Simultaneous occurrence of Hodgkin disease and tuberculosis: report of three cases.

Abstract: Tuberculosis (TB) has been described in association with malignancies including Hodgkin disease (HD). We report three cases of simultaneous occurrence of TB and HD. In two of these cases clinical symptoms improved after TB treatment was instituted and before HD was diagnosed. Fever recurrence in one case and persistence of mediastinal lymphadenopathy in the other, however, prompted consideration of an additional diagnosis. Interestingly, in one these two patients, both TB and HD diagnosis were obtained from the same lymph node. Since both diseases share many symptoms and signs, physicians faced with initial therapeutic failure when caring for HD and TB patients should be aware of the possibility of the simultaneous occurrence of both diseases.

Key Words: Hodgkin disease, immunohistochemistry, lymph nodes, tuberculosis

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Tuberculosis (TB) has been extensively described in association with various malignancies, especially Hodgkin disease (HD). This association is known to occur at rates that are almost always greater than those encountered in the general population. (1-3) The overlap of symptoms of TB and HD may lead to misdiagnosis, causing the late recognition of either one of these diseases. Furthermore, the introduction of immunosuppressive chemotherapy together with the immunologic changes already present in patients with HD may worsen the clinical course of TB, should this disease not be promptly recognized and adequately treated. We report here three instances of simultaneous HD and TB infection, all three occuring within a period of six months in the city of Sao Paulo, the largest Brazilian metropolitan area.

Case Reports

Patient 1

A human immunodeficiency virus (HIV)-negative 41-year-old male presented with a 3 cm right cervical anterior lymph node without fever, loss of weight, sweating, cough, pain, or any other constitutional symptoms. The physical examination was otherwise normal as were his laboratory tests. A chest radiograph showed an apical cavitated lesion in the right upper lobe, which was confirmed by chest computed tomographic (CT) scan. A videothoracoscopy with lung and lymph node biopsies was then performed. A stain for acid-fast bacilli was positive in the lung biopsy specimen, and after culture was confirmed as Mycobacterium tuberculosis. The cultures from the cervical lymph node specimen were negative. Conventional microscopy and immunohistochemical examination of the lymph node biopsy showed Hodgkin disease, mixed cellularity type. The patient was then started on rifampin, isoniazid, and pyrazinamide (RIP) and sent to our care. He was staged as Ann Arbor IA and underwent three cycles of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD), followed by radiotherapy using an "involved field" technique. Treatment for both diseases was completed successfully without any major toxicity, and the patient is in remission 11 months after both diseases were diagnosed.

Patient 2

A 40-year-old HIV-negative female physician was first evaluated with a 1-month history of right axillary lymph node enlargement (8 cm) associated with daily fever with no other symptoms. There were no other abnormalities on physical examination. Thorax CT scan showed upper mediastinal lymph node enlargement. A fine-needle aspiration of axillary lymph node was performed and subjected to cultures that returned positive for M tuberculosis. After two months on RIP regimen the fever disappeared, the axillary lymph node regressed 90% in size, but the mediastinal lymph nodes did not decrease in size. The patient was then sent to our care. A mediastinoscopy with lymph node biopsy was performed and showed Hodgkin disease, nodular sclerosis type. The patient was staged as Ann Arbor IA and underwent three cycles of ABVD followed by radiotherapy using an "involved field" technique. Treatment for both diseases was completed and complicated only by a mild actinic pneumonitis that resolved spontaneously. The patient is in remission 10 months after the diagnosis of HD.

Patient 3

A 49-year-old HIV-negative male patient was admitted with poor appetite and a loss of 20 kg in the previous 18 months associated with daily fever for the month prior to admission. Physical examination showed hepatomegaly, splenomegaly, lymph node enlargement bilaterally in the neck and supraclavicular area as well as in the left axillary and right inguinal chains. Abdominal and thoracic CT scans showed hepatomegaly, splenomegaly, and intra-abdominal lymph nodes up to 2 cm in size. A surgical biopsy of the inguinal lymph node was performed and stained positively for acid-fast bacilli, later confirmed by culture as M tuberculosis. The patient was discharged on RIP regimen and remained without fever for 1 week. Twelve days after discharge he was readmitted with relapse of fever. By that time the conventional microscopy and immunohistochemical examination of the lymph node came back showing HD, nodular sclerosis type. The patient was staged as Ann Arbor IVB because he had a positive bone marrow biopsy for HD. As of this writing he is receiving treatment with ABVD (8 cycles planed) 5 months after the diagnosis of HD. The fever disappeared completely following the second day of chemotherapy.

Discussion

The difficulty of performing a differential diagnosis between HD and TB is illustrated by Fox's (4) review in 1926 of the pathologic samples from the six initial cases described by Thomas Hodgkin, (5) which in one case revealed TB and no evidence of HD. After almost two centuries, and now with modern diagnostic technologies, the differential diagnosis between TB and HD still remains a challenge, as was evident from two of the cases described here, in which HD was not promptly diagnosed. (2) This difficulty in differentiating between HD and TB is in large part due to the common symptoms and signs shared by both disorders, which include fever, weight loss, night sweats, cough, hepatosplenomegaly, and enlarged lymph nodes. As a result, misdiagnosis and/or a delayed diagnosis of either TB or HD may occur.

As we could see in all three cases here presented, TB and HD may occur simultaneously. In fact, in a large series from a comprehensive cancer hospital, Kaplan et al (1) reported 201 patients with malignancies complicated by TB. In this report, the greater risk of TB reactivation occurred in the HD patients (96/10,000 patients) when compared with other malignancies. Melero et al, (3) reporting six cases of TB in lymphoma patients (5 HD patients), also described a higher occurrence of TB in these patients when compared with the general population.

Interestingly, the immunologic changes that usually accompany HD are believed to be a predisposing factor for TB. The mechanisms of susceptibility for TB in HD patients are, however, not completely known, but a complex cellular immunodeficiency has been attributed to HD. This deficiency may be grossly explained by a TH2 cellular response leading to high levels of IL5 and IL10, and is characterized by delay of response in hypersensitivity skin tests, increased production of polyclonal antibodies, higher levels of circulating immunocomplexes, increased counts of circulating eosinophils, decreased activity of NK cells, and high levels of IL2. (6)

In the present report, except for occupation in one patient (a physician), HD appears to be the only predisposing factor for TB. All of the patients tested negative for HIV, none of them had either a previous documented episode of TB, known contact with TB patients (except for the physician), lived in highly crowded habitations, or had any immunodeficiency, a personal history of alcoholism or any kind of chronic infection. In all three cases here presented, both diseases were diagnosed simultaneously and in one of our patients, both TB and HD diagnoses were based on the same pathologic sample, although the final diagnosis of both diseases was not done at the same time. In two of our cases it was possible to observe an initially positive clinical response to TB treatment, but with recurrence of fever in one and a persistence of radiological abnormalities in the other case, which completely resolved only after starting polychemotherapy for HD.

A formal epidemiologic evaluation was not the goal of this report and was not possible, but it can be speculated that there is a relatively higher occurrence of TB in HD patients in Brazil, as has already been described in Argentina and the United States. (1,3) This concomitance might be even more frequent in Brazil when compared with northern countries due to a relatively higher occurrence of TB in our population. (7) We conclude that physicians taking care of TB or HD patients should be aware of the potential for association between both diseases, and the possibility of concomitance must be entertained, particularly in cases of a relapse following initial progress, or an unusual delay in radiological response to TB treatment.

The life of every man is a diary in which he means to write one story
and writes another; and his humblest hour is when he compares the volume
as it is with what he vowed to make it.
--James M. Barrie

Accepted January 8, 2004.

Copyright [c] 2004 by The Southern Medical Association

0038-4348/04/9707-0696

References

1. Kaplan MH, Armstrong D, Rosen P. Tuberculosis complicating neoplastic disease-a review of 201 cases. Cancer 1974;33:850-858.

2. Pitlik SD, Fainstein V, Bodey GP. Tuberculosis mimicking cancer-a reminder. Am J Med 1984;76:822-825.

3. Melero M, Gennaro O, Dominguez C, et al. Tuberculosis en pacientes con linfomas. Medicina (Buenos Aires) 1992;52:291-295.

4. Fox X. Remarks on microscopical preparations made from some of the original tissue described by Thomas Hodgkin. Ann Med History 1926;8:370-374.

5. Hodgkin T. On some morbid appearances of the absorbent glands and spleen. Medical Chirurgical Transaction 1832;17:69-97.

6. Diehl V, Mauch PM, Harris NL. Hodgkin's Disease, in DeVita JR VT, Hellman S, Rosenberg SA (eds): Cancer Principles and Practices of Oncology. Philadelphia, Lippincott Williams & Wilkins, 2001, pp 2339-2387.

7. Ruffino-Netto A. Tuberculosis: the neglected calamity. Rev Soc Bras Med Trop 2002;35:51-58.

RELATED ARTICLE: Key Points

* The association of Hodgkin disease and tuberculosis is not uncommon.

* Comprehensive histologic evaluation, including immunohistochemical techniques, of the lymph nodes of patients presenting with fever and adenopathy is advised.

* In patients undergoing treatment for tuberculosis, persistence of lymph node enlargement or fever despite adequate therapy may indicate underlying lymphoma.

Luciano JM Costa, MD, Christina T. Gallafrio, MD, Francisco OS Franca, MD, and Auro del Giglio, MD, FACP 

From the Division of Medical Oncology, University of Colorado Health Sciences Center, Denver, CO, the Division of Infectious Disease, University of Sao Paulo, and the Department of Hematology and Medical Oncology, ABC Foundation School of Medicine, Sao Paulo, Brazil.

This work was done at the Division of Infectious Disease, University of Sao Paulo School of Medicine and Department of Hematology and Medical Oncology, ABC Foundation, School of Medicine.

Reprint requests to Luciano Jose Megale Costa, MD, 6780 E Cedar Ave, Apt 308, Denver, CO, 80224.