease). The modal age of 45 to 49 for invasive carcinoma reported in the 1972 Statistics Canada data probably results from incorporation in these data of cases of microinvasive carcinoma. The modal ages for cases shown in Table IV should be regarded as the critical ages for operational considerations, but they do not, of course, conflict with the longer concept of natural history as presented above. It should also be noted that the discrepancy between the total number of cases of in situ carcinoma and the combined number of invasive cases Table IV-Estimated number of cases of carcinoma of the cervix in Canada* No. of carcinoma cases MicroOccult and clinical Age (yr) In situt invasive invasive § 2009 15 18 (12) 20-24 39 35 (35) 25-29 2913 1908 48 50 (66) 30-34 88 60 (77) 35-39 1238 92 (92) 40-44 921 66 80 121 (119) 45-49 599 145 (112) 50-54 395 41 55-59 250 17 129 (110) 60-64 171 62 95 (82) 103 18 73 (58) 65-69 73 0 72 (63) 70-74 41 99 (73) 75+ 44 989 (899) Total 10624 515 *Calculated by applying age-specific rates from British Columbia to the Canadian population for 1972. tDerived from incidence rates for 1966-70. jDerived from total disease rates for 1969-73. Derived from combined total disease rates for 1969-73 (in parentheses, numbers of cases registered with Statistics Canada in 1972 as invasive carcinoma of cervix; Ontario data not includad).

cannot be regarded as an indication of regression. It largely disappears when, as in the cohort study in British Columbia, allowance is made for negative error due to false-negative results of initial examination, persistence of in situ carcinoma without progression, cohort effects, and the fall-off in the population at older ages from migration and death from other causes. Within the past decade there have been studies demonstrating disparity between the predictions of theoretical models and clinical observations of in situ carcinoma, particularly in the later age groups.40'41 The cohort study in British Columbia has the potential for resolving this disagreement. Conclusion The natural history of carcinoma of the cervix, with its precursor states of dysplasia and in situ change, as well as the anatomic availability of the cervix for repeated examination, are all circumstances particularly suited to a screening program. It would appear that the great majority of invasive cancers of the cervix could be prevented by detection and treatment in the dysplastic or in situ state. However, the biologic variation of this tumour and practical difficulties in achieving total population coverage with screening suggest that, even with the most efficient screening program, invasive cancer of the cervix will not be totally eliminated. As more accurate information concerning the total spectrum of this disease becomes available we will be able to estimate with greater accuracy the expected success rate of screening programs of any particular design. References mallatie cancerose. Giorn Servire Progr Pathol Terap 2: 507, 1842 2. GAGNON F: Contribution to the study of the etiology and prevention of cancer of the cervix of the uterus. Am J Obstet Gynecol 60: 516, 1950 3. DoLL R, PAYNE P, WATERHOUSE J (eds): Cancer incidence in Five Continents, International Union Against Cancer, Berlin, SpringerVerlag, 1966 (vol 1), 1972 (vol 2) 4. HILL GB: Mortality from malignant neoplasm of the uterus since 1950. World Health Stat Rep 28: 323, 1975 5. Statistics Canada: New primary sites of malignant neoplasms in Canada by census district, cat no 82-207 (annual), Ottawa, Information Canada, June 1972 (1969-70), June 1973 (1971), Mar 1975 (1972) 6. MACKAY EN, SELLERS AH: The Ontario cancer incidence survey, 1964-1966: a new approach to cancer data acquisition. Can Med Assoc / 109: 489, 1973 7. Statistics Canada: Causes of Death in Canada: provinces by sex and Canada by sex and age, cat no 84-203 (annual), Ottawa, Information Canada, Oct 1971 (1969), Dec 1971 (1970), Nov 1972 (1971), Mar 1974 (1972) 8. CLEMMESEN J: Statistical studies in the aetiology of malignant neoplasms. II. Basic tables. Acta Pathol Microbiol Scand 1 (suppi 174): 277, 1965 9. Ro'ricrn ID: A comparison review of key epidemiological studies in cervical cancer related to current searches for transmissible agents. Cancer Res 33: 1353, 1973 10. MELAMED MR. Koss LG, FLEHINGER BJ, et al: Prevalence rates of uterine cervical carcinoma in situ for women using the diaphragm or contraceptive oral steroids. Br Med 1 3: 195, 1969

1012 CMA JOURNAL/JUNE 5, 1976/VOL. 114

11. Second report of the special committee appointed by the minister of national health and welfare to advise the health protection branch on all aspects of the safety and efficacy of oral contraceptives marketed in Canada. Rx Bull 6 (suppl 1): 20, 1975 12. BERAL V: Cancer of the cervix: a sexually transmitted infection? Lancet 1: 1037, 1974 13. ADAM E, RAwis WE, MELNICK JL: The association of herpesvirus type 2 infection and cervical cancer. Prey Med 3: 122, 1974

14. RAWLS WE, ADAM E, MELNICK JL: An analysis of seroepidemiological studies of herpesvirus type 2 and carcinoma of the cervix. Cancer Res 33: 1477, 1973

15. AURELIAN L: Persistence and expression of the herpes simplex virus type 2 genome in cervical tumor cells. Cancer Res 34: 1126,

1974 16. FRENKEL N, ROIZMAN B, CAssAs E, et al: A DNA fragment of herpes simplex 2 and its transcription in human cervical cancer tissue. Proc Nail Acad Sd USA 69: 3784, 1972 17. RAPP F, DUFF R: Transformation of hamster embryo fibroblasts by herpes simplex viruses type 1 and type 2. Cancer Res 33: 1527, 1973

18. HOLLINSHEAD AC, LEE OB, CHRETIEN PB,

et al: Antibodies to herpesvirus nonvirion antigens in squamous carcinomas. Science 182: 713, 1973 19. KESSLER II: Perspectives on the epidemiology of cervical cancer with special reference to the herpesvirus hypothesis. Cancer Res 34:

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cervical epithelium (chap 3), in Early Histological Diagnosis of Cervical Cancer, op cit, p 21 32. RICHART RM: Natural history of cervical interepithelial neoplasia. Mod Treat 5: 748, 1968 33. HERTIG AT, MANSELL H: What is carcinoma in situ of the cervix? in Progress in Gynaecology, vol 3, Maws JV, SrURGIS SH (eds), New York, Grune, 1957, pp 520-34 34. BOYD JT, DOLL R: A study of the aetiology of carcinoma of the cervix uteri. Br I Cancer 18: 419, 1964 35. Ciiius.roPuERsON WM, PARKER JE: Relation of cervical cancer to early marriage and childbearing. N Engl I Med 273: 235, 1965 36. WYNDER EL: Epidemiology of carcinoma in

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Cervical cancer screening programs. I. Epidemiology and natural history of carcinoma of the cervix.

Cervical cancer screening programs* I. Epidemiology and natural history of carcinoma of the cervix Terms used in this report: The International Classi...
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