Refractory/Relapsed Classic Hodgkin Lymphoma Mimicking Disseminated Tuberculosis

Abstract

Background/Objectives: Classic Hodgkin lymphoma (cHL) is a predominantly curable B-cell malignancy. However, primary refractory and relapsed (R/R) cHL remain therapeutic challenges, especially in regions with high tuberculosis (TB) prevalence, where clinical and radiologic features overlap and can obscure the correct diagnosis. This article, presenting a case of R/R cHL mimicking disseminated TB, reviews the evolving paradigm in R/R cHL management. Methods: A 30-year-old Middle Eastern male with advanced nodular sclerosis cHL initially achieved a complete remission (CR) with escalated BEACOPP chemotherapy. Shortly afterward, he developed respiratory symptoms and diffuse miliary pulmonary nodules, highly suggestive of disseminated TB. Despite extensive negative TB workup, including QuantiFERON-TB Gold testing, sputum acid-fast bacilli (AFB) staining, and PCR, his imaging raised concern for recurrent cHL. Due to the small size and diffuse distribution of nodules, biopsy was unfeasible, prompting empiric salvage therapy with DEHAP-Carbo, brentuximab vedotin (BV), and nivolumab. Results: The rapid and robust metabolic response on PET/CT supported lymphoma relapse rather than TB. Following four cycles of this combined regimen, he proceeded to autologous stem cell transplantation and achieved a second CR. Conclusions: This case highlights the diagnostic difficulties in differentiating cHL relapse from TB in endemic regions, emphasizes the critical role of PET/CT in guiding therapy when histopathological confirmation is impractical, and illustrates the impact of novel immunotherapies in improving outcomes. By underscoring the importance of early diagnostic suspicion and multimodal assessment, this article also reviews the evolving paradigm in R/R cHL management, where personalized approaches and targeted agents increasingly complement or replace traditional chemotherapy regimens.

1. Introduction

Hodgkin lymphoma (HL) accounts for approximately 10% of all lymphomas and 0.5% of global cancer diagnoses annually, ranking as the 26th most common malignancy worldwide. It primarily affects individuals aged 25–35 and those over 60, with a slight male predominance, except for nodular sclerosis cHL (NSCHL), which is more common in females. cHL is defined by CD30+/CD15+ Hodgkin Reed-Sternberg (HRS) cells, which, despite comprising <5% of the tumor mass, drive an immunosuppressive tumor microenvironment. The global incidence of HL was 0.98 per 100,000 in 2020, with rising trends particularly among females, younger individuals, and populations from Asian countries, highlighting the need for further epidemiologic investigations [1,2,3]. Lymphoma is often misdiagnosed as TB, especially in smear-negative cases, owing to their overlapping symptoms, leading to delays in treatment and potential disease progression. TB remains a major health burden in developing countries. In 2022, around 10.6 million people worldwide fell ill with TB, with the highest burden in South-East Asia, Africa, and the Western Pacific. Eight countries, including India, Indonesia, and Nigeria, accounted for over two-thirds of global cases. The TB incidence rate has risen for two consecutive years due to COVID-19-related disruptions, reversing years of progress [4,5]. The challenge is further compounded by the fact that TB can coexist with lymphoma, making diagnosis even more complex. Current TB guidelines do not clearly specify when to consider alternative diagnoses in smear-negative cases. To minimize diagnostic delays, clinicians should include lymphoma in the differential diagnosis early in the workup and prioritize definitive tests such as molecular diagnostics and histopathological examinations of biopsies [6,7,8,9].

2. Case Presentation

A 30-year-old Middle Eastern male presented with a history of refractory cHL (nodular sclerosis subtype). Patient was born in Syria to parents of Syrian origin and had received the Bacillus Calmette-Guérin (BCG) vaccine at birth, He initially noticed an enlarged left neck lymph node in November 2022, accompanied by night sweats and persistent constipation. At the time of diagnosis, his CBC showed the following results: hemoglobin (HGB) was 13.6 g/dL, white blood cell count (WBC) was 7.0 × 10⁹/L, mean corpuscular volume (MCV) was 78.0 fL, mean corpuscular hemoglobin (MCH) was 25.8 pg, and platelet count (PLT) was 301.0 × 10⁹/L. In addition, C-reactive protein (CRP) was elevated at 23.7 mg/dL, alanine aminotransferase (ALT) was 67 U/L, and aspartate aminotransferase (AST) was 36 U/L. There was no history of TB exposure or significant comorbidities.

Physical examination in November 2022 revealed a firm enlarged lymph node in the left cervical chain (approximately 2–3 cm). There were no palpable axillary or inguinal nodes at that time. He reported B symptoms, including intermittent fevers, drenching night sweats, and unintentional weight loss (around 5 kg). An excisional biopsy of the cervical lymph node was performed, confirming cHL. Histopathology showed characteristic Reed-Sternberg cells that were positive for CD30 and CD15 on immunohistochemistry, consistent with cHL. Staging investigations revealed advanced disease: a positron emission tomography/computed tomography (PET/CT) scan demonstrated widespread FDG-avid lymphadenopathy and extranodal involvement. Notably, there were bulky lymph nodes in the left neck and mediastinum, multiple pulmonary nodules up to 2–3 cm in size, and skeletal lesions in several vertebrae (e.g., T6, T12, L5) and the pelvic bones. Overall, he was staged as Stage IVB Hodgkin lymphoma due to lung and bone involvement with B symptoms. At diagnosis, the patient’s International Prognostic Score (IPS) was calculated to be 2, based on his male gender and advanced-stage (IV) disease, indicating a relatively favorable risk profile.

The patient’s treatment course and response are summarized chronologically below and illustrated in Scheme 1.

• March 2023: Initiated first-line chemotherapy with ABVD regimen (doxorubicin, bleomycin, vinblastine, dacarbazine) in accordance with the 2018 ESMO Clinical Practice Guidelines for cHL [10]. He completed 2 cycles of ABVD by March 2023. The treatment was fairly tolerated; however, an interim PET/CT in May 2023 showed a progressive disease. While many lesions regressed, there remained active disease (Deauville 5 uptake) in some sites, indicating persistent Stage IV disease. For example, residual FDG uptake was noted in cervical nodes (SUVmax~4–5, down from 6+), and new uptake appeared in certain bone lesions (T12 vertebral lesion SUV increased to 7.2). This indicated primary refractory disease with poor response to ABVD.
• May 2023: Owing to the incomplete response and progression in a spinal lesion (T12) causing back pain, the case was discussed in a multidisciplinary tumor board. Since second-line chemotherapy drugs were briefly in short supply, a decision was made to deliver localized radiotherapy (RT) to the most metabolically active bone lesions. The patient received external beam radiotherapy (EBRT) using a 3D conformal technique. A total dose of 30 Gy in 10 fractions was delivered over 10 days, targeting the T12 and L5 vertebral lesions, both of which showed persistent high FDG uptake on PET/CT. The treatment was well-tolerated, with no acute toxicities, and provided significant symptomatic relief from back pain.
• June–September 2023: Treatment was intensified to an escalated BEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) for 4 cycles. BEACOPP was chosen due to its higher efficacy in poor-risk or refractory cHL. By September 2023, a repeat PET/CT showed a partial remission. Most initial sites had become metabolically inactive, and all visceral lesions resolved. Only a single small left axillary lymph node (~15 × 10 mm) showed mildly elevated FDG uptake (SUV~7.8, Deauville score 4), suggesting a residual focus of disease. No other abnormal uptake was noted in the mediastinum, lungs, abdomen, or bones, and prior hotspots like the T12 vertebra had become hypometabolic (likely post-RT effect).
• October–November 2023: Given the PET findings of a residual active node, he received 2 additional cycles of BEACOPP (total 6 cycles). Restaging PET/CT in November 2023 confirmed complete metabolic remission, with no detectable FDG-avid disease (Deauville score 1–2 in all prior sites). He was considered to be in full remission at this point. Clinically, his lymphadenopathy and systemic symptoms had resolved. The patient transitioned to routine surveillance.
• January 2024: Two months after achieving remission, the patient developed new respiratory and systemic symptoms. He reported a persistent cough (initially dry, later with scant sputum), progressive dyspnea on exertion, and recurrence of drenching night sweats. There was no fever initially, but mild fever developed after a couple of weeks (temperature~38 °C). Given his recent lymphoma history, this constellation of “B symptoms” raised concern for an early relapse. However, infectious causes were also considered in the differential diagnosis, especially TB, which is endemic in the region and can cause similar pulmonary and constitutional symptoms. On examination, no obvious lymph node enlargement was noted in the periphery, and chest auscultation revealed diffuse crackles. Laboratory work-up was performed, during the evaluation for suspected relapse revealed a hemoglobin level of 11.8 g/dL, white blood cell count was 7.2 × 10³/µL, absolute neutrophil count of 4.8 × 10³/µL and lymphocyte count of 1.7 × 10³/µL. Platelet count was normal at 329 × 10³/µL. Notably, CRP was markedly elevated at 104.5 mg/L, and renal and hepatic function tests were within normal ranges. A chest X-ray was unremarkable aside from a mild interstitial pattern.
• February 2024: The patient underwent a comprehensive evaluation for potential post-remission complications. Due to the suspicion of TB, a QuantiFERON-TB Gold interferon-gamma release assay was performed, which yielded a negative result, effectively ruling out both latent and active TB infection. Additionally, sputum studies, including an acid-fast bacilli (AFB) stain and PCR testing for Mycobacterium TB also returned negative. To definitively exclude TB, a culture was performed, though it required approximately two months to return negative. Empiric broad-spectrum antibiotics did not improve his cough or fevers, making a typical bacterial pneumonia unlikely. A high-resolution CT and subsequent PET/CT scan of the chest were obtained. Imaging revealed new mediastinal and hilar lymphadenopathy with hypermetabolic activity, as well as multiple small, miliary-pattern pulmonary nodules with moderate FDG uptake (SUV ranges 4–6). These findings were highly suspicious for recurrent lymphoma. Given the short interval since remission, this represented a relapse of Hodgkin lymphoma, rather than a new infection. A biopsy of the mediastinal lymph nodes was considered; however, after consulting multiple interventional radiologists, it was deemed inaccessible due to the small size of the lymph nodes, which exhibited a miliary pattern. Given the patient’s medical history and the urgency of initiating treatment, the clinical team opted to proceed with salvage therapy for relapsed Hodgkin lymphoma.
• March–July 2024 (Salvage Therapy): The patient was initiated on salvage chemotherapy for R/R cHL using the DEHAP-Carbo regimen (dexamethasone, cytarabine, cisplatin or carboplatin) according to the ESMO guidelines [10], combined with the novel agents nivolumab (a PD-1 checkpoint inhibitor) and brentuximab vedotin (BV; an anti-CD30 antibody–drug conjugate). The goal was to achieve a deep remission prior to autologous stem cell transplantation. After completing two cycles, a PET/CT in May 2024 demonstrated a marked metabolic response, with nearly all lesions becoming PET-negative except for one area with minimal residual uptake (Deauville score 5, SUV~4.5). Based on this result, the transplant committee recommended an additional two cycles of BV and nivolumab to further deepen the remission. The patient completed all four cycles between April and July 2024, and a follow-up PET/CT on 1 August 2024, confirmed a second CR, with no abnormal FDG uptake.
  During treatment, the patient experienced several adverse events. Most notably, he had a generalized tonic–clonic seizure following the second cycle. A contrast-enhanced brain MRI ruled out central nervous system involvement or metastatic disease, and the seizure was attributed to chemotherapy-induced neurotoxicity. He was started on antiepileptic medication, with no recurrence reported. Other toxicities included gastrointestinal disturbances (alternating constipation and diarrhea, abdominal pain, nausea, vomiting), febrile episodes, diffuse musculoskeletal pain, peripheral neuropathy, fatigue, alopecia, somnolence, and easy bruising. These were managed symptomatically throughout the treatment course.
• August 2024: The case was presented to the institutional Bone Marrow Transplant Committee. Given his young age and second remission status, the consensus was to proceed with high-dose therapy and autologous bone marrow transplant (BMT) (autologous hematopoietic stem cell transplantation) as consolidation. On 24 August 2024, the patient was admitted for transplant. The patient underwent stem cell mobilization from 23 August to 26 using filgrastim (a recombinant human G-CSF; 300 mcg/0.5 mL) at a dose of 4 ampoules per day, followed by peripheral blood stem cell collection on 27 and 28 August, the patient underwent high-dose chemotherapy CEM (melphalan, etoposide, carboplatin) and subsequent reinfusion of his previously harvested stem cells. The transplant course was uneventful apart from expected neutropenia; there were no major infections or organ toxicities. He engrafted successfully and was discharged in early October 2024. At discharge, given his history of rapid relapse, a post-transplant PET/CT scan was performed immediately after discharge, which confirmed a complete metabolic remission (CMR), supporting a favorable initial response. The initial plan was to initiate maintenance therapy with BV and nivolumab for 12 months to reduce the risk of recurrence. However, due to the high cost of BV, which the patient could not afford, the decision was made to proceed with nivolumab monotherapy at a dose of 100 mg every 4 weeks for 12 months as a maintenance strategy.

As of the last follow-up post-transplant (January 2025), the patient remained in remission clinically and radiologically. Plans were made for close surveillance and maintenance therapy with nivolumab. This case highlights an unusually aggressive disease course with an early relapse that initially mimicked an infectious process.

3. Discussion

Classic HL and TB share many clinical features, such as fever, weight loss, night sweats, cough, and lymphadenopathy, often leading to diagnostic delays and misdiagnosis. The challenge is further compounded by the potential reactivation or worsening of TB due to cHL treatment with immunosuppressive therapy. Pulmonary involvement in HL is uncommon, making differentiation from TB particularly difficult. Both diseases can present with similar radiological and clinical findings [9,11,12]. While biopsy remains the gold standard for differentiation, in some cases, like the case we are presenting, obtaining a biopsy for definitive diagnosis may be challenging. This article presents a case of R/R cHL mimicking disseminated TB. The case is the basis of a review of the evolving paradigm in R/R cHL management.

Case Discussion

This case highlights the diagnostic and therapeutic complexities of managing refractory cHL, particularly when relapse mimics an infectious process such as TB. The patient initially achieved complete remission following BEACOPP but later presented with respiratory symptoms and systemic “B symptoms”, raising concerns for both lymphoma recurrence and TB, which is endemic in the region. The presence of small, miliary-pattern nodules in the lungs, a hallmark finding in disseminated TB, further complicated the differentiation between the two diseases; biopsy was not feasible due to the small size and diffuse distribution of the miliary nodules, making histopathological confirmation of lymphoma not feasible (Figure 1).

Despite an extensive TB workup, including QuantiFERON-TB Gold assay, sputum AFB staining, PCR, and mycobacterial culture, all results were negative. However, given the possibility of false negatives, particularly with cultures requiring at least two months for definitive results, uncertainty remained. With the urgency of addressing a potential lymphoma relapse, a decision was made to initiate salvage chemotherapy with two cycles of DEHAP-Carbo while closely monitoring the patient’s response. Notably, his symptoms improved significantly following the initial two cycles, suggesting a lymphoma-driven process rather than an infectious one. And thus, TB was excluded, A subsequent PET/CT scan confirmed a favorable response, with a marked reduction in FDG-avid disease (Figure 2).

Encouraged by this response, the treatment strategy was adjusted to maximize remission depth before autologous stem cell transplantation (ASCT). The patient received two additional cycles of DEHAP-Carbo in combination with BV and nivolumab to put the patient in deeper remission. By the end of these four cycles, a PET/CT scan confirmed a second CR, allowing for safe progression to ASCT as consolidation therapy.

This case underscores several critical aspects of cHL management. First, the clinical and radiological overlap between HL relapse and TB can lead to diagnostic uncertainty, particularly in endemic regions. The presence of miliary nodules in our patient strongly suggested TB, yet the rapid response to lymphoma-directed therapy reinforced the diagnosis of relapsed HL. Second, when biopsy is not feasible, PET/CT remains a crucial tool for assessing disease progression and treatment response. Lastly, the integration of novel targeted therapies such as brentuximab vedotin and nivolumab played a key role in deepening remission, ultimately improving transplant outcomes. Moving forward, maintenance nivolumab therapy is planned to prolong remission, emphasizing the evolving role of immunotherapy in high-risk HL management.

4. Conclusions

The presented case underscores the complexity of distinguishing between relapsed/refractory cHL and TB, particularly in regions where TB prevalence is high and diagnostic overlap frequently leads to clinical dilemmas. The occurrence of miliary pulmonary lesions closely resembling disseminated TB emphasizes the importance of maintaining a broad differential diagnosis, even when initial laboratory assessments appear reassuring. In scenarios where tissue biopsy is unfeasible, the strategic use of PET/CT imaging becomes invaluable in guiding clinical decisions and therapy initiation. Furthermore, the notable therapeutic response observed with salvage therapy utilizing BV and nivolumab highlights the emerging role of targeted and immunotherapeutic agents in refractory cHL management. As treatment paradigms evolve, combining novel therapies with established modalities such as ASCT continues to enhance remission durability and improve patient outcomes. Clinicians should therefore adopt individualized, multimodal strategies, prioritizing early consideration of malignancy recurrence in ambiguous clinical presentations to mitigate delays and optimize prognosis.