235

European Journal of Obstetrics & Gynecology and Reproductive Biology, 43 (1992) 235-241 0 1992 Elsevier Science Publishers B.V. All rights reserved 002%2243/92/$05.00

EUROBS

01274

Prevalence, diagnosis and treatment of lower genital neoplasia in women with human immunodeficiency virus infection A. Spinillo, P. Tenti, R. Zappatore, G. Barbarini, A. Maccabruni, L. Carratta and S. Guaschino Departments of Obstetrics & Gynaecology, Pathology and Infectious Diseases, UniLbersityof Pacia. IRCCS Policlinico, S. Matteo. Papia, Italy Accepted

for publication

29 August

1991

Summary The prevalence of lower genital neoplasia and Human Papilloma-virus-related genital lesions were evaluated in a cohort of 75 women with Human Immunodeficiency Virus type 1 (HIV-11 infection at different stages of HIV disease. The overall rate of cervical intraepithelial neoplasia (GIN) in the group studied was 29.3% (22/75). Eight out of 10 high-grade CIN lesions contained ‘high-risk’ HPV-DNA 16/18 and/or 31/35/51 as demonstrated by ‘in situ’ hybridization with biotinylated probes. Vulvar and/or perianal condylomata were histologically diagnosed in 14 patients (18.7%); nine of these biopsies contained detectable HPV-DNA which was always related to HPV 6/11. The rate of high-grade CIN in symptomatic HIV-infected patients was 28% (7/25) as compared to 6% (3/50) of the other cases (P = 0.022). CD4 lymphocyte counts, white blood cell counts, CD4+/CD8+ cell ratio and percentage of CD4+ lymphocytes were lower in patients with high-grade CIN in comparison to the patients with negative colposcopical and/or cytological examination. After adequate standard treatment (cryotherapy, electrocauterization, cold-knife conization) only one case of CIN 2 recurred during the 2 years of follow-up period. The prevalence of lower genital neoplasia and HPV-related lesions among HIV-infected women is high and seems to correlate with the severity of HIV disease. Human

immunodeficiency

virus infection:

Lower genital

neoplasia;

Introduction It is well known that immunodepression due to radiotherapy, chemotherapy or immunosuppressive drugs increases the risk of lower genital

Correspondence: Dr. A. Spinillo, Department and Gynaecology, IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.

of Obstetrics P. le Golgi 2.

Human

papillomavirus

infection

neoplasia [ll. Immunosuppression has been considered a cofactor in the progression of Human Papillomavirus (HPV)-related neoplasia of the male and female anogenital tract [2]. Infection with Human Immunodeficiency Virus (HIV) is at present probably the most common and severe form of immunodeficiency worldwide. There is some evidence linking HIV-induced immunosuppression to the development of HPV-related neoplasia of the male and female genital tracts [3-51.

236

The purpose of this study was to evaluate the prevalence of genital tract HPV-related lesions and the rate of intraepithelial lower genital neoplasia in a cohort of HIV seropositive women at different stages of HIV disease. Patients and Methods The study comprises 75 women (mean age: 25 years; range: B-39, all HIV-l seropositive, seen as outpatients for periodic follow-up visits at the Department of Infectious Disease of the University of Pavia over a 2 year period. Sixty patients had a history of intravenous drug abuse, whereas in the remaining 15 cases HIV infection was acquired by heterosexual contact. HIV antibody status was determined by ELISA method and confirmed by Western blot. At the visit, after careful physical examination, a blood sample was drawn for the evaluation of immunological markers (white blood cells, lymphocytes, CD4+, CDS+ cell counts) of HIV infection. HIV-p24 antigenemia by ELISA method (Abbott Diagnostics Rome) was also determined. After informed consent, a gynecological examination and a Pap smear were performed. A standard colposcopic examination was performed in all the patients after the Pap smear result was available. Colposcopy was always added to cytology in order to perform an effective screening of vaginal and vulvar HPV-related lesions. Whenever indicating by abnormal colposcopy and/or abnormal Pap smear, multiple targeted punch biopsies were taken from perineal, vulvar, vaginal and/or cervical lesions suggesting HPV infection and/or intraepithelial neoplasia. Each biopsy specimen was processed for standard histologic examination. In order to evaluate the rate of HPV infection, ‘in situ’ hybridization analysis was carried out with a commercially available kit (PATHO-GENE. ENZO diagnostics. New York) which uses biotin-labelled probes of HPV-DNA 6/11,16/18 and 31/35/51. The ‘in situ’ hybridization was performed on routine paraffine sections, in high stringency conditions according to the manufacturer’s recommendations. Cryotherapy and/or electrocauterization were used to treat perianal and vulvar condylomata.

Low-grade cervical intraepithelial neoplasia (CIN 1) [6] was treated with electrocauterization under colposcopic guide. All the CIN 3 cases and those CIN 2 lesions which were either large or showed extension into the endocervical canal were treated by cold-knife conization. Electrocauterization was used in the case of small size CIN 2 lesions away from endocervical junction. Follow-up visits, which included Pap smear and colposcopy, were scheduled at &month intervals for patients with CIN and/or other HPV-related lesions and at 1 year intervals for the patients who resulted negative (Pap smear and colposcopy) at the first examination. Statistical analysis was carried-out with chisquare test for categorical variables. Kruskal-Wallis one-way analysis of variance and WilcoxonMann-Whitney test were used to test differences between continuous numerical variables. The nonparametric approach was chosen because the data were skewed and variances in the different groups were not homogeneous 171. Results Table I summarizes the stage of HIV infection, according to the CDC classification system IS], in the patients studied, stratified by risk group. Twenty-five patients (33.3%) had symptomatic infection (group IV) and 14 (18.6%) had AIDS. Multiple cervical biopsies because of suspected colposcopic lesions and/or abnormal cytology, were obtained in 25 patients; the results of histologic examination and in situ hybridization are reported in Table II. The rate of cervical intraep-

TABLE I Distribution of the patients according to the CDC classification system and risk group of HIV infection IV drug abusers

Heterosexuals

n

n

III IVa-c IVC-I

29 11 7 13

Total

60

II

% 48.3 18.3 11.7 21.7 100

10 4 1 15

Total

% 66.7 _ 26.6 6.7 100

39 11 11 14 75

CIN2-HPV CIN3-HPV NEG. TOTAL

1 1 3 12

a The suffix HPV denotes

1 1

_ _

2 _ 5

1 the associated

signs tkoylocytotic

1

1

5

2

_

4

1

_ _

1

3

1 _ 3

5 3 25

atypia)

ithelial neoplasia (GIN) in the group studied was 29.3% (22/75) whereas the rate of CIN 3 lesions was 6.7% (5/75X All but one high-grade cervical lesion (GIN 2-3) had HPV-related changes as diagnosed by histologic examination and 80% (g/10) contained detectable HPV-DNA 16/18 and/or 31/35/51 by in situ hybridization analysis, Vulvar and/or perianal condylomata were colposcopically and histologically diagnosed in 14 cases (18.7%) (8 cases associated with cervical lesions and 2 cases associated with vaginal condylomas). In situ hybridization analysis of vulvar and/or vaginal biopsy specimens detected HPVDNA, which was always related to HPV 6/11, in 9 cases (64.3%). Finally, a grade 2 vulvar intraepithelial neoplasia WIN 2) with HPV-related changes and containing HPV-DNA 16/18 was TABLE

suggesting

HPV infection

in routine

histological

diagnosed in one case (1.3%). In Table III are reported the rates of some risk factors for cervical neoplasia in relation to the severity of cervical lesions. In our experience, in these patients it was difficult to assess exactly the number of lifetime sexual partners and to obtain accurate informations about contraceptive behaviour because drug addiction was often associated with amenorrhoea, high sexual promiscuity, prostitution and inconstant use of condom before HIV seroconversion. However, no differences among the three groups (negative, low-grade CIN and high-grade GIN) could be found for mean age, mean age at coitarche, cigarette smoking, number of patients with more than 10 lifelong sexual partners, use of oral contraceptives or risk group of HIV infection. Table IV reports the distribution of CIN

III

Risk factors

for CIN in the patients

Mean age (SD) Mean age at coitarche No. of i.v. abusers

(SD)

t% 1

studied Negative (n = 531

(n = 121

High-grade (?I = 10)

24.6

(4.8)

26.2

(3.11

26.8

(5.21

15.9

(1.8)

15.1

(1.9)

14.9

(2.4)

Low-grade

CIN

43

(81.1)

9

(751

8

(801

41

(77.31

8

(66.71

7

(701

No. with more than 10 lifetime sexual partners t%)

29

(54.7)

7

(58.3)

7

(701

No. of current or past oral contraceptive users t%)

33

(62.3)

8

(66.71

7

(701

No. of current

or ex-smokers

(%)

examination.

CIN

238 TABLE

IV

Prevalence

of cervical

intraepithelial

neoplasia

(GIN) stratified

by stage of HIV disease

CDC group II

Negative Low-grade High-grade

CIN CIN

IV a-c

III n

%

n

%

n

%

32 5 2

82.1 12.8 5.1

7 3 1

63.6 27.3 9.1

8 1 2

72.7 9.1 18.2

6 3 5

42.8 21.5 35.7

markers

and cervical Negative bl= 53) Mean (SD) (95% c.i.)

intraepithelial

at the time of the examination as compared to 20% (13/65) of the other cases (Corrected x2 = 8.67; P = 0.0032). The mean values of the main immunological markers involved in HIV infection stratified by the severity of the cervical lesions are shown in Table V. Kruskal-Wallis one-way analysis of variance and Wilcoxon-Mann-Whitney test demonstrate that CD4 lymphocyte counts, white blood cell counts, CD4+/CD8+ cell ratio and percentage of CD4+ lymphocytes are the values that correlate best to the severity of the cervical lesion. Cryotherapy, electrocauterization and local excision were used for the treatment of anogenital

neoplasia

Low-grade CIN (n = 12) Mean (SD) (95% c.i.)

High-grade CIN (n = 10) Mean (SD) (95% c.i.1

X2

P

192 (106) * * (116-269) 364 (194) (225-503) 1323 (572) (914-l 733) 4 250 (3 028) * (2083-6416) 0.54 (0.17) * * (0.41-0.67) 14.8 (6.5) * * (10.2-19.5) 27.3 (8.5) (21.2-33.4)

11.7

0.0029

CD4/mm’

385 (188)

330 (191)

CD8/mm3

(333-437) 568 (261)

(209-451) 599 (499)

Lymph/mm”

(496-640) 1769 (582)

(281-916) 1728 (654) (1312-2 144) 5 108 (1952) (3 867-6 348) 0.63 (0.22) (0.49-0.77) 17.6 (5.4) (14.2-21.1) 29.9 (11.1) (22.9-37.1)

WBC/mm3 CD4 +/CD8

CD8+

53 12 10

V

Immunological

CD4+

Total

%

lesions in relation to the stage of HIV infection according to the CDC classification system. The rate of CIN was 44% (11/25) in symptomatic group (IV) in comparison to 22% (11/50) of the other patients (x2 = 3.89 P = 0.0485). Equally, high grade lesions were more frequent among group IV patients (7/25) with respect to the other cases (3/50) (Corrected x2 = 5.2; P = 0.022). The global rate of p24 antigen detection was 26.7% (20/75); p24 antigen was detected more frequently among CIN patients (11/22 vs. 9/53; Corrected x2 =. 7.06; P = 0.0073) than negative cases. Seventy percent (7/10) of patients with high-grade cervical lesions were p24 positive

TABLE

IV c-l

n

+

(%) (%)

** P < 0.01, *

(1609-l 930) 5 253 (1591) (4 815-5 692) 0.74 (0.47) (0.61-0.88) 21.2 (7.3) (19.2-23.2) 31.2 (9.1) (28.7-33.7)

P < 0.05 in comparison

to negative

cases (Wilcoxon-Mann-Whitney

test).

5.39

0.0672

5.09

0.0785

6.19

0.0453

7.72

0.0210

9.46

0.0088

1.75

0.42

239

condylomata and vulvar intraepithelial neoplasia. As stated previously, all the low-grade lesions were treated with electrocauterization under colposcopic guide. Cold-knife conization was carried out in 6 out of the 10 high-grade lesions, whereas the last four cases (small size and peripheral CIN 2 lesions) were treated with electrocauterization. At present, all the patients with CIN have completed at least 12 months of follow-up. Two patients out of seven (28.6%) with AIDS and high-grade cervical lesion died due to HIV disease within 1 year from surgical procedures. In the remaining eight cases of high grade lesion, only one recurrence (11.1%) was diagnosed and treated at one year follow-up. No recurrences were recorded among low-grade CIN patients but two out of three patients with CIN 1 and AIDS died of immunodeficiency. Finally, 5 out of 14 (35.7%) patients with anogenital condylomata required further treatments within 1 year because of recurrence.

Discussion

The relationship existing between the immune status of the host and the development of HPV infection is well established. The risk of cervical carcinoma in women immunosuppressed because of renal transplantation is increased [1,2,9], and the clinical behaviour of HPV-related lesions seems more aggessive in immunodepressed patients [l]. Moreover, the number of OKT-4 and OKT-8 lymphocytes infiltrating HPV-related lesions has been shown to influence the recurrence and progression rate of cervical neopIasia [lo]. At present, HIV infection is probably the most important cause of immunosuppression worldwide and the spread of the virus among females is a matter of concern [ll]. As expected, the prevalence of HPV-related lesions among homosexual patients with AIDS has been shown to be increased [5]. On the other hand, only a few reports have focused attention on the possibility of a high rate of HPV-related lesions in HIV-infected women [4,12-141. In a recent study [El, HPVDNA has been detected in 40% of cytological

cervicovaginal samples of HIV infected women, but the authors do not report the rate of histologically diagnosed cervical neoplasia. In a report of 77 patients screened colposcopically, CIN lesions were more severe, extensive and often multifocal in 25 HIV-positive women than in HIV-negative controls (Tarricone NJ et al. VI International Conference on AIDS. San Francisco, 20-24 June 1990). In the present cohort study, the rate of cervical intraepithelial neoplasia, among HIV-infected women, was almost 30% and severe lesions were constantly associated with the detection of highrisk HPV-DNA type 16/18 and/or 31/35/51. It is obvious that HIV-seropositive women represent a high-risk category for HPV-related genital neoplasia mainly because of sexual behaviour. Moreover, heroin-addicted women outside methadone treatment programs often do not receive adequate primary health care, routine Pap screening and educational support. Contrary to the suggestions reported by some authors 141,our findings clearly indicate that the occurrence of CIN was associated with the severity of the immunodepression. Five out of 14 patients (35.7%) with AIDS had high-grade CIN, and globally 7 out of the 10 cases of high-grade CIN were among patients belonging to category IV of the CDC classification. However, in the study of Feingold et al. 1151,all seven women with AIDS were HPV-positive, and six had cytological abnormalities suggesting intraepithelial neoplasia. In a recent report [16] of the New York City cases, squamous intraepithelial lesions were more frequent and often multifocal in HIV-positive women as compared to HIV-negative, and seven women (19%) of a consecutive series of 37 patients who had invasive cervical carcinoma and who were less than 50 years were HIV-positive. In the present study, as a result of the association between the severity of immunodepression and the prevalence of intraepithelial lesions, immunological markers such as CD4 lymphocyte counts, CD4+ lymphocyte percentage and CD4+/CD8+ cell ratio were lower in patients with high-grade cervical lesions as compared to the negative cases. The detection of p24-HIV antigen in serum is coincident with either acute

240

infection or with a late fall, in advancing disease, of anti-HIV antibody titers [17]. The rate of p24HIV antigen detection at the entry of the present study was higher in CIN cases than in controls. Stratification by stage of HIV infection showed that this was an effect of the prevalence of category IV patients among CIN cases, thus the occurrence of CIN do not seem to have predictive value regarding p24 antigenemia. Concerning treatment, to our knowledge no clinical trials of treatment of cervical intraepithelial neoplasia in HIV infected women have been reported. In this study the rate of recurrence of CIN colposcopitally and histologically ascertained was similar to that recorded for patients with similar lesions but HIV seronegative seen at the same Department. The only exception was the high recurrence rate, often requiring many sessions of treatment, of vulvar and vaginal condylomata in presence of HIV infection. The relation between HIV infection and HPV-related lesions is complex. The prevalence of HPV infection in the general population varies from 2 to 28%, depending on the study group [18]. HIV-infected females should be considered a high-risk group for the development of HPV-related lesions both because of sexual behaviour and, possibly, because of virus-induced immunodepression. In this context, only large, well-controlled studies, could distinguish between the effect of the sexual behaviour from that of immunodepression on the occurrence of HPV-related lesions and other sexually transmitted diseases. Moreover, genital ulcers or mucosal disruption caused by syphilis, herpes simplex or HPV facilitate both the acquisition and transmission of HIV 1191. Since it has been suggested that HIV-infected women with genital warts are up to five times more likely to transmit HIV infection [ll], close cytological and colposcopic screening and surveillance of these patients should be established. Finally, the question of whether the presence of HIV-induced immunosuppression can modify the natural history of cervical dysplasia is still controversial, but early diagnosis, treatment and close successive follow-up seems a reasonable ap-

proach for women.

cervical

lesions

in

HIV-positive

References 1 Sillman F, Stanek A, Sedlis A et al. The relationship between human papillomavirus and lower intraepithelial neoplasia in immunosuppressed women. Am J Obstet Gynecol 1984;150:300-338. 2 Gissmann L. Linking HPV to cancer. Clin Obstet Gynecol 1989;32:141-147. 3 Bradbeer C. Is infection with HIV a risk factor for cervical intraepithelial neoplasia? Lancet (Lett) 1987;ii:1277-1278. 4 Spurret B, Jones DS, Stewart G. Cervical dysplasia and HIV infection. Lancet (Lett) 1988;i:237-238. 5 Frazer IH, Medley G, Crapper RM et al. Association between anorectal dysplasia human papillomavirus and human immunodeficiency virus infection in homosexual men. Lancet 1986;ii:657-660. 6 Richart RM. A modified terminology for cervical intraepithelial neoplasia. Obstet Gynecol 1990;75:131-133. 7 Godfrey K. Comparing the means of several groups. N Engl J Med 1985;313:1450-1456. 8 Centers for Disease Control. Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. MMWR 1987;36(Suppl lS):3S-15s. 9 Carson LF, Twiggs LB, Fukushima M et al. Human genital papilloma infections: an evaluation of immunologic competence in the genital neoplasia-papilloma syndrome. Am J Obstet Gynecol 1986;155:784-789. 10 Syrianen K, Mantyjarvi R, Vayrynan M et al. Assessing the biological potential of human papillomavirus infections in cervical carcinogenesis. Cancer Cells 1987;5:281-289. 11 Alexander NJ. Sexual transmission of human immunodeficiency virus: virus entry into the male and female genital tract. Fertil Steril 1990;54:1-18. 12 Henry MJ, Stanley MW, Cruikshank S, Carson L. Association of human immunodeficiency virus-induced immunosuppression with human papillomavirus infection and cervical intraepithelial neoplasia. Am J Obstet Gynecol 1989;160:352-353. 13 Caubel P, Foulques H, Katlama C, Fassin D, Blondon J, Lefranc JP. Epidemiologic des lesions cervico-vaginales et vulvaires a papillomavirus chez les femmes s&o-positives pour le virus HIV: etude priliminaire sur une serie continue de 39 patientes. Gynecologie 1989;40:414-419. 14 Schrager LK, Friedland GH. Maude D et al. Cervical and vaginal squamous abnormalities in women infected with human immunodeficiency virus. J Acq Immun Def Syndr 1989;2:570-575. 15 Feingold AR, Vermud SH, Burk RD et al. Cervical cytologic abnormalities and Papillomavirus in women infected with Human Immunodeficiency Virus, J Acq Immun Def Syndr 1990;3:896-903.

241 16 Maiman M, Fruchter R. Klein R et al. Risk for cervical disease in HIV-infected women. New York City. MMWR 1990;39:846-849. 17 Goudsmit J, Lange JMA. Paul DA, Dawson GJ. Antigenemia and antibody titers to core and envelope antigens in AIDS, AIDS-related complex and subclinical human immunodeficiency virus infection. J Infect Dis 1987;133:558564.

18 Stone KM, Epidemiologic aspects of genital HPV infection. Clin Obstet Gynecol 1989;32:112-115. 19 Quinn TC, Glasser D, Cannor RO et al. Human immunodeficiency virus infection among patients attending clinics for sexually transmitted diseases. N Engl J Med 1988: 31X:197-203.

Prevalence, diagnosis and treatment of lower genital neoplasia in women with human immunodeficiency virus infection.

The prevalence of lower genital neoplasia and Human Papilloma-virus-related genital lesions were evaluated in a cohort of 75 women with Human Immunode...
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