Etiopathogenesis, diagnostic evaluation, and management of ovarian tuberculosis: A systematic review.

INTRODUCTION Genito-urinary tuberculosis is the second most frequent location for extrapulmonary tuberculosis, after the lymphatic system.[1] Genital tuberculosis represents 15–20% of extrapulmonary tuberculosis,[2] which accounts for 15% of all the incident cases of tuberculosis (7 million) that were notified globally in 2018.[3] Ovaries have been reported to be the second[4] to third[5,6] most common organs involved after endometrium and fallopian tubes. Ovarian involvement has been reported to be around 10% to 30%[4,5,7] of patients with female genital tuberculosis (FGTB) in various sources. Though tuberculosis involving ovaries is commonly reported, isolated ovarian disease is rare.[8] Various theories of pathogenesis also describe ovarian involvement secondary to fallopian tubes, be it secondary hematogenous/lymphatic spread, or primary via infected semen.[7] FGTB when presenting as abdominopelvic mass and masquerading as ovarian carcinoma is a diagnostic challenge. The possibility of malignancy warrants aggressive surgical intervention, with post-operative histopathology unveiling the actual etiology, a medically manageable disease. This article aims to present and share a review of the English-language literature on ovarian tuberculosis to gain a better understanding of etiopathogenesis and diagnostic methods and to provide guidelines for its management.

The search strategy, inclusion and exclusion criteria, and primary and secondary outcomes were defined before the search. The systematic search of the literature was performed on Pubmed and Medline from 1950 to 2020 according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement [Figure 1]. All resulting titles, abstracts, and full text, when available, were read and kept for reference. Specific MeSH (Medical Subject Headings) terms included “ovarian tuberculosis,” “diagnosis,” “cytology,” “staining and culture,” “Polymerase chain reaction,” “histopathology,” “imaging studies,” “medical management,” and “surgical intervention.” Observation prospective and retrospective studies, and case reports and series were included in this study for the full review. Exclusion criteria included patients with a history of radiation therapy to the abdomen and pelvis and a history of any form of surgical intervention on the female genital tract system for any other pathology. Data were extracted by one author independently and then compared. The study author provided additional data if incomplete data were noted. Titles/abstracts considered potentially relevant were retrieved for review of the full manuscript. The list of full manuscript meeting inclusion criteria was compared, and any disagreements were resolved by discussion and consensus. The outcome measures were chosen to assess the effectiveness of various diagnostic methods and treatment modalities. The primary outcome measures were: For diagnostic evaluation: Clinical manifestations, pathological findings including macroscopic as well as microscopic features, laparoscopic findings and biopsy technique, culture and staining techniques, the role of various imaging studies Management: Lacunae in management guidelines, the role of medical therapy and surgical intervention, and choice of surgery. The secondary outcome measures were evaluated to assess other parameters: Assessment of clinical parameters, prognosis and spread, differential diagnosis, complications, and follow-up.

We retrieved 42 manuscripts meeting our criteria from the search and 30 manuscripts were included in the study. There were 9 case series and 21 manuscripts with review of the literature.

Etiopathogenesis Ovarian involvement in TB may occur in two forms, namely, perioophoritis and oophoritis.[9] Perioophoritis is the more common form and results from the spread of infection to the ovaries directly from the tubes. Oophoritis is relatively rare and results from hematogenous spread to the ovaries.[9] Patients who develop extrapulmonary tuberculosis (EPTB) including ovarian TB have been reported to have some risk factors or comorbid conditions.[10] Patients with congenital or acquired pathologies resulting in abnormal host-defense mechanisms such as acquired immunodeficiency syndrome (AIDS) and leukemia are at increased risk of developing TB at such rare sites.[10] The immunodeficiency virus (HIV), diabetes mellitus, chemotherapeutic agents, and other immunosuppressive medications have been associated with an increasing incidence of ovarian TB.[10] Ovarian TB can be due to primary or secondary infection.[7] In primary tuberculous infection, there is no evidence of TB elsewhere. Primary and isolated ovarian TB is a rare occurrence. Ovarian involvement is usually secondary to tuberculous foci in the fallopian tubes and/or endometrium or pulmonary infection or as a part of multifocal abdominal TB or disseminated TB. In the female genital tract, the most common site is the endometrium followed by the fallopian tubes and ovary. The possible routes of tuberculous infection of the ovary are[11] as follows: - (1) Direct spread through tuberculous lesions in contiguous structure: This is the most common route of involvement of ovaries.[12] The primary focus could be on the endometrium or tubes. Direct involvement of ovaries from semen has also been reported.[12] In such a spread, the center of the ovary usually gets affected. Direct spread also occurs from peritoneal tuberculous lesions. - (2) Hematogenous spread: This is considered to be the second most common route of spread of tuberculous lesions and affects the peripheral or outer surface of the ovaries initially.[13] - (3) Lymphatic dissemination: Lymphatic dissemination occurs from pelvic lymph nodes and involves the outer surface initially. This is a rare form of spread and results in isolated ovarian lesions. - (4) Superinfection of a malignant lesion: Immunocompromised state associated with ovarian cancer acts as a pre-disposing factor. - (5) Reactivation of a dormant bacillus in an immunosuppressed patient: This mode of involvement is seen in cases with a heavy bacterial load such as patients with peritoneal tuberculosis involving the gastrointestinal tract and mesentery. Based on the mode of involvement, ovarian TB can be classified into the following: - (1) Local, with isolated involvement of the ovary in the form of a primary complex with caseation of the associated pelvic lymph nodes. Dissemination of infection from draining lymph nodes is a common mode of involvement in patients with AIDS and other immunocompromised states. - (2) Ovarian TB developing secondary to pulmonary TB or gastrointestinal TB. - (3) As a part of the multifocal involvement of the female genital tract. - (4) Miliary TB, as a part of generalized TB resulting in the involvement of the ovary as well. This is usually associated with immunosuppressed states. Diagnostic evaluation Diagnosis of ovarian TB is difficult and misdiagnosis is common. Diagnosis is often made after major surgical resection on final histopathological examination. Diagnosis of isolated ovarian TB is challenging. The definition/criteria for diagnosis of ovarian TB is given in Table 1. Clinical evaluation Clinical features of ovarian TB are vague and non-specific; presentation depends upon manifestations of TB. Various manifestations of ovarian TB are: - Tubo-ovarian mass - Abscess formation - Sinus formation - Intra-ovarian nodule formation. The disease picture in female genital tuberculosis depends upon the extent of organ involvement. The age of presentation for ovarian TB is 20–40 years with a mean age of 25 years.[7] The youngest reported patient was 14 years old.[10] In a prospective study on gynecological TB, the mean age was 25.6 years, and most of the patients fell within the age range of 17–36 years.[6] In up to 11% of cases, patients may be symptomatic.[14] The symptoms are non-specific. The most common symptom is vague pain in the left or right lower quadrant. The most common presenting clinical picture is infertility.[6] In a study by Mondal et al.,[15] the most common presenting feature was infertility (65–70%) followed by pelvic/abdominal pain (50–55%), and menstrual disturbances (20–25%). The constitutional symptoms of TB such as anorexia, weight loss, night sweats, and evening rise in temperature have been reported in up to 45% of patients. In patients diagnosed with isolated involvement of ovaries, the most common clinical finding is the presence of an abdominal mass (54%) which mimics malignancy followed by ascites present in 31% of cases.[14-17] Pathology The mode of involvement is the best predictor of the number, site, and size of ovarian tuberculous involvement. Generally, ovarian tuberculous lesions are solitary. Nodular lesions are small while abscesses may be large and multiple. Miliary lesions are multiple. Macroscopy The affected part of the ovary is mild to moderately enlarged in most cases. Diffuse massive enlargement of the ovary is rare. Two clinicopathological patterns of involvement are described: perioophoritis and oophoritis. Perioophorits is the most common form of tuberculous involvement of the ovary in which the tuberculous process starts from the tube and involves the ovary with an extension of the lesion from the periphery (tunica) toward the center (parenchyma). In such cases, fibrinous exudate is seen on the surface of the ovary. This results in a tubo-ovarian mass, which is frequently adherent to the omentum and intestines. Oophoritis is a relatively rare condition in which infection starts in the stroma of the ovary, presumably from a hematogenous source that produces a caseating granuloma within the parenchyma. In TB oophoritis, typical tubercles or larger foci with caseous centers may be recognized on cross-sections in the hilum of the ovary.[18] Pathologically, ovarian TB may have the following variations: - (1) Non-specific focal enlargement - (2) Multiple hard nodules - (3) Multiple cystic lesions - (4) Non-specific diffuse enlargement. Microscopy The hallmark of tuberculosis caused by Mycobacterium tuberculous bacillus is the presence of numerous epitheloid granulomas composed of aggregates of macrophages, epitheloid cells, and Langhans giant cells with variable degrees of central caseous necrosis in the ovarian cortex and medulla. The lesions vary in size from 1 mm to >2 cm. Fibrosis may develop in relation to granulomas. In a study by Mondal et al.,[15] caseation was seen in 3 out of 10 cases of ovarian TB. Pelvic lymph nodes may show caseating granulomas. Laboratory evaluation Many laboratory abnormalities may be seen in an ovarian TB patient; however, there is no specific laboratory test to diagnose this pathology. These abnormalities reflect the systemic involvement, development of complications, and/or sequelae of the disease process. In uncomplicated cases, the differential leukocyte counts and liver and renal function tests are usually within the normal range. Decreased hemoglobin and serum albumin levels, markedly elevated erythrocyte sedimentation rate (ESR), and positive tuberculin test support the diagnosis of tuberculous pathology. Approximately 60% of patients show strongly positive tuberculin test. C-reactive protein may also be raised in complicated cases. HIV antibody testing should also be done, as up to 46% of cases have been found to be HIV positive. CA-125 is an antigenic determinant that is expressed in non-mucinous epithelial ovarian carcinomas, and the raised levels are found in more than 80% of cases.[8,19] The positive predictive value of CA-125 for malignancy in post-menopausal women is nearly 95%. However, in pre-menopausal women, the raised levels can be seen in benign conditions such as endometriosis, fibroids, pelvic inflammatory disease, and chronic inflammatory pathology like tuberculosis.[20] In ovarian TB cases, its level almost never rises above 500 U/ml.[8,20] Simsek et al.[21] have shown that decreasing levels of CA-125 correlate with the resolution of the disease on antituberculous treatment (ATT). They suggested that serial measurements should be used to determine treatment efficacy. Chronic inflammatory conditions including TB reduce ovarian reserve. Hormonal markers help predict ovarian reserve. High levels of follicle-stimulating hormone (FSH) and estradiol and low levels of inhibin B and anti-Mullerain hormone on days 2–4 of the menstrual cycle are suggestive of low ovarian reserve. Staining, culture, and polymerase chain reaction (PCR) assay Specimen for acid-fast bacilli (AFB) staining, culture, and PCR may be obtained from pus present in the ovary itself or periovarian collection, endometrial aspirates, ascitic fluid, and tissue for biopsy. In fluids and tissues, M. tuberculosis is detected in 10–60% of cases.[22] The success rate of identifying AFB is maximum with the ovarian biopsy specimen followed by pelvic aspirated fluids in the range of 20–40%.[22] In case of an abscess, pus aspiration should always be done under image guidance and it may also show bacilli. In a patient with disseminated TB or in presence of multiple foci of tuberculous lesions, bacilli may also be isolated from other sources such as sputum, bronchus, and urine. Microbiologic culture is the gold standard for the definitive diagnosis;[6] however, a negative culture does not exclude the diagnosis of genital TB. Akbulut et al.[23] reported that Ziehl Neelson (ZN) stain and pathological examination can be negative in 90% of cases. PCR assay helps in supporting the diagnosis of TB occurring at an uncommon site such as an ovary and in conjunction with other non-invasive modalities, it helps diagnose ovarian TB and a major surgical procedure for diagnostic evaluation can be avoided. PCR can pick up more extrapulmonary TB patients as compared to conventional methods and it is superior to smear and culture in detecting Mycobacterium tuberculosis (MTB) (8). Many PCR assay techniques have been devised for the detection of specific nucleic acid sequences of MTB and other mycobacteria. Bhanothu et al.[22] concluded that amplification of the 19 kDa antigen gene in combination with the TRC4 element is a successful multigene PCR for the diagnosis of mycobacterial infection among endo-ovarian tissue biopsies. The sensitivity of PCR is similar to culture but inferior to biopsy and the advantage is that the results can be obtained within a day; Bhanothu et al.[6] concluded that the logical time of diagnosis by multigene PCR was 6.48 h. Drug susceptibility cannot be reliably determined with PCR assay. The reported specificity of the PCR assay is 100%, and the sensitivity is up to 86.63%. It has been suggested that PCR assay should not be used in isolation as a primary diagnostic tool. PCR assay in combination with culture improves diagnostic accuracy.[6,8,22] Denue et al.[23] recommended bacteriological cultivation, ZN staining for AFB, and PCR analysis for a definite diagnosis. Gudu[13] concluded that for definitive diagnosis, culture and PCR should be done. Imaging studies Imaging studies have low specificity, as the appearance of malignant and infective ovarian lesions is similar; moreover, ascites, omental involvement, and lymphadenopathy are often associated features in both types of ovarian pathologies. Chest X-ray Chest X-ray should always be done to confirm any associated pulmonary tubercular lesion as in up to 10% of cases, ovarian involvement is secondary to pulmonary TB. Ultrasonography (USG) USG is an excellent imaging modality for initial evaluation and preliminary screening. In addition to detecting gross findings such as ovarian or tubo-ovarian mass, abscess in and around the ovary, ascites, and associated peritoneal and gastrointestinal lesions, USG will also confirm the presence of a suspected space-occupying ovarian lesion such as a cystic or solid nodular ovarian lesion. Conventional USG shows diffuse enlargement of the ovary, the isolated lesion appears as a focal hypoechoic lesion at or adjacent to the ovary that may sometimes show central liquefaction.[5,9] It may also show bilateral solid adnexal masses with scattered small calcifications and fluid in the pouch of Douglas,[24] but it has only a limited role in the diagnosis of genital TB as there is no specific feature suggestive of the tuberculous lesion. Doppler USG helps predict ovarian reserve by showing ovarian volume and ovarian blood flow.[11] Malhotra et al. suggested that females with a good ovarian reserve will show optimal blood flow patterns.[11] USG is non-invasive with no radiation hazard; because of resolution limitations, computed tomography (CT) scan is often required to confirm the nature of the lesion. Contrast-enhanced computed tomography scan (CECT) CT scan typically detects lesions greater than 0.5 cm in diameter; even smaller lesions may be visualized with newer contrast-enhanced spiral techniques. CT features are non-specific and often resemble other inflammatory or neoplastic cystic lesions of the ovary. CT scan findings are in the form of focal mass lesions or complex mass lesions with collections.[25,26] In the presence of pelvic and abdominal masses, CT is a useful imaging modality, especially when a lesion resembles a malignant ovarian tumor. In TB, there may be low-density ascites and multiple pelvic, abdominal, hepatic, and splenic lesions with or without significant lymphadenopathy. Computerized axial tomography can also help in the delineation of tubo-ovarian masses.[27] CT has the drawback of poorer soft-tissue characterization in the pelvis compared with magnetic resonance imaging (MRI). In our preliminary experience, CT scanning in pelvic TB does not show a high degree of specificity. Hysterosalpingography (HSG) HSG is an economical technique that remains the initial investigation of choice in the assessment of tubal factor infertility in low-income societies; it is an invaluable tool for the investigation of the female genital tract. In patients with tubo-ovarian masses and also in isolated lesions of the ovary, it confirms the presence of tubal and/or endometrial lesions of tuberculous origin.[27] MRI In modern gynecology, MRI is increasingly being used for the investigation of abdominal and pelvic masses.[29] It allows better soft tissue characterization than CT and can help to avoid a laparotomy in patients with TB, which is not without risk. Women with tubercular tubo-ovarian masses and peritoneal TB are a particularly important subgroup because the differential diagnosis in these patients is ovarian cancer. MRI can help to localize pelvic lesions and identify their origin more accurately. In patients with pyosalpinx complicated by a tubo-ovarian abscess, T2-weighted spiral MRI may show shading or hypointense areas because of the high protein content; inflammatory changes are seen in the surrounding tissues.[28,29] MRI is also useful when fistulae or tuberculous tracts are formed. Tubercular tubo-ovarian masses on MRI usually present as complex adnexal masses with a large amount of ascites and may demonstrate thickened tubes or nodularities along the tubo-ovarian surface with or without lymphadenopathy. On MRI, the walls of tubercular tubo-ovarian masses are often irregular; the signal intensity on T2-weighted images can be low and the inner walls might be septated or nodular.[28,29] Dense adhesion of the tubo-ovarian masses to the uterus or other adjacent organs occurs in up to 50% of patients with genital TB (29). Loculated fluid collections with internal septations are often found in the cul-de-sac and other portions of the peritoneal cavity.[29] The present study demonstrates the usefulness of MRI in the detection of tubo-ovarian masses caused by TB. This imaging technique could help to avoid a laparotomy in patients with genital TB because the differential diagnosis of tubo-ovarian mass lesions is ovarian cancer. However, MRI has limitations and gives only non-specific diagnostic findings in patients with tubercular tubo-ovarian masses. Clinicians should not rely solely on MRI findings for the diagnosis of genital TB if ovarian cancer is a potential differential diagnosis, to avoid missing the correct diagnosis. Role of image-guide fine needle aspiration cytology (FNAC)/biopsy Obtaining image-guided FNAC and/or biopsy specimen is an important method to increase the pre-operative diagnostic accuracy of ovarian TB. USG/CT-guided transvaginal or transabdominal biopsies may also be obtained for pre-operative diagnosis.[22] Also, the trauma of major laparoscopic or open surgery under general anesthesia for diagnostic purposes can be avoided. Role of diagnostic laparoscopy and laparotomy with frozen section Diagnostic laparoscopy is indicated when other non-invasive and less invasive imaging modalities fail to diagnose ovarian TB in a clinically and epidemiologically suspected case.[6,22] This is important because ovarian TB mimics ovarian malignancy. The treatment of malignancy is extensive surgery while ovarian TB can be managed with medical therapy. Diagnostic laparoscopy is preferred over laparotomy.[6,22] It facilitates visualization of the entire abdominal cavity. In addition to ovaries, the entire female genital tract can be examined. Any other focus of TB in the gastrointestinal system can be seen and tissue for biopsy can be obtained. The tissue obtained should be a frozen section. It helps in deciding on the completion of surgery and further management becomes simpler. Lymph nodes, mesentery, omentum, and the presence of minimal fluid in the pouch of Douglas can be obtained for adenosine deaminase, staining, culture, and PCR assay.[30] Treatment There is a lack of management guidelines for ovarian TB because of the rarity of the disease. The management of ovarian TB consists of medical treatment and surgical intervention. The choice of therapy depends on the age at presentation, clinical manifestation and presence of any associated complication especially infertility, the stage at which the diagnosis is made, the immunological status of the patient, and the type of disease-whether reactive or occurring as a new pathology or a part of disseminated disease. The principles of treatment are given in Table 2. Once a correct diagnosis has been made, ovarian TB is curable with standard medical therapy.[6,10,22] According to WHO guidelines, isolated EPTB with no past history of TB should be considered as a new case and ATT should be given for 6 months; the treatment regimen consists of 2 months of intensive phase with four drugs - isoniazid (5 mg/kg BW/day), rifampicin (10 mg/kg BW/day), pyrazinamide (30 mg/kg BW/day), and ethambutol (20 mg/kg Bw/day), subsequently continuation phase with two drugs isoniazid and rifampicin for 4 months. The best results of ATT are seen in patients with isolated ovarian tuberculosis without abscess formation. Isolated EPTB is associated with a lower bacillary burden than pulmonary disease. Therefore, isolated EPTB such as ovarian tuberculosis can be treated with standard short-course regimens that are effective for pulmonary disease. However, a disseminated disease with tuberculous ovarian involvement needs to be treated with 12 months of chemotherapy.[6,7,10,22] USG is the investigation of choice for follow-up and also in guiding the duration of therapy. Liver enzymes should be assessed weekly in patients with associated hepatic TB or any other form of hepatic pathology.[24] CT and MRI are better USG for confirmation of complete resolution of the pathology and also in patients requiring any form of surgical intervention during the course of ATT.[28] Indications of surgical intervention - (1) Tuberculous abscess formation. - (2) When imaging studies and image-guided FNAC and CNB fail to diagnose ovarian TB and malignancies cannot be ruled out. - (3) When surgery is indicated for the involvement of other parts of the abdominal cavity. - (4) When the disease fails to show a complete clinical response with ATT. - (5) In presence of complications such as infertility requiring some form of intervention and rupture of an abscess cavity into the adjacent hollow or peritoneal cavity. Surgical intervention - (1) Image-guided aspiration and percutaneous tube drainage: They are indicated in a solitary abscess or adnexal collection with no coexisting TB of the uterus or fallopian tubes and intra-abdominal pathology. If image-guided simple aspiration of abscess cavity or collection is planned, then the patient might have to undergo repeated aspiration and should be explained about the possibility of multiple aspirations at frequent intervals. This procedure should be carried out under optimum antibiotic cover to prevent secondary infection. Aspiration provides the material for culture and also gives valuable diagnostic and bacteriologic data. This simple procedure also saves the trauma of major surgical exploration. Image-guided percutaneous tube drainage is an effective procedure and is preferred over simple aspiration. Pre- and post-procedure standard ATT should be continued. - (2) Exploratory laparotomy with surgical drainage of pus/collection: This can be done either laparoscopically[6,22]or by open procedure.[10] This is not the preferred method and is indicated for treatment failures of needle aspiration/percutaneous drainage or for patients with coexisting intra-abdominal pathologies. - (3) Extensive surgery such as hysterectomy and bilateral sapingo-opherectomy is needed when no definite diagnosis could be made or in presence of an associated malignant pathology of the genital tract.[10] Complications Complications in ovarian TB develop because of missed or delayed diagnosis. The common complications are infertility, ectopic pregnancy, multiple abortions, and rupture of the abscess cavity into the hollow viscera. Other complications are hypercoagulable states, embolism, and intestinal obstruction secondary to adhesion formation. Prognosis and follow-up Response to the standard therapy can be assessed by improvement in symptoms and signs, normalization of laboratory parameters, and radiological regression of disease. For follow-up, during each visit, along with a detailed clinical assessment, a hemogram, serum albumin, and liver function test should be done. USG should also be done monthly for the first six months. The first CT scan needs to be done after the completion of ATT. A CT scan can be done early if there is no clinical improvement or clinical deterioration or in presence of static disease on USG.

AND RECOMMENDATIONS Tuberculous involvement of the ovary is a rare manifestation of a common infective pathology caused by Mycobacterium tuberculosis. Misdiagnosis is common, and therefore the diagnosis often gets delayed. Histopathological examination is the diagnostic modality of choice. Ovarian TB patients respond well to standard ATT. Surgical intervention is indicated for medical therapy failure and complications. The authors recommend the following: - There are no specific features in imaging studies. However, CECT should always be done to rule out the disseminated nature of TB, the status of the fallopian tubes, uterus, and cervix, and also to rule out any other intra-abdominal pathology requiring surgical intervention. - As the disease is medically curable, try and make all efforts to diagnose the pathology with non-surgical diagnostic modalities in suspected cases to save patients from the trauma of major surgical resection. - Image-guided biopsy and histopathological examination are the best and most direct ways to diagnose. In patients with high levels of suspicion with negative biopsy for TB, laparoscopy should be done. When it is not possible to differentiate between TB and malignancy, the intra-operative frozen section helps to diagnose this rare pathology. - Surgical intervention is indicated for non-responsive disease and complications. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Biopsy; etiopathogenesis; medical management; ovarian tuberculosis; surgery