Abnormal cervical cytology in adolescents: A literature review

JOURNAL OF ADOLESCENT HEALTI-I 1992;13:643-650

LITERATURE REVIEW

CAROL

F. RQYE,

R.N.,

M.S.,

C.l?.N.P

This article reviews the literature on the subject of cervical cytological abnormalities in teenagers, defined as a Papanicolaou (Pap)smear result more severe than inflammation. There is discussion of the increasing prevalence of this problem in adolescents. Behavioral and biologic risk factors are examined. The role of the human papillomavirus, widely believed to be the etiologic agent, is addressed. Atypia, its relationship to cervical malignancies, and its management are reviewed. The possible role of the human immunodeficiency virus in the increasing prevalence of cytological abnormalities in teens is considered. KEY WORDS:

Adolescence Cervix diseases Papillomaviruses Sex behavior Sexually transmitted diseases

The increase in sexual activity among teenagers has

been well documented (l-6). The 1988 National Survey of Family Growth data (7) suggests that 4.1% of all never-married teenage girls had engaged in sexual intercourse before age 14 years, and 68.2% before age 20 years. From 1972 to 1981 there was a 52.9% increase in the number of teenage girls from metropolitan areas experiencing sexual intercourse (8). A recent national survey of high school students found that 54.2% of adolescents in grades 9-12 report ever having had sexual intercourse (9). The frequency of sexually transmitted diseases (STDs) in

From the Columbia University School of Nursing, New York, New York. Address reprint requests to: Carol F. Ruye, Columbia Universify School of Nursing, 630 West 268th Street, New York, N.Y. 10032. Manuscript accepted luly 8, 1992.

adolescents has risen concomitantly (lo), and teenagers and young adults currently have the highest prevalence rates for most STDs (11). One apparent result is the increasing prevalence of cervical cytological abnormalities in this age group. This paper reviews the relevant literature. For present purposes, the term “cytological abnormalities” refers to any Papanicolaou (Pap) smear result which is more severe than inflammation (i.e., atypia, cervical intraepithelial neoplasial I-III, carcinoma-in-situ, or invasive carcinoma). The importance of the less severe abnormalities lies in their potential for progression to carcinoma.

Prevalence of CytologicaZAbnormalities in Adulescents Although cervical dysplasia and carcinoma have been considered disorders of middle-aged women (12), the prevalence of cervical intraepithelial neoplasia (CIN) in young women is increasing worldwide according to reports from South Africa (12), Australia (13,14), England (15,16), and the United States (17-22). Schwartz and Weiss (19) analyzed prevalence rates of adenocarcinoma of the cervix in white women in nine geographic regions of the United States, and found that the prevalence has increased in women under age 35 years since the 1970s. The prevalence of abnormal cervical cytology in adoles,cents has increased over the last 20 years (Table I). Rosenthal et al. (19) reviewed a convenience sample of smears obtained in California and found that the rate of abnormal cervical cytology rose from 2% in 1973 (with moderate to severe dysplasia being the highest level of abnormality) to 6% in 1978 (with carcinoma-in-situ or invasive carcinoma being the

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Table 1. *valence of Abnormal Pap Smears in Adolescents Authors (ref. no.) Hein et al. (23) Rosenthal

et al. (18)

Year

country

Comments

Rate of abnormal cytology

n

1977 United States

403

3%

Early neoplasia

1982 United States

2

<2% (in 1973) 5% (in 1978)

University Health Service atypia

Sadeghi et al. (17)

1984 United States 194,069

1.97%

CIN I-III or atypia

Shafer et al. (21)

1985 United States

148

2%

Mild to moderate dysplasia (14.8% without endocervical cells)

McQuiston (20)

1989 United States

93

17%

University Health Service abnormal or HPV atypia with or without dysplasia

Learmonth et al. (12) 1990 South Africa

10,361

>14%

atypia, CIN I-III, HPV, or invasive cancer

1991 United States

37

18.4%

ages 14-19 years atypia, CIN II

Roye (22)

CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus.

highest level of abnormality). In 1977 Hein et al. (23) reported results of 403 Pap smears from sexually active adolescents admitted to a youth detention center in the Bronx, New York. Inflammation was seen in 149 (37%) and early neoplasia in 14 (3%). Sadeghi et al. (17), in a 1984 review of data from the Cancer Screening Services, found that 1.9% of 15 to 19-year olds had abnormal cervical cytology. McQuiston (20) in 1989 found that 17% of a small convenience sample of women presenting to a university-based health service, had abnormal cytology. In the Learmonth et al. 1990 sample of 10,361 South African women under 19 years of age, more than 14% had abnormal cervical cytology (12). A study by Roye (22) of 37 inner-city teenage mothers in 1991 revealed an 18% rate of cytological abnormalities. The rate of inflammation was 58%.

Risk Factovs There are two widely accepted behavioral risk factors for Pap smear abnormalities: (a) young age at first coitus, (less than 16 or 18 years of age) (14,17,2432); and (b) multiple sexual partners (17,26-29,33). Of the two, early age at first intercourse appears to be the more significant risk factor. Several other risk factors have received attention, but their role in cervical neoplasia is more controversial; notably oral contraceptive use (and the protective effect of barrier methods of contraception) (34) and smoking (35). These factors potentially have a latent effect on cervical carcinogenesis in older women.

Early Age at First Coitus Sadeghi et al. (17) examined a sample of more than 194,000 Pap smears of teenagers; the majority of those with abnormal cytology gave a history of sexual intercourse before age 15 years, prompting the conclusion that early age of sexual activity was the most critical factor in the development of cervical carcinoma in adulthood. A study (36) of a group of prostitutes who began having intercourse after age 18 years showed a prevalence of cervical abnormalities of only 10.7/1000, despite their high rate of STDs and history of multiple partners. This compares to a prevalence of 18.8/10!)0 for 15- to 1Byears olds in the study by Sadeghi et al. The significance of early age at first coitus is thought to be related to the biologic changes that occur in the cervix during puberty. The adolescent cervix appears to be especially vulnerable to the initiation of carcinogenesis (25,33,37,38). Edibiri (38) suggests that the increased mitotic activity present during normal physiologic growth of the cervix during puberty increases susceptibility to carcinogenesis. Mosciki et al. (37) studied a nonrandom sample of 178 adolescents in a teen colposcopy clinic. In their report, they discussed the rapid physiologic change in cervical epithelium during puberty, reflecting the physiologic immaturity of the transformation zone where neoplasia originates. Adolescents have a preponderance of metaplastic and columnar cells on the ectocervix, which may make it especially vulnerable to human papillomavirus (HPV), other sexually transmitted agents, and subsequent neoplastic

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ABNORMAL CERVICAL CYTOLOGY: A LITERATURE REVIEW

change. Their study, which examined several factors that may affect CIN in adolescence, found that age of menarche was the only factor which significantly differed between subjects with CIN and three comparison groups. The mean age of menarche among subjects with CIN was 1 year later than for those -without GIN. On the other hand, Zaninetti et al. (39) studied 126 teens in Italy with abnormal Pap smears, and found that neither young age at first coitus nor menarcheal age was associated with increased risk of Pap smear abnormalities. Their entire sample experienced coitus at an early age, however, and had a young menarcheal age. Such homogeneity in the population studied would explain the lack of significant association with these factors. The time span between initiation of coitus and development of cervical pathology is variable. Edibiri (38), in a case control study of 125 women with confirmed diagnoses of CIN presenting in a colposcopy clinic in England, found that the mean time span between age at first coitus and diagnosis of CIN was 9-14 years, with a maximum of 47 years, and a minimum of less than 1 year. Silcocks and Moss (40) state that a rapidly progressive form of cervical carcinoma (having a preclinical detectable phase of less than 12 months) in younger women had been suggested. They were, however, unable to demonstrate such an entity and suggested that laboratoryerrors, and increasednumbers of women being screened may explain the perception of a new rapidly progressive form of the disease.

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study of 759 Latin American women with invasive carcinoma of the cervix, reported that the the number of steady partners (greater than 3 months) related more to risk than the number of nonsteady partners. In the previously cited study by Zaninetti et al. (39), having more than one sexualpartner was the only significant behavioral risk factor associated with increased risk of cervical neoplasia. They postulate that multiple partners implies increased exposure to an etiologicviral agent. Smoking In an extensive review of the literature relating smoking to cervical cancer, Winkelstein (35) reports that 26 of 33 studies have shown a positive association between these two factors. He described serious methodologicalflaws in some of those which did not find such an association, Winkelstein (35) postulates that the effect of smoking on development of cervicalcancer may requirea latent period, and thus may not be manifest in adolescents. Winkelstein (35) provides compelling biologic support for the association between cervical carcinoma and smoking: smoking-relatedcancers and cervical carcinoma are predominantlyof squamous cell histology; smoking-relatedsecond primary tumors occur with greater than expected frequencyin women with cervical cancer; there are higher concentrations of nicotine and cotinine in the cervical mucous of women with in-situ cervicalcarcinoma. Contraceptive Method

Multiple Sexual Partners No studies of’ the relationshipbetween number of sexual partners and cervical carcinoma addressed adolescents exclusively. This risk factor is particularly relevant for adolescents, as adolescence is a time when much sexual experimentation occurs. In a case-control study (25) of 117 Australian-born women with confirmed diagnoses of CIN III, those with seven or more partners had a six fold increased risk of developing cervical carcinoma compared with women with one or no partner. Clarke et al. (33) investigated 234 women in Canada with histologitally confirmed cervical dysplasia. They concluded that women with two to five partners had a relative risk of 3.4 of developing cervical dysplasia when compared to women with one sexual partner. The relative risk increased to 5.1 for those with six or more partners. Herrero et al. (24), in a case-matched

Studies have lookedat the associationbetween contraceptive method and risk of HPV and/or cervical neoplasia (31,41,42) Parazzini et al. (41) cite nine studies which show decreased rates of cervicalneoplasia among “ever-users” of barrier methods of contraception.Their study of more than 600 women in Italy with invasive cervical carcinoma or CIN showed a greater protectiveeffectof barriermethods at older ages. Brinton et al. (34) studied the relationship between oral contraceptive use and invasive cervical cancer. In a case-control study of women (ages 2074 years) in five metropolitan areas, they found a relationship between oral contraceptive use and cervical cancer with extended use (greater than 5 or 7 years). They also found that the risk from use of oral contraceptives was greatest for those women who had never used barrier methods. It should be

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noted that owing to the age of their subjects, the likelihood is that many of them were exposed to higher estrogen dose oral contraceptives than are generally prescribed today. The association between contraceptive method and risk of cervical neoplasia is less clear in adolescents. Some authors have examined the relationship between oral contraceptive use and HPV (a suspected etiologic agent for cervical cancer-see discussion below) in adolescents. A study of 661 adolescents (42) revealed no difference in HPV infection rate for teens who use oral contraceptives, barrier methods, or no contraception, after adjusting for number of lifetime partners. Ley et al. (31), however, found a strong association between current and former oral contraceptive use and HPV infection in a young adult population independent of correlated variables such as sexual activity. The use of spermicidal barrier me ods decreased the risk in the group who “ever used” contraceptives. It could be that any possible protective effect of barrier contraceptives on development of cervical cancer in adolescents requires several years of follow-up in order to account for the presumed latency of cervical cancer. Riologic Agents Sexually transmitted viral agents appear to play an important role in the development of CIN (28,29,31,38,43,44)+There is strong evidence linking HPV to cancer of the cervix (27-29,31,43-45). HPV types 16 and 18 have been convincingly linked to cervical cancer (28,31,39), while HPV types 31,33, and 35 are also likely to be etiologically related (32,42,46). One researcher (28) states that it is still unclear whether HPV may be only a marker of sexual activity. Franceschi et al. (43), in an epidemiologic study of 1008 women attending an STD Clinic in England, found that genital herpes, once thought to be a causative factor in cervical cancer, did not play such a role; and that HPV was the likely causative organism. Another researcher (29) agrees that repeated evidence shows no causative role for herpes. Reid (29), reviewing scientific data on the STD responsible for cervical dysplasia and carcinoma, found evidence of subclinical HPV infection in 91% of women undergoing hysterectomy for preinvasive or invasive cervical cancer compared with a prevalence rate of 12.5% in matched controls. He commented that the morphologic continuum of change in the colposcopic appearance of subclinical HPV

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infection and CIN III gives further weight to the role of HPV in the genesis of cervical cancer. Borst et al. (47) found the presence of HPV 16 in 46% of subjects with atypia (n = 50), 46% of subjects with GIN (n = 124) and 11.6% of subjects with normal Pap smears (n = 112). Hording et al. (48), in a study of women with invasive or preinvasive cervical carcinoma (n = 164), found HPV 16 or 18 DNA in the cervical swabs of 33% of patients with invasive cervical carcinoma, 59% of those with carcinoma-in-situ or severe dysplasia, and 40% of patients with Iowgrade dysplasia. Mosciki et al. (42) studied 661 sexually active adolescents and found that 51% of the subjects with an abnormal smear were positive for HPV, compared with 13% of those with normal cytology. The most prevalent HPV types in that study were Types 16,18,31,33, and 35, precisely those with oncogenic potential. Similarly, Martinez et al. (46), in a study of 89 sexually active adolescents, found a significant difference in HPV prevalence in those with abnormal cytology (48%) and those with normal cytology (3%) (Table 2). Rosenfeld (11) commented that current belief holds that infection with HPV is an essential prerequisite for the development of cervical cancer. However, because only a small fraction of the large number of patients with HPV develop malignancies, there are possible host factors, such as immune system. compromise (49), exposure to cigarette smoke (35), multiple episodes of new infection (11,30,31), and black race (31). Evidence for an association between HPV and cervical dysplasia was strengthened by a recent study of 107 sexually active white, middle-class adolescents, which found that patients with HPV DNA, detected by means of Southern blot analysis, were more likely to have had more than two sexual partners, to have been sexually active for more than 2 years, to have had menarche before age 12 years, and to have a history of STDs (50); a similar set of behavioral and biologic risk factors as for abnormal cytology (except for early age of menarche). Prevalence of HPV In Adolescents Recent studies have found an HPV prevalence rate in adolescents of 15%-38% (32,42,50) leading some researchers to suggest that HPV may be the most common STD among U.S. adolescents (32,42). The rates were high among suburban white adolescents (32%) (50) as well as inner-city minority teens (38%) (32).

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ABNORMAL CERVICAL CYTOLOGY: A LITERATURE REVIEW

Table 2. Prevalence of Human Papillomaviru;

(HIT) in Patients with Abnormal Cervical Cytology

Author (year) ref. no.

Reid (1983)

647

Prevalence of HPV

Pap result or diagnosis

Age group

%

Adult

neoplasia matched controls

91 12.5

Borst et al. (1991) 4?

Adult

CIN normal Pap

46 11.6

Hording et al. (1991) 48

Adult

invasive carcinoma carcinoma in situ or severe dysplasia low-grade dysplasia

33 59 48

Mosciki et al. (1998) 42

Adolescent

abnormal smear normal smear

51 13

Martinez et al. (1988) 46

Adolescent

abnormal smear normal smear

48 3

29

CIN, cervical intraepithelia neoplasia.

Atypia: Its significance and treatment Atypical Pap smear results in adolescents have become more frequent (22,23); however, there is no single accepted protocol for the management of patients with atypia. Recently, researchers have examined the significance of atypia and found it to be a serious problem with important implications for potential development of cervical malignancies. Reiter (51) found that 25% of 494 patients with atypia (Class II Pap smears) had persistent atypia on repeat Pap. CIN I, II, or III was diagnosed in 44.5% of 110 patients with persistent atypia. Morrison et al. (52) also found CIN in 25% of 139 patients who underwent colposcopically directed biopsy for atypia (Class II Pap smears). Of these patients, 85% had CIIU I, and 15% had CIN II. Kaminski et al. (45) found a similar rate of pathology in women with atypical smears-23.4% of women under the age of 40 years. In this study, atypia was defined as cells with nuclear areas of 75-125 Frn’. In a study by Davis et al. (53) 32% of 400 patients had persistence of atypia (cells with a nucleus 1.5-2 times the size of normal and with slight alterations in morphology) or worse on repeat cytology; 33% of these had CIN. Importantly, they state that 30 (39%) of the 77 patients in their study with CIN had had a negative repeat smear. Borst et al. (47) concluded that a significant number of women with atypical Pap smear results have underlying CIN. There is no agreement on the timing and sequence of follow-up procedures for atypia. Ridgley et al. (54) suggest an interval of 4-6 months for repeat Pap smear after one atypical smear. They found

that 50% of 117 women who had a repeat smear within 4 months had a second abnormal result, compared with 24% of the 21 women who had the Rap smear repeated after 4 months. Reiteret al. (51) had similar findings. They found that persistence of atypia was significantly more likely if the repeat examination occurred after l-2 months, rather than after 3-4 months. Unexplainably,reversion to normal was significantlylower when the Pap smear was repeated after 5-6 months, rather than 3-4 months. Other investigators advocate use of colposcopy for further evaluation of atypia. Morrisonet al. (S2) suggest that cytologic atypia is an early expression of CIN and endorse routine colposcopy for women with persistence (second atypical Pap), even mild, reactive atypia. They state that this protocol allows those with transient atypical Pap smears to avoid colposcopy. They do not, however, suggest a time intervalbetween the first atypicalPap smear and the repeat Pap. Borst et al. (47) state that colposcopically directed biopsy should be the standard of care for abnormalities detected on Pap smears. Davis et al. (53) recommendcontinuedfollow-upeven when the first repeat smear is negative, because repeat cytology was reported as negative in 11% of their patients with biopsy-provendysplasia.They recommendcolposcopy, or serial follow-up smears when colposcopy is not possible.Kaminskiet al. (45) found that women (younger than 4Gyears of age) with atypia had a significantlyhigher prevalenceof positive biopsy findings than older women. They, therefore, recommend colposcopy for those with persistent atypia, particularly in younger women.

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Human lmmunotieficiency Virus and Cervical Cytologic Abnormalities The association between the human immunodeficiency virus (HIV) and cervical neoplasia has recently received attention. The risk of gynecologic cancers appears to be greater in immunosuppressed women (49), as evidenced by the unusually high rate of cervical dy’splasia in HIV-infected women. One report describes a rate of abnormal Pap smears in HIV-infected women which is S-10 times the expected rate (551, It is not clear, however, whether life style variables were controlled for in that report. Schrager et al (49) found a significantly higher prevalence (31%) of cervical and/or vaginal atypia or ClN in a group of HIV-infected women (n = 35) compared with a seronegative group (4%) of female sexual partners of HiV-infected men (n = 23). In their study I-WV-induced changes appeared to occur more rapidly in HIV-positive women than is reported in sexually active women in general (49). These authors therefore suggest careful and frequent pelvic examinations for HIV-infected patients. The relationship between HIV and Pap smear results in teenagers is not specifically addressed in the literature reviewed. The adult data may, however, have implications for teenagers who are, as a group, at increased risk for HIV, HPV, and Pap smear abnormalities owing to their high rates of unprotected intercourse. Since the mid-1980s, there has been a parallel increase in cytological abnormalities in teens (Table 1) and HIV in adult and adolescent women. Nationally, the proportion of acquired immunodeficiency syndrome (AIDS) cases among women increased from 7% before 1985 to 11% of cases reported in the first 6 months of 1989 (56). There has been a parallel increase in HIV seroprevalence in female adolescents, particularly when compared with rates for males. For example, the male:female ratio of HIV seroprevalence in adolescent military recruits is 0.5:1 (57). The simultaneous increase in Pap smear abnormalities and HIV seroprevalence in female adolescents suggests the need for investigation of a possible relationship of these factors.

Summary There has been an increase in cervical

cytological

abnormalities in adolescents in recent years. Many stwk point to two primary behavioral risk factors for Cervical IIIa&IXtnCies: early age at first coitus and multiple sexual partners. Therefore sexually active

adolescents are at high risk for this malignancy. Smoking and oral contraceptive use (or lack of barrier method) appear to pose some risk for older women, but do not appear to be a major risk factor in adolescent cervical abnormalities, because their effects seem to become evident only after a latent period. Biologically, the immaturity of the pubertal cervix appears to make it more vulnerable to carcinogenesis via HPV, the viral agent which is widely implicated in cervical carcinogenesis. There is persuasive evidence from clinical and histologic studies associating HPV with cervical cancer. Additionally, many researchers believe that HPV may be the most prevalent STD among American adolescents. The implications of a cytological diagnosis of atypia are not clear; however, atypia is now recognized as a serious finding that presents an increased risk for CIN. Patients with atypia require close follow-up with repeat Pap smears or colposcopy. Finally, the relationship between HIV seropositivity and cervical cancer was discussed. There appears to be a higher rate of atypia or CIN in HIVinfected women, and the rate of HPV-induced change in these women appears to be higher than expected. Since the early 198Os, there has been an increase both in the rates of cytological abnormalities in teens and HIV in females. Because they share some risk factors, and because immune status may affect the development of cervical malignancies, research is needed to define whether there is a relaationship between these two variables in adolescents.

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