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Dysplasia and carcinoma in situ of the uterine cervix: Prevalence in very young women (under age 22)
Dysplasia and carcinoma in situ of the uterine cervix: Prevalence in very young women (under age 22) A one-year study in a health plan population
RICHARD N. SNYDER, M.D. YOLANDA ORTIZ, C.T.(A.S.C.P.) SAMONA WILLIE, B.S., C.T.(A.S.C.P.) (l.A.C.)
.J.
KAREN
North
.J.
Holl~wood
COVE, M.D.
and Los Angeles, California
An increased number of cervical epithelial abnormalities has been observed in women up to and including 21 years of age. The prevalence and incidence of dysplasia in adolescents and young women is increasing at a time when the incidence of cervical carcinoma is decreasing. We studied 247 women under age 22 with "other than negative" cytologic diagnoses identified during a one-year period (197 3) in which approximately 27,500 women in this age group were screened. The prevalence rates of "other than negative" cytology and "other than negative" cytology with confirmed histopathologic abnormalities were 9/1,000 and 2.711,000, respectively. Repeat smears and/or tissue specimens were obtained in over 70 per cent of these cases. The majority of abnormalities identified were mild or moderate dysplasia; however eight severe dysplasias and three carcinomas in situ were identified. Fifty-nine per cent of these women had a history of one or more pregnancies. Our findings emphasize the presence of dysplasia and carcinoma in situ in young women and suggest the need for re-evaluation of the age at which initiation of the Papanicolaou smear should be considered.
C E R v 1 CAL intraepithelial neoplasia or dysplasia occuring in very young women is now recognized as a developing medical and public health problem. Ferguson8 reported 72 "other than negative" Papanicolaou smears among a group of 1,500 women under age 19, 10 of whom had histologically proved carcinoma in situ. Other reports confirm the observation of a varying prevalence of dysplasia and carcinoma in situ in young women with differences in occurrence
rate in the various communities and socioeconomic groups studies.t-1. 9. 13-16, 19, 22. 2s. 2s. 29, ao We have studied the 1973 prevalence of "other than negative" cytologic diagnoses and the incidence of confirmed histologic abnormality and/or follow-up cytology in women under 22 years old. The population studied was drawn from a prepaid health plan population without economic or social barriers to prevent access to quality medical care. Our findings emphasize the importance of providing routine cytology studies for sexually active women, regardless of age. We consider the finding of a 9/1,000 "other than negative" cytology prevalence rate sufficient to warrant investigating this young patient population.
From the Department of Patholog;y and the Regional Cytolog;y Laboratory, Southern California Permanente Medical Group, and the Kaiser Foundation Hospital. Presented in part at the Fifth International Congress of Cytolog;y, Miami Beach, Florida, May 31, 1974.
Material and methods In 1973, 219,907 women of all ages were examined by the Papanicolaou smear technique (307,000 slides); 27,508 (12.5 per cent) of these women were younger than 22 years old. All were members of the Southern California Kaiser Permanente Health Plan. Cytologic
Received for publication january 21, 1975. Accepted June 4, 1975. Reprint requests: Dr. Ricoord N. Snyder, Department of Patholog;y, Southern California Permanente Medical Group, 1510 N. Edgemont St., Lm Angeles, California 90027.
751
April!, 1976 Am. J. Obstet. Gvnecol.
752 Snyder et al.
Table I. Cytodiagnostic terminology "Key word" category Abnormal
Inconclusive
Negative
Unsatisfactory
Some examples of descriptive cytodiagnoses Mild to moderate dysplasia of any type (keratinizing, nonkeratinizing, metaplastic, mixed) Severe dysplasia versus carcinoma in situ of any type Invasive carcinoma, cervix; adenocarcinoma; metastatic tumor; sarcoma Atypical cellular changes not explained solely by infection, repair, or prior therapy and/or cannot exclude mild dysplasia of cervix Benign squamous metaplasia, cellular changes or metaplasia due to bacteria. Parasites (Trichomonas), fungi, herpes, and/or repair reaction Air dried, too few cells, too bloody, slide not properly identified at origin
27,508 Patients examined cytologically (12.5% of all patients) 247 Patients with "other than negative" cytology 208 Patients with histology and/or repeat cytology 118 Patients with histologic examination 62 Patients with mild or moderate dysplasia 8 Patients with severe dysplasia 3 Patients with carcinoma in situ 45 Patients whose biopsies revealed various nondysplastic diagnoses 90 Patients with one or more subsequent cytology examinations 39 Patients without further follow-up at this time
and histologic diagnoses by two cytopathologists at the regional centralized cytology laboratory and by 14 histopathologists were incorporated in this report. Correlations were made without any review of histopathologic specimens. Our cytology reports incorporate cytodiagnostic terminology as noted in Table I. In addition, a "key word" notation of "negative," "inconclusive," or "abnormal" was provided, since in our experience, as well as that of others, some nongynecologist physicians do not readily appreciate the diagnostic and therapeutic implications of dysplasia. 10• 11, 17, 20, 21, 24, 28
All patients with "other than negative" cytology were recalled to the appropriate follow-up clinic or physician for further evaluation. Repeat cytology and/or random or colposcopic biopsies were obtained where appropriate and were followed by diagnostic cervical conization when clinically indicated. The interval between repeat cytology examination was at the discretion of the patient's physician. Vaginitis and cervicitis were treated if necessary. Pregnancies were
managed according to established procedures for such patients. Histologic specimens were studied on slides stained with hematoxylin-eosin, with multiple levels cut routinely in patients having conization.
Results Of the 27,508 patients under age 22 screened by cytology, 24 7 patients had "other than negative" cytodiagnoses (inconclusive-rule out dysplasia; mild-moderate dysplasia; severe dysplasia-carcinoma in situ; microinvasive carcinoma; invasive carcinoma). These data are summarized in Table II. Two hundred and eight patients had further cytologic and/or histologic studies. These 208 patients formed the definitive group of our study. One hundred and eighteen patients had histopathologic studies of biopsies and/ or conizations, yielding 62 cases of mild or moderate dysplasia, eight cases of severe dysplasia, and three cases of carcinoma in situ. Forty-five patients had nondysplastic tissue diagnoses on biopsy (Table Ill). Of the patients studied by repeat cytology, 42 again had "other than negative" cytologic examinations. and 48 reverted to "negative." However, 30 of these smears with negative reversion were repeated within an eight-week period (see below). No cases of invasive carcinoma were identified in any women under age 22. Thirty-nine patients have had no known follow-up at the time of this study. Table IV lists the age distribution of the 118 patients with tissue examination and the diagnosis. The preponderance of proved dysplasia or carcinoma in situ occurred in the group over 17 years old. Onlv one of the 12 patients 17 years old or younger had severe dysplasia. The relationship between initial and subsequent cytodiagnosis, time interval between smears, and correlation with histopathology are shown in Table V. Of 56 patients with repeat smears and histopathologic studies, the initial cytology identified 36 patients with subsequent tissue-proved dysplasia, while only seven additional patients with dysplasia were identified by the second screening following an initial "inconclusive" cytology. In 21 of these 36 patients with dysplasia, the same diagnoses were made on both cvtology specimens. Thirteen biopsies were negative for dysplasia after an initial "inconclusive" or ''abnormal'' cytology diagnosis. Of 129 patients having two Papanicolaou smears, 60 had a diagnosis less severe in classification on the second smear. Forty-one of these 60 had repeat smears within eight weeks. Of those 77 cases with the same or a more severe diagnosis on the second smear, only 13 had been repeated within eight weeks.
Dysplasia and carcinoma in situ in young women 753
Volume 124 Number 7
Table III. Cytology-histology correlation of 118 patients under age 22 Histopathology diagnosis
Cytology interpretation
No. of cases
Inconclusive Mild to moderate dysplasia Severe dysplasia to carcinoma in situ
34 80
Total
Carcinoma in situ
4
2
ll8
3
Severe dysplasia
Mild or moderate dysplasia
Squamous metaplasia, trichomonas changes, herpes, cervicitis, polyp, condyloma, "no pathologic diagnosis"
2 5
14 47
18 27
8
62
45
Table IV. Age distribution and histopathologic diagnoses Histologic diagnosis
Age of patient
No. in age group
14 15 16 17 18
1 1 6 8 18 26 28 30 118
19
20 21 Total
Carcinoma in situ
Severe dysplasia
Mild-motkrate dysplasia
Squamous metaplasia, Trichomonas, herpes, cervicitis, pol_vp, condylorr14, no pathologic abnormality
I
4 6 2 1 3
Thirteen patients had a repeat cytology smear taken simultaneously at the time of tissue biopsy. All13 initial cytodiagnoses correlated with the proved histologic abnormality of dysplasia; however, nine of the repeat smears were interpreted as "negative." All of these 13 repeat smears had been obtained at an interval of less than eight weeks. Of the 118 patients with tissue examinations, 73 had dysplasia or carcinoma in situ, while biopsies from 45 patients revealed a variety of nondysplastic inflammatory, reparative, or metaplastic lesions. Sixteen of 34 "inconclusive" smears were from women in whom biopsy or conization demonstrated dysplastic histology. Fifty-three of 80 patients with "mild to moderate" dysplasia and four of four patients with "severe dysplasia-carcinoma in situ" had proved dysplasia or carcinoma in situ (Table Ill). One hundred and twenty-three of the 108 patients with initial "other than negative" cytology and with repeat cytology or tissue examination had a history of one or more pregnancies. The association of age and parity is shown in Fig. 1. The morphologic types of dysplasia noted in cytology in 85 nulliparous patients
2 2 2
l 8
ll
14 10 16 62
1 2 5 10 14
12 45
are shown in Table VI. Not included in our study was one case of vaginal adenosis and one case of vaginal clear cell adenocarcinoma detected by cytology. Neither cellular nor serologic studies of possible herpesvirus infection were done.
Comment Cytology studies are indicated for all women visiting gynecologists or obstetricians. Sexually active women, whether pregnant or not, regardless of young age, must be considered to be at risk for the development of cervical carcinoma in situ and dysplasia. 1• 2 • 4 -u. ta-ta, ts. 22 25 26 29 • • • Our detection in this one-year study of 73 patients with histologically confirmed dysplasia or carcinoma in situ and an additional 174 patients with one or more "other than negative" cytodiagnoses represents a prevalence rate of 2. 7I l ,000 and 9/ l ,000, respectively. Approximately 62 per cent of the 118 patients with tissue examinations had proved dysplasia or carcinoma in situ (Table VII). A comparison of our findings with those of previous investigators is found in Table VIII. Many of the variations in the prevalence and
754 Snyder et al.
April I, 1976 Am . .J. Obstet. Gynecol.
25 I
NUMBER OF
1
PREGNANCIES I
0
20
ffl ~
I I I I I I I
1
2 3 6
I
~
~ 10
z
CASES
85 93 28 1
1
I
15
~
NUMBER OF
i!
5
12
12
AGE
Fig. 1. Number of pregnancies per patient by age (Total: 208 cases).
Table V. Cytologic and histologic correlation related to interval between repeat cytology in 56 patients
Repeat cytology <2 months First same as second First less severe than second First more severe than second
16
No.
Keratinizing Nonkeratinizing
36 17 II 21
Metaplastic
3
Indeterminate or mixed
2
2
5
4
4
13
7
incidence of"other than negative" cytology may be due to the population studied. The socioeconomic status was an important factor in several previous epidemiologic studies of cervical disease.'· 5 • 23 • 27 • 30 Gravidity and coital activity seem to have an important role in the pathogenesis of dysplasia and carcinoma. Findings similar to those in our 123 patients with a history of past or current pregnancy and early onset of sexual activity with multiple gravidity have been reported.L 2, 4-9, 13-16, 22, 23, 25-27, 29, ao Kaufman and 14
Dysplasia
Histology negative
Cytology Repeat cytology >2 months First same as second First less severe than second First more severe than second
Table VI. Cytologic pattern of dysplasia in 85 nulliparous patients
Leeds noted that 75 per cent of their 58 patients with severe dysplasia or carcinoma in situ were parous. Wallace and Slankard 29 found that 11 of 44 patients with documented dysplasia or carcinoma in situ in their teen-age population had been pregnant one or more times. Bibbo and associates' found that 0.99 per cent of patients with "other than negative" cytology were 15 years old or younger and were patients at Planned Parenthood or obstetric clinics. 1 The prevalence and incidence of carcinoma in situ and invasive carcinoma of the cervix have been
Table VII. Summary of findings 12.5%
of all patients studied were under age 22 (27, 508/219, 907) 0.9% of patients under age 22 had "other than negative" cytology (247/27,508 or 9/1,000) 0.76% of patients under age 22 with "other than negative" cytology had repeat cytology and/ or histologic study (208/27,508 or 7.6/1,000) 0.27% of all patients under age 22 with histologically proved dysplasia or carcinoma in situ (73/27,508 or 2.711,000) 61.9% of patients biopsied who were under age 22 had histologically proved dysplasia or carcinoma in situ (73/118)
decreasing in the past few decades. Linden and Dunn 18 reported a shift in detection of cervical carcinoma as carcinoma in situ from 30 per cent to greater than 90 per cent over a 10 year period. No change in the incidence of cervical carcinoma in patients I 0 to 19 years old was noted in California during the years I 950 to 1969, during which time an increase in the incidence of carcinoma of the uterine corpus and vagina was noted. 18
Several studies bear upon the predictive value of cytology, since it is· apparent than an "other than negative" cytology interpretation does not implv a
Dysplasia and carcinoma in situ in young women 755
Volume 124 Number 7
Table VIII. Comparison with previous studies on dysplasia in the very young woman Population Year studied Ferguson 8 Ferguson 9 Christopherson and Parker• Kaufman and associates 15 Kaufman and associates 13 Wallace and Slankard 29 Davies and Kel!y6 Slate and associates 25 Present authors
1961 1967 1965 1965 1970 1973 1971 1972 1973
2,300 5,061 1,199 10,246 7,520 411 40,000 27,508
Other than negative Tissue Severe Carcinoma Rate of "other than Rate of histologically in situ cytology diagnoses dysplasia negative" cytology* confirmed disease t 77 167 32 302 51 14 1,325 247
56 120 6 7 49 44 1 256 73
11 ?
8
10 16 0 2 4 12 0 3
33.4/1,000
24.3/1,000
26.6/1,000 29.4/1,000 6.7/1,000 34.0/1,000 33.3/1,000 8.9/1,000
1.111,000 5.8/1,000 4.8/1,000 5.8/1,000 2.4/1,000 6.4/1,000 2.7/1,000
*Composite rate of"other than negative" cytology: 23.0/1,000. tComposite rate of histologically confirmed dysplasia or carcinoma: 5.2/1,000.
uniform progression for the disease process present. 10• 17, 20 • 21 · 24 • 28 Factors affecting the accuracy of cytologic-histologic correlations include the number and capabilities of observers, the possible errors of sample and technique, interpreter bias, and the time interval between the initial "other than negative" cytology and the repeat cytology or tissue specimen.10-12· 17 · 20 · 21 • 24 • 28 The phenomenon of "false negativity" or lesser degrees of abnormality detected on repeat cytology specimens obtained at inappropriately short intervals (less than eight weeks), while well recognized by cytologists and pathologists, is not commonly appreciated by clinicians. This may unwittingly cause a dilemma in evaluating the significance of the smear and the subsequent management of a patient with an initial "other than negative" cytodiagnosis. Our studies in these young women support those of others in noting the high rate of false negativity or lower readings on "short interval" and prebiopsy repeat smears. 10• 17 • 20 · 24 · 28 We consider eight weeks or two menstrual cycles the minimum time interval before repeating a smear unless colposcopy, biopsy, or another procedure is deemed clinically necessary for a patient's management.
Still to be evaluated are those young women who as yet have had no further follow-up after "other than negative" cytology and those women whose repeat cytology reverted to negative, especially those repeated at short intervals. The progression-regression controversy concerning the development of significant intraepithelial neoplasia or dysplasia has yet to be resolved. 21 · 24 • 28 Regardless of the ultimate factors indentified as important in carcinogenesis, early exposure leads to an early risk of adverse response. Dysplasia and carcinoma in situ of the uterine cervix are prevalent in young women at a previously underestimated rate. An awareness that these lesions may occur in young women in early years of sexual activity mandates cytologic studies to identify those patients requiring careful, thoughtful, and appropriately early management. The authors acknowledge the assistance of Ms. Carol Goldenberg, MLS, Ms. Judith Dowd, MLS, and Ms. Marilyn Love in preparing the manuscripts and Mr. Don Broun in preparing the illustrations.
REFERENCES I. Bibbo, M., Keebler, C. M., and Weid, G. L.: Prevalence and incidence rates of cervical atypia,]. Reprod. Med. 6:
2. 3. 4. 5. 6.
79, 1971. Boutselis, ]. D.: Intraepithelial carcinoma of the cervix associated with pregnancy, Obstet. Gynecol. 40: 657, 1972. Christopherson, W. M.: The risk of cervical cancer in teen-aged girls, J. A. M. A. 194: 176, 1965. Christopherson, W. M., and Parker, J.: Relation of cervical cancer to early marriage and childbearing, N. Engl. J. Med. 273: 235, 1965. Creasman, W. T., and Rutledge, F.: Carcinoma in situ of the cervix. An analysis of 861 patients, Obstet. Gynecol. 39: 373, 1972. Davies, S. W., and Kelly, R. M.: Intraepithelia1 carcinoma
7. 8. 9. 10. 11. 12.
of the cervix uteri in women aged under 35 years, Br. Med.J. 4:525, 1971. Diddle, A. W., and Watts, J.: Cervical carcinoma in women under 30 years of age, AM.]. 0BSTET. GYNECOL. 7,45, 1962. Ferguson, J. H.: Positive cancer smears in teenage girls, J. A.M. A. 178: 365, 1961. Ferguson, J. H.: Why some adolescents need cytologic screening, Ann. N.Y. Acad. Sci. 142: 654, 1967. Figge, D. C., Bennington, ]. L., and Schweid, A. 1.: Cervical cancer after initial negative and atypical vaginal cytology, AM. j. 0BSTET. GYNECOL. 108: 422. 1970. Gondos, B., Townsend, D. E., and Ostergard, D. R.: Cytologic diagnosis of squamous dysplasia and carcinoma of the cervix, AM. J. OssTET. GYNECOL. 110: 107, 1971. Holmquist, N.D., McMahan, C. A., and Williams, 0. D.:
756 Snyder et al. Arn.
13. 14.
1.5. 16.
17. 18. 19. 20. 21.
Variability in classification of carcinoma in situ of the uterine cervix, Arch. Pathol. 84: 334, 1967. Kaufman, R. H., Burmeister, R. E., and Spjut, H. J.: Cervical cytology in the the teenage patient, AM. ]. 0BSTET. GYNECOL. 108: 515, 1970. Kaufman, R. H., and Leeds, L. T.: Cervical and vaginal cytology in the child and adolescent, Pediatr. Clin North Am. 19: 547, 1972. Kaufman, R. H., Spjut, H. ]., and Carrig, S.: Cervicovaginal cytology in the teenage patient, Acta. Cytol. 9: 314, 1965. Kling, T. G., and Buchsbaum, H. J.: Cervical carcinoma in women under twenty-one years of age, Obstet. Gynecol. 42: 205, 1972. Koss, 1.. G.: Detectection of carcinoma of uterine cervix, J. A. M.A. 222: 699, 1972. Linden, G., and Dunn. J. E., Jr.: Earlier Diagnosis of cervical cancer, Calif. Med. 105: 331, 1966. Linden. G., and Henderson, B.: Genital tract cancers in adolescents and young adults, N. Engl. J. Med. 286: 760, 1972. Nyirjesy, 1.: Atypical or suspicious cervical smears. J. A.M. A. 222:691, 1972. Richart, R. M., and Barron, B. A.: A follow-up study of
22. 23. 24. 25.
26. 27. 28. 29. 30.
April I, 1976 GynecoL
J. Obstet.
patients with cervical dysplasia, AM. J. 0BSTET. GvNECOL. 105: 386, 1969. Rotkin, I. D.: Adolescent coitus and cervical cancer: Associations of related events with increased risk, Cancer Res. 27: 603, 1967. Rotkin, I. D., and Cameron. T. R.: Clusters of variables influence risk of cervical cancer, Cancer 21: 663, 1968. Sedlis, A., Cohen, A., and Sail, S.: The fate of cervical dysplasia, AM. J. 0BSTET GvNECOL. 107: 1065, 1970. Slate, T. A .. Sandell, J. E., and Merritt, J. W.: The prevalence and significance of abnormal smears in teenagers, presented at the Twentieth Annual Meeting of the American Society of Cytology, November, 1972. Speert, H.: Cervical cancer in young girls, AM . .J. OssTET. GYNECOL. 54: 982, 1947. Stern, E., and Dixon, W. ].: Cancer of the cervix-A biometric approach to etiology, Cancer 14: 153, 1961. Villa Santa, U.: Diagnosis and prognosis of cervical dysplasia, Obstet. Gynecol. 38: 811, I 971. Wallace, D. L., and Slankard, J. E.: Teenage cervical carcinoma in situ, Obstet. Gynecol. 41: 697, 1973. Wynder, E. I..: Epidemiology of carcinoma in situ of the cervix, Obstet. Gynecol. Survey 24: 697, 1969.
RICHARD N. SNYDER, M.D. YOLANDA ORTIZ, C.T.(A.S.C.P.) SAMONA WILLIE, B.S., C.T.(A.S.C.P.) (l.A.C.)
.J.
KAREN
North
.J.
Holl~wood
COVE, M.D.
and Los Angeles, California
An increased number of cervical epithelial abnormalities has been observed in women up to and including 21 years of age. The prevalence and incidence of dysplasia in adolescents and young women is increasing at a time when the incidence of cervical carcinoma is decreasing. We studied 247 women under age 22 with "other than negative" cytologic diagnoses identified during a one-year period (197 3) in which approximately 27,500 women in this age group were screened. The prevalence rates of "other than negative" cytology and "other than negative" cytology with confirmed histopathologic abnormalities were 9/1,000 and 2.711,000, respectively. Repeat smears and/or tissue specimens were obtained in over 70 per cent of these cases. The majority of abnormalities identified were mild or moderate dysplasia; however eight severe dysplasias and three carcinomas in situ were identified. Fifty-nine per cent of these women had a history of one or more pregnancies. Our findings emphasize the presence of dysplasia and carcinoma in situ in young women and suggest the need for re-evaluation of the age at which initiation of the Papanicolaou smear should be considered.
C E R v 1 CAL intraepithelial neoplasia or dysplasia occuring in very young women is now recognized as a developing medical and public health problem. Ferguson8 reported 72 "other than negative" Papanicolaou smears among a group of 1,500 women under age 19, 10 of whom had histologically proved carcinoma in situ. Other reports confirm the observation of a varying prevalence of dysplasia and carcinoma in situ in young women with differences in occurrence
rate in the various communities and socioeconomic groups studies.t-1. 9. 13-16, 19, 22. 2s. 2s. 29, ao We have studied the 1973 prevalence of "other than negative" cytologic diagnoses and the incidence of confirmed histologic abnormality and/or follow-up cytology in women under 22 years old. The population studied was drawn from a prepaid health plan population without economic or social barriers to prevent access to quality medical care. Our findings emphasize the importance of providing routine cytology studies for sexually active women, regardless of age. We consider the finding of a 9/1,000 "other than negative" cytology prevalence rate sufficient to warrant investigating this young patient population.
From the Department of Patholog;y and the Regional Cytolog;y Laboratory, Southern California Permanente Medical Group, and the Kaiser Foundation Hospital. Presented in part at the Fifth International Congress of Cytolog;y, Miami Beach, Florida, May 31, 1974.
Material and methods In 1973, 219,907 women of all ages were examined by the Papanicolaou smear technique (307,000 slides); 27,508 (12.5 per cent) of these women were younger than 22 years old. All were members of the Southern California Kaiser Permanente Health Plan. Cytologic
Received for publication january 21, 1975. Accepted June 4, 1975. Reprint requests: Dr. Ricoord N. Snyder, Department of Patholog;y, Southern California Permanente Medical Group, 1510 N. Edgemont St., Lm Angeles, California 90027.
751
April!, 1976 Am. J. Obstet. Gvnecol.
752 Snyder et al.
Table I. Cytodiagnostic terminology "Key word" category Abnormal
Inconclusive
Negative
Unsatisfactory
Some examples of descriptive cytodiagnoses Mild to moderate dysplasia of any type (keratinizing, nonkeratinizing, metaplastic, mixed) Severe dysplasia versus carcinoma in situ of any type Invasive carcinoma, cervix; adenocarcinoma; metastatic tumor; sarcoma Atypical cellular changes not explained solely by infection, repair, or prior therapy and/or cannot exclude mild dysplasia of cervix Benign squamous metaplasia, cellular changes or metaplasia due to bacteria. Parasites (Trichomonas), fungi, herpes, and/or repair reaction Air dried, too few cells, too bloody, slide not properly identified at origin
27,508 Patients examined cytologically (12.5% of all patients) 247 Patients with "other than negative" cytology 208 Patients with histology and/or repeat cytology 118 Patients with histologic examination 62 Patients with mild or moderate dysplasia 8 Patients with severe dysplasia 3 Patients with carcinoma in situ 45 Patients whose biopsies revealed various nondysplastic diagnoses 90 Patients with one or more subsequent cytology examinations 39 Patients without further follow-up at this time
and histologic diagnoses by two cytopathologists at the regional centralized cytology laboratory and by 14 histopathologists were incorporated in this report. Correlations were made without any review of histopathologic specimens. Our cytology reports incorporate cytodiagnostic terminology as noted in Table I. In addition, a "key word" notation of "negative," "inconclusive," or "abnormal" was provided, since in our experience, as well as that of others, some nongynecologist physicians do not readily appreciate the diagnostic and therapeutic implications of dysplasia. 10• 11, 17, 20, 21, 24, 28
All patients with "other than negative" cytology were recalled to the appropriate follow-up clinic or physician for further evaluation. Repeat cytology and/or random or colposcopic biopsies were obtained where appropriate and were followed by diagnostic cervical conization when clinically indicated. The interval between repeat cytology examination was at the discretion of the patient's physician. Vaginitis and cervicitis were treated if necessary. Pregnancies were
managed according to established procedures for such patients. Histologic specimens were studied on slides stained with hematoxylin-eosin, with multiple levels cut routinely in patients having conization.
Results Of the 27,508 patients under age 22 screened by cytology, 24 7 patients had "other than negative" cytodiagnoses (inconclusive-rule out dysplasia; mild-moderate dysplasia; severe dysplasia-carcinoma in situ; microinvasive carcinoma; invasive carcinoma). These data are summarized in Table II. Two hundred and eight patients had further cytologic and/or histologic studies. These 208 patients formed the definitive group of our study. One hundred and eighteen patients had histopathologic studies of biopsies and/ or conizations, yielding 62 cases of mild or moderate dysplasia, eight cases of severe dysplasia, and three cases of carcinoma in situ. Forty-five patients had nondysplastic tissue diagnoses on biopsy (Table Ill). Of the patients studied by repeat cytology, 42 again had "other than negative" cytologic examinations. and 48 reverted to "negative." However, 30 of these smears with negative reversion were repeated within an eight-week period (see below). No cases of invasive carcinoma were identified in any women under age 22. Thirty-nine patients have had no known follow-up at the time of this study. Table IV lists the age distribution of the 118 patients with tissue examination and the diagnosis. The preponderance of proved dysplasia or carcinoma in situ occurred in the group over 17 years old. Onlv one of the 12 patients 17 years old or younger had severe dysplasia. The relationship between initial and subsequent cytodiagnosis, time interval between smears, and correlation with histopathology are shown in Table V. Of 56 patients with repeat smears and histopathologic studies, the initial cytology identified 36 patients with subsequent tissue-proved dysplasia, while only seven additional patients with dysplasia were identified by the second screening following an initial "inconclusive" cytology. In 21 of these 36 patients with dysplasia, the same diagnoses were made on both cvtology specimens. Thirteen biopsies were negative for dysplasia after an initial "inconclusive" or ''abnormal'' cytology diagnosis. Of 129 patients having two Papanicolaou smears, 60 had a diagnosis less severe in classification on the second smear. Forty-one of these 60 had repeat smears within eight weeks. Of those 77 cases with the same or a more severe diagnosis on the second smear, only 13 had been repeated within eight weeks.
Dysplasia and carcinoma in situ in young women 753
Volume 124 Number 7
Table III. Cytology-histology correlation of 118 patients under age 22 Histopathology diagnosis
Cytology interpretation
No. of cases
Inconclusive Mild to moderate dysplasia Severe dysplasia to carcinoma in situ
34 80
Total
Carcinoma in situ
4
2
ll8
3
Severe dysplasia
Mild or moderate dysplasia
Squamous metaplasia, trichomonas changes, herpes, cervicitis, polyp, condyloma, "no pathologic diagnosis"
2 5
14 47
18 27
8
62
45
Table IV. Age distribution and histopathologic diagnoses Histologic diagnosis
Age of patient
No. in age group
14 15 16 17 18
1 1 6 8 18 26 28 30 118
19
20 21 Total
Carcinoma in situ
Severe dysplasia
Mild-motkrate dysplasia
Squamous metaplasia, Trichomonas, herpes, cervicitis, pol_vp, condylorr14, no pathologic abnormality
I
4 6 2 1 3
Thirteen patients had a repeat cytology smear taken simultaneously at the time of tissue biopsy. All13 initial cytodiagnoses correlated with the proved histologic abnormality of dysplasia; however, nine of the repeat smears were interpreted as "negative." All of these 13 repeat smears had been obtained at an interval of less than eight weeks. Of the 118 patients with tissue examinations, 73 had dysplasia or carcinoma in situ, while biopsies from 45 patients revealed a variety of nondysplastic inflammatory, reparative, or metaplastic lesions. Sixteen of 34 "inconclusive" smears were from women in whom biopsy or conization demonstrated dysplastic histology. Fifty-three of 80 patients with "mild to moderate" dysplasia and four of four patients with "severe dysplasia-carcinoma in situ" had proved dysplasia or carcinoma in situ (Table Ill). One hundred and twenty-three of the 108 patients with initial "other than negative" cytology and with repeat cytology or tissue examination had a history of one or more pregnancies. The association of age and parity is shown in Fig. 1. The morphologic types of dysplasia noted in cytology in 85 nulliparous patients
2 2 2
l 8
ll
14 10 16 62
1 2 5 10 14
12 45
are shown in Table VI. Not included in our study was one case of vaginal adenosis and one case of vaginal clear cell adenocarcinoma detected by cytology. Neither cellular nor serologic studies of possible herpesvirus infection were done.
Comment Cytology studies are indicated for all women visiting gynecologists or obstetricians. Sexually active women, whether pregnant or not, regardless of young age, must be considered to be at risk for the development of cervical carcinoma in situ and dysplasia. 1• 2 • 4 -u. ta-ta, ts. 22 25 26 29 • • • Our detection in this one-year study of 73 patients with histologically confirmed dysplasia or carcinoma in situ and an additional 174 patients with one or more "other than negative" cytodiagnoses represents a prevalence rate of 2. 7I l ,000 and 9/ l ,000, respectively. Approximately 62 per cent of the 118 patients with tissue examinations had proved dysplasia or carcinoma in situ (Table VII). A comparison of our findings with those of previous investigators is found in Table VIII. Many of the variations in the prevalence and
754 Snyder et al.
April I, 1976 Am . .J. Obstet. Gynecol.
25 I
NUMBER OF
1
PREGNANCIES I
0
20
ffl ~
I I I I I I I
1
2 3 6
I
~
~ 10
z
CASES
85 93 28 1
1
I
15
~
NUMBER OF
i!
5
12
12
AGE
Fig. 1. Number of pregnancies per patient by age (Total: 208 cases).
Table V. Cytologic and histologic correlation related to interval between repeat cytology in 56 patients
Repeat cytology <2 months First same as second First less severe than second First more severe than second
16
No.
Keratinizing Nonkeratinizing
36 17 II 21
Metaplastic
3
Indeterminate or mixed
2
2
5
4
4
13
7
incidence of"other than negative" cytology may be due to the population studied. The socioeconomic status was an important factor in several previous epidemiologic studies of cervical disease.'· 5 • 23 • 27 • 30 Gravidity and coital activity seem to have an important role in the pathogenesis of dysplasia and carcinoma. Findings similar to those in our 123 patients with a history of past or current pregnancy and early onset of sexual activity with multiple gravidity have been reported.L 2, 4-9, 13-16, 22, 23, 25-27, 29, ao Kaufman and 14
Dysplasia
Histology negative
Cytology Repeat cytology >2 months First same as second First less severe than second First more severe than second
Table VI. Cytologic pattern of dysplasia in 85 nulliparous patients
Leeds noted that 75 per cent of their 58 patients with severe dysplasia or carcinoma in situ were parous. Wallace and Slankard 29 found that 11 of 44 patients with documented dysplasia or carcinoma in situ in their teen-age population had been pregnant one or more times. Bibbo and associates' found that 0.99 per cent of patients with "other than negative" cytology were 15 years old or younger and were patients at Planned Parenthood or obstetric clinics. 1 The prevalence and incidence of carcinoma in situ and invasive carcinoma of the cervix have been
Table VII. Summary of findings 12.5%
of all patients studied were under age 22 (27, 508/219, 907) 0.9% of patients under age 22 had "other than negative" cytology (247/27,508 or 9/1,000) 0.76% of patients under age 22 with "other than negative" cytology had repeat cytology and/ or histologic study (208/27,508 or 7.6/1,000) 0.27% of all patients under age 22 with histologically proved dysplasia or carcinoma in situ (73/27,508 or 2.711,000) 61.9% of patients biopsied who were under age 22 had histologically proved dysplasia or carcinoma in situ (73/118)
decreasing in the past few decades. Linden and Dunn 18 reported a shift in detection of cervical carcinoma as carcinoma in situ from 30 per cent to greater than 90 per cent over a 10 year period. No change in the incidence of cervical carcinoma in patients I 0 to 19 years old was noted in California during the years I 950 to 1969, during which time an increase in the incidence of carcinoma of the uterine corpus and vagina was noted. 18
Several studies bear upon the predictive value of cytology, since it is· apparent than an "other than negative" cytology interpretation does not implv a
Dysplasia and carcinoma in situ in young women 755
Volume 124 Number 7
Table VIII. Comparison with previous studies on dysplasia in the very young woman Population Year studied Ferguson 8 Ferguson 9 Christopherson and Parker• Kaufman and associates 15 Kaufman and associates 13 Wallace and Slankard 29 Davies and Kel!y6 Slate and associates 25 Present authors
1961 1967 1965 1965 1970 1973 1971 1972 1973
2,300 5,061 1,199 10,246 7,520 411 40,000 27,508
Other than negative Tissue Severe Carcinoma Rate of "other than Rate of histologically in situ cytology diagnoses dysplasia negative" cytology* confirmed disease t 77 167 32 302 51 14 1,325 247
56 120 6 7 49 44 1 256 73
11 ?
8
10 16 0 2 4 12 0 3
33.4/1,000
24.3/1,000
26.6/1,000 29.4/1,000 6.7/1,000 34.0/1,000 33.3/1,000 8.9/1,000
1.111,000 5.8/1,000 4.8/1,000 5.8/1,000 2.4/1,000 6.4/1,000 2.7/1,000
*Composite rate of"other than negative" cytology: 23.0/1,000. tComposite rate of histologically confirmed dysplasia or carcinoma: 5.2/1,000.
uniform progression for the disease process present. 10• 17, 20 • 21 · 24 • 28 Factors affecting the accuracy of cytologic-histologic correlations include the number and capabilities of observers, the possible errors of sample and technique, interpreter bias, and the time interval between the initial "other than negative" cytology and the repeat cytology or tissue specimen.10-12· 17 · 20 · 21 • 24 • 28 The phenomenon of "false negativity" or lesser degrees of abnormality detected on repeat cytology specimens obtained at inappropriately short intervals (less than eight weeks), while well recognized by cytologists and pathologists, is not commonly appreciated by clinicians. This may unwittingly cause a dilemma in evaluating the significance of the smear and the subsequent management of a patient with an initial "other than negative" cytodiagnosis. Our studies in these young women support those of others in noting the high rate of false negativity or lower readings on "short interval" and prebiopsy repeat smears. 10• 17 • 20 · 24 · 28 We consider eight weeks or two menstrual cycles the minimum time interval before repeating a smear unless colposcopy, biopsy, or another procedure is deemed clinically necessary for a patient's management.
Still to be evaluated are those young women who as yet have had no further follow-up after "other than negative" cytology and those women whose repeat cytology reverted to negative, especially those repeated at short intervals. The progression-regression controversy concerning the development of significant intraepithelial neoplasia or dysplasia has yet to be resolved. 21 · 24 • 28 Regardless of the ultimate factors indentified as important in carcinogenesis, early exposure leads to an early risk of adverse response. Dysplasia and carcinoma in situ of the uterine cervix are prevalent in young women at a previously underestimated rate. An awareness that these lesions may occur in young women in early years of sexual activity mandates cytologic studies to identify those patients requiring careful, thoughtful, and appropriately early management. The authors acknowledge the assistance of Ms. Carol Goldenberg, MLS, Ms. Judith Dowd, MLS, and Ms. Marilyn Love in preparing the manuscripts and Mr. Don Broun in preparing the illustrations.
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