Lester Chitsulo e, Newton Kumwenda e, Svein Gunnar Gundersen a, Ingela Krantz f, Hermann Feldmeier b
a Ullevaal Centre for International Medicine, Research Forum, Department of Infectious Diseases, Ullevaal Hospital, University of Oslo, 0407 Oslo, Norway b Institute of Tropical Medicine and Faculty of Medicine, Free University, Berlin, Germany
¢ Department of Gynaecology and Obstetrics, Frauenklinik Finkenau, and Ki~rber AIDS Research Laboratory, Department of Pathology,
Bernhard-Nacht-Institut fiir Tropenkrankheiten, Hamburg, Germany d Department of Pathology, Ullevaal Hospital, University of Oslo, 0407 Oslo, Norway
e Ministry of Health and Environmental Affairs, Lilongwe, Malawi r Nordic School of Public Health,
G~teborg and Department of International Health Care Research (IHCAR), Karolinska Institutet, Stockholm, Sweden
Abstract
A total of 51 women with urinary schistosomiasis haematobium were examined in order to identify diagnostic indicators for female genital schistosomiasis (FGS). Patients were selected at random from the outpatient department of the Mangochi District Hospital, Malawi. The medical histories were recorded according to a pre-designed questionnaire and the women were subjected to a thorough gynaecological examination including colposcopy and photographic documentation of lesions. Microscopy of genital biopsies revealed that 33 of the 51 women had S. haematobium ova in cervix, vagina and/or vulva in addition to the presence of ova in urine. The most sensitive diagnostic procedure was bedside microscopic examination of a wet cervix biopsy crushed between two glass slides, which revealed 25 of the 33 genital infections. There was a significant correlation between the size of genital lesions and the number of ova counted per mm 2 of crushed tissue. Women with FGS had significantly more tumours in the vulva than women with schistosomiasis limited to the urinary tract. Most of the observed genital pathology could easily be identified by the naked eye, but colposcopic examination yielded valuable additional information like the demonstration of
240 E.F Kjetland et al./Acta Tropica 62 (1996) 239-255
neovascularisation around cervical sandy patches. Few of the symptoms previously regarded as indicators for FGS could be linked to the presence of schistosome ova in genital tissue. Husbands of infertile women with FGS had children with other women significantly more often than husbands of women who only had urinary schistosomiasis. This, together with the finding that the majority of the divorced women had FGS, indicates that the manifestation of this disease may have implications for the marital and sexual life of the affected women.
Schistosomiasis of the vagina was reported as early as 1899 from Egypt (Madden, 1899) and the multifaceted clinical manifestations of schistosomiasis of the female genital tract were described in detail already at the beginning of this century (Madden, 1910; Gibson, 1925). Post mortem studies and histological sectioning of surgical material, especially from the southern part of Africa, have underlined the considerable degree of morbidity associated with schistosome egg granulomas in the female reproductive organs (Gelfand and Ross, 1953; Berry, 1966; Bland and Gelfand, 1970). Population-based studies in Schistosoma haematobium endemic areas have shown that up to 75% of the women may suffer from lesions of the uterine cervix, vagina or vulva (Renaud et al., 1989; Szela et al., 1993). Female genital schistosomiasis (FGS) has been suggested to cause infertility (Bullough, 1976; E1- Mahgoub, 1972, 1982), abortion (des Ligneris, 1921), pre-term delivery (Siegrist and Siegrist-Obimpeh, 1992), and life-threatening conditions like extra uterine preg- nancy (des Ligneris, 1921; Okonofua et al., 1990; Ville et al., 1991). Menstrual disorders, lower abdominal or back ache, vaginal discharge, dyspareunia and bleed- ing intercourse may also be related to FGS (Williams, 1967; Bland and Gelfand, 1970; Youssef et al., 1970; Wright et al., 1982). Moreover, a broad range of epithelial lesions, tumours and ulcers have been associated with the presence ofS. haematobium ova in the lower genital tract (Gibson, 1925; Badawy, 1962; Youssef et al., 1970; Wright et al., 1982). Conflicting results exist regarding a possible causal association between FGS and genital cancers (Charlewood et al., 1949; Williams, 1967; Bland and Gelfand, 1970; Youssef et al., 1970; Coelho et al., 1979; Lowe et al., 1981; Wright et al., 1982; E1 Tabbakh and Hamza, 1989; Szela et al., 1993; Moubayed et al., 1994, 1995). More recently, circumstantial evidence has been put forward indicating that FGS may facilitate the spread and the local propagation of agents of sexually transmitted diseases (STDs), especially of HIV (Feldmeier et al., 1994, 1995a).
So far, few attempts have been made to systematise female genital morbidity caused by schistosome infections and no diagnostic guideline has been established (Friedberg et al., 1991; Feldmeier et al., 1995b). In order to develop a rational approach to the diagnosis of schistosome lesions in the lower female reproductive tract a pilot study was carried out in rural Malawi in women consulting the out-patient department of a district hospital for various complaints.
E.F Kjetland et al./.4cta Tropica 62 (1996) 239-255 241
2. Materials and methods
2.1. Study area
After approval by the Medical Ethical Committee of Malawi, the study was performed from April to June 1994 at Mangochi District Hospital, which serves the population near Lake Malawi. S. haematobium is endemic in the area, giving rise to both urinary and genital lesions (Bullough, 1976; Wright et al., 1982; Wolfe et al., 1993), whereas S. mansoni is not found. Transmission takes place at the lake shore and the affluents, but presumably also along irrigation channels of rice fields and small ponds. The population is a mixture of the Yao tribe, who are mainly Muslims, and the ruling Chichewa tribe, most of whom are Christians. Many are illiterate. Official languages are Chichewa and English. The main crops are rice, maize and peanuts.
2.2. Study population and design
Irrespective of their complaints, all females of childbearing age who attended the out-patient department of the hospital before lunch time, and who were willing to provide a urine sample, were screened for S. haematobium ova by means of urine filtration. If ova were detected, the women were invited for further investigation after informed consent had been obtained and after being told to feel free to withdraw at any time.
Virgins, pregnant women (as indicated by the medical history and confirmed by a HCG pregnancy test in urine) and postmenopausal women were excluded. Women who declined a gynaecological examination or biopsy were not admitted to the study. However, excluded women were offered equal medical service and referred to the hospital staff if necessary. Pregnant women with schistosomiasis were asked to come back for treatment after delivery.
2.3. Urine examination
Ova found in the morning urine were not quantified for technical reasons. S. haematobium urine-positive women admitted to the study were offered food and beverages at lunch time and 60 min later another urine sample was collected. The whole micturition volume was filtered through polycarbonate membranes of 14/zrn mesh size and 25 mm diameter, stained with trypan blue and the schistosome ova were quantified as previously described (Feldmeier et al., 1979). This procedure ensured that circadian variation of egg excretion influenced the results less, thereby providing a more accurate estimate of the true intensity of infection (Doehring et al., 1983). The noon-time urine was also tested for haemoglobin, leukocytes and protein by a dip-stick method (Feldmeier et al., 1982), the results of which will be published elsewhere (Gundersen et al., 1996).
242 E.F. Kjetland et al./Acta Tropica 62 (1996) 239-255
2.4. Medical history and clinical examination
Many of the women had never been subject to a gynaecological examination. Most of them had not given birth in hospital and some had never even been in a modern bed. Questions were asked in a relaxed atmosphere, to prepare them for the gynaecological examination and make them see the relevance of the different steps. The medical procedure was explained in detail and equipment shown in advance in order to familiarise the patients with the situation. It was emphasised that the consultation was confidential and voluntary.
Data were recorded in accordance with a modified WHO questionnaire. The questionnaire was discussed, pre-tested and adapted to local decorum. Personal data were obtained in order to allow tracing in case of later demonstration of cancer or other curable illnesses in specimens shipped overseas. Each woman was asked a number of questions related to previous and present urinary symptoms, gynaecologi- cal complaints, pregnancies, deliveries, contraception, menstruation, sexual history, sexually transmitted diseases and previous medical treatment. If the woman was hesitant about the nature of the question, she was explained why the question was asked. Women who were supposedly not able to become pregnant (primary infertile) and women who had borne fewer children than desired (secondary infertile) were asked if their husbands had children with other women. Particular attention was paid to the local culture and traditions regarding child spacing, intercourse, genital application of herbs or other remedies. All questions were asked by the physician and repeated in the local language by the nurse/interpreter.
A thorough gynaecological examination was performed starting with external inspection, and thereafter, internal inspection with a speculum using the colposcope as a light source. Smears were obtained by a wooden spatula followed by vaginal lavage, biopsy and bimanual palpation. The findings were grouped according to those recorded by naked eye in the first phase of the examination (reported in this paper) and those recorded with the help of the colposcope reported elsewhere (Helling-Giese et al., 1996). A portable colposcope with built-in camera using a 220 V electricity supply was used. Colposcopic findings were documented by making photographs of all abnormalities. The records included a description of the epithe- lium, blood vessels, demarcation, peripheral reaction and discharge separately for cervix, vagina, vulva and perineum/perianal area. All women were weighed and received supervised treatment with praziquantel at one dose of 40 mg/kg body weight.
2.5. Lavage, smears, biopsies and other samples
Epithelial material from cervix and suspected lesions was obtained by a wooden spatula and smeared on different slides. The first smear from the endo- and ectocervix was fixed for later PAP staining for cytological examination. The second was dyed with Diff Quick stain for quantification of eosinophils. The third was Gram-stained to screen for N. gonorrhoeae. The fourth was tested with KOH for the presence of
E.F. Kjetland et al./Acta Tropica 62 (1996) 239-255 243
Gardnerella. The fifth was stained with 0.5% trypan blue and examined bedside for S. haematobium ova.
At the end of the examination, but before biopsies were taken, 5 ml of saline were instilled into the vagina and aspirated into a syringe, as described by Belrc et al. (1989).
After that biopsies were taken routinely from the cervices in all 51 women, and in addition from suspected lesions in any part of the lower genital tract, if the woman consented. The women got ten condoms for the coming weeks. Each biopsy was divided into 4 pieces by scissors. Three pieces were stored in formaldehyde for later histological examination. These biopsies were examined after traditional stain- ing with HE. In selected cases immunohistochemistry for human papilloma virus (HPV) was done. HPV was diagnosed by histological demonstration of koilocytosis (perinuclear halo) and/or a positive immunofluorescence reaction. The fourth piece was crushed between two glass slides together with a drop of 0.5% trypan blue in physiological saline to facilitate the differentiation between viable and dead ova and examined microscopically bedside. Eggs were quantified per mm 2 tissue according to a method previously described for rectal biopsies (Feldmeier et al., 1981).
Five millilitres of venous blood were drawn and allowed to clot at room temper- ature. Serum was tested locally for the presence of antibodies against T. pallidum using the VDRL test in suspected cases. The rest of the serum was kept frozen.
2.6. Data processing and statistical analysis
A questionnaire and examination record form and database were constructed by File Maker Pro 2.0 on a portable Macintosh PowerBook computer, from which the data were imported to Stat View for analysis. Non-parametric statistical tests were chosen because the data were not normally distributed and variances differed con- siderably. The Spearman rank correlation coefficient test, the Mann-Whitney U-test and the Kruskal-Wallis test were applied where appropriate. Epi-info was used for analyses of odds ratios. For comparison of groups, ordinary chi-square tests with Yate's correction were used, or Fisher's exact test (two-sided) where expected values were below 5.
3. Results
The median age of the 51 women included in the study was 22 years (range 15-47). Forty (78%) were married, 7 (14%) divorced, 2 were widowed and 2 were single. Most were Muslims of the Yao tribe (75%), only one Lomwe and the rest Chichewa, which reflects the distribution of these ethnic groups in the area. In 18 women ova were found only in the urine, whereas in 33 (65%) S. haematobium ova were also demonstrated in at least one genital biopsy. These 33 were defined as having female genital schistosomiasis (FGS).
Ova detected in crushed biopsies were usually brown or blue. Sometimes only egg shells were seen. Table 1 shows the anatomical distribution of the ova detected by
In 17 patients biopsies were also taken from locations other than cervix. The results are expressed as number of positive/number of biopsies performed (%). *Positive biopsies only.
the examination of crushed tissue and/or by histological examination of formalin- fixed parts of the same biopsies. Twenty-five cases of FGS were identified by crushed biopsies routinely taken from the cervix (with or without suspected lesions). Biopsies taken from suspected lesions at other sites increased the number of cases to 27. Six additional cases were detected by the demonstration of ova by later microscopy of histological sections of parts of the same biopsies: 4 from cervix alone, 1 from vagina alone and one both from cervix and vagina. There was no significant difference between ova densities of the examined crushed biopsies in the different levels of the lower genital tract (Table 1). There was no correlation between the location of ova and the number of previous pregnancies.
Median S. haematobium ova excretion per 10 ml of urine was 5 (range 0.2-52.8). There was no significant difference in the number of ova in women with FGS compared to the women who only had urinary schistosomiasis. Fig. 1 shows the egg loads in urine and crushed cervical tissue by age. There was a clear tendency towards higher egg loads in both urine and cervical tissue in the younger women, although the differences between the age groups were not significant. A semi-quantitative average diameter estimate was calculated per woman for suspected lesions in cervix, vagina and vulva and was related to the number of S. haematobium ova per mm 2 crushed tissue, as an indication of genital parasite load. A significant positive correlation was found between average lesion diameters and S. haematobium ova per mm z tissue (Fig. 2) (rho=0.461; P=0.0013).
The smears obtained by a wooden spatula added little to the diagnosis. Wet cervical smears examined bedside revealed ova in only 1 case which was also diagnosed by crushed biopsy. Gardnerella was diagnosed in 3 women and gonorrhoea in 2. The PAP and eosinophil smear results will be published elsewhere. VDRL was performed in 3 cases; none were positive.
Tables 2 and 3 show the age, ethnic background, marital status and relative prevalence of various commonly reported complaints of women with and without FGS. The median age of the two groups was similar. Yao (Muslim) women had FGS significantly more often than the other ethnic groups (P = 0.03). A comparable
E.F. Kjetland et al./Acta Tropica 62 (1996) 239-255 245
v-q
¢6
70
60
50
40
30
20
10
0 I |
I I~ 10"19 2 0 - ' 2 9 30"39 >i0
6
i 5
10"19 [ [i i,t I
20"29 30"39 >40 Age groups (years)
Fig. 1. Schistosoma haematobium eggs per I0 ml urine and per mm 2 cervical tissue according to the age of the patients (means by age group).
number of women were married in the two groups. Women with FGS more often claimed to be secondary infertile, although the difference between the groups was not statistically significant. A significantly larger number of primary or secondary infertile women in the FGS group claimed that their husbands/partners had children with other women (P= 0.05) (Table 3). Besides this, there were no si~ificant differ- ences between the groups regarding complaints described as typical for female genital schistosomiasis in the literature.
Most of the pathology recorded (kind of discharge, bleeding, erythema, petechiae, ecchymosis, blisters, swellings, leukoplakia and inflammations) was equally divided among the two groups of women. Table 4 shows the results of the most frequent clinical findings. More papillomatous tumours were found in vagina (Fig. 3a) and
246 E.F. Kjetland et al./Acta Tropica 62 (1996) 239-255
16
14
~ 0
' 1 I •
i
i •
i
D
6 ' 14 ,0] r i i i i i ? i
-5 0 5 10 15 20 25 S. haematobium ova per ram2 tissue
Fig. 2. Average diameter of genital lesions observed in 33 women with Schistosoma haematobium ova in genital tissues in relation to the number of ova per mm z of crushed biopsy tissue.
test if any expected value under 5) of ethnic and marital status in 51 Malawi women with Schistosoma haematobium eggs in the urine, with (FGS +) and without (FGS - ) female genital schistosomiasis indicated by eggs of the same parasite shown in genital biopsies
FGS + FGS - OR (95% CI) P-value (n = 33) (n = 18)
Median age (range) in years 22 (15-47) 23 (17-38) Yao tribe 29 10 Chichewa tribe 4 7 Lomwe tribe 0 1 Married 25 15 Divorced 6 1
0 .63 0.11-3.27 0.73 3.78 0.38-92.30 0.40
If less than the total number of women are applicable, this is indicated in the denominator.
vu lva (F ig . 3b) in the F G S group c o m p a r e d to the rest, a difference which was signif icant for lesions in the vu lva (P = 0.04). Also eros ions and ulcers o f the vulva (Fig . 3c) were found m o r e of ten in the w o m e n wi th F G S ( P = 0 . 0 8 ) . The lesions were of ten f o u n d b leed ing even af ter very gentle examina t ion , as can be seen f rom the p h o t o g r a p h s .
C o l p o s c o p y a d d e d some m o r e i n fo rma t ion on the lesions observed by the n a k e d eye. In 2 w o m e n wi th F G S , sandy pa tches o f the cervix w o u l d have been ove r looked wi thou t the help o f the co lposcope . F u r t h e r m o r e , one m o r e e ros ion and one p o l y p were revealed in the vag ina a n d one e ros ion in the vulva t h rough co lposcopy . Moreove r , the co lposcop ic examina t i on f requent ly revealed a concentr ic neovascu la r -
E.F. Kjetland et al./Acta Tropica 62 (1996) 239-255 247
test if any expected value under 5) of various symptoms in 51 Malawi women with Schistosoma haematob- ium eggs in the urine, with (FGS+) and without (FGS-) female genital schistosomiasis indicated by eggs of the same parasite shown in genital biopsies. If less than the total number of women are applicable, this is indicated in the denominator
FGS + FGS - OR (95% CI) P-value (n=33) (n=18)
Infertility, primary* 6/31 3/16 1.04 (0.18-6.45) 1.00 Infertility, secondary* 13/31 2/16 5.06 (0.83-39.28) 0.09 Partner children w/other women 15/17 2/5 11.25 (0.75-289.59) 0.05 Remedies for dry sex 2/28 3/16 0.33 (0.03-2.97) 0.34 Dysuria 22 15 0.40 (0.07-1.99) 0.32 Incontinence 6 4/17 0.72 (0.14-3.80) 0.72 Menorrhagia 13/26 3/12 3.00 (0.54-18.45) 0.27 Low abdominal pain 24 13 1.03 (0.23-4.44) 1.00 History of tumour/polyp 3 3 0.50 (0.07-3.69) 0.65 History of genital ulcer 14 5 1.92 (0.47-8.08) 0.46 History of painful genital lesion 10/20 6/9 0.50 (0.07-3.35) 0.45 Postcoital bleeding 4 1/17 2.21 (0,19-57.50) 0.65 Dyspareunia 16/31 9/17 0.95 (0.24-3.68) 0.83
*See the text for definitions.
isation around the sandy patches (Fig. 3d). Colposcopy also made possible proper photographic documentat ion and subsequent discussions with a gynaecologist.
Further histological examination of the biopsies showed 1 case of squamous cell carcinoma (in a woman with FGS) and 2 cases of dysplasia (one woman with FGS and one without). Evidence of human papil loma virus (HPV) , either by morphologi- cal demonstrat ion of koilocytosis (perinuclear halo) and/or positive reaction on immunohistochemistry, was found in 15 women (11 with FGS and 4 without; P = 0.4053). Evidence of HPV infection was equally divided between the women who had papil lomatous and/or polypous growths and those who did not have such tumours. The woman with cancer had no evidence of HPV infection with the methods used, whereas the two women with dysplasia were HPV-positive (P = 0.1 ).
4. Discussion
In an outpatient department in rural Malawi an impressively high proport ion (65%, 33/51) of Schistosoma haematobium infected women of fertile age had parasite ova in the lower part of their reproductive tract. This is of similar magnitude to that found in village-based studies f rom other endemic areas (Renaud et al., 1989; Szela et al., 1993).
Microscopic examination of wet crushed biopsies detected ova in a frequency similar to that of histological sectioning when comparing divided pieces of cervical, vaginal and vulval tissues. This allows diagnosis of FGS to be performed at the
test if any expected value under 5) of various clinical findings in 51 Malawi women with Schistosoma haematobium eggs in the urine, with (FGS +) and without (FGS - ) female genital schistosomiasis indicated by eggs of the same parasite shown in genital biopsies
FGS + F G S - OR (95% CI) P-value (n = 33) (n = 18)
c. In vulva Papillomatous tumour 8 0 - - 0.04 Erosions/ulcers 6 0 - - 0.08
d. In perineum Papillomatous tumours 1 1 0.53 (0.01-21.37) 1.00 Erosions/ulcers 3 1 1.70 (0.13-46.82) 1.00
If less than the total number of women are applicable, this is indicated in the denominator.
bedside and would prevent unnecessary surgery on clinical suspicion of malignancy in situations where histological service is non existant or unacceptably delayed. However, histological examination is necessary in order to diagnose concomitant pathology such as malignancy and human papilloma virus (HPV) infection.
A biopsy taken from the uterine cervix--from a lesion or from the defined standard site--was the single most efficient diagnostic procedure in this study. If the results of microscopy of bedside wet crushed tissue and histopathological exami- nation of a formalin-fixed part of the same cervical biopsy were added, this procedure secured the diagnosis in all but 2 of the cases. Little additional information was gained by biopsies from FGS-suspected lesions in the vagina, vulva or perineum. This is of considerable practical interest since a cervical biopsy is almost painless whereas biopsies from vagina and vulva are painful. Our observation that the cervix is the topographic site most suitable for the detection of ova is also supported by histopathological studies (Badawy, 1962; Youssef et al., 1970; Gelfand et al., 1971; Friedberg et al., 1991). Post-mortem quantification of egg load of female genital organs by a digestion technique has shown up to 20 000 eggs per gram of cervical tissue and much less in vagina/vulva (Edington et al., 1975, Gelfand et al., 1971).
Fig. 3. Colposcopic photographs of lesions containing X haematobium ova in different locations (3a, 3b and 3c are from the same woman): (a) Tumourous growth with S. haematobium ova in vagina. (b) Tumourous growth with S. haematobiurn ova in introitus. (c) Ulcers with S. haematobium ova of the labia majore. (d) Sandy patches of the cervix with concentric neo-vascularisation.
250 E.F. Kjetland et aL /Acta Tropica 62 (1996) 239-255
However, in our study too few biopsies were taken from the vagina and the vulva to allow a definite conclusion on this issue. When the egg load was expressed as ova per mm 2 of wet compressed tissue, similar numbers were found at the 3 topographic sites, although the highest counts were observed in the cervix and vagina with up to 20 and 26 eggs per mm 2, respectively. Such egg densities are similar to those observed in the rectal mucosa in patients with intestinal schistosomiasis due to S. intercalatum (Feldmeier et al., 1981). The sizes of the observed genital lesions estimated from their diameters--irrespective of the location of the lesion--correlated significantly with the number of S. haematobium per mm 2 of compressed tissue. Thus the size of a lesion might be used as an indication of the actual parasite load in genital tissue.
Previous studies have shown ova in cytological smears (Youssef et al., 1962; Berry, 1966, 1971; Shennan and Gelfand, 1971; Berry, 1976; Swart and van der Merwe, 1987). In the present study, however, we found eggs only in one woman by bedside microscopy of wet cervical smears obtained with a wooden spatula. This smear was the last one taken, which might be a practical reasons for low egg recovery. Another reason might be the comparatively low parasite load, as indicated by the low egg output in the urine and the few eggs present per mm 2 of compressed genital tissue. Moreover, histological sectioning of the biopsies indicated that the majority of the ova, unlike in the intestinal tract, were lodged in the stroma under a thicker epithelial lining of the genital mucosa than in the intestine and might thus be difficult to obtain by a smear technique (Helling-Giese et al., 1996).
It would be of practical importance to find indicators (symptoms and signs) of FGS. However, we were unable to find such 'tracer' symptoms in the small group studied. Although secondary infertility, a history of menorrhagia, genital ulcers and postcoital bleeding all showed increased odds ratios when comparing women with and without FGS, the differences were not statistically significant. Other symptoms previously reported to be indicative for FGS like lower abdominal pain, incontinence or dyspareunia were similar in both groups. Surprisingly, the detailed medical history showed that the majority of the infertile women with FGS admitted that their partner had children with other women, whereas this was not the case among those without FGS (P=0.05). Based on previous observations that FGS may cause infertility (E1-Mahgoub, 1972; Bullough, 1976; E1-Magoub, 1982; Harouny and Pedersen, 1988) and that women with FGS may experience sexual intercourse as a painful event (Friedberg et al., 1991; Feldmeier et al., 1995b), it is tempting to speculate that the higher number of partners having children with other women in the FGS group might be related to such problems. It might indicate that husbands of women with FGS are dissatisfied with their wives as a sex partner or as a child provider. Consequently he could choose sex with other women, resulting in children born to these women. This hypothesis is supported by our finding that women with FGS were more often divorced than women without FGS, even though this difference was not statistically significant and might be confounded by ethnic and religious differences in the two groups. Since the numbers are too small to allow a multivariate analysis of relevant factors, clarification of these issues must await future studies with larger patient groups.
E.F Kjetland et al./Acta Tropica 62 (1996) 239-255 251
In accordance with observations made by other authors (Gibson, 1925; Badawy, 1962; Williams, 1967; Youssef et al., 1970) our study demonstrated an increased incidence of polypoid and papillomatous lesions and of ulcerations of women with FGS. This tendency was clear-cut for the vulva, but there was also a tendency with respect to papillomatous turnouts in the vagina. A tumorous growth of the introital area locally called 'mawuka' was mentioned by many of the women. Even though a history of 'mawuka' could not be significantly related to genital schistosomiasis, this locally recognised lesion should be further investigated as a possible indicator of tumours induced by sequestered eggs.
Sandy patches, representing eggs near the mucosal surface, which have been mentioned in the literature as pathognomonic for genital schistosomiasis (Gibson, 1925; Badawy, 1962; Youssef et al., 1970; Friedberg et al., 1991) were also observed in this study. Sometimes they were hardly detectable by the naked eye and would have been easily overlooked without the colposcope, similar to what has been observed previously (Youssef, 1957,Youssef et al., 1970). Moreover, amplification through the colposcope almost consistently revealed concentric blood vessels around the sandy grains. This finding has never been described before and warrants further investigation. Since intact live as well as disrupted dying schistosome eggs have the potential to initiate the development of small blood vessels (Freedman and Ottesen, 1988) the concentrically arranged blood vessels surrounding the sandy grains may indicate such a process of neovascularisation. The pathological occurrence of small blood vessels in the outer layer of the genital epithelium could explain the observation of easy contact bleeding in this and previous studies (Bland and Gelfand, 1970). It may also be of importance in facilitating transmission and dissemination of agents of STDs (Feldmeier et al., 1994, 1995a). Finally it might be assumed that extensive neovascularisation implies a risk for the rapid spread of cervical cancer supposed to originate from malignant cell transplantation in egg granulomas by some authors (Charlewood et al., 1949; Badawy, 1962; Youssef et al., 1962, 1970).
There is evidence that HPV plays a causative role in the development of genital carcinomas (zur Hausen, 1989). However, HPV-induced koilocytosis is difficult to demonstrate in cancer tissue, and when immunohistochemistry is negative, as in our case, the relation between HPV and cancer can sometimes be difficult to demonstrate. However, evidence of HPV infection was found in both cases with cervical dysplasia. The squamous cell cancer case and one of the dysplasia cases had concomitant FGS, whereas the last woman with dysplasia was FGS-negative. The theory of cervical cancer risk related to schistosome infection has been controversial. Schistosome- related epithelial papillomatous growths have been clinically mistaken for malignan- cies (El Tabbakh and Hamza, 1989). Hyperplasia of cervical epithelium and its clinical counterpart, leukoplakia, was previously thought to be premalignant (Charlewood et al., 1949; Badawy, 1962; Youssef et al., 1962, 1970). Even though S. haematobium ova have been found within genital cancer tissues, large series have not shown any increased incidence of cervical carcinoma in women with genital schistosomiasis and, conversely, no accumulation of schistosomiasis has been found in women with cervical carcinoma (Williams, 1967; Bland and Gelfand, 1970; Coelho et al., 1979; Lowe et al., 1981; Wright et al., 1982; Schwartz, 1984; E1 Tabbakh and
252 E.F. Kjetland et al./Acta Tropica 62 (1996) 239-255
Hamza, 1989; Friedberg et al., 1991; Szela et al., 1993; Moubayed et al., 1994, 1995). Convincing also is the fact that cervical cancer is equally frequent in African countries without endemic schistosomiasis (Wright et al., 1982). A correlation between human papilloma virus (HPV) and carcinoma of cervix in these areas has however been shown (Szela et al., 1993; Moubayed et al., 1995).
The study was designed as a small-scale pilot study and therefore has several limitations. A single quantitative urine examination is not sufficient to determine the intensity of S. haematobium infections. Moreover, the biopsies were rather small, after having been divided into 4 pieces in order to have material for various purposes. The selection of the biopsy site in cervix was more or less arbitrary and, for ethical reasons, biopsies were not routinely taken from vagina or vulva, precluding a definite conclusion on the distribution of ova within the lower reproductive tract. It may therefore be assumed that even though no ova could be shown in genital tissue of 18 women, some of these might also have had genital schistosomiasis. This could also explain some of the overlapping of symptoms and signs in the two groups. The most important shortcoming, though, is the fact that laboratory facilities at the study site were gravely insufficient to exclude all other reproductive tract infections. Brabin et al. (1995) in rural Nigeria have recently reported prevalences of repro- ductive tract infections in women of similar age of 40.4%, half of which were STDs. Thus, there is an urgent need for future studies to address the differential diagnosis of FGS and common STDs.
Nevertheless, the following conclusions seem to be warranted. Firstly, irrespective of the endemic area and independent of the intensity and degree of urinary tract schistosomiasis, S. haematobium infection also leads to genital manifestations. In the present study this was found in the majority of women. This is not unexpected, taking into account the complex vascularization of the female pelvis. Secondly, in women of childbearing age the cervix seems to be the main target organ. Since the size of the lesions correlates with the number of ova present in mucosal tissue and because neovascularization is best seen at cervix level, lesions at the cervix could be both indicative of the presence of FGS in the lower reproductive tract as well as pathognomonic for the existence of egg granuloma in epithelial or subepithelial tissue. Thirdly, symptoms and signs associated with FGS of the cervix and vagina may considerably overlap with those caused by agents of common STDs. Fourthly, the recorded lesions were often bleeding even after very careful manipulation, which might have an impact on sexual HIV transmission. Finally, it seems that FGS may have far-reaching consequences for the marital and sexual life of the affected women.
Acknowledgements
This investigation was supported by a Director's Initiative Grant from UNDP/WB/WHO Special Programme for Research and Training in Tropical Diseases (TDR). It also received support from the Research Forum and the Department of Infectious Diseases, Ullevaal University Hospital and Norwegian Lions International. We are indebted to the Mangochi District Hospital staff under
E.F Kjetland et al./Acta Tropica 62 (1996)239-255 253
the leadership of Dr. V. van Oosterzee and Dr. F. van der Velde. Special thanks go to Ms. R. Maziyaya, Mr. Kalua, Mr. A. Mazombe, Mr. E. Chikadza and Mrs. R. Gibson for their kind cooperation. Leisegang Feinmechanik Optik GmbH & Co. provided an excellent photocolposcope.
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