LANGERHANS' CELL HISTIOCYTOSIS ASSOCIATED WITH HODGKIN'S DISEASE: A CASE REPORT
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1 LANGERHANS' CELL HISTIOCYTOSIS ASSOCIATED WITH HODGKIN'S DISEASE: A CASE REPORT Myung S. Shin, MD, Scott E. Buchalter, MD, and Kang-Jey Ho, MD, PhD Birmingham, Alabama A patient who developed pulmonary Langerhans' cell histiocytosis after chemotherapy for nodular sclerosing Hodgkin's disease is presented. Twenty-one cases of Langerhans' cell histiocytosis associated with Hodgkin's disease have been reported in the literature. Such in association seems to be more than fortuitous. The possibilities of a common etiological agent inducing both Hodgkin's disease and Langerhans' cell histiocytosis and of a reactive proliferation of Langerhans' cells after radiotherapy or chemotherapy for Hodgkin's disease are discussed. (J NatI Med Assoc ;86:65-69.) Key words * Langerhans' cell histiocytosis * Hodgkin's disease Langerhans' cells are the antigen-presenting histiocytes bearing HLA-D/DR antigens, possessing Fc receptors, and residing in the skin, the mucosa of certain organs, and lymphoid tissue. Abnormal proliferation of such cells covers a spectrum of rare disorders, collectively called histiocytosis X or, more properly, Langerhans' cell histiocytosis. 1-4 Such disorders include Letterer-Siwe disease, Hand-Schuller-Christian disease, and eosinophilic granuloma, corresponding, respectively, to acute disseminated, multifocal, and unifocal variants of Langerhans' cell histiocytosis.1-3 Despite its From the Departments of Radiology, Medicine (Pulmonary), and Pathology, School of Medicine, University of Alabama at Birmingham, and Veterans Affairs Medical Center, Birmingham, Alabama. Requests for reprints should be addressed to Dr M.S. Shin, Dept of Radiology, University of Alabama Hospital, Birmingham, AL rare occurrence, Langerhans' cell histiocytosis has been shown to be associated with Hodgkin's disease before or after radiotherapy and chemotherapy.5-12 This article reports a patient with nodular sclerosing Hodgkin's disease treated with chemotherapy, followed by the development of pulmonary Langerhans' cell histiocytosis 9 months after the initial diagnosis of Hodgkin's disease. The literature is reviewed, and the possible relationship between Langerhans' cell histiocytosis and Hodgkin's disease is discussed. CASE REPORT Nine months before her initial hospitalization and 1 month after giving birth, a 20-year-old woman began to suffer from dry cough and easy fatigability. The pregnancy and delivery had been uneventful. She had a 14-kg weight gain during pregnancy, but a 28-kg weight loss 1 month postpartum. Three months before admission, she became.pregnant again and noticed increasing cough productive of yellow sputum and shortness of breath. Physical examination revealed left chest dullness on percussion with rhonchi and markedly diminished breath sounds. A chest radiograph showed a large, fairly homogeneous mass involving nearly the entire left hemithorax (Figure 1). Open-lung biopsy of the mass revealed nodular sclerosing Hodgkin's disease characterized histologically by thick bands of collagen fibers that were birefringent under polarized light, numerous typical and atypical Reed-Sternberg cells, and abundant lacunar cells in a background of a mixed cellularity composed of lymphocytes, plasma cells, and a few eosinophils. Further evaluation classified the disease as stage IIIB with spleen and para-aortic lymph node involvement. The patient underwent a therapeutic abortion, fol- JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 86, NO. 1 65
2 - ~ ~~~~~~~~ ~ ~~~ ~ ~ ~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~ '.... Figure 1. The initial chest radiograph of the present case taken 6 years ago revealing a large anterior mediastinal mass protruding into the left thoracic cavity with a small amount of pleural effusion. lowed by three alternating courses of mechiorethamine, vincristine, procarbazine, and prednisone/doxorubicin, bleomycin, vinbiastine, and dacarbazine (MOPP/ ABVD) chemotherapy over a period of 7 months. The chemotherapy was relatively free of complications except for one episode of deep vein thrombosis of her left lower extremity. Peripheral white blood cell counts were within normal limits. At this time, the chemotherapy was interrupted as the patient became pregnant again. Clinically, the patient had no more evidence of Hodgkin's disease. A chest radiograph showed a remarkable reduction in the size, but not total resolution, of the mediastinal mass. Two months later, the patient presented with fever and chills that were less intensive than those with which she had originally presented. A chest radiograph and computed tomography revealed diffuse reticulonodular infiltrate in both lungs (Figures 2 and 3). Pulmonary infection was suspected, but sputum cultures for bacteria and fungi were negative. Open-lung biopsy revealed fibrosis and calcification of the residual left hilar mass with no evidence of Hodgkin's disease and nodular lung lesions characterized by an interstitial proliferation of mononuclear cells with vesicular, oval, reniform or indented nuclei, small nucleoli, and abundant, often vacuolated, cytoplasm admixed with Figure 2. Chest radiograph of the same patient taken 9 months later after six courses of chemotherapy for Hodgkin's disease showing remarkable reduction in size of the mediasti. nal mass but also numerous small reticular and nodular opacities in both lungs. eosinophils, lymphocytes, and plasma cells. The diagnosis of Langerhans' cell histiocytosis was confirmed by immunohistochemical evidence of S- 100 protein positivity of the mononuclear cells and electron microscopic demonstration of the presence of intracytoplasmic Birbeck granules in these cells (Figure 4). No specific treatment for Langerhans' cell histiocytosis was given. After delivery of a healthy baby at full term, the patient received two courses of bleomycin, cyclophosphamide, vinblastine, procarbazine, and prednisone (BCVPP) chemotherapy. Follow-up chest radiography revealed shrinkage of the nodular lesions in the lungs. The residual interstitial lung disease remained unchanged for 4 years while the Hodgkin's disease remained in remission. DISCUSSION Langerhans' cells are important antigen-presenting histiocytes in the body characterized by dendritic cytoplasmic processes and the presence of large amounts of cell-surface class II HLA molecules.34 They are most numerous in the epidermis of the skin, but also exist in the mucosa of the oral cavity, stomach, and uterine cervix, and in lymphoid tissue including lymph 66 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 86, NO. 1
3 ...::...: ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.... Figure 3. CT scan of the same patient at the level of subcarina revealing numerous small nodules in both lungs. nodes, thymus, and tonsils.13 Diffuse autonomous proliferation of Langerhans' cells results in generalized histiocytosis or Letterer-Siwe syndrome, usually in patients younger than 3 years of age.'3 This is considered to be a neoplastic transformation of the Langerhans' cells. Localized or multifocal proliferation of Langerhans' cells, on the other hand, is a reactive or hypersensitivity process that runs, as a general rule, a rather benign course. Most patients experience spontaneous remission with or without residual fibrous scarring.1'3 It is such a benign variant of Langerhans' cell histiocytosis that is associated with Hodgkin's disease. The pulmionary Langerhans' cell histiocytosis in the patient described here is such an example that underwent spontaneous remission with residual interstitial pulmonary fibrosis. To date, a total of 21 cases of Langerhans' cell histiocytosis associated with Hodgkin's disease have been reported in the literature.5'13 From the time course of their appearance they can be divided into three groups: I. Hodgkin's disease and Langerhans' cell histiocytosis coexisted in the same lymph nodes at the time of diagnosis in 14 cases LangTerhans' cell histiocytosis appeared after radiotherapy and chemotherapy for Hodgkin's disease in seven cases, including our patient.8-9' Langerhans' cell histiocytosis preceded the development of Hodgkin's disease in one case: Among those patients with known described histopathology of the original Hodgkin's disease, 12 were diaganosed as nodular sclerosis and 3 as mixed cellularity.8'12 Nodular sclerosis seems to be the most Figure 4. Ultrastructure of the lung lesion showing a Langerhans' cell containing numerous Birbeck granules (arrows) (original magnification x ). Inset: Higher magnification (x ) of the Birbeck granule (solid arrow) and membrane-bound disk-like lamellar bodies (open arrows). common subclass of Hodgkin's disease that is associated with Langerhans' cell histiocytosis. The anatomical distribution of such Langerhans' cell histiocytosis varied from patient to patient. The disease was limited to lymph nodes in 14 cases, to lungs in 5 cases, to gingiva and mandible, to lungs and rib, and to bone, lungs, lymph nodes, and brain in 1 case each.5'3 Because of the small number of cases, it is unclear whether such an association of Langerhans' cell histiocytosis with Hodgkin's disease is statistically significant or fortuitous. Barnes et all' and Colby et al'4 found two cases of Langerhans' cell histiocytosis among 659 patients with Hodgkin's disease yielding a 0.3% chance of such association. Because the development of pulmonary Langerhans' cell histiocytosis might masquerade as an infectious or a neoplastic process and the lesions usually resolved spontaneously or after treatment, it is conceivable that the true frequency of the association of Langerhans' cell JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 86, NO. 1 67
4 Neoplastic transformation of monocytes Etiological agent (?) Non-neoplastic reactive proliferation of Langerhans cells Hodgkin's Langerhans disease cell histiocytosis Radiotherapy and/or chemotherapy Figure 5. Diagram outlining the possible relationship between Hodgkin's disease and Langerhans' cell histiocytosis. histiocytosis with Hodgkin's disease could be much higher. In view of the rare occurrence of Langerhans' cell histiocytosis, particularly after adolescence," 3 such an association seems to be more than incidental. There are several possible relationships between Hodgkin's disease and Langerhans' cell histiocytosis as discussed below: * Hodgkin's disease induces Langerhans' cell histiocytosis. This is unlikely because Langerhans' cell histiocytosis may precede the development of Hodgkin's disease. Frederiksen and Thommeson5 reported a patient with Langerhans' cell histiocytosis involving the mandible and gingiva who developed cervical lymphadenopathy 1 year later, which on biopsy revealed Hodgkin's disease. * Radiotherapy and/or chemotherapy for Hodgkin's disease leads to the development of Langerhans' cell histiocytosis (Figure 5). This is a distinct possibility, but, at the most, it can apply to only one third of the cases (7 of 22 cases). Langerhans' cells are rarely found in normal lung tissue, but increase in number in hypersensitivity pneumonitis or fibrotic lung disorder.'5 Therefore, radiotherapy to the chest and systemic chemotherapy might cause lung injury with subsequent activation and proliferation of the Langerhans' cells. * Langerhans' cell histiocytosis may represent a specific cell-mediated immune response to Hodgkin's disease. This is supported by the following evidence: coexistence of Langerhans' cell histiocytosis with Hodgkin's disease in the same lymph node prior to radiotherapy and chemotherapy, their close topographic association, and remission of Langerhans' cell histiocytosis following the remission of Hodgkin's disease.'2 However, the facts that the incidence of such coexistence is quite low (0.3%),10,14 and that Hodgkin's disease itself already represents a tissue response to Reed-Sternberg cells do not favor such a notion. * A common etiological agent induces both Hodgkin's disease and Langerhans' cell histiocytosis (Figure 5). Current evidence favors the view that the malignant cells of Hodgkin's disease are of monocytic origin.'6 Although weakly or not at all phagocytic, Langerhans' cells also belong to the monocyte-histiocyte group.'5 These two types of cells all possess Fc receptors, bear HLA-D/DR antigens, and are capable of processing and presenting antigens to immunocompetent T-cells. Furthermore, patients with Hodgkin's disease or with Langerhans' cell histiocytosis all have immunological derangement, particularly suppressor T-cell abnormality.9'17 It has been reported that T-cells in patients with Langerhans' cell histiocytosis lack histamine H2 surface receptors, which can be corrected successfully with thymic extract.17 Epidemiologic studies have suggested that an infectious agent may be responsible for Hodgkin's disease, and virus-like particles have been found in the cells derived from Hodgkin's tissue.'8 Therefore, it is possible that a common etiological agent might induce both Hodgkin's disease and Langerhans' cell histiocytosis in the same patients. SUMMARY The association of Langerhans' cell histiocytosis with Hodgkin's disease seems to be more than incidental. Such an association might be due to either a common etiological agent that induces both diseases or Langerhans' cell proliferation caused by tissue damage secondary to radiotherapy and chemotherapy for Hodgkin's disease. The awareness of such an association could prevent unnecessary therapy for Langerhans' cell histiocytosis. Literature Cited 1. Favara BE, McCarthy RC, Mierau GW. Histiocytosis X. Hum Pathol ;1 4: Elema JD, Atmosoerodjo-Briggs JE. Langerhans cells and macrophages in eosinophilic granuloma. An enzymehistochemical, enzyme-cytochemical, and ultrastructural study. Cancer 1984;54: Komp DM. Langerhans' cell histiocytosis. N Engl J Med ;31 6: Johnston RG Jr. Monocytes and macrophages. N Engl J Med. 1988;318: Frederiksen P, Thommesen P. Histiocytosis X, III: clinical value of serial biopsies. Acta Radiol Oncol. 1978; 1 7: Williams JW, Dorfman RF. Lymphadenopathy as the initial manifestation of histiocytosis X. Am J Surg Pathol ;3: JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 86, NO. 1
5 7. Kjeldsberg CR, Kim H. Eosinophilic granuloma as an incidental finding in malignant lymphoma. Arch Pathol Lab Med. 1980;1 04: L'Hoste RJ Jr, Arrowsmith WR, Leonard GL, McGaw H. Eosinophilic granuloma occurring in a patient with Hodgkin's disease. Hum Pathol. 1982;1 3: Sajjad SM, Luna MA. Primary pulmonary histiocytosis X in two patients with Hodgkin's disease. Thorax. 1982;37: Barnes BF, Colby TV, Dorfman RF. Langerhans' cell granulomatosis (histiocytosis X) associated with malignant lymphomas. Am J Surg Pathol. 1983;7: Lyon JM, Pezzimenti J, Kranwinkel RN. The development of histiocytosis X in patients with Hodgkin's lymphoma. Conn Med. 1985;49: Neumann MP, Frizzera G. The coexistence of Langerhans' cell granulomatosis and malignant lymphoma may take different forms: report of seven cases with a review of the literature. Hum Pathol. 1986;1 7: Shanley DJ, Lerud KS, Luetkehans TJ. Development of pulmonary histiocytosis X after chemotherapy for Hodgkin's disease. AJR Am J Roentgenol. 1990;1 55: Colby TV, Hoppe RT, Warnke RA. Hodgkin's disease: a clinicopathologic study of 659 cases. Cancer 1981;49: Kawanami 0, Basset F, Ferrans VJ, Soler P, Crystal RG. Pulmonary Langerhans' cells in patients with fibrotic lung disorders. Lab Invest. 1981;44: Payne SU, Wright DH, Jones KJM, Judd MA. Macrophage origin of Reed-Sternberg cells: an immunohistochemical study. J Clin Pathol ;35: Osband ME, Lipton JM, Lavin P. Histiocytosis X: demonstration of abnormal immunity, T-cell histamine H2- receptor deficiency, and successful treatment with thymic extract. N Engl J Med. 1981;304: Vianna NJ, Polan AK. Epidemiologic evidence for transmission of Hodgkin's disease. N Engl J Med ;289: CARE plants the most wonderful seeds on earth. _ WP:..=- Seeds of self-sufficiency that help starving people become healthy, productive people. And we do it village by village by village. Please help us turn cries for help into the laughter of hope.
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