The Hematology Journal (2003) 4, 78–81 & 2003 The European Hematology Association All rights reserved 1466-4680/03 $25.00 www.nature.com/thj Pulmonary tuberculosis in children with Hodgkin’s lymphoma Zeynep Karakas*,1, Leyla Agaoglu1, Baki Taravari1, Ebru Saribeyoglu1, Ayper Somer2, Nermin Guler3, Aysegul Unuvar1, Sema Anak1, Isik Yalcin2 and Omer Devecioglu1 1 2 Department of Pediatrics, Division of Hematology/Oncology, Istanbul School of Medicine, Istanbul University, Istanbul, Turkey; Division of Infection/Immunology, Istanbul, Turkey; 3Division of Pneumology, Istanbul, Turkey The clinical presentation of tuberculosis (TB) and Hodgkin’s lymphoma (HL) with pulmonary involvement is similar and raises problems of differential diagnosis. It may also be difficult to distinguish TB from relapsed lymphoma. The purpose of this study was to evaluate the association of HL and pulmonary TB and to discuss differential diagnosis. Medical records of 70 children were reviewed retrospectively. A total of 27 patients (38%) had mediastinal–pulmonary involvement initially. Systemic symptoms were present in 37 (52%) patients. In all, 14 patients (20%) had pulmonary TB; three of them were diagnosed as having TB before HL, two of them had TB and HL concomittantly at initial diagnosis, seven of them during lymphoma therapy and two of them after the cessation of lymphoma treatment. PPD was positive (410 mm) only in seven patients. In all, 11 patients with pulmonary TB had diffuse pulmonary infiltrations and mediastinal enlargement at lung contrast-enhanced computed tomography and X-ray, which was difficult to differentiate from HL. Biopsies were performed in five patients. No mortality because of the infection was seen. Only one patient had been lost as relapsed-resistant HL. To evaluate mediastinal lymphadenopathies is very crucial and the differential diagnosis is difficult; hence the association between HL and the TB must be considered especially in countries where TB is highly endemic. The Hematology Journal (2003) 4, 78–81. doi:10.1038/sj.thj.6200219 Keywords: Hodgkin’s lymphoma; tuberculosis; immunocompromised patients Introduction Patients and methods Hodgkin’s lymphoma (HL) is one of the most common malignancies seen in childhood. In HL, immune deficiency is a well-described condition. Especially, cellular immune deficiency can lead to infections with intracellular pathogens (CMV, Herpes Simplex, HIV, Candida albicans, Aspergillus, Pneumocystitis carinii and Mycobacterium sp.).1 In endemic regions, pulmonary tuberculosis can precede HL. It can also be seen at HL diagnosis, during or after the treatment. The association of HL with tuberculosis (TB) makes it complicated to differentiate the diagnosis because of similarities in the clinical course, laboratory tests and imaging procedures. There are no comprehensive studies on differential diagnosis between HL and tuberculosis, except for some case reports.2–4 Medical records of 70 children with ages between 3 and 17 years, which were treated between 1988 and 2001, were reviewed retrospectively. A total of 53 (75.7%) patients were male, while 18 (24.3%) were female. According to the Ann Arbor classification, 11 patients (15.7%) had clinical stage I, 21 (30%) patients had stage II, 34 (48.5%) had stage III and 4 (5.7%) had stage IV. The most common histological subtype was the mixed type (48, 68.5%), followed by nodular sclerosing in 13 (18.5%), lymphocyte depletion in six (8.5%) and lymphocyte predominance in three (4.5%). In all, 27 patients (38%) had mediastinal and pulmonary involvement initially. Systemic symptoms were present in 37 (52%) such as fever, weight loss and night sweats. Results *Correspondence: Z Karakas, Department of Pediatric Hematology/ Oncology, Istanbul School of Medicine, Istanbul University, 34390 Capa/Istanbul, Turkey; Tel: þ 90 212 635 1189; Fax: þ 90 212 6314170, þ 90 212631 1312; E-mail: zeynepkar@hotmail.com Received 8 July 2002; accepted 30 October 2002 In all, 14 patients (20%) had pulmonary TB. Three of them were diagnosed before the diagnosis of HL, two of them had concomitant HL and TB at the time of diagnosis, seven of them developed TB during treatment, and two of them after the cessation of HL Pulmonary TB in children with HL Z Karakas et al Biopsy Biopsy+BAL Cure Cure Dead 4 5 5  + + + + + 40 48 78 + + + Hilar enlargement infiltration Infiltration Mediastinal LAP Previous Together During treatment +  + Mixed Mixed Nodular sclerosing % not available 3 1 4 10 Y 4Y 15 Y 12 13 14 F M F Biopsy Biopsy Cure Cure NA% Cure Cure Cure NA% Cure NA% Cure Cure 3 2 2 2 2 2 3 2 2 4 2 + +         + + +  +  +    + + 130 35 40 35 18 7 25 56 110 20 70     + + +   +  Bilateral infiltration Hilar enlargement Mediastinal LAP Normal Right Hilar enlargement Hilar enlargement Infiltration Hilar enlargement Hilar enlargement Right Hilar enlargement Hilar enlargement Together Previous During treatment During treatment During treatment Previous After treatment During treatment During treatment During treatment After treatment + + +   +   +  + Nodular sclerosing Mixed Mixed Nodular sclerosing Lymphocyte-depleted Mixed Lymphocyte-depleted Mixed Mixed Mixed Nodular sclerosing 3 3 3 2 3 2 3 1 3 3 1 15 Y 9Y 5Y 4Y 5Y 11 Y 7Y 4Y 6Y 4Y 11 Y 1 2 3 4 5 6 7 8 9 10 11 F M F M M M M F M F M PPD X-ray Mediastinal Hodgkin/Tbc involvement Sex Stage Pathology Age No A 4-year-old male patient was admitted to our clinic with cervical swelling and cough. The PPD was 18 mm, and the erythrocyte sedimentation rate (ESR) was 48 mm/h. A cervical lymph node biopsy revealed mixed-type HL (stage I). At the time of diagnosis, positive family history, positive PPD test, crepitation at lung bases, positive findings on chest X-ray and CT suggested pulmonary TB (Figure 1). Thorax CT showed mediastinal LAP and diffuse infiltration. The patient was discussed at our council of tumor including pediatric infectious disease, pediatric oncology subspecialists, pediatric surgeons, pediatric radiation therapists, pathologists and radiologists, and the final descision was that the radiologic pulmonary changes were because of TB infection. He started to receive chemotherapy (2 OPPA þ 2 COP) and involved field radiotherapy combined with anti-TB treatment (five drugs). After receiving 6 months of anti-TB treatment and as crepitation at the lung bases persisted, a control CT was performed, which showed marked bronchiectasis. As resistant TB was suggested because of positive family history, radiotherapy (RT) was delayed for 2 months and anti-TB treatment was continued for Table 1 Characteristics of children with Hodgkin’s lymphoma and tuberculosis Case report ESR Thorax Family Number of drugs Result Biopsy (mm/h) CT history used for Tbc treatment treatment. Cough was the most frequent symptom (7 patients, 50%), followed by fever (5 patients, 35.7%), weight loss (1 patient, 7%), night sweat (1 patient, 7%), malasia (1 patient, 7%). The history of TB was present in five (35.7%) families. In 11 (78.5%) patients, the erythrocyte sedimentation rate was found to be above 20 mm/h. The PPD test was 410 mm in 7 (50%) patients. In all, 13 (92%) patients with pulmonary TB had diffused infiltration or mediastinal enlargement on lung X-ray graphs, while only one patient (8%) had a normal lung X-ray imaging. Thoracic computed tomography (CT) imaging was performed in nine patients showing mediastinal lymphadenopathy (LAP) and/or parenchymal infiltration. Sputum culture (gastric lavage in patients who cannot give sputum) did not show any colonization of Mycobacterium tuberculosis, while two patients had acid-resistant bacteria. Bronchoalveolary lavage (BAL) was performed in one patient, which revealed acidresistant bacteria followed by biopsy to confirm the diagnosis. Five patients underwent biopsy for differential of relapsed HL and TB. Two patients were diagnosed as pulmonary TB concomitant with HL (Table 1). Eight patients diagnosed before 1990 were treated with isoniazid (INH) plus rifampin (RMP) for suspected TB infection. The remaining six patients diagnosed after 1990 received INH and RMP, supplemented during the first 2 months with pyrazinamide because of proven infection (ie family history, PPD positivity, CT changes and BAL/biopsy). No mortality was detected due to infection; only one patient had been lost due to resistant HL. The presented case demostrates the common problems associated with concomitant TB and HL. Biopsy 79 The Hematology Journal Pulmonary TB in children with HL Z Karakas et al 80 Figure 1 CT on diagnosis. another 6 months. The patient remained in remission and in the meanwhile he suffered from nonspecific pulmonary infections. After 3 years, the patient presented with lower extremity paralysis and had a spinal mass on CT. Moreover, he had mediastinal multiple LAP, bronchiectasis, peribronchial thickening and left pleural effusion was found on the thorax CT (Figure 2). Paravertebral biopsy showed relapsed HL, while thoracoscopic biopsy revealed chronic granulomatous lesions with positive acid-resistant bacteria in gastric lavage. Anti-TB treatment with five drugs combined with chemotherapy (ABVD) and spinal RT was started. After 6 months, the patient suffered from a herpes zoster infection, and the antiviral treatment was completed uneventfully. After 1 year, he came in with a productive cough and fever and he had multiple mediastinal LAPs with parenchymal infiltration, which suggested an HL relapse (Figure 3). However, differential diagnosis between relapse and TB could not be made despite positive findings in Ga-67 scintigraphy because of the high risk of TB and anti-TB treatment was initiated again. As thorax CT showed the same findings, a thoracotomy was planned. Preoperative sputum culture revealed Candida albicans and the operation was delayed while the patient received antifungal therapy (itraconazole þ fluconazole) for 1 month. After antifungal treatment, a thoracotomy was performed and the biopsy did not show lymphoma. It revealed only nongranulomatous inflammatory changes. Anti-TB treatment was continued for 1 year. He is now doing well on routine follow-ups. Discussion The purpose of this study is to evaluate the association of HL and pulmonary TB and to discuss the differential diagnostic problems. In developing countries, children can only be diagnosed with a major symptom of TB at the profound stage. Having contact with an adult who has active TB is extremely important for diagnosis. The only available laboratory test usually is an acid-fast smear of sputum, which the child rarely produces. The The Hematology Journal Figure 2 CT showing bronchiectasis. Figure 3 CT before thoracoscopy. clinical presentation is misleading as the signs and symptoms of the two diseases are similar, that is, fever, cough, weakness, night sweating and weight loss. The PPD test can be helpful in differential diagnosis, but as a result of impaired cellular immunity it can be negative even in patients with TB.5,6 The plane X-ray imaging is the first choice in visualization of the lesions, but all lesions are not visible. Thoracic CT is a more sensitive modality, but is not specific in differentiation between TB and HL.7 Despite the availability of an effective, relatively inexpensive therapy, TB remains the leading infectious disease in the world. The clinical expression of the disease is intimately connected to the immune status of the host.5 Cell-mediated immunity plays a critical role in the control of mycobacterial infections. T cells elaborate an array of cytokines capable of activating macrophage bacterial activities.8 It is this cell-mediated response to infection with Mycobacterium tuberculosis that apparently controls the spread of primary infection. Factors that compromise this cell-mediated immunity such as AIDS, therapy with corticosteroids or Pulmonary TB in children with HL Z Karakas et al 81 malignancy may permit the infection to spread and cause symptomatic disease.8 TB in compromised patients frequently becomes far advanced before it is recognized by the physician. Multiple drug therapy is always indicated.6 In our study, among nine patients in which thoracic CT was performed, the radiologic differentiation could not be made. As a result, Ga-67 scintigraphy is a more specific imaging modality. We could only perform it in one case because it is an expensive test, which did not help us for differential diagnosis. It identifies sites of epithelial and lymphoreticular tumor as well as areas of inflammation and infection. Three-dimensional single-proton emission computed tomography (SPECT) and positron emission tomography (PET) imaging might be useful, although newer techniques are not sufficient for differential diagnosis as hypermetabolic lesions are not specific for malignant tissue.9,10 Although a biopsy is an invasive procedure with higher risks, it remains the most specific and sensitive diagnostic procedure. To culture acid-fastresistant bacteria in patients who were treated for TB is usually not possible. As a result of immune suppression in patients with HL, concomitant TB risk is higher in especially endemic areas. Concomitant TB infection at the time of diagnosis can be misleading and therefore delay the diagnosis of HL.11 TB infection occurring during or after the therapy can be difficult to differentiate between resistant or relapsed disease. The differential diagnosis between HL and TB is based on information obtained from clinical and family history, physical examination, laboratory findings, PPD test and imaging study. In selected patients, BAL or biopsy should be performed. The careful use of basic diagnostic tools could prevent serious clinical errors related to TB. References 1 Lanzkowsky P. Hodgkin’s lymphoma. In: Lanzkowsky P (ed.) Manual of Pediatric Hematology and Oncology, 3rd edn. Academic Press: London, 1999, pp 413–443. 2 Melero M, Gennaro O, Dominguez C, Sanchez Avalos JC. Tuberculosis in patients with lymphomas. Medicina 1992; 52: 291–295. 3 Hormann K, Garbrecht M. 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