Abstract

Introduction. Female genital schistosomiasis (FGS), infection of Schistosoma spp. trem- atode in the gynaecological apparatus, is the most neglected sexual and reproductive health condition in sub-Saharan Africa with an estimated of 20-120 million cases. The ectopic entrapment of Schistosome eggs after oviposition can occur in 0.5% of cases in fallopian tubes and ovaries.
The case. We report a case of 38-years-old woman assessed for a 10 year history of infertility. On ultrasound, multiple cystic formations were observed in the ovary. Histology after oophorectomy to exclude malignancy showed granulomatous formations surrounding Schistosoma spp. eggs in proximity of corpus luteus and haemorragicum.
Discussion. Ectopic Schistosome oviposition, seen in the ovary and fallopian tubes as in our case, can be a potential cause of reproductive organ damage and complications such as infertility, ectopic pregnancy, miscarriage, premature birth, low birth weight, and even maternal death.
Conclusions. More studies are needed on ovarian FGS and its impact on women fertility to guide specific interventions targeting vulnerable population of childbearing age, con- tributing to the NTD WHO 2030 aim of eliminating schistosomiasis as a matter of public health.

Introduction

Reported for the first time in 1899 in Egypt, the definition of female genital histochemical (FGS) refers to the pathophysiology manifestations of Schistosoma spp. trematode infestations in the gynaecological apparatus ¹². FGS is the most neglected gynaecological condition in sub-Saharan Africa ³. Its prevalence, which is likely to be underestimated, has been estimated to be 20-120 million cases ¹.

In most cases, FGS is caused by untreated Schistosoma haematobium (S. haematobium), which is acquired through contact with cercaria-infested water sources used by girls and women in their daily activities ⁴. FGS can occur in approximately half (33 to 75%) of infected females, which means about 40 million girls and women². However, migration of Schistosoma spp. eggs outside the usual gastrointestinal and urinary excretion route, with entrapment in ectopic tissues, has been documented in different anatomic regions ^5,6; fallopian tubes and ovaries ^7,8 are among these aberrant sites reached by eggs after oviposition.

In addition to S. haematobium, other Schistosoma species have been observed in these aberrant locations, including S. mansoni and S. japonicum ^{8 9}. The numerous anastomoses of portal vein circulation with veins draining the internal genital organs and communications between ovarian veins and superior and inferior mesenteric veins could explain how S. mansoni eggs can arrive in female genital organs ¹⁰. Deposition of Schistosoma eggs causes reproductive organ damage and a variety of health complications such as infertility, ectopic pregnancy, miscarriage, premature birth, low birth weight, and even maternal death ¹¹.

Infertility has been reported as a manifestation of this specific gynaecological involvement, with serious socioeconomic consequences such as stigma, divorce, and socioeconomic burden among affected women ^7,8.

We present a case of ovarian schistosomiasis in a patient with secondary infertility, as well as a review of the current literature on this neglected ectopic involvement of this parasitic disease.

Case presentation

A 38-years-old woman from Mbeya, Tanzania, was referred to the Mother and Child Health Department at Consolata Hospital, to carry out investigations for a 10 year history of infertility. The patient’s anamnesis was absent of any acute or chronic conditions or previous surgery. An abdominal ultrasound assessment was performed, and numerous cysts were observed in the ovaries.

The patient underwent oophorectomy to exclude malignancy of the lesion. On pathological assessment of the surgical sample from the ovary, stained by haematoxylin-eosin, corpus luteum haemorragicum and albicans were observed, surrounded by numerous granulomatous inflammatory processes, elicited by numerous Schistosoma spp eggs. No speciation could be performed, because no eggs spine was visible in the available sections. There was no evidence of neoplastic tissue (Fig. 1).

The patient lived in a tanzanian region where schistosomiasis is not-endemic, and did not report any schistosomiasis history in anamnesis, and the time and modality of exposure could not be defined. Because at the time of histological reporting the patient had been discharged, no urinary nor faecal parasitological investigations could be carried out to allow speciation and assess active infestation. The patient was lost to follow-up, and no treatment could be given for the parasitological condition.

Review of literature

To contextualise our case in the frame of what was previously reported in literature on the topic of ovarian schistosomiasis, a review was conducted consulting PubMed, Scopus and EMBASE databases, using as key words “Schistosomiasis AND ovarian”. Case reports and case series were included. Descriptive analysis was performed using statistical software JASP, version 14. Anagraphic details, clinical presentation and diagnosis, Schistosoma species involved and anatomical location of invasion, therapeutic management and outcomes were summarised. Continuous variables were reported as means and standard deviation, categorical and qualitative variables were given as frequencies and percentages.

A total of 27 cases were included ^8-10,12-29. The number included our case report. The mean age of patients was 32.9±9.8 years, ranging from 15 to 51 years. The majority (23/27; 85.2%) lived in endemic regions, a minority were immigrants or travellers. Pelvic pain was the most frequent complaint (present in 21/27 cases; 77.8%), followed by infertility (5/27 cases; 18.5%). Infertility was the reason for seeking care in our case. Isolated ovarian schistosomiasis occurred in 9/27 patients (33.3%) including our case, but in 7/27 cases (26%) it co-occurred with ovarian tumour and in 3/27 cases (11.1%) with ectopic pregnancy. S. mansoni was detected in 12/23 (44%), S. haematobium in 9/23 (33.3%).

S. japonicum was reported in 2 cases. Differently from other reports, the Schistosoma species could not be detected in our case, because of the lack of a visible spine in the eggs observed in the histological specimen. Interestingly in 9/11 patients the laboratory investigations (stool, urine or placenta) were negative; in 3 of these cases a positivity for anti-Schistosome antibody was reported. We could not perform laboratory investigations, due to the fact that a final diagnosis was reached after discharge from hospital. Surgery was carried out in 22/27 (81.5%) of cases, and explorative laparoscopy in 2. Surgery was performed in our case in the suspect of malignancy, as also occurred in other reports in which schistosomiasis mimicked an oncological lesion ^19,21. The majority of the few available follow-up were clinically successful, except for one case that required a cycle of praziquantel after a first treatment with oxamniquine, to clear infection with rectal biopsy positivity at 20 months follow-ups from first diagnosis ¹⁴.

Cases are summarised in Table I. Details on anagraphic data, clinical presentation, parasitology details, surgical treatment of the cases reviewed, including our case report, are summarised in Table II.

Discussion

In this case report we described the ovarian involvement of Schistosoma infestation in a patient hospitalised for clinical assessment of infertility. Consolata Hospital routinely assists patients afferent from different regions of Tanzania. While several cases of FGS were assessed, considering the endemicity of schistosomiasis in Lake Zone regions, this is the first case where Schistosoma eggs were visualised in the ovary on the histological investigation at our Centre. As previous case reports have emphasised, infertility is a matter of great concern to patients with schistosomiasis, due not only to the physical challenges associated with the condition, but also to its psychological and social implications ¹³. The importance of any additional report or study providing inputs to better understand this neglected ectopic involvement of this parasitic disease cannot be overlooked.

Ovarian invasion by Schistosoma spp. eggs has been described in previous case reports, as occasional finding during investigations for benign conditions including tube-ovarian abscess, pelvic adhesions, ovarian cysts, ectopic pregnancy, and tubal ligation ^8,30. Schistosomiasis lesions were also reported as a mimicker of tumour lesions in some cases, such as the current one ^10,21 or were observed as co-occurrent with malignancy, including teratomas ^12,18, mucinous cystadenocarcinoma of the intestinal type and papillary serous carcinoma ³¹. The histological investigations carried out in our case, with analysis of specimens from ovarian cyst stained with haematoxylin-eosin excluded the presence of malignancy (Fig. 1).

It has been reported that the ovary represents only 0.5% of ectopic sites of schistosomiasis involvement, and up to 50% of cases involving the female genital tract, according to different estimates ¹⁰. Still there could be a concern for under-reporting bias. Lesions involving the upper genital tract are, in fact, more difficult to discern by routine clinical examination than those involving the lower tract, explaining the paucity of available data on the prevalence of this condition and it’s exact morbidity ^8,10.

Even though S. haematobium is the most frequently involved species in cases where the ovary is involved, Schistosoma mansoni (S. mansoni) and Schistosoma japonicum (S. japonicum) can also reach the fallopian tubes and ovaries through the anastomoses of the anorectal plexus through the recto-vaginal septa ^8,19. It has been estimated that between 6 and 27% of women with intestinal schistosomiasis temporarily suffer from pathological conditions induced by the accidental presence of S. mansoni eggs in their genital organs ¹⁹.

Ovarian invasion by Schistosoma eggs, described in cases of FGS ⁷, is favoured by the anatomical pattern of venous drainage of the pelvis and the physiological lack of valves in venous vasculature in this anatomical region ^1,7,10,19 (Fig. 1). Moving from the mesenteric veins and anorectal venous plexus, the adult male-female pairs of S. haematobium reach the uterovaginal plexus. In this location, helminths produce eggs that migrate into different loci in the genital tract (vagina, cervix, uterus, fallopian tubes) and can finally reach ovaries, as in our case ^1,19. Additionally, some studies have suggested that the development of the microvascular network of preovulatory follicles through angiogenesis during reproductive life and pregnancy may facilitate the implantation of ectopic schistosomiasis in this specific location ³¹. Finally, additional mechanisms suggested explaining the ectopic finding of eggs in the ovary are the arterial embolization of the S. mansoni eggs in presence of congenital cardiovascular defects or arteriovenous shunts and oviposition after the migration of the helminths ³¹.

The pathogenesis of female-genital involvement is triggered by the immune response to the presence of eggs trapped in different locations of the female genital tract, with the formation of granulomas and induction of angiogenesis around the site of Schistosoma’s egg deposition ¹. Histopathological findings include Schistosoma’s eggs in ovarian parenchyma, which can be more or less calcified, generally surrounded by a granulomatous inflammatory reaction rich in giant cells of the foreign body type ³⁰, similarly to the present case findings. It is of interest to emphasise that angiogenesis around entrapped eggs could explain the finding of the ovarian haemorrhage in our case, which could also be misinterpreted as a haemorrhagic corpus luteus at histopathological examination, if the pathologist is not aware of this possibility (Fig. 1).

The clinical presentation in cases of Schistosoma spp. ovarian invasion may occur many years after exposure to the parasite ⁸. Gynaecological complications like amenorrhoea, menstrual irregularities, and menorrhagia can occur ²⁸. In our case, infertility was the reason for the patient referring to the hospital for further investigations, leading to ovary schistosomiasis diagnosis. We speculated that the diagnosed schistosome infection could explain the secondary infertility, even though we could not further confirm this hypothesis or understand the mechanisms behind it, due to the patient loss to follow-up and lack of additional investigations. Infertility is among the described complications of ovarian involvement in schistosomiasis infection ^1,13, mainly through two mechanisms ³².

The first consists in the functional and anatomical disorders secondary to granuloma formation in tubes ³². As recently described by Adepetu et al., sterility may be secondary to the formation of granulomas in the mucosa of the fallopian tubes, leading to sterile salpingitis, local fibrosis, fibrotic scars, and tubal occlusion ⁷. Granulomatous reactions near the hilum of the ovary may also cause hilar obstruction, with para-ovarian adhesions resulting in anovulation ⁷.

The second mechanism is through the local hormonal homeostasis impairment ³². A hormonal interplay between the host and parasite could contribute to schistosomiasis-induced hypogonadism ³³ due to the Schistosoma’s ability to synthesise and release oestradiol ³². Additionally, Santos et al. have suggested that the metabolism of oestrogens and the production of estrogenic-DNA adducts and reactive oxygen species (ROS) can also be implicated in a pathway underlying S. haematobium-promoted host cell DNA damage and the statistical association observed between S. haematobium infection and reduced fertility ³².

Sterility could additionally be a result of surgical treatment for emergency complications of ovarian involvement by the parasitic disease; this calls for the need for specialist management of patients to address issues of future fertility ¹³. Physiopatological mechanisms potentially leading to infertility in patients with schistosomiasis are summarised in Figure 2.

Praziquantel is the therapy of choice for schistosomiasis ^8,31,34 and has been reported as effective to treat symptoms of FGS ^13,35 and achieving parasite clearance ²⁸. The available praziquantel in most endemic communities is donor-supplied for mass chemotherapy targeting school children, leaving out other populations at risk ¹. In our case, the patient had left the hospital before the availability of the final pathology report, and was lost to follow-up. No specific treatment for the parasitology condition could be given. This emphasises the importance of not losing patients after the diagnosis.

Both the oncogenic features and the impairment of hormonal homeostasis with infertility concerns observed in FGS cases, and, specifically, in cases involving the ovary, call for additional investigations that could guide the integration of actual programmes to reach this specific population and their needs.

Conclusions

FGS can result in significant morbidities among the infected women and girls if necessary measures are not taken ranging from early and prompt diagnosis and treatment. Therefore, we advise taking the following actions; firstly, physicians and gynaecologists treating patients in or from endemic areas for any of Schistosome spp should always consider schistosomiasis in the differential diagnosis of upper genital tract disease, even years after exposure, to provide a prompt diagnosis of parasitosis. Laboratory investigations on stool or urine samples, that were reported as negative in some cases of upper genital involvement, should be integrated with serological assessment. Secondly, enhancing awareness of this potential clinical scenario could help with history-taking, investigations, and precise diagnoses to prevent unnecessary surgical treatment or to better guide surgical management of overlapping conditions of surgical and parasitological interest. Lastly, further studies that could address the issue of fertility impairment in FGS, of which ovary involvement seems to be frequently reported, are needed to reach this vulnerable population and its specific needs. Finally, the co-occurrence with oncological diagnosis, reported in some cases in literature, should be deeply investigated, to determine any extended oncogenic effect of Schistosoma spp beyond the urinary system.

ACKNOWLEDGEMENTS

N/A.

CONFLICTS OF INTEREST

Authors declare no conflict of interest.

FUNDING

Authors received no funds for this work.

AUTHORS’ CONTRIBUTIONS

EE conceptualization, case management and extrapolation of clinical and pathology data from patient’s record. VS review of cases published in literature. EE, VS Writing of first draft. EE and MM analysis of pathology specimen. EE, VS and VM MM review of literature, interpretation, manuscript writing and approval of final draft. VS medical illustration.

ETHICAL CONSIDERATION

Witnessed informed consent was obtained from the patient for anonymized publication of data from the clinical report.

Figures and tables

Figure 1.(A) Venous drainage anatomy favouring Schistosoma’s eggs reaching the ovary. Utero-vescical plexus and inferior rectal veins drain in the internal iliac vein. The superior rectal vein drains in the superior mesenteric vein and portal system; the ovarian plexus drains in the vena cava on the right, in renal vein on the left. Contiguity between venous vessels and plexus and depletion of valves in these vessels in these regions favour Schistosoma eggs (S. haematobium but also S. mansoni) spreading to the female genital tract. (B) pictorial view of the ovary section. Granuloma’s around Schistosoma spp eggs (arrow) are present. (C) Haematoxyline and eosin 400X. (D-H) histology sections-haematoxyline and eosin of the ovary showing Schistosoma eggs surrounded by granulomatous reaction. (G) original magnification. The picture is original work by co-author Valeria Silvestri.

Figure 2.Pathophysiology of infertility in FGS involving the ovary. Granuloma formation, impairment of hormonal homeostasis due to parasitic oestrogen synthesis, DNA damage, consequences of surgery can all lead to infertility in this specific setting.

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