Introduction

Toxoplasmosis is a zoonotic infection caused by Toxoplasma gondii, which is transmitted by contaminated food or water, undercooked meat, or transplacentally [1, 2]. It has various clinical subtypes, including acute, CNS, congenital, ocular, or disseminated toxoplasmosis. The most common presentation is flu-like symptoms with lymphadenopathy, usually observed in the posterior cervical region, axillary, inguinal, or anterior chest wall [3]. Rarely, generalized lymphadenopathy or hepatosplenomegaly can occur. Histologic examination alongwith serologic studies are required for establishing diagnosis. Globally, seroprevalence is estimated to be 30–50%, with higher rates in Latin America and Western Africa. In a study from India an overall seropositivity of 21%, with IgG and IgM seropositivity of 5.7% and 15.3%, respectively [4, 5].

Case Series

Retrospective data analysis was done for patients presenting as lymphadenopathy to our institute during the period of January 2021 to December 2022. These patients had undergone lymph node excision biopsy and histopathological evaluation with haematoxylin and eosin stained slides. Biopsies showing the classically described triad of reactive lymphoid follicles, monocytoid cells along with non-necrotizing epithelioid microgranulomas were included in study and serological testing for toxoplasma was undertaken where possible. None of the patient were seropositive for Human immunodeficiency virus (HIV), Hepatitis B and C virus, which were done as part of prebiopsy workup.

Out of the eight cases histologically suspected to be toxoplasma lymphadenitis, predominantly were males (male: female ratio 7:1). The mean age of the population was 24.25 ± 9.8 years. Cervical lymphadenopathy was the most frequent complaint with three cases showing generalized lymphadenopathy on radiological evaluation. The mean size of lymph node was 2.6 cm (1.3–4.5 cm). All patients had complete blood counts and peripheral smear examination within normal limit. Table 1 shows the relevant clinical features of enrolled patients.

Table 1 Epidemiological and clinical features of the cases
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Histomorphology features in the lymph nodes showed preserved architecture with minimal capsular involvement. The classical triad of florid follicular hyperplasia with prominent germinal centres showing indistinct margins and numerous tingible body macrophages (Fig. 1), numerous microgranulomas (collections of epithelioid cells with less than 25 nuclei) (Fig. 2) diffusely scattered in interfollicular and paracortical regions with few seen abutting the mantle zones and monocytoid B cells characterized by an abundant pale eosinophilic cytoplasm, indented nuclei with inconspicuous nucleoli and open chromatin were seen. These cells are commonly located in the perivascular region or adjacent to sinuses (Fig. 3). None of the cases showed necrosis, macrogranulomas or giant cells.

Fig. 1
figure 1

Photomicrograph show the enlarged and expanded follicles with reactive germinal centre

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Fig. 2
figure 2

Numerous clusters of epithelioid histiocytes are seen in interfollicular areas of the lymph node. A cluster of epithelioid histiocytes is seen encroaching a germinal centre (arrow)

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Fig. 3
figure 3

- Monocytoid B cells expansion in sinuses and perivascular location

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Six out of eight patients underwent serological test for Toxoplasma IgM and IgG antibodies by chemiluminescent microparticle immunoassay. The cut off points for positive results for IgM and IgG were > 0.60 IU/mL and > 3 IU/mL, respectively. All six patients showed positivity for IgG with mean titres of 1068 IU/mL, however, all but one showed positivity for IgM antibodies with mean titres of 24.5 IU/mL.

Discussion

In Indian subcontinent, persistent lymphadenopathy is common, due to infections like tuberculosis or haematolymphoid malignancies [6]. In this study, all patients had a history of lymph node enlargement lasting more than one month, leading to concerns and subsequent evaluation through lymph node biopsy. Although none of the patients had fever or weight loss at presentation, few reported a history of fever during detailed evaluation. The above presentation is typical in acute toxoplasmosis infection, where patients may be asymptomatic or experience an indolent flu-like symptoms not necessitating hospital visit. Lymph node enlargement may occur, generally clinically insignificant, or unnoticeable. These enlarged lymph nodes may persist for up to three months before subsiding.

Immune response against Toxoplasma is triggered when the parasite enters the draining lymph nodes and are captured by subcapsular sinus macrophages. In the early stages of infection, neutrophils clusters maybe seen within lymph nodes with high infection rates. Later stages, cytotoxic T cells move to these sites of infection and form antigen-specific clusters alongwith infected macrophages at the subcapsular sinus containing the parasites [7,8,9]. As a result, when these nodes are morphologically evaluated, the parasite is not detected. Instead, the various immunological reactions to the parasite can be observed in the form of the histopathological triad. In immunocompromised hosts, parasites evade elimination causing life-threatening infection, mostly affecting the central nervous system. They form cysts containing bradyzoites. The presence of tachyzoites within the cyst wall is the most common histopathological feature in this scenario. A granulomatous reaction to it is also commonly observed.

In a large retrospective study conducted at a tertiary referral hospital in India, lymph node excision biopsy was performed on 1724 patients, with tuberculous adenitis being observed in 31% of cases, malignancy in 26%, and non-specific lymphadenitis in 31% [6]. The remaining patients could not be attributed a specific etiology. Another study anticipated that 15% of unexplained lymphadenopathy is due to toxoplasmosis, typically affecting the cervical lymph nodes [10]. In our series, all patients presented with cervical lymphadenopathy, and three had generalized lymphadenopathy. The definitive diagnosis is usually established through lymph node biopsy of the most representative enlarged node. Excision biopsy is the preferred method as it allows for an evaluation of the entire nodal architecture, which is essential for arriving at a diagnosis. The diagnosis of reactive lymphadenitis often marks the end of the diagnostic evaluation.

In the present study, the histopathological triad was observed in 100% of cases. However, a study by Eapen et al. showed triad was highly specific (96.6%), with sensitivity of only 44.4% [11]. Out of the nine cases of toxoplasmosis in the above study, the limiting factor was the presence of monocytoid B cells, which were only seen in four. Microgranulomas are the most definitive feature of toxoplasmosis, as follicular hyperplasia and monocytoid cells can be seen in other conditions like infectious mononucleosis and rarely Hodgkin lymphoma. In the present study, cases received for an opinion were mainly diagnosed as Hodgkin lymphoma elsewhere. Firstly, the immunoblastic proliferation can mimic Reed-Sternberg (RS) cells, secondly, granulomas are also a feature described in Hodgkin lymphoma. Immunohistochemistry can help to exclude the lymphomatous process, as the immunoblasts are positive for CD20 and CD30, while RS cells are predominantly CD20 negative.

Serology testing for IgG and IgM antibodies is required for diagnosis of toxoplasmosis. IgM titers typically increase after one-week upto three months, gradually declining, reaching low levels after a year. IgG antibodies, on the other hand, appear two weeks after infection, peak at three months and may persist for the patient’s lifetime [12]. When IgM titers are low, an IgG avidity test is performed to confirm the infection timeline, with low levels indicating acute infection [13].

Follow-up of patients showed regression of lymphadenopathy, indicating a self-limiting infection. Other studies have also emphasized that symptoms are self-limiting and resolve within one to two months in 60% of immunocompetent patients, without antiparasitic treatment. However, 25% of patients may take two to four months to return to normal, and it may take four to six months in 8% of cases. Reactivation of the infection may occur if the patient becomes immunosuppressed [14].

Infected women, particularly during pregnancy, can lead to fatal congenital toxoplasmosis infections, pregnancy loss, stillbirth, and intrauterine malformations in the foetus. These infections are also part of the TORCH spectrum [15].

In conclusion, a good clinical examination, histomorphology, substantiated with serology, can aid the diagnosis of toxoplasma lymphadenitis. The presence of the triad comprising follicular hyperplasia, microgranulomas, and monocytoid B cells should raise suspicion for this condition. The accurate and timely identification of this condition can end the diagnostic evaluation chain.