- Email: [email protected]
The natural history of cervical intraepithelial neoplasia
Current OBCJETRlCS
&
GYNAECOLOGY Mini symposium: Pre-malignant disease of the cervix
The natural history of cervical intraepithelial neoplasia
M. C. Anderson
Introduction
Cervical intraepithelial neoplasia (CIN) forms part of a spectrum of epithelial changes of the cervix which may precede the development of invasive carcinoma. Investigations into the natural history of CIN are hampered by many problems: _ inconsistent criteria for entry into the studies - inconsistency of diagnosis - short follow up times _ the effect of biopsies on the natural history - progression to invasive disease cannot knowingly be observed. All available data must therefore be considered unreliable, with regard both to progression and regression within the intraepithelial phase and to the progression of CIN to invasive carcinoma. The only firm conclusions that can be drawn are: - some examples of CIN 1 will appear to progress to CIN 3 _ some examples of CIN will regress _ some examples of CIN will appear to develop into invasive squamous cell carcinoma - some examples of CIN may remain unchanged - many examples of invasive squamous cell carcinoma are preceded by CIN - a few examples of invasive squamous cell carcinoma are not preceded by an intraepithelial phase that can be demonstrated using current screening intervals. The figures frequently quoted to accompany these statements are inaccurate; it is unlikely that reliable information will ever be available.
The management of a woman with cervical intraepithelial neoplasia (CIN) should be based on an understanding of the natural history of the disease, in terms of the likelihood of the lesion either to regress, to progress to a more severe form of CIN or to progress to invasive cancer as well as the length of time over which these changes take place. It has to be admitted, however, that, despite its perceived importance and the fact that a great deal has been written about it over the past three decades, very little reliable information is actually available on the natural history of CIN. It is convenient to consider the natural history of CIN in two separate stages: first, the way in which the grades of CIN relate to each other and, secondly, the relation between CIN and invasive carcinoma. This distinction is sensible because of the different approaches required and because most studies have concentrated on one or other of these aspects of behaviour but rarely on both. The relation between the grades of cervical intraepithelial neoplasia The concept of cervical intraepithlial
Before discussing the behaviour of CIN, it is relevant to re-state the current views on its nature. Figure 1 is a diagrammatic representation of the range of epithelial changes of the cervix. Cervical intraepithelial neoplasia occupies only part of this continuous spectrum of change, with minor degrees of ‘atypia’ (to which the term ‘basal abnormalities of uncertain significance’ has recently been applied’) and squamous metaplasia at one end. It is important to recognise
FRCOC FRCPath, Senior Lecturer and Honorary Consultant, Department of Histopathology, University Hospital, Queens Medical Centre, Nottingham, NG7 2UH, UK
Dr. M. C. Anderson
Currenr Obsrelrics 0 I991 Longman
and Gynmcology Group UK Ltd
(1991) 1. 124-129
neoplasia
124
THE NATURAL
HISTORY
OF CERVICAL
INTRAEPITHELIAL
NEOPLASIA
125
Fig. 1 - The spectrum of cervical epithelial abnormalities. The central graded scale represents the reality of the epithelial changes in the cervix. This is superimposed upon the usually applied subdivisions. The histological features of human papillomavirus infection may be seen at all points of the spectrum. HPV= Human papillomavirus. BAUS= Basal abnormalities of uncertain significance. (Based on a scheme suggested by Professor E. Burghard?“)
that any divisions within this spectrum, either distinguishing between CIN 1, CIN 2 and CIN 3, separating CIN from the basal abnormalities of uncertain significance, or separating the latter from benign squamous metaplasia, are artificial and arbitrary. This concept of CIN raises a number of questions that relate to the investigation of the natural history of CIN and these in turn affect the validity of studies intended to shed light on its natural history. Progression and regression in cervical intraepithelial neoplasia
The arrows at the top and bottom of Figure 1 refer to the most widely accepted views on the behaviour of CIN: the upper arrow indicates that the more severe an abnormality is, the greater is the chance that it will progress to an even more severe form of CIN and to invasive carcinoma. The lower arrow indicates the converse, that the milder an abnormality is, the greater is the chance of it regressing to an even milder form of CIN or to squamous metaplasia. The concept of CIN developing by a sequence of gradual, stepwise events, starting at CIN 1 and progressing through CIN 2 to CIN 3, until invasive potential is acquired, is not founded on scientific data but is based on cytological studies, which sample the cervix as a whole and do not yield information regarding the behaviour of the epithelium at one fixed point on the cervix. The transformation zone of the cervix is rarely uniform; it is usually a patchwork of areas of benign metaplasia, CIN 1, CIN 2 and CIN 3. This almost universal finding of different grades of CIN on the same cervix argues against a stepwise progression from a minor abnormality to a more severe
one.2 There is no agreement whether the origin of CIN is unicellular or multicellular; however, proponents of the multicellular theory would accept that CIN 1 may develop in one area and CIN 2 or CIN 3 in another area at a later date. Repeat cervical cytology in this instance would suggest a stepwise progression of the disease whereas the reality would be that a newly formed clone of severely abnormal cells has developed within the transformation zone adjacent to or even within areas of milder abnormality. A logical extension of this argument is that a clone of severely abnormal cells may develop ab initio without a preceding area of mild abnormality being present in the transformation zone. In other words, the hypothesis would support a suggestion that CIN 3 may arise without being preceded by even a short phase of CIN 2 or CIN 1. This is borne out by the clinical experience that many women who present with CIN 3 have had recent cytology that has been entirely normal. It is, unfortunately, impossible to determine whether CIN 3 develops in a gradual, stepwise fashion through the minor grades of abnormality or by a process that is punctuated by the emergence of new clones of abnormal cells. Repeat biopsies cannot be taken from the same targetted area of epithelium; the first biopsy would remove the piece of epithelium under study so that the appearances of the same area of follow-up biopsy would be meaningless in terms of natural history. The accuracy of diagnosis of cervical intraepithelial neoplasia
Even though it can be questioned whether or not an individual example of CIN inevitably progresses
126
CURRENT
OBSTETRICS
AND GYNAECOLOGY
gradually through the grades of abnormality before developing invasive potential, the spectrum of disease illustrated in Figure 1 accurately reflects the wide range of histological appearances that are present in a population of women with cervical abnormalities. It must be emphasised that the dividing lines that need to be introduced in this spectrum to allow a distinction to be made between the grades of CIN and, indeed, to distinguish CIN from those disorders that do not warrant the diagnosis of CIN are artificial and arbitrary and do not occupy hxed and reproducible points on the scale. Consequently, a considerable degree of subjectivity exists in the histological diagnosis of CIN, as applied both to its grading and to its recognition. The diagnostic inconsistency that results from this subjectivity has been highlighted in the past for dysplasia and carcinoma in situ3 and more recently for CIN. 4*5 These studies have shown that there is both interobserver and intraobserver variation in diagnosis. Furthermore, the more recent studies indicate that the diagnostic inconsistencies, both interobserver and intraobserver, become less marked as the degree of abnormality increases, suggesting that a diagnosis of CIN 3 is robust but that the distinction between minor degrees of CIN and between CIN and non-CIN ‘atypias’ is unreliable.4s5 These comments refer to the histological diagnosis of CIN. Studies of the consistency of the cytological diagnosis have not been done but, as the underlying concepts are the same, similar results would be expected. Colposcopy is the third diagnostic method that is employed; its accuracy as a precise method of determining the grade of CIN has never been claimed, although many practitioners unfortunately expect the technique to have greater accuracy than it can hope to achieve. There is therefore no reliable yardstick against which a diagnosis of CIN can be measured; studies in which both the entry point and the end point are subjective and arbitrary cannot be relied upon. The results of studies Attempts to clarify the relation between the grades of CIN have involved recruiting women with minor degrees of abnormality and following them for a period of time. Follow up has been by cytology alone,6 cytology and colpomicroscopy,’ cytology and biopsy,*,’ cytology, colposcopy and biopsy”,” and cytology and co1poscopy.‘* There are flaws in all these studies: - inconsistent criteria for entry into the study - lack of reliability of histological, cytological and colposcopic diagnoses, as discussed above, at all points of the study - uncertainty about the meaning of progression and regression, as discussed above - follow up periods that are too short - taking a biopsy interferes with the natural history of the disease.’
Most of the work referred to here was done a few years ago, before the CIN terminology was in use and so the terms dysplasia and carcinoma in situ are used. Richart & Barron’ followed patients with a cytological diagnosis of dysplasia for several years. No biopsies were taken and follow up was by cytology and colpomicroscopy. In an attempt to avoid the inclusion of false positives, patients were not admitted until they had 2 abnormal smears. The authors found that the median transit times for progression from mild, moderate and severe dysplasia to carcinoma in situ were 58 months, 38 months and 12 months respectively. The regression rate was only 6% and the authors attributed this low figure to the fact that biopsies were not taken. They believed that the taking of even a small piece of tissue from a CIN materially altered its natural history. Johnson et al,* on the other hand, found a regression rate of 50.4% in patients with dysplasia who were followed by cytology and biopsy over periods of up to 10 years. In the same interval only 1.4% progressed to carcinoma in situ. When Galvin et al9 looked at the grades of dysplasia individually, they found that, of the mild abnormalities, 53.9% regressed and 16.6% progressed, whereas the reverse was true for the severe changes, with 17.1% regressing and 65.7% progressing to carcinoma in situ. Many authors have produced comparable results, using biopsies13 and cytology.6 Campion et al’* followed 100 women with CIN 1 for a period of up to only 30 months; 26% progressed to CIN 3 within 19 months and 7% regressed to normal by the end of the study. Recent authors have avoided quoting progression rates, being aware of the impossibility of obtaining reliable results.lO+ll These large studies have, however, provided interesting information on regression rates. Fletcher et al, lo followed 666 women who initially had mild or moderate dyskaryosis by cytology over a period of 4.5 years and found that 24% reverted to a normal cell pattern sustained in several smears over 18 months. In an even larger group of patients, Robertson et al’ ’ found that 46% of women with mild dyskaryosis returned to having normal smears over a 2-year period. The detailed results from these studies are not consistent but they do confirm the general tendencies of progression and regression outlined above; a woman with CIN is at risk of a higher grade of CIN developing but, if the CIN is of mild degree, there is a chance that it may regress. The available evidence does not allow these risks to be quantified with any precision. The relation between cervical intraepithelial neoplasia and invasive carcinoma The traditional assumptions Large sums of money are spent in the UK and in other developed countries on cervical screening pro-
THE NATURAL
HISTORY
grammes, the aim of which is to reduce the mortality and morbidity from cervical cancer by diagnosing and treating the precursors in asymptomatic women. The validity of these programmes is based on 2 assumptions: - Cervical intraepithelial neoplasia progresses to invasive carcinoma if left untreated _ Invasive squamous cell carcinoma of the cervix is preceded by a demonstrable intraepithelial phase. The greater the proportion of cases in which these 2 statements are true, the more worthwhile the screening programmes are. Clearly, if only a small proportion of women with CIN would eventually develop carcinoma, then the cost is very high for each case of invasive carcinoma prevented, because many women will be treated who would never develop cancer. This cost should be measured not just in terms of the use of scarce resources but also in terms of the harm caused to the population being screened; the anxiety of a woman who has an abnormal smear and the possible physical damage of unnecessary treatment must be balanced against the benefits. Secondly, a programme designed to prevent cervical cancer by treating precursors cannot hope to succeed if even a small proportion of invasive carcinomas are not preceded by a demonstrable intraepithelial phase. Limitations of investigations into the relation between cervical intraepithelial neoplasia and invasive carcinoma It is impossible to design a study to ascertain the relation between CIN and invasive carcinoma because: - The end-point of such a study is the development of invasive carcinoma. Such a study would be morally indefensible as women cannot be subjected to the increased risk to life that the development of even an early invasive carcinoma would impart, particularly as the disease would initially be diagnosed in the preinvasive phase - A confident diagnosis of CIN with the certain exclusion of invasive disease has to be made at the start of the trial. For this to be done, the whole transformation zone needs to be examined; cytology, colposcopy and punch biopsies are not sufficiently reliable. This leads to treatment of the CIN in most instances, so that follow up to determine the natural history is meaningless. It is apparent therefore that the precise relation between CIN and invasive carcinoma of the cervix will never be known. Nevertheless, a small number of studies have been carried out in the past and these will now be discussed. The results of studies The results from the work of Petersen and of Kottmeier are the most well known with regard to the
OF CERVICAL
INTRAEPITHELIAL
NEOPLASIA
127
relationship between CIN and invasive carcinoma. Kottmeier’s initial results showed that 8 out of 59 women whose carcinoma in situ was not treated developed invasive carcinoma, a percentage of 13.6, which has been widely quoted.14 In 1955, however, Kottmeier admitted that many of his original diagnoses were incorrect and that only 14 of the patients had acceptable carcinoma in situ. 8 of these women eventually developed invasive carcinoma, giving a figure of 57% over a period of 10 years. Later still, Kottmeier reported that 3 1 women had been followed for at least 12 years and that 22 (71%) of these had developed invasive disease.15 34 out of 127 women (26%) with ‘epithelial atypia’ reported by Petersen ultimately developed invasive carcinoma.i6 In a fuller account of the same patients, he admitted that only 67 of them had a recognisable abnormality still present at the end of the first year to follow up.” Of these 67 who remained in the series, % eventually developed invasive carcinoma. These amended results from Kottmeier and Petersen are not often quoted, unfortunately; they may well give a more reliable indication of the malignant potential of CIN than these authors’ earlier figures. McIndoe et al” analysed 948 women who had carcinoma in situ (CIN 3) diagnosed by histology, most of whom had cone biopsies. Of this group, 131 continued to have abnormal cytology, indicative of residual disease. No further treatment was given to these patients but they were carefully followed. After 10 years, 18% had developed invasive carcinoma and after 20 years the figure has risen to 36%. Of those whose cytology was normal after the initial treatment, 1.5% developed invasive carcinoma and 0.8% developed recurrent carcinoma in situ. In terms of relative risk, these authors conclude that a woman who has an abnormal smear after histological diagnosis of carcinoma in situ has a 24.8 times risk of developing invasive carcinoma when compared with a woman with a normal smear. In addition, a woman who has apparently been successfully treated for carcinoma in situ has a relative risk of 3.2. Many other studies are recorded in the literature. The results vary widely and they all suffer from the same criticisms of uncertainty of diagnosis at the time if entry into the trial and/or the methods of diagnosis interfering with the natural history of the disease. Length of natural history Another relevant factor which must be taken into consideration when planning screening programmes and determining the management of women with CIN is the duration of the preinvasive phase of the disease. Most of the evidence, both cytological7 and epidemiological,” suggests that CIN takes 10 years to become invasive, although a slightly more recent analysis of a statistical model puts forward a range of 3- 10 years for the carcinoma in situ phase.” These figures are supported by the fact that women with
128
CURRENT OBSTETRICS AND GYNAECOLOGY
CIN 3 are, on the whole, some 10-l 5 years younger than women with invasive carcinoma. There have been disquieting reports, however, of young women developing invasive carcinoma of the cervix who had recent negative cytology.2’s22 There are several explanations for these occurrences.23 The most obvious is that some of the smears were false negatives and would have been found to contain malignant cells on review. Others may have been genuine false negatives, in which the tumour did not exfoliate cells and none were present in the smears. It is impossible to escape the conclusion, however, that, at least in some of these women, there had been a real progression from a normal cervix to invasive carcinoma in the short length of time between the taking of the smear and the carcinoma being diagnosed, as little as 6 months in some examples. In an attempt to explain this phenomenon, it seems reasonable to speculate that, although the mean time interval for the progression through CIN to invasive carcinoma may be 10-l 5 years, a very few women will fall at the 2 extremes of the distribution curve of the length of natural history (Fig. 2). This means that some will have such a long natural history that progression to invasion will never occur in the course of a lifetime; these women would be classed as nonprogressors. On the other hand, there may be some at the other extreme, in whom the natural history of the disease runs a very rapid course, measured in months rather than years; these may be the patients described in the above reports. This hypothesis presumes that one disease process is occurring and that the difference in the behaviour in different women, whereby some seem to have no demonstrable intraepithelial phase, is the result of extreme variations in the length of the natural history of the same disease; it is not necessary to invoke a hypothesis of a different disease to explain the rapid progression that occasionally occurs. Whether external factors, such as infec-
Fig. 2 -A hypothetical representation of the distribution of the length of the intraepithelial phase of cervical carcinoma in a population of women. If the distribution follows this normal pattern, a very small proportion of women will be at each extreme and will either develop invasive carcinoma very rapidly (at the left-hand extreme) or not at all (at the right-hand extreme). The figures quoted are largely hypothetical, based on available date. SD = Standard deviatioh
tion by viruses or other agents, or internal factors, such as the state of the local or generalized immune system, affect the rate at which invasive disease develops is unknown. Conclusion Although at first sight there appears to be a considerable amount of information available about the natural history of CIN, this is largely based on questionable hypotheses that have been tested by unreliable studies. There is still a great deal to be learnt about this subject but it is unlikely that a complete understanding will ever be achieved, References 1. Anderson MC, Brown CL, Buckley CH, Fox H, Jenkins D, Lowe DG, Manners BT, Melcher D, Robertson AJ, Wells M. Current views on cervical intraepithelial neoplasia. J Clin Path01 1991 (in press) 2. Burghardt E, t)stiir AG. Site and origin of squamous cervical cancer: a histomorphologic study. Obstet Gynecol 1983; 62: 117-127 3. Cocker J, Fox H, Langley FA. Consistency in the histological diagnosis of epithelial abnormalities of the cervix uteri. J Clin Path01 1968; 21: 67-70 4. Ismael SM, Colclough AB, Dinnen JS, Eakins D, Evans DMD. Gradwell E. O’Sullivan JP. Summerell JM. Newcombe dG. Observer’ variation in h&topathological’ diagnosis and grading of cervical intraepithelial neoplasia. Br Med J 1989; 298: 707-710 5. Robertson AJ, Anderson JM, Swanson Beck J et al. Observer variability in histopathological reporting of cervical biopsy specimens. J Clin Path01 1989; 42: 231-238 Fox CH. Biologic behaviour of dysplasia and carcinoma in situ. Am J Obstet Gynecol 1967; 99: 960-974 Richart RM, Barron BA. A follow-up study of patients with cervical dysplasia. Am J Obstet Gynecol 1969; 105: 386-393 Johnson LD, Nickerson RJ, Easterday CL, Stuart RS, Hertig AT. Epidemiologic evidence for the spectrum of change from dysplasia through carcinoma in situ to invasive cancer. Cancer 1968; 22: 901-914 9. Galvin GA, Jones HW, TeLinde RW. The significance of basal-cell hyperactivity in cervical biopsies. Am J Obstet Gynecol 1955; 70: 808-821 10. Fletcher A, Metaxas N, Grubb C, Chamberlain J. Four and a half year follow up of women with dyskaryotic smears. Br Med J 1990; 301: 641-644 11. Robertson JH, Woodend BE, Crozier EH, Hutchinson J. Risk of cervical cancer associated with mild dyskaryosis. Br Med J 1988; 297: 18-21 12. Campion MJ, McCance DJ, Cuzick J, Singer A. Progressive potential of mild cervical atypia: prospective cytological, colposcopic, and virologic study. Lancet 1986; ii: 237-240 13. Hall JE, Walton L. Dysplasia of the cervix. A prospective study of 206 cases. Am J Obstet Gynecol. 1968; 100: 662-67 1 14. Kottmeier HL. Carcinoma of the female genitalia. Baltimore: Williams & Wilkins, 1953, 374 15. Kottmeier HL. fivolution et traitment des 6oithtliomas. Rev. Fr Gynecol Obstet 1961; 56: 821-826 16. Petersen 0. Precancerous changes of the cervical epithelium in relation to manifest cervical carcinoma. Acta radio1 1955; Supplement 127: 74-87 17. Petersen 0. Spontaneous course of cervical precancerous conditions. Am J Obstet Gynecol 1956; 72: 1063-1071 18. M&doe WA, McLean MR, Jones RW, Mullins PR. The invasive potential of carcinoma in situ of the cervix. Obstet Gynecol 1984; 64: 451-458 19. Fidler HK, Boyes DA, Worth AJ. Cervical cancer detection in British Columbia. J Obstet Gynaecol Br Comm 1968; 75: 392-404 20. Barron BA, Cahill MV, Richart RM. A statistical model of
THE NATURAL HISTORY OF CERVICAL INTRAEPITHELIAL the natural history of cervical neoplastic disease: the duration of carcinoma in situ. Gynecol Oncol 1978; 6: 196-205 21. Berkeley AS, LiVolsi VA, Schwartz PE. Advanced squamous cell carcinoma of the cervix with recent normal Papanicolaou tests. Lancet 1980; ii: 376-377 22. Prendiville W, Guillebaud J, Bamford P, Beilby J, Steele SJ.
NEOPLASIA
129
Carcinoma of cervix with recent normal Papanicolaou tests. Lancet 1980; ii: 853-854 23. MacGregor JE. Rapid onset cancer of the cervix. (Leader) Br Med J 1982; 284: 441-442 24. Burghardt E. Early histological diagnosis of cervical cancer. Friedman EA (ed) Major problems in obstetrics and gynecology, ~016. Saunders; Philadelphia, 1973: 27
&
GYNAECOLOGY Mini symposium: Pre-malignant disease of the cervix
The natural history of cervical intraepithelial neoplasia
M. C. Anderson
Introduction
Cervical intraepithelial neoplasia (CIN) forms part of a spectrum of epithelial changes of the cervix which may precede the development of invasive carcinoma. Investigations into the natural history of CIN are hampered by many problems: _ inconsistent criteria for entry into the studies - inconsistency of diagnosis - short follow up times _ the effect of biopsies on the natural history - progression to invasive disease cannot knowingly be observed. All available data must therefore be considered unreliable, with regard both to progression and regression within the intraepithelial phase and to the progression of CIN to invasive carcinoma. The only firm conclusions that can be drawn are: - some examples of CIN 1 will appear to progress to CIN 3 _ some examples of CIN will regress _ some examples of CIN will appear to develop into invasive squamous cell carcinoma - some examples of CIN may remain unchanged - many examples of invasive squamous cell carcinoma are preceded by CIN - a few examples of invasive squamous cell carcinoma are not preceded by an intraepithelial phase that can be demonstrated using current screening intervals. The figures frequently quoted to accompany these statements are inaccurate; it is unlikely that reliable information will ever be available.
The management of a woman with cervical intraepithelial neoplasia (CIN) should be based on an understanding of the natural history of the disease, in terms of the likelihood of the lesion either to regress, to progress to a more severe form of CIN or to progress to invasive cancer as well as the length of time over which these changes take place. It has to be admitted, however, that, despite its perceived importance and the fact that a great deal has been written about it over the past three decades, very little reliable information is actually available on the natural history of CIN. It is convenient to consider the natural history of CIN in two separate stages: first, the way in which the grades of CIN relate to each other and, secondly, the relation between CIN and invasive carcinoma. This distinction is sensible because of the different approaches required and because most studies have concentrated on one or other of these aspects of behaviour but rarely on both. The relation between the grades of cervical intraepithelial neoplasia The concept of cervical intraepithlial
Before discussing the behaviour of CIN, it is relevant to re-state the current views on its nature. Figure 1 is a diagrammatic representation of the range of epithelial changes of the cervix. Cervical intraepithelial neoplasia occupies only part of this continuous spectrum of change, with minor degrees of ‘atypia’ (to which the term ‘basal abnormalities of uncertain significance’ has recently been applied’) and squamous metaplasia at one end. It is important to recognise
FRCOC FRCPath, Senior Lecturer and Honorary Consultant, Department of Histopathology, University Hospital, Queens Medical Centre, Nottingham, NG7 2UH, UK
Dr. M. C. Anderson
Currenr Obsrelrics 0 I991 Longman
and Gynmcology Group UK Ltd
(1991) 1. 124-129
neoplasia
124
THE NATURAL
HISTORY
OF CERVICAL
INTRAEPITHELIAL
NEOPLASIA
125
Fig. 1 - The spectrum of cervical epithelial abnormalities. The central graded scale represents the reality of the epithelial changes in the cervix. This is superimposed upon the usually applied subdivisions. The histological features of human papillomavirus infection may be seen at all points of the spectrum. HPV= Human papillomavirus. BAUS= Basal abnormalities of uncertain significance. (Based on a scheme suggested by Professor E. Burghard?“)
that any divisions within this spectrum, either distinguishing between CIN 1, CIN 2 and CIN 3, separating CIN from the basal abnormalities of uncertain significance, or separating the latter from benign squamous metaplasia, are artificial and arbitrary. This concept of CIN raises a number of questions that relate to the investigation of the natural history of CIN and these in turn affect the validity of studies intended to shed light on its natural history. Progression and regression in cervical intraepithelial neoplasia
The arrows at the top and bottom of Figure 1 refer to the most widely accepted views on the behaviour of CIN: the upper arrow indicates that the more severe an abnormality is, the greater is the chance that it will progress to an even more severe form of CIN and to invasive carcinoma. The lower arrow indicates the converse, that the milder an abnormality is, the greater is the chance of it regressing to an even milder form of CIN or to squamous metaplasia. The concept of CIN developing by a sequence of gradual, stepwise events, starting at CIN 1 and progressing through CIN 2 to CIN 3, until invasive potential is acquired, is not founded on scientific data but is based on cytological studies, which sample the cervix as a whole and do not yield information regarding the behaviour of the epithelium at one fixed point on the cervix. The transformation zone of the cervix is rarely uniform; it is usually a patchwork of areas of benign metaplasia, CIN 1, CIN 2 and CIN 3. This almost universal finding of different grades of CIN on the same cervix argues against a stepwise progression from a minor abnormality to a more severe
one.2 There is no agreement whether the origin of CIN is unicellular or multicellular; however, proponents of the multicellular theory would accept that CIN 1 may develop in one area and CIN 2 or CIN 3 in another area at a later date. Repeat cervical cytology in this instance would suggest a stepwise progression of the disease whereas the reality would be that a newly formed clone of severely abnormal cells has developed within the transformation zone adjacent to or even within areas of milder abnormality. A logical extension of this argument is that a clone of severely abnormal cells may develop ab initio without a preceding area of mild abnormality being present in the transformation zone. In other words, the hypothesis would support a suggestion that CIN 3 may arise without being preceded by even a short phase of CIN 2 or CIN 1. This is borne out by the clinical experience that many women who present with CIN 3 have had recent cytology that has been entirely normal. It is, unfortunately, impossible to determine whether CIN 3 develops in a gradual, stepwise fashion through the minor grades of abnormality or by a process that is punctuated by the emergence of new clones of abnormal cells. Repeat biopsies cannot be taken from the same targetted area of epithelium; the first biopsy would remove the piece of epithelium under study so that the appearances of the same area of follow-up biopsy would be meaningless in terms of natural history. The accuracy of diagnosis of cervical intraepithelial neoplasia
Even though it can be questioned whether or not an individual example of CIN inevitably progresses
126
CURRENT
OBSTETRICS
AND GYNAECOLOGY
gradually through the grades of abnormality before developing invasive potential, the spectrum of disease illustrated in Figure 1 accurately reflects the wide range of histological appearances that are present in a population of women with cervical abnormalities. It must be emphasised that the dividing lines that need to be introduced in this spectrum to allow a distinction to be made between the grades of CIN and, indeed, to distinguish CIN from those disorders that do not warrant the diagnosis of CIN are artificial and arbitrary and do not occupy hxed and reproducible points on the scale. Consequently, a considerable degree of subjectivity exists in the histological diagnosis of CIN, as applied both to its grading and to its recognition. The diagnostic inconsistency that results from this subjectivity has been highlighted in the past for dysplasia and carcinoma in situ3 and more recently for CIN. 4*5 These studies have shown that there is both interobserver and intraobserver variation in diagnosis. Furthermore, the more recent studies indicate that the diagnostic inconsistencies, both interobserver and intraobserver, become less marked as the degree of abnormality increases, suggesting that a diagnosis of CIN 3 is robust but that the distinction between minor degrees of CIN and between CIN and non-CIN ‘atypias’ is unreliable.4s5 These comments refer to the histological diagnosis of CIN. Studies of the consistency of the cytological diagnosis have not been done but, as the underlying concepts are the same, similar results would be expected. Colposcopy is the third diagnostic method that is employed; its accuracy as a precise method of determining the grade of CIN has never been claimed, although many practitioners unfortunately expect the technique to have greater accuracy than it can hope to achieve. There is therefore no reliable yardstick against which a diagnosis of CIN can be measured; studies in which both the entry point and the end point are subjective and arbitrary cannot be relied upon. The results of studies Attempts to clarify the relation between the grades of CIN have involved recruiting women with minor degrees of abnormality and following them for a period of time. Follow up has been by cytology alone,6 cytology and colpomicroscopy,’ cytology and biopsy,*,’ cytology, colposcopy and biopsy”,” and cytology and co1poscopy.‘* There are flaws in all these studies: - inconsistent criteria for entry into the study - lack of reliability of histological, cytological and colposcopic diagnoses, as discussed above, at all points of the study - uncertainty about the meaning of progression and regression, as discussed above - follow up periods that are too short - taking a biopsy interferes with the natural history of the disease.’
Most of the work referred to here was done a few years ago, before the CIN terminology was in use and so the terms dysplasia and carcinoma in situ are used. Richart & Barron’ followed patients with a cytological diagnosis of dysplasia for several years. No biopsies were taken and follow up was by cytology and colpomicroscopy. In an attempt to avoid the inclusion of false positives, patients were not admitted until they had 2 abnormal smears. The authors found that the median transit times for progression from mild, moderate and severe dysplasia to carcinoma in situ were 58 months, 38 months and 12 months respectively. The regression rate was only 6% and the authors attributed this low figure to the fact that biopsies were not taken. They believed that the taking of even a small piece of tissue from a CIN materially altered its natural history. Johnson et al,* on the other hand, found a regression rate of 50.4% in patients with dysplasia who were followed by cytology and biopsy over periods of up to 10 years. In the same interval only 1.4% progressed to carcinoma in situ. When Galvin et al9 looked at the grades of dysplasia individually, they found that, of the mild abnormalities, 53.9% regressed and 16.6% progressed, whereas the reverse was true for the severe changes, with 17.1% regressing and 65.7% progressing to carcinoma in situ. Many authors have produced comparable results, using biopsies13 and cytology.6 Campion et al’* followed 100 women with CIN 1 for a period of up to only 30 months; 26% progressed to CIN 3 within 19 months and 7% regressed to normal by the end of the study. Recent authors have avoided quoting progression rates, being aware of the impossibility of obtaining reliable results.lO+ll These large studies have, however, provided interesting information on regression rates. Fletcher et al, lo followed 666 women who initially had mild or moderate dyskaryosis by cytology over a period of 4.5 years and found that 24% reverted to a normal cell pattern sustained in several smears over 18 months. In an even larger group of patients, Robertson et al’ ’ found that 46% of women with mild dyskaryosis returned to having normal smears over a 2-year period. The detailed results from these studies are not consistent but they do confirm the general tendencies of progression and regression outlined above; a woman with CIN is at risk of a higher grade of CIN developing but, if the CIN is of mild degree, there is a chance that it may regress. The available evidence does not allow these risks to be quantified with any precision. The relation between cervical intraepithelial neoplasia and invasive carcinoma The traditional assumptions Large sums of money are spent in the UK and in other developed countries on cervical screening pro-
THE NATURAL
HISTORY
grammes, the aim of which is to reduce the mortality and morbidity from cervical cancer by diagnosing and treating the precursors in asymptomatic women. The validity of these programmes is based on 2 assumptions: - Cervical intraepithelial neoplasia progresses to invasive carcinoma if left untreated _ Invasive squamous cell carcinoma of the cervix is preceded by a demonstrable intraepithelial phase. The greater the proportion of cases in which these 2 statements are true, the more worthwhile the screening programmes are. Clearly, if only a small proportion of women with CIN would eventually develop carcinoma, then the cost is very high for each case of invasive carcinoma prevented, because many women will be treated who would never develop cancer. This cost should be measured not just in terms of the use of scarce resources but also in terms of the harm caused to the population being screened; the anxiety of a woman who has an abnormal smear and the possible physical damage of unnecessary treatment must be balanced against the benefits. Secondly, a programme designed to prevent cervical cancer by treating precursors cannot hope to succeed if even a small proportion of invasive carcinomas are not preceded by a demonstrable intraepithelial phase. Limitations of investigations into the relation between cervical intraepithelial neoplasia and invasive carcinoma It is impossible to design a study to ascertain the relation between CIN and invasive carcinoma because: - The end-point of such a study is the development of invasive carcinoma. Such a study would be morally indefensible as women cannot be subjected to the increased risk to life that the development of even an early invasive carcinoma would impart, particularly as the disease would initially be diagnosed in the preinvasive phase - A confident diagnosis of CIN with the certain exclusion of invasive disease has to be made at the start of the trial. For this to be done, the whole transformation zone needs to be examined; cytology, colposcopy and punch biopsies are not sufficiently reliable. This leads to treatment of the CIN in most instances, so that follow up to determine the natural history is meaningless. It is apparent therefore that the precise relation between CIN and invasive carcinoma of the cervix will never be known. Nevertheless, a small number of studies have been carried out in the past and these will now be discussed. The results of studies The results from the work of Petersen and of Kottmeier are the most well known with regard to the
OF CERVICAL
INTRAEPITHELIAL
NEOPLASIA
127
relationship between CIN and invasive carcinoma. Kottmeier’s initial results showed that 8 out of 59 women whose carcinoma in situ was not treated developed invasive carcinoma, a percentage of 13.6, which has been widely quoted.14 In 1955, however, Kottmeier admitted that many of his original diagnoses were incorrect and that only 14 of the patients had acceptable carcinoma in situ. 8 of these women eventually developed invasive carcinoma, giving a figure of 57% over a period of 10 years. Later still, Kottmeier reported that 3 1 women had been followed for at least 12 years and that 22 (71%) of these had developed invasive disease.15 34 out of 127 women (26%) with ‘epithelial atypia’ reported by Petersen ultimately developed invasive carcinoma.i6 In a fuller account of the same patients, he admitted that only 67 of them had a recognisable abnormality still present at the end of the first year to follow up.” Of these 67 who remained in the series, % eventually developed invasive carcinoma. These amended results from Kottmeier and Petersen are not often quoted, unfortunately; they may well give a more reliable indication of the malignant potential of CIN than these authors’ earlier figures. McIndoe et al” analysed 948 women who had carcinoma in situ (CIN 3) diagnosed by histology, most of whom had cone biopsies. Of this group, 131 continued to have abnormal cytology, indicative of residual disease. No further treatment was given to these patients but they were carefully followed. After 10 years, 18% had developed invasive carcinoma and after 20 years the figure has risen to 36%. Of those whose cytology was normal after the initial treatment, 1.5% developed invasive carcinoma and 0.8% developed recurrent carcinoma in situ. In terms of relative risk, these authors conclude that a woman who has an abnormal smear after histological diagnosis of carcinoma in situ has a 24.8 times risk of developing invasive carcinoma when compared with a woman with a normal smear. In addition, a woman who has apparently been successfully treated for carcinoma in situ has a relative risk of 3.2. Many other studies are recorded in the literature. The results vary widely and they all suffer from the same criticisms of uncertainty of diagnosis at the time if entry into the trial and/or the methods of diagnosis interfering with the natural history of the disease. Length of natural history Another relevant factor which must be taken into consideration when planning screening programmes and determining the management of women with CIN is the duration of the preinvasive phase of the disease. Most of the evidence, both cytological7 and epidemiological,” suggests that CIN takes 10 years to become invasive, although a slightly more recent analysis of a statistical model puts forward a range of 3- 10 years for the carcinoma in situ phase.” These figures are supported by the fact that women with
128
CURRENT OBSTETRICS AND GYNAECOLOGY
CIN 3 are, on the whole, some 10-l 5 years younger than women with invasive carcinoma. There have been disquieting reports, however, of young women developing invasive carcinoma of the cervix who had recent negative cytology.2’s22 There are several explanations for these occurrences.23 The most obvious is that some of the smears were false negatives and would have been found to contain malignant cells on review. Others may have been genuine false negatives, in which the tumour did not exfoliate cells and none were present in the smears. It is impossible to escape the conclusion, however, that, at least in some of these women, there had been a real progression from a normal cervix to invasive carcinoma in the short length of time between the taking of the smear and the carcinoma being diagnosed, as little as 6 months in some examples. In an attempt to explain this phenomenon, it seems reasonable to speculate that, although the mean time interval for the progression through CIN to invasive carcinoma may be 10-l 5 years, a very few women will fall at the 2 extremes of the distribution curve of the length of natural history (Fig. 2). This means that some will have such a long natural history that progression to invasion will never occur in the course of a lifetime; these women would be classed as nonprogressors. On the other hand, there may be some at the other extreme, in whom the natural history of the disease runs a very rapid course, measured in months rather than years; these may be the patients described in the above reports. This hypothesis presumes that one disease process is occurring and that the difference in the behaviour in different women, whereby some seem to have no demonstrable intraepithelial phase, is the result of extreme variations in the length of the natural history of the same disease; it is not necessary to invoke a hypothesis of a different disease to explain the rapid progression that occasionally occurs. Whether external factors, such as infec-
Fig. 2 -A hypothetical representation of the distribution of the length of the intraepithelial phase of cervical carcinoma in a population of women. If the distribution follows this normal pattern, a very small proportion of women will be at each extreme and will either develop invasive carcinoma very rapidly (at the left-hand extreme) or not at all (at the right-hand extreme). The figures quoted are largely hypothetical, based on available date. SD = Standard deviatioh
tion by viruses or other agents, or internal factors, such as the state of the local or generalized immune system, affect the rate at which invasive disease develops is unknown. Conclusion Although at first sight there appears to be a considerable amount of information available about the natural history of CIN, this is largely based on questionable hypotheses that have been tested by unreliable studies. There is still a great deal to be learnt about this subject but it is unlikely that a complete understanding will ever be achieved, References 1. Anderson MC, Brown CL, Buckley CH, Fox H, Jenkins D, Lowe DG, Manners BT, Melcher D, Robertson AJ, Wells M. Current views on cervical intraepithelial neoplasia. J Clin Path01 1991 (in press) 2. Burghardt E, t)stiir AG. Site and origin of squamous cervical cancer: a histomorphologic study. Obstet Gynecol 1983; 62: 117-127 3. Cocker J, Fox H, Langley FA. Consistency in the histological diagnosis of epithelial abnormalities of the cervix uteri. J Clin Path01 1968; 21: 67-70 4. Ismael SM, Colclough AB, Dinnen JS, Eakins D, Evans DMD. Gradwell E. O’Sullivan JP. Summerell JM. Newcombe dG. Observer’ variation in h&topathological’ diagnosis and grading of cervical intraepithelial neoplasia. Br Med J 1989; 298: 707-710 5. Robertson AJ, Anderson JM, Swanson Beck J et al. Observer variability in histopathological reporting of cervical biopsy specimens. J Clin Path01 1989; 42: 231-238 Fox CH. Biologic behaviour of dysplasia and carcinoma in situ. Am J Obstet Gynecol 1967; 99: 960-974 Richart RM, Barron BA. A follow-up study of patients with cervical dysplasia. Am J Obstet Gynecol 1969; 105: 386-393 Johnson LD, Nickerson RJ, Easterday CL, Stuart RS, Hertig AT. Epidemiologic evidence for the spectrum of change from dysplasia through carcinoma in situ to invasive cancer. Cancer 1968; 22: 901-914 9. Galvin GA, Jones HW, TeLinde RW. The significance of basal-cell hyperactivity in cervical biopsies. Am J Obstet Gynecol 1955; 70: 808-821 10. Fletcher A, Metaxas N, Grubb C, Chamberlain J. Four and a half year follow up of women with dyskaryotic smears. Br Med J 1990; 301: 641-644 11. Robertson JH, Woodend BE, Crozier EH, Hutchinson J. Risk of cervical cancer associated with mild dyskaryosis. Br Med J 1988; 297: 18-21 12. Campion MJ, McCance DJ, Cuzick J, Singer A. Progressive potential of mild cervical atypia: prospective cytological, colposcopic, and virologic study. Lancet 1986; ii: 237-240 13. Hall JE, Walton L. Dysplasia of the cervix. A prospective study of 206 cases. Am J Obstet Gynecol. 1968; 100: 662-67 1 14. Kottmeier HL. Carcinoma of the female genitalia. Baltimore: Williams & Wilkins, 1953, 374 15. Kottmeier HL. fivolution et traitment des 6oithtliomas. Rev. Fr Gynecol Obstet 1961; 56: 821-826 16. Petersen 0. Precancerous changes of the cervical epithelium in relation to manifest cervical carcinoma. Acta radio1 1955; Supplement 127: 74-87 17. Petersen 0. Spontaneous course of cervical precancerous conditions. Am J Obstet Gynecol 1956; 72: 1063-1071 18. M&doe WA, McLean MR, Jones RW, Mullins PR. The invasive potential of carcinoma in situ of the cervix. Obstet Gynecol 1984; 64: 451-458 19. Fidler HK, Boyes DA, Worth AJ. Cervical cancer detection in British Columbia. J Obstet Gynaecol Br Comm 1968; 75: 392-404 20. Barron BA, Cahill MV, Richart RM. A statistical model of
THE NATURAL HISTORY OF CERVICAL INTRAEPITHELIAL the natural history of cervical neoplastic disease: the duration of carcinoma in situ. Gynecol Oncol 1978; 6: 196-205 21. Berkeley AS, LiVolsi VA, Schwartz PE. Advanced squamous cell carcinoma of the cervix with recent normal Papanicolaou tests. Lancet 1980; ii: 376-377 22. Prendiville W, Guillebaud J, Bamford P, Beilby J, Steele SJ.
NEOPLASIA
129
Carcinoma of cervix with recent normal Papanicolaou tests. Lancet 1980; ii: 853-854 23. MacGregor JE. Rapid onset cancer of the cervix. (Leader) Br Med J 1982; 284: 441-442 24. Burghardt E. Early histological diagnosis of cervical cancer. Friedman EA (ed) Major problems in obstetrics and gynecology, ~016. Saunders; Philadelphia, 1973: 27