The impact of tuberculosis misdiagnosis in Hodgkin lymphoma patients

Sir,

Both lymphoma and tubercular lymphadenopathy can present with similar clinical features, including fever, weight loss, and lymph node enlargement¹. This overlap poses a significant diagnostic challenge, particularly in low/middle-income countries (LMICs), where tuberculosis (TB) is far more prevalent than lymphoma^2,3. Due to limitations in healthcare infrastructure, patients presenting with these symptoms in LMICs are frequently started on empirical anti-tubercular therapy without a definitive diagnosis^4,5. Recent advancements in the treatment of Hodgkin Lymphoma, such as the use of antibody-drug conjugates and checkpoint inhibitors, are associated with extremely high cure rates. However, due to high costs, these novel agents are often out of reach for most patients, and physicians have to rely on standard ABVD therapy, or use novel strategies such as low-doses of these agents to achieve cure⁶. For patients with Hodgkin lymphoma who are misdiagnosed and initially treated with empirical anti-tubercular therapy, the impact of this delay on their clinical outcomes remains unclear. We aimed to evaluate the consequences of such misdiagnosis through this study.

The study was a retrospective analysis conducted in a tertiary care centre in North India after approval from the Institute Ethics Committee of Postgraduate Institute of Medical Education and Research, Chandigarh, India. Case records of all individuals aged ≥12 yr with newly diagnosed Hodgkin Lymphoma treated at our centre between January 2018 and March 2023 were reviewed. Patient records were reviewed, and information regarding which patients had a previous diagnosis of TB and had received empirical anti-tubercular therapy from an alternate centre before presenting to us was noted. We have previously reported our unit’s experience and different treatment protocols used at our center^7-10. Statistical analysis was performed with R version 4.4.0 and SPSS version 25.

Records for 293 patients with newly diagnosed Hodgkin Lymphoma treated at our centre during the study period were available and included in this study for analysis. Among these, 37 (12.6%) received empirical anti-tubercular therapy before establishing an Hodgkin Lymphoma diagnosis. The most common basis of prescribing anti-tubercular therapy in these patients was clinico-radiological, which was seen in 20 patients (54.1%). In addition, 16 participants (43.2%) were diagnosed with TB due to the presence of granulomatous inflammation on fine-needle aspiration (FNA) cytology.

Baseline characteristics are highlighted in the table. Participants who received empirical anti-tubercular therapy had a longer duration of symptoms (9 months vs. 5 months; P<0.001) and also had a higher incidence of advanced stage disease (86.5% vs. 60.9%; P-0.002). Patients who received empirical anti-tubercular therapy also had lower serum albumin levels (3.35 vs. 3.84 g/L; P=0.014). Fewer participants received Adriamycin, Bleomycin, Vinblastine and Dacarbazine as initial therapy among those who received empirical anti-tubercular therapy (86.1% vs. 96%; P=0.013). This possibly contributed to the poor performance status and low albumin levels among those who received empirical anti-tubercular therapy, which required 1-2 cycles of ‘pre-phase’ kind of therapy. In addition, two participants had clinical jaundice and anti-tubercular therapy-induced hepatitis at presentation, which necessitated alternate regimens initially. Complete response rates (68.8% vs. 74.8%; P=0.469) and overall response rates (78.2% vs. 81.3%, P=0.797) were comparable between the two groups. The median follow up for the entire cohort was 29 months [Interquartile range (IQR) 16-54 months]. There was no difference in the event-free survival (P=0.67) and overall survival (P=0.56) among participants who did and did not receive empirical anti-tubercular therapy in this study.

More than 10 per cent of the participants in our study group received empirical anti-tubercular therapy before their diagnosis of Hodgkin lymphoma, which led to a longer duration of symptoms prior to therapy initiation, a higher stage of disease, lower serum albumin, and a lower proportion of patients receiving adriamycin, bleomycin, vinblastine and dacarbazine as first-line therapy. Encouragingly, despite these factors, there was no difference in response rates to chemotherapy and survival among those who did and did not receive empirical anti-tubercular therapy in this study.

Inaccurate and overzealous use of anti-tubercular therapy in individuals with lymphadenopathy is a common, yet under-reported issue in countries where tuberculosis is endemic. In a recent multi-center study from India, almost 30 per cent of children with Hodgkin Lymphoma initially received anti-tubercular therapy⁵. Similar to this study, they also found children who received empirical anti-tubercular therapy to have higher stage disease, but equivalent outcomes in terms of event-free survival and overall survival. Similarly, studies from Africa suggest that 10-90 per cent of patients received empirical anti-tubercular therapy before a lymphoma diagnosis is established^11,12. Forty-three per cent of participants in the present study who received empirical anti-tubercular therapy underwent a fine needle aspiration study, which revealed granulomatous inflammation. Hodgkin Lymphoma may be associated with a marked granulomatous reaction without necrosis, which can mimic tuberculosis, especially if immuno-histochemistry (IHC) is not done^13,14. This issue may be circumvented by using immunohistochemistry stains where the resources are available, or by performing a core biopsy¹⁵.

The encouraging aspect of the present study is that the participants who received empirical anti-tubercular therapy still had comparable outcomes in terms of response rates and overall survival. Many of them received a pre-phase kind of therapy before definitive chemotherapy was given, which may have helped improve their performance status and overall outcome. Additionally, with improvements in supportive care, most patients can be salvaged to have good outcomes.

Our study did have some limitations. It was retrospective in nature, and as such, many details may not have been noted in the case record sheet, and relevant information may not have been captured for all patients. Additionally, the number of patients who were misdiagnosed as tuberculosis and continued to take anti-tubercular therapy and never made it to a hospital to get their definitive diagnosis and therapy for lymphoma could not be quantified. Hence, the actual number of patients with lymphoma who received empirical anti-tubercular therapy, and their outcomes, is hard to ascertain.

Overall, this study highlights a significant health problem in India, which is also seen in many low- and middle- income countries where tuberculosis is endemic. These findings underscore the need for improved diagnostic algorithms and access to biopsy for accurate diagnosis of lymphoma in tuberculosis-endemic regions.