- Email: [email protected]
Rapidly progressive cervical cancer: The Connecticut experience
Rapidly progressive cervical cancer: The Connecticut experience Peter E. Schwartz, MD," Olympia Hadjimichael, MPH, b David M. Lowell, MD, c Maria J. Merino, MD, d and Dwight Janerich, DDS ~ New Haven, Connecticut, and Bethesda, Maryland A review is presented of 15 years of clinical experience working with women who developedcervical cancer Within a short interval after the last reported negative Papanicolaou smear. Our initial report concerned isolated cases in which women were diagnosed with invasive cervical cancer within 1 year of a reported normal Papanicolaou smear. Our second report focused on a 10-year review of the Yale-New Haven Hospital experience, during which 40 of 555 women had rapidly progressive invasive disease; 35 cases (87.5%) occurred in women younger than 40 years old and almost all of the 40 diagnosed because of persistent symptoms despite a recent normal Papanicolaou smear. Our final experience is a population-based study of all women in Connecticut who developed cervical cancer between 1985 and 1990. A total of 118 of 481 (24.5%) participants were diagnosed with cervical cancer within 3 years of their last true-negative Papanicolaou smear. Adenocarcinomas occurred in 38 cases (32.2%). These data suggest that rapidly occurring cervical cancer may be a manifestation of endocervical carcinomas that have been inadequately screened. (Am J Obstet Gynecoi 1996;175:1105-9.)
Key words: Rapidly progressive cervical cancer, Papanicolaou smear screening
Cervical cancer is generally considered a slowly evolving disease that begins as mild dysplasia and progresses over as many as 10 or more years to invasive carcinoma? It is precisely this presumed gradual evolution, in addition to effective treatment of preinvasive conditions, that lends the Papanicolaou smear its preventive value and helps determine optimal screening intervals. However, other factors besides timely Papanicolaou smears and treatment if needed affect the incidence of cervical cancer. For example, the recent decade has witnessed a steady increase in this disease among young white women, presumably a well-screened population groupfl In Connecticut, the state with the oldest populationbased cancer registry in the United States (established in 1941), the incidence of cervical cancer began to decline even before the widespread introduction of Papanicolaou smear screening in 1956. 3 One factor contributing to this reduction could have been the practice by Connecticut physicians after World War II of p e r f o r m i n g total hysterectomies in preference to supracervical hysterectomies for the management of benign gynecologic disorders. Overall, Papanicolaou smear screening appears to
From the Department of Obstetrics and Gynecology,° Department of Epidemiology, b and Department of Pathology,c University of Connecticut School of Medicine, and the Department of Pathology, d National Cancer Institute. P~print requests: Peter,E. Schwartz, MD, Department of Obstetrics and Gynecology, Connecticut University School of Medicine, 333 Cedar St., New Haven, CT 06520. 0002-9378/96 $5.00 + 0 6/0/76934
have been effective in Connecticut: the rate of cervical carcinoma in situ has essentially plateaued in the past 15 years, which suggests that the screening needs of the target population that participates in screening, that is, women at high risk for cervical cancer, are being addressed. 4 However, signs began to appear in the late 1970s of an atypical natural history of cervical cancer in some women. In these cases the interval between the last negative Papanicolaou smear and the diagnosis of invasive disease was unusually short, sometimes only a few months. Initial reports of these cases were anecdotal, but a comprehensive study supported by a Clinical Cancer Research Unit (CCRU) grant in 1985 enabled us to examine the p h e n o m e n o n of "rapidly progressive" cervical cancer more closely. 4 The investigations conducted under CCRU support built on questions generated by earlier reports of the Yale-New Haven Medical Center retrospective study. ~'6
Yale-New Haven Retrospective Study A large retrospective study of invasive cancer of the cervix was reported from the Yale-New Haven Medical Center in 1983. 6 It included women with cervical cancer who were followed up for as long as 25 years. Results were similar to those in most other cervical cancer studies in that the stage of cancer was the single most important prognostic factor. 7-1°Histologic type was also important, as evidenced by the fact that women with squamous cell carcinomas had a statistically significant better overall 1105
1106
Schwartz at al.
survival (p= 0.002) than those with a d e n o c a r c i n o m a s and a trend toward a better disease-free survival (p = 0.1). Within any of the I n t e r n a t i o n a l Federation of Gynecologists and Obstetricians (FIGO) stages, t u m o r size was the most i m p o r t a n t factor in disease-free survival (p = 0.006), as well as in local-regional control (p = 0.023). Age was strongly associated with overall survival, with w o m e n 55 years (median age of the cervical cancer p o p u l a t i o n at the Yale-New Haven Medical Center) or younger, stage for stage, surviving l o n g e r than older w o m e n over the 25-year follow-up period. In contrast, w o m e n 55 years old or younger actually had p o o r e r local-regional control of their cancer with radiation therapy than did older w o m e n (p= 0.02). This subset of w o m e n received radiation therapy almost exclusively and did better than younger patients who also were almost exclusively treated with radiation therapy.
"Rapidly progressive" cervical cancer In 1975 our group began to be interested in the cases of w o m e n whose disease did not seem to c o n f o r m to the usual pattern of cervical cancer evolution. We initially r e p o r t e d on 10 w o m e n with cervical cancer who reportedly had negative Papanicolaou snmars within 1 year before their diagnosis. 5 All but one were treated with prim a r y radiation therapy but ultimately died of cervical cancer. T h e one e x c e p t i o n was a 20-year-old patient with a 6 cm stage IB cancer of the cervix who u n d e r w e n t a primary radical hysterectomy, received pelvic radiation therapy after surgery, and was alive and well 10 years later. Between 1975 and 1984, 40 w o m e n had Papanicolaou smear histories that suggested the presence of a f o r m of rapidly progressive disease, n Thirty-five (88%) of these patients had had at least one negative Papanicolaou smear within 1 year before the diagnosis of invasive cancer (range, <1 to 17 months), and half had had a negative smear within 6 m o n t h s of diagnosis, n A n o t h e r distinctive feature of the "rapidly progressive" g r o u p was its age: these were very young women, with a m e d i a n age of 32 years (range, 20 to 54 years), versus the m e d i a n age of 55 years (as m e n t i o n e d previously) for w o m e n with cervical cancer at our institution. 6' ~ Thirty-five (88%) of the 40 w o m e n in the rapidly progressive g r o u p were younger than 40 years w h e n their cervical cancer was diagnosed. Twenty-eight of the 40 w o m e n (70%) had stage I disease w h e n diagnosed. Slightly m o r e than half (21) had poorly differentiated carcinomas (either squamous or adenocarcinoma). Twenty-eight w o m e n (70% of the entire group) had stage IB disease. The only m e m b e r s of this patient subgroup who survived were the 19 w o m e n who had u n d e r g o n e radical surgery as the primary m e t h o d of m a n a g e m e n t . Fifteen of the 19 patients with stage IB disease treated with a type III radical hysterectomy and bilateral pelvic l y m p h a d e n e c t o m y were alive and well a m e d i a n of 31 m o n t h s (range, 8 to 54 months) at the time
October 1996 AmJ Obstet Gyr,ecol
of that report. Four patients with stage IB cancer who u n d e r w e n t type III radical hysterectomies, bilateral pelvic lymphadenectomies, and postoperative pelvic radiation therapy were alive and well a m e d i a n time of 251½ m o n t h s (range, 17 to 109 months). For reasons we do n o t understand, radiation therapy was n o t effective for patients with stage IB cervical cancer. Seven patients with stage IB disease treated with radiation therapy alone died of cancer a m e d i a n of 15 m o n t h s after diagnosis (range, 9 to 29 months). T h e two r e m a i n i n g patients with stage IB cancer who died had simple hysterectomies as part of their treatment. Radiation therapy was completely ineffective in all 12 patients with advanced disease, all of w h o m ultimately died of cervical cancer. In the entire series of patients with "rapidly progressive" invasive cervical cancer, n o t one was cured with radiation therapy, regardless of the stage of the cancer. A review of the Papanicolaou smears in this group showed that 12 of 22 Papanicolaou smears that could be reviewed were true negative Papanicolaou smears. Five were inadequate because of a lack of endocervical cells. Five were false negatives because dysplastic cells were present that were not followed up.
Prospective study of cervical cancer in Connecticut T h e r e p o r t of rapidly progressive cervical cancer in w o m e n treated at the Yale-New Haven Medical Center was anecdotal and its findings could n o t be generalized beyond this group. 11 However, in 1985 we were recipients of a CCRU grant, and one of the four projects supported by that grant was a cervical cancer project. T h e aims of this project were to improve early detection m e t h o d s for cervical cancer and to develop interventions that we h o p e d could ultimately eliminate cervical cancer in the state of Connecticut. To begin to accomplish these aims, we e n r o l l e d all w o m e n in C o n n e c t i c u t diagnosed with cervical cancer between March 1, 1985, and March 1, 1990 (incident cases). We developed a rapid accession program, whereby registrars from the 35 hospitals in Connecticut r e p o r t e d all patients who developed this disease to the Connecticut T u m o r Registry. T h e Registry was notified within 4 m o n t h s of all cases diagnosed. T h e CCRU was then inf o r m e d and could proceed to attempt to contact physicians to accrue the patients into the study. O f the 666 w o m e n d i a g n o s e d with cervical cancer in the study period, 481 agreed to b e c o m e participants, and 400 actually participated. ~2 Eighty-one w o m e n participated as surrogates because a subject either did n o t speak English or had died. Forty-two patients refused to participate, 79 patients could n o t be e n r o l l e d because their physicians refused to participate, 37 subjects m o v e d or were lost to follow-up; 27 subjects died and could n o t be replaced by a surrogate. Participants were interviewed by
Volume 175, Number 4, Part 2 _&nJ Obstet Gynecol
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Table I. Invasive cervical cancer cases (n = 481) by c o m m i t t e e review category and cell type % squamous (n =385)
Never screened Ever screened Misread as normal Known or assumed to have correctly read smear, time between last screening and diagnosis Short interval, <3 yr Long interval, 3-5 yr Excessive interval, >5 yT incomplete follow-up was required
% adenocarcinoma (n = 78)
% adenosquamous ( n = 18)
No.
%
No.
%
No.
%
119
86.9
15
10.9
3
2.2
26
78.8
6
18.2
1
3.0
74 23 98 45
62.7 82.1 86.7 86.5
38 4 11 4
32.3 10.3 9.7 7.7
6 1 4 3
5.1 3.6 3.6 5.8
From Janerich DT, Hadjimichael O, Schwartz PE, Lowell DM, Meigs J-W; Merino MJ, et al. The screening histories of women with invasive cervical cancer, Connecticut. AmJ Public Health 1995;85:791-4. ©1995 by the American Public Health Association.
t e I e p h o n e using a pretested, structured questionnaire. I n f o r m a t i o n was o b t a i n e d on sociodemographics, gynecologic screening history, reproductive and coital history, and sources and frequency of medical care. All physicians were contacted who may have previously p e r f o r m e d Papanicolaou smears for these patients, and cytology slides were r e q u e s t e d f r o m all laboratories to which patients' slides had b e e n sent. A total of 82 (69.5%) Papanicolaou smears f r o m the 118 w o m e n who r e p o r t e d they had a Papanicolaou smear within 3 years of a diagnosis of invasive cervical cancer were reviewed by pathologists participating in the study. Overall reports or smears were reviewed for 232 (67.4%) of the 334 w o m e n who had ever had Papanicolaou smears. A medical review c o m m i t t e e was established that reviewed all medical reports and all Papanicolaou smear findings. T h e committee, c o m p o s e d of a gynecologic oncologist, a cytopathologist, and an epidemiologist, put the subjects into one of four categories based on the reason for failure: (1) those who d e v e l o p e d cervical cancer in the absence of prior screening; (2) those who had u n d e r g o n e prior screening but whose Papanicolaou smear reports were d e t e r m i n e d to be false negatives by our pathology review; (3) those screened and diagnosed with invasive cervical cancer but whose disease was either treated as a preinvasive disease or n o t treated because of patient refusal of further evaluation and t r e a t m e n t or physician failure to follow through; and (4) those who had b e e n screened without cancer being detected but then d e v e l o p e d invasive cervical cancer. W o m e n in this fourth g r o u p were considered to have rapidly progressive cervical cancer. We defined "rapidly progressive" cervical cancer as cancer o c c u r r i n g within 3 years of the last true negative Papanicolaou smear, an interval chosen because that p e r i o d corresponds to the r e c o m m e n d a t i o n s of the A m e r i c a n Cancer Society for cervical cancer screening. T h e results of the CCRU Cervical Cancer Project are as follows. W o m e n in the first category, those who had never
b e e n screened, m a d e up the largest group, 137 of 481 (28.5%) (Table I). The average age of this u n s c r e e n e d group was 641A years, an older population c o m p a r e d with the rest of the groups. In the second group, the falsenegative Papanicolaou smears consisted of only 33 of 481 (6.9%) women. However, w h e n one considers only the 137 slides that could be o b t a i n e d and reread, 29 (21.2%) had some evidence of p r e m a l i g n a n t abnormalities, indicating the n e e d for further follow-up. T h e third g r o u p had 52 subjects (10.8%) who had i n c o m p l e t e follow-up, either because of patient refusal to participate in further evaluations or because their physicians did n o t recomm e n d follow-up or evaluation after an a b n o r m a l Papanicolaou smear. T h e fourth group, which consisted of 118 w o m e n and m a d e up almost one fourth of the subjects, was the "rapidly progressive" group. All these w o m e n had less than a 3-year interval f r o m tile time of the last Papanicolaou smear to the time they developed invasive cervical cancer. T h e i r average age was 42.3 years. In addition, a group of 113 w o m e n (23.5%) had a screening interval of m o r e than 5 years without a Papanicolaou smear before their cancer diagnosis. T h e average age in this g r o u p was 49.7 years. Twenty-eight w o m e n had a screening interval of 3 to 5 years (Table I). Almost all participants, regardless of the category into which they were placed, had symptoms at the time of diagnosis, that is, vaginal bleeding, spotting after intercourse, a b d o m i n a l pain, vaginal discharge, or difficulty urinating. W o m e n in the "rapidly progressive" g r o u p t e n d e d to be from h i g h e r s o c i o e c o n o m i c groups than w o m e n in the never screened category, with m o r e education and h i g h e r incomes. No significant differences were seen between the groups in n u m b e r of pregnancies, exposure to birth control pills, or early age at first intercourse. H a l f of the patients, regardless of category, had had intercourse before the age of 18 years. Most patients with "rapidly progressive" cervical cancer (64.3%) had smoked in the past, but many had quit smoking. W o m e n
1108 Schwartz et at.
in other groups had not generally been as successful in stopping smoking. Adenocarcinoma was diagnosed in 32.2% of the "rapidly progressive" cases and adenosquamous carcinoma in another 5.1%: the remaining 62.7% had squamous cell carcinoma. This proportion of adenocarcinomas was much higher than originally expected in the unscreened group (10.4%) and in the group consisting of women who had received Papanicolaou smear screening at some point in their lives (12.4%). The mean patient ages in years (+SD) was 52.0 (14.9) for squamous carcinoma, 50.1 (14.9) for adenocarcinoma, and 49.9 (13.0) for adenosquamous carcinoma. Most of the patients (76; 69.4%) in the "rapidly progressive" group or in the group who had had screening at some time in their lives (74 women or 65.5%), had stage I disease versus only 42.2% of subjects from the unscreened population. Twenty-nine of the 38 subjects (76.3%) with adenocarcinoma in the rapidly progressive group were diagnosed within 18 months of the last negative Papanicolaou smear, as were 42 of the 74 patients (56.8%) with squamous cell cancers. We reviewed the adequacy of the last negative Papanicolaou smear before the diagnosis of cancer in 70 cases. Thirty-four had endocervical cells present, 15 did not, and in 21 it was not stated whether endocervical cells were present. The presence or absence of endocervical cells in the Papanicolaou smear did not have any effect on the diagnosis in the women specifically evaluated for that purpose. Unfortunately, when this study began, pathologists were not required to state whether endocervical cells were present. Comment
In conclusion, we consider it unlikely that the phenome n o n of "rapidly progressive" cervical cancer exists. The high n u m b e r of adenocarcinomas among our study population suggest that women categorized as having "rapidly progressive" disease actually had endocervical cancer that had not been adequately screened With the then current Papanicolaou smear screening. We can speculate about some of the reasons for this inadequate screening. During the time of this study, most physicians in Connecticut used an Ayre spatula and a cotton-tipped applicator stick to obtain Papanicolaou smear cytologic specimens. As a result of our findings, letters were sent to all physicians in the state, recommending that they continue to use the Ayre spatula, but in addition to use the cytobrush in preference to the cotton-tipped applicator stick for endocervical cytologic sampling. This advice was given because we believed physicians were not adequately sampling the endocervical canal with the cotton-tipped applicator stick.
October 1996 AmJ ObstetGynecol
Women should insist that their primary care physicians obtain Papanicolaou smears on a regular basis. Women in our study in the unscreened group often visited physicians as frequently as every month but did not have Papanicolaou smears performed. This was because in most cases they were postmenopausal and were seeing internists. In our experience, advancing age is not a valid reason to terminate or alter the schedule of Papanicolaou smear screening. Gynecologic symptoms are extremely important in alerting physicians of the need to perform Papanicolaou smears. The fact that most women in our series had stage 1B disease reflects the fact that they had symptoms, with pain, discharge, or bleeding. Many continued to return to their doctors despite negative Papanicolaou smears, insisting that something be done. Not surprisingly, their symptoms did not respond to vaginal preparations given for "discharge," presumed based on infectious disease, nor to hormone therapy when abnormal vaginal bleeding was attributed to dysfunctional uterine bleeding. Physicians must evaluate women with unexplained gynecologic symptoms and carefully follow up their cases. Colposcopy and biopsy definitely have a role in the evaluation of the cause of unexplained pain, discharge, or bleeding in the presence of a normal Papanicolaou smear. Applying the Connecticut data nationally, almost half (6760 of 13,000) of the cases of of cervical cancer occurring annually may be associated with inadequate Papanicolaou smear screening intervals or no screening. If all women have at least a triennial Papanicolaou smear as recommended by the American Cancer Society, we could dramatically reduce the incidence of invasive cancer of the cervix in the United States. REFERENCES
1. Gustafsson L, Adami HO. Natural history of cervical neoplasia: consistent results obtained by identification technique. BrJ Cancer 1989;60:132-41. 2. Larsen NS. Invasive cervical cancer rising in young white females. J Natl Cancer Inst 1994;86:6-7. 3. HestonJF, KellyJAB, MeigsJW, FlanneryJT. Forty-fiveyears of cancer incidence in Connecticut: 1935-79 (NCI Monograph 70). Washington, D.C.: U.S. Government Printing Ofrice, 1986:2,385. 4. Janerich DT, Hadjimichael O, FlanneryJ. Strategy for elimination of invasivecervical cancer in Connecticut. Conn Med 1985;49:746-53. 5. Berkeley AS, LivolsiVA, Schwartz PE. Advanced squamous cell carcinoma of the cervix and the normal Pap tests. Lancet 1980;2:375-6. 6. Kapp DS, Fischer D, Gutierrez E, Kohorn E, Schwartz PE. Pretreatment prognostic factors in carcinoma of the uterine cervix: a multivariate analysis of the effect of age, stage, histology, and blood counts on survival.IntJ Pad Oncol Biol Phys 1983;9:445-55. 7. Kottmeier HL, editor. Annual report on the results of treatment in carcinoma of-the uterus, vagina and ovary: statements of results obtained in 1959-1968. Stockholm: Interna-
Volume t75, Number 4, Part 2 Am J Obstet G)~aecol
fional Federation of Gynecology and Obstetrics, 1976;16:912, 171,249-51. 8. Jampolis S, Andras EJ, Fletcher GH. Analysis of sites and causes of failures of irradiation in invasive squamous cell carcinoma of the intact uterine cervix. Radiology 1975;115: 681-5. 9. Piver MS, Chung WS. Prognostic significance of cervical lesion size and pelvic node metastases in cervical carcinomas. Obstet Gynecol 1975;46:507-10. 10. ThomsonJM, SprattJS. Treatment policies affecting survival
Schwartz et al.
1109
in patients with carcinoma of the cervix. Radiology 1978; 127:771-4. 11. Schwartz PE, Merino MJ, Curnen MGMcC. Clinical management of patients with invasive cervical cancer following a negative Pap smear. YaleJ Biol Med 1988;61:327-38. 12. Janerich DT, Hadjimichael O, Schwartz PE, Lowell DM, Meigs JW, Merino MJ, et al. The screening histories of women with invasive cervical cancer, Connecticut. AmJ Public Health 1995;85:791-4.
Key words: Rapidly progressive cervical cancer, Papanicolaou smear screening
Cervical cancer is generally considered a slowly evolving disease that begins as mild dysplasia and progresses over as many as 10 or more years to invasive carcinoma? It is precisely this presumed gradual evolution, in addition to effective treatment of preinvasive conditions, that lends the Papanicolaou smear its preventive value and helps determine optimal screening intervals. However, other factors besides timely Papanicolaou smears and treatment if needed affect the incidence of cervical cancer. For example, the recent decade has witnessed a steady increase in this disease among young white women, presumably a well-screened population groupfl In Connecticut, the state with the oldest populationbased cancer registry in the United States (established in 1941), the incidence of cervical cancer began to decline even before the widespread introduction of Papanicolaou smear screening in 1956. 3 One factor contributing to this reduction could have been the practice by Connecticut physicians after World War II of p e r f o r m i n g total hysterectomies in preference to supracervical hysterectomies for the management of benign gynecologic disorders. Overall, Papanicolaou smear screening appears to
From the Department of Obstetrics and Gynecology,° Department of Epidemiology, b and Department of Pathology,c University of Connecticut School of Medicine, and the Department of Pathology, d National Cancer Institute. P~print requests: Peter,E. Schwartz, MD, Department of Obstetrics and Gynecology, Connecticut University School of Medicine, 333 Cedar St., New Haven, CT 06520. 0002-9378/96 $5.00 + 0 6/0/76934
have been effective in Connecticut: the rate of cervical carcinoma in situ has essentially plateaued in the past 15 years, which suggests that the screening needs of the target population that participates in screening, that is, women at high risk for cervical cancer, are being addressed. 4 However, signs began to appear in the late 1970s of an atypical natural history of cervical cancer in some women. In these cases the interval between the last negative Papanicolaou smear and the diagnosis of invasive disease was unusually short, sometimes only a few months. Initial reports of these cases were anecdotal, but a comprehensive study supported by a Clinical Cancer Research Unit (CCRU) grant in 1985 enabled us to examine the p h e n o m e n o n of "rapidly progressive" cervical cancer more closely. 4 The investigations conducted under CCRU support built on questions generated by earlier reports of the Yale-New Haven Medical Center retrospective study. ~'6
Yale-New Haven Retrospective Study A large retrospective study of invasive cancer of the cervix was reported from the Yale-New Haven Medical Center in 1983. 6 It included women with cervical cancer who were followed up for as long as 25 years. Results were similar to those in most other cervical cancer studies in that the stage of cancer was the single most important prognostic factor. 7-1°Histologic type was also important, as evidenced by the fact that women with squamous cell carcinomas had a statistically significant better overall 1105
1106
Schwartz at al.
survival (p= 0.002) than those with a d e n o c a r c i n o m a s and a trend toward a better disease-free survival (p = 0.1). Within any of the I n t e r n a t i o n a l Federation of Gynecologists and Obstetricians (FIGO) stages, t u m o r size was the most i m p o r t a n t factor in disease-free survival (p = 0.006), as well as in local-regional control (p = 0.023). Age was strongly associated with overall survival, with w o m e n 55 years (median age of the cervical cancer p o p u l a t i o n at the Yale-New Haven Medical Center) or younger, stage for stage, surviving l o n g e r than older w o m e n over the 25-year follow-up period. In contrast, w o m e n 55 years old or younger actually had p o o r e r local-regional control of their cancer with radiation therapy than did older w o m e n (p= 0.02). This subset of w o m e n received radiation therapy almost exclusively and did better than younger patients who also were almost exclusively treated with radiation therapy.
"Rapidly progressive" cervical cancer In 1975 our group began to be interested in the cases of w o m e n whose disease did not seem to c o n f o r m to the usual pattern of cervical cancer evolution. We initially r e p o r t e d on 10 w o m e n with cervical cancer who reportedly had negative Papanicolaou snmars within 1 year before their diagnosis. 5 All but one were treated with prim a r y radiation therapy but ultimately died of cervical cancer. T h e one e x c e p t i o n was a 20-year-old patient with a 6 cm stage IB cancer of the cervix who u n d e r w e n t a primary radical hysterectomy, received pelvic radiation therapy after surgery, and was alive and well 10 years later. Between 1975 and 1984, 40 w o m e n had Papanicolaou smear histories that suggested the presence of a f o r m of rapidly progressive disease, n Thirty-five (88%) of these patients had had at least one negative Papanicolaou smear within 1 year before the diagnosis of invasive cancer (range, <1 to 17 months), and half had had a negative smear within 6 m o n t h s of diagnosis, n A n o t h e r distinctive feature of the "rapidly progressive" g r o u p was its age: these were very young women, with a m e d i a n age of 32 years (range, 20 to 54 years), versus the m e d i a n age of 55 years (as m e n t i o n e d previously) for w o m e n with cervical cancer at our institution. 6' ~ Thirty-five (88%) of the 40 w o m e n in the rapidly progressive g r o u p were younger than 40 years w h e n their cervical cancer was diagnosed. Twenty-eight of the 40 w o m e n (70%) had stage I disease w h e n diagnosed. Slightly m o r e than half (21) had poorly differentiated carcinomas (either squamous or adenocarcinoma). Twenty-eight w o m e n (70% of the entire group) had stage IB disease. The only m e m b e r s of this patient subgroup who survived were the 19 w o m e n who had u n d e r g o n e radical surgery as the primary m e t h o d of m a n a g e m e n t . Fifteen of the 19 patients with stage IB disease treated with a type III radical hysterectomy and bilateral pelvic l y m p h a d e n e c t o m y were alive and well a m e d i a n of 31 m o n t h s (range, 8 to 54 months) at the time
October 1996 AmJ Obstet Gyr,ecol
of that report. Four patients with stage IB cancer who u n d e r w e n t type III radical hysterectomies, bilateral pelvic lymphadenectomies, and postoperative pelvic radiation therapy were alive and well a m e d i a n time of 251½ m o n t h s (range, 17 to 109 months). For reasons we do n o t understand, radiation therapy was n o t effective for patients with stage IB cervical cancer. Seven patients with stage IB disease treated with radiation therapy alone died of cancer a m e d i a n of 15 m o n t h s after diagnosis (range, 9 to 29 months). T h e two r e m a i n i n g patients with stage IB cancer who died had simple hysterectomies as part of their treatment. Radiation therapy was completely ineffective in all 12 patients with advanced disease, all of w h o m ultimately died of cervical cancer. In the entire series of patients with "rapidly progressive" invasive cervical cancer, n o t one was cured with radiation therapy, regardless of the stage of the cancer. A review of the Papanicolaou smears in this group showed that 12 of 22 Papanicolaou smears that could be reviewed were true negative Papanicolaou smears. Five were inadequate because of a lack of endocervical cells. Five were false negatives because dysplastic cells were present that were not followed up.
Prospective study of cervical cancer in Connecticut T h e r e p o r t of rapidly progressive cervical cancer in w o m e n treated at the Yale-New Haven Medical Center was anecdotal and its findings could n o t be generalized beyond this group. 11 However, in 1985 we were recipients of a CCRU grant, and one of the four projects supported by that grant was a cervical cancer project. T h e aims of this project were to improve early detection m e t h o d s for cervical cancer and to develop interventions that we h o p e d could ultimately eliminate cervical cancer in the state of Connecticut. To begin to accomplish these aims, we e n r o l l e d all w o m e n in C o n n e c t i c u t diagnosed with cervical cancer between March 1, 1985, and March 1, 1990 (incident cases). We developed a rapid accession program, whereby registrars from the 35 hospitals in Connecticut r e p o r t e d all patients who developed this disease to the Connecticut T u m o r Registry. T h e Registry was notified within 4 m o n t h s of all cases diagnosed. T h e CCRU was then inf o r m e d and could proceed to attempt to contact physicians to accrue the patients into the study. O f the 666 w o m e n d i a g n o s e d with cervical cancer in the study period, 481 agreed to b e c o m e participants, and 400 actually participated. ~2 Eighty-one w o m e n participated as surrogates because a subject either did n o t speak English or had died. Forty-two patients refused to participate, 79 patients could n o t be e n r o l l e d because their physicians refused to participate, 37 subjects m o v e d or were lost to follow-up; 27 subjects died and could n o t be replaced by a surrogate. Participants were interviewed by
Volume 175, Number 4, Part 2 _&nJ Obstet Gynecol
Schwartz et N.
1107
Table I. Invasive cervical cancer cases (n = 481) by c o m m i t t e e review category and cell type % squamous (n =385)
Never screened Ever screened Misread as normal Known or assumed to have correctly read smear, time between last screening and diagnosis Short interval, <3 yr Long interval, 3-5 yr Excessive interval, >5 yT incomplete follow-up was required
% adenocarcinoma (n = 78)
% adenosquamous ( n = 18)
No.
%
No.
%
No.
%
119
86.9
15
10.9
3
2.2
26
78.8
6
18.2
1
3.0
74 23 98 45
62.7 82.1 86.7 86.5
38 4 11 4
32.3 10.3 9.7 7.7
6 1 4 3
5.1 3.6 3.6 5.8
From Janerich DT, Hadjimichael O, Schwartz PE, Lowell DM, Meigs J-W; Merino MJ, et al. The screening histories of women with invasive cervical cancer, Connecticut. AmJ Public Health 1995;85:791-4. ©1995 by the American Public Health Association.
t e I e p h o n e using a pretested, structured questionnaire. I n f o r m a t i o n was o b t a i n e d on sociodemographics, gynecologic screening history, reproductive and coital history, and sources and frequency of medical care. All physicians were contacted who may have previously p e r f o r m e d Papanicolaou smears for these patients, and cytology slides were r e q u e s t e d f r o m all laboratories to which patients' slides had b e e n sent. A total of 82 (69.5%) Papanicolaou smears f r o m the 118 w o m e n who r e p o r t e d they had a Papanicolaou smear within 3 years of a diagnosis of invasive cervical cancer were reviewed by pathologists participating in the study. Overall reports or smears were reviewed for 232 (67.4%) of the 334 w o m e n who had ever had Papanicolaou smears. A medical review c o m m i t t e e was established that reviewed all medical reports and all Papanicolaou smear findings. T h e committee, c o m p o s e d of a gynecologic oncologist, a cytopathologist, and an epidemiologist, put the subjects into one of four categories based on the reason for failure: (1) those who d e v e l o p e d cervical cancer in the absence of prior screening; (2) those who had u n d e r g o n e prior screening but whose Papanicolaou smear reports were d e t e r m i n e d to be false negatives by our pathology review; (3) those screened and diagnosed with invasive cervical cancer but whose disease was either treated as a preinvasive disease or n o t treated because of patient refusal of further evaluation and t r e a t m e n t or physician failure to follow through; and (4) those who had b e e n screened without cancer being detected but then d e v e l o p e d invasive cervical cancer. W o m e n in this fourth g r o u p were considered to have rapidly progressive cervical cancer. We defined "rapidly progressive" cervical cancer as cancer o c c u r r i n g within 3 years of the last true negative Papanicolaou smear, an interval chosen because that p e r i o d corresponds to the r e c o m m e n d a t i o n s of the A m e r i c a n Cancer Society for cervical cancer screening. T h e results of the CCRU Cervical Cancer Project are as follows. W o m e n in the first category, those who had never
b e e n screened, m a d e up the largest group, 137 of 481 (28.5%) (Table I). The average age of this u n s c r e e n e d group was 641A years, an older population c o m p a r e d with the rest of the groups. In the second group, the falsenegative Papanicolaou smears consisted of only 33 of 481 (6.9%) women. However, w h e n one considers only the 137 slides that could be o b t a i n e d and reread, 29 (21.2%) had some evidence of p r e m a l i g n a n t abnormalities, indicating the n e e d for further follow-up. T h e third g r o u p had 52 subjects (10.8%) who had i n c o m p l e t e follow-up, either because of patient refusal to participate in further evaluations or because their physicians did n o t recomm e n d follow-up or evaluation after an a b n o r m a l Papanicolaou smear. T h e fourth group, which consisted of 118 w o m e n and m a d e up almost one fourth of the subjects, was the "rapidly progressive" group. All these w o m e n had less than a 3-year interval f r o m tile time of the last Papanicolaou smear to the time they developed invasive cervical cancer. T h e i r average age was 42.3 years. In addition, a group of 113 w o m e n (23.5%) had a screening interval of m o r e than 5 years without a Papanicolaou smear before their cancer diagnosis. T h e average age in this g r o u p was 49.7 years. Twenty-eight w o m e n had a screening interval of 3 to 5 years (Table I). Almost all participants, regardless of the category into which they were placed, had symptoms at the time of diagnosis, that is, vaginal bleeding, spotting after intercourse, a b d o m i n a l pain, vaginal discharge, or difficulty urinating. W o m e n in the "rapidly progressive" g r o u p t e n d e d to be from h i g h e r s o c i o e c o n o m i c groups than w o m e n in the never screened category, with m o r e education and h i g h e r incomes. No significant differences were seen between the groups in n u m b e r of pregnancies, exposure to birth control pills, or early age at first intercourse. H a l f of the patients, regardless of category, had had intercourse before the age of 18 years. Most patients with "rapidly progressive" cervical cancer (64.3%) had smoked in the past, but many had quit smoking. W o m e n
1108 Schwartz et at.
in other groups had not generally been as successful in stopping smoking. Adenocarcinoma was diagnosed in 32.2% of the "rapidly progressive" cases and adenosquamous carcinoma in another 5.1%: the remaining 62.7% had squamous cell carcinoma. This proportion of adenocarcinomas was much higher than originally expected in the unscreened group (10.4%) and in the group consisting of women who had received Papanicolaou smear screening at some point in their lives (12.4%). The mean patient ages in years (+SD) was 52.0 (14.9) for squamous carcinoma, 50.1 (14.9) for adenocarcinoma, and 49.9 (13.0) for adenosquamous carcinoma. Most of the patients (76; 69.4%) in the "rapidly progressive" group or in the group who had had screening at some time in their lives (74 women or 65.5%), had stage I disease versus only 42.2% of subjects from the unscreened population. Twenty-nine of the 38 subjects (76.3%) with adenocarcinoma in the rapidly progressive group were diagnosed within 18 months of the last negative Papanicolaou smear, as were 42 of the 74 patients (56.8%) with squamous cell cancers. We reviewed the adequacy of the last negative Papanicolaou smear before the diagnosis of cancer in 70 cases. Thirty-four had endocervical cells present, 15 did not, and in 21 it was not stated whether endocervical cells were present. The presence or absence of endocervical cells in the Papanicolaou smear did not have any effect on the diagnosis in the women specifically evaluated for that purpose. Unfortunately, when this study began, pathologists were not required to state whether endocervical cells were present. Comment
In conclusion, we consider it unlikely that the phenome n o n of "rapidly progressive" cervical cancer exists. The high n u m b e r of adenocarcinomas among our study population suggest that women categorized as having "rapidly progressive" disease actually had endocervical cancer that had not been adequately screened With the then current Papanicolaou smear screening. We can speculate about some of the reasons for this inadequate screening. During the time of this study, most physicians in Connecticut used an Ayre spatula and a cotton-tipped applicator stick to obtain Papanicolaou smear cytologic specimens. As a result of our findings, letters were sent to all physicians in the state, recommending that they continue to use the Ayre spatula, but in addition to use the cytobrush in preference to the cotton-tipped applicator stick for endocervical cytologic sampling. This advice was given because we believed physicians were not adequately sampling the endocervical canal with the cotton-tipped applicator stick.
October 1996 AmJ ObstetGynecol
Women should insist that their primary care physicians obtain Papanicolaou smears on a regular basis. Women in our study in the unscreened group often visited physicians as frequently as every month but did not have Papanicolaou smears performed. This was because in most cases they were postmenopausal and were seeing internists. In our experience, advancing age is not a valid reason to terminate or alter the schedule of Papanicolaou smear screening. Gynecologic symptoms are extremely important in alerting physicians of the need to perform Papanicolaou smears. The fact that most women in our series had stage 1B disease reflects the fact that they had symptoms, with pain, discharge, or bleeding. Many continued to return to their doctors despite negative Papanicolaou smears, insisting that something be done. Not surprisingly, their symptoms did not respond to vaginal preparations given for "discharge," presumed based on infectious disease, nor to hormone therapy when abnormal vaginal bleeding was attributed to dysfunctional uterine bleeding. Physicians must evaluate women with unexplained gynecologic symptoms and carefully follow up their cases. Colposcopy and biopsy definitely have a role in the evaluation of the cause of unexplained pain, discharge, or bleeding in the presence of a normal Papanicolaou smear. Applying the Connecticut data nationally, almost half (6760 of 13,000) of the cases of of cervical cancer occurring annually may be associated with inadequate Papanicolaou smear screening intervals or no screening. If all women have at least a triennial Papanicolaou smear as recommended by the American Cancer Society, we could dramatically reduce the incidence of invasive cancer of the cervix in the United States. REFERENCES
1. Gustafsson L, Adami HO. Natural history of cervical neoplasia: consistent results obtained by identification technique. BrJ Cancer 1989;60:132-41. 2. Larsen NS. Invasive cervical cancer rising in young white females. J Natl Cancer Inst 1994;86:6-7. 3. HestonJF, KellyJAB, MeigsJW, FlanneryJT. Forty-fiveyears of cancer incidence in Connecticut: 1935-79 (NCI Monograph 70). Washington, D.C.: U.S. Government Printing Ofrice, 1986:2,385. 4. Janerich DT, Hadjimichael O, FlanneryJ. Strategy for elimination of invasivecervical cancer in Connecticut. Conn Med 1985;49:746-53. 5. Berkeley AS, LivolsiVA, Schwartz PE. Advanced squamous cell carcinoma of the cervix and the normal Pap tests. Lancet 1980;2:375-6. 6. Kapp DS, Fischer D, Gutierrez E, Kohorn E, Schwartz PE. Pretreatment prognostic factors in carcinoma of the uterine cervix: a multivariate analysis of the effect of age, stage, histology, and blood counts on survival.IntJ Pad Oncol Biol Phys 1983;9:445-55. 7. Kottmeier HL, editor. Annual report on the results of treatment in carcinoma of-the uterus, vagina and ovary: statements of results obtained in 1959-1968. Stockholm: Interna-
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fional Federation of Gynecology and Obstetrics, 1976;16:912, 171,249-51. 8. Jampolis S, Andras EJ, Fletcher GH. Analysis of sites and causes of failures of irradiation in invasive squamous cell carcinoma of the intact uterine cervix. Radiology 1975;115: 681-5. 9. Piver MS, Chung WS. Prognostic significance of cervical lesion size and pelvic node metastases in cervical carcinomas. Obstet Gynecol 1975;46:507-10. 10. ThomsonJM, SprattJS. Treatment policies affecting survival
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in patients with carcinoma of the cervix. Radiology 1978; 127:771-4. 11. Schwartz PE, Merino MJ, Curnen MGMcC. Clinical management of patients with invasive cervical cancer following a negative Pap smear. YaleJ Biol Med 1988;61:327-38. 12. Janerich DT, Hadjimichael O, Schwartz PE, Lowell DM, Meigs JW, Merino MJ, et al. The screening histories of women with invasive cervical cancer, Connecticut. AmJ Public Health 1995;85:791-4.