Correspondence 2057 Discussion and possibly direct cytotoxicity effect by free radical-mediated oxidative DNA damage.5,7,8 Most of thalidomide side effects Histiocytic sarcoma is a very rare malignant proliferation and such as drowsiness, weakness, dizziness, tingling, numbness or its definition remains controversial.1 The International Lympho- skin rash, appear dose related, and only 10–30% of patients ma Study Group published recently a classification.2 According must discontinue the treatment because of side effects. Neuro- to this classification, our patient presented histiocytic sarcoma pathy is observed more frequently in women and older patients. defined by CD68 þ and CD1aÀ. Owing to systemic involve- In this case, after almost 3 years of thalidomide use, the boy is ment, the diagnosis was consistent with ‘malignant hystiocyto- well without severe side effects. Nevertheless, complete sis’. Interestingly, of the 18 cases of granulocytic sarcoma remission has not been obtained and several bone sites of reported by Pileri, three had systemic presentation of the disease disease remain stable. Different therapeutic questions remain to and two of whom previously presented acute lymphoblastic be discussed: how long thalidomide must be continued? What or myelodysplasia. Most histiocytic sarcomas are kind of positive effect is expected? Is the patient now able to treated as high-grade non-Hodgkin’s but the prog- receive aggressive in order to cure THL and if so, nosis seems very poor.1,3 The pathogenesis of the histiocytic what kind of chemotherapy? sarcomas is not well understood. In the case reported here, the This case report confirms the rare but possible development of etiologic role of the previous ALL and transplantation, or the high histiocytic sarcoma after a lymphoblastic neoplasm and shows immunosuppression level using novel drug as MMF is unknown. the potential efficiency of thalidomide in histiocytic cell The EBV genome was expressed neither by blood cells or by proliferation and its good tolerance in a single child. tumor cells. The patient presented a 100% donor chimerism in 1 1 blood but the exact tumor origin, donor or recipient, remains JH Dalle Unite´ Prote´ge´eA,Hoˆpital Jeanne de Flandre, P Leblond1 Lille, France; unknown. Three other cases of histiocytic sarcoma following 2 A Decouvelaere2 Service d’Anatomie Pathologique, therapy for lymphoblastic neoplasms were published in one I Yakoub-Agha3 Hoˆpital Calmette, Lille, France; adult and two children. Neither had been transplanted before the 4 3Unite´ de Greffes Me´dullaires, Service de 4 C Preudhomme diagnosis of histiocytic sarcoma. Nevertheless, the histiocytic B Nelken1 Maladie du Sang, Hoˆpital Claude Huriez, sarcoma observation is too rare to conclude about the role of 1 Lille, France; F Mazingue 4 previous hematological malignancy, transplantation or intensive Laboratoire d’he´matologie, Hoˆpital Calmette, Lille, France immunosuppression on its pathogenesis. All three patients reported by Soslow received intensive References chemotherapy as histiocytic sarcoma treatment and two were alive with disease at the time of last follow-up. The very 1 Elghetany MT. True histiocytic : is it an entity? Leukemia precarious clinical status of our patient at the time of histiocytic 1997; 11: 762–764. sarcoma diagnosis associated with the relative recent bone 2 Pileri SA, Grogan TM, Harris NL, Banks P, Campo E, Chan JK et al. marrow transplantation (9 months) did not permit the use of Tumours of histiocytes and accessory dendritic cells: an immuno- aggressive chemotherapy. Even vinblastine has not been histochemical approach to classification from the International tolerated more than a few weeks. After DLI failed, we did a Lymphoma Study Group based on 61 cases. Histopathology 2002; trial of thalidomide therapy. Although thalidomide was with- 41: 1–29. 3 Ralfkiaer E, Delsol G, O’Connor NT, Brandtzaeg P, Brousset P, drawn in the early 1960s because of its severe teratogenic Vejlsgaard GL et al. Malignant lymphomas of true histiocytic effects, it is being used again for the past few years to treat a origin. A clinical, histological, immunophenotypic and genotypic variety of diseases such as inflammatory disease (as Crohn’s study. J Pathol 1990; 160: 9–17. disease or Behcet’s syndrome) in addition to a variety of cancers, 4 Soslow RA, Davis RE, Warnke RA, Cleary ML, Kamel OW. True such as colon cancer and glioma and, in , multiple histiocytic lymphoma following therapy for lymphoblastic neo- myeloma as reported by Rajkumar et al.5 In hematology, plasms. Blood 1996; 87: 5207–5212. 5 Rajkumar SV, Dispenzieri A, Fonseca R, Lacy MQ, Geyer S, Lust JA thalidomide is also used for severe, extensive and refractory et al. Thalidomide for previously untreated indolent or smoldering cutaneous chronic GVHD that resemble sclerodermia. A recent multiple myeloma. Leukemia 2001; 15: 1274–1276. review reported the use of thalidomide in pediatric patients and 6 Bessmertny O, Pham T. Thalidomide use in pediatric patients. Ann concluded that ‘it should be used as a last resort when all other Pharmacother 2002; 36: 521–525. therapies fail’.6 Thalidomide presents different potential me- 7 Baidas S, Tfayli A, Bhargava P. Thalidomide: an old drug with new chanisms of antitumoral activity: angiogenic properties by clinical applications. Cancer Invest 2002; 20: 835–848. 8 Gupta D, Treon SP, Shima Y, Hideshima T, Podar K, Tai YT et al. vascular endothelial growth factor and basic fibroblast growth Adherence of multiple myeloma cells to stromal factor inhibition, regulation (inhibition of TNF-a cells upregulates vascular endothelial growth factor secretion: production, stimulation of IL-2 production), apoptosis induction therapeutic applications. Leukemia 2001; 15: 1950–1961.

Hairy cell leukemia and : a case report and review of the literature

Leukemia (2003) 17, 2057–2059. doi:10.1038/sj.leu.2403074 with 600–800 diagnoses per year in the United States. The median age at the time of diagnosis is 52 years with a male to TO THE EDITOR female ratio of 4:1.1 Given current therapy with purine nucleoside analogues, the prognosis of HCL is favorable, with Hairy cell leukemia (HCL) is a hematologic neoplasm char- progression-free survival estimated to be 70% at 4 years.2 acterized by infiltration of the bone marrow and by Secondary malignancies have frequently been described in abnormal with prominent hair-like projections. HCL, with an estimated two-fold risk for development of solid The disorder is rare, constituting roughly 2% of adult tumors among patients treated with purine analogues.3 Received: 25 March 2003; accepted: 28 May 2003 A number of nonmalignant disorders have also been associated

Leukemia Correspondence 2058 with HCL. There are also several reports suggesting an association with systemic immunologic disorders such as scleroderma, polymyositis and various vasculitides. Among the vasculitides, represents the most frequently associated disorder, with 18 reports in the medical literature to date. It has been suggested that a common membrane antigen occurs in leukemia cells and vascular endothelium, leading to a vasculitis via a crossreacting antibody.4 Four cases of scler- oderma occurring with HCL have been previously described in the literature. A humoral or cell-mediated response initiated by leukemia cells is thought to be responsible. Alternatively, fibrosis triggered by hairy cells in the bone marrow may occur in an extramedullary distribution, mimicking the clinical symptoms of scleroderma.5 To date, two reports exist describing a concomitant diagnosis of HCL and sarcoidosis.6,7 We now Figure 1 Bronchoscopic biopsy specimen from the patient report a third case and suggest a possible association of the two demonstrating presence of noncaseating granuloma consistent with sarcoidosis. disorders. A 71-year-old patient developed tender skin nodules in the right lower extremity followed by bilateral ankle edema and then development of erythema nodosum in the left lower extremity in November 2000. A biopsy obtained 1 month later showed a noncaseating inflammatory infiltrate with multi- nucleated giant cells without evidence of caseating necrosis. A chest roentgenogram showed no . The patient underwent rheumatologic evaluation that showed a normal angiotensin converting enzyme level, a positive antinuclear antibody, and otherwise negative serologies. Bronchoscopic biopsy in February 2002 again showed noncaseating granuloma consistent with a diagnosis of sarcoidosis (Figure 1). The patient was then treated with high-dose corticosteroids although she soon developed generalized osteopenia and a pelvic fracture. In May 2002, the patient developed asymptomatic leuko- penia. Blood examination showed WBC 2.75 Â 109 with 43.4% segmented , 38.8% lymphocytes and 15.3% mono- Figure 2 Peripheral smear from the patient demonstrating cytes, hemoglobin 12.9 g/dl and 125 Â 109/l. Peripheral presence of a hairy cell (arrow). Note the presence of fine, outward smear demonstrated reduced leukocytes with atypical lympho- cytoplasmic projections. cytes displaying cytoplasmic projections (Figure 2). The bone marrow aspirate showed progressive maturation of all lineages with an M:E ratio of 0.6, erythroid preponderance with a Table 1 results myeloid left shift, and TRAP-stain positivity in numerous cells. Biopsy sections showed a variable cellularity (15–50%) with Marker Gate 1 Gate 2 several aggregates of abnormal lymphoid cells with round, central nuclei and clear cytoplasm. Immunophenotyping was CD3 70 negative for bcl-1 and bcl-6 and positive for bcl-2, CD3, CD20 CD11c 94 CD19 14 and CD68. CD25 90 Flow cytometry was performed on a peripheral blood CD103 90 specimen with gating for cells of lymphoid origin (approxi- FMC7 100 mately 25% of total cells). T cells comprised 70% of the k o1 specimen and B cells 14%. Table 1 summarizes the results of l 4 flow cytometry. Gate 1 represents CD45+ cells (25% of total) and gate 2 represents Shortly after the development of osteoporosis, corticosteroid CD19+ cells (12% of total). therapy was tapered. Following the diagnosis of HCL, the patient received 1 week of intravenous chemotherapy with the (2-chlorodeoxyadenosine, 0.09 mg/ blance to hairy cell leukemia (splenic lymphoma with villous kg/day). A repeated TRAP stain on a peripheral smear in July lymphocytes, SL VL; and HCL-variant, HCL-V), but these 2002 was negative. The patient was seen in February 2003. typically lack expression of the aforementioned hairy cell Blood examination at this time showed continued remission, surface antigens.8 In two previous reports of HCL with with WBC 4.08 Â 109 with 76.5% segmented neutrophils and sarcoidosis, the diagnosis of HCL occurred 12 years following 10.8% monocytes, hemoglobin 11.8 g/dl and platelets the diagnosis of sarcoidosis,6 and in the other patient the 210 Â 109/l. diagnoses were concurrent.7 Coexpression of B-cell marker CD19 with CD11c, CD25, In the prior reports, it was hypothesized that defects in T CD103 and FMC7 as well as morphologic features on bone lymphocytes allowed for B-cell proliferation into both HCL and marrow and peripheral smear strongly suggest a diagnosis of sarcoid. In the setting of sarcoidosis, T cells participate in hairy cell leukemia arising 18 months after the diagnosis of antigen recognition and amplification of local cellular immune sarcoidosis. Two disorders in particular bear histologic resem- responses. This immune response is achieved through the

Leukemia Correspondence 2059 expression of various cytokine mediators. Recent studies appear to have a molecular basis. With further study, this demonstrate the presence of cells of T helper 1 phenotype in interplay may serve to explain the relationship between organs affected by sarcoidosis. Cells of T helper 1 phenotype numerous other lymphoproliferative and systemic immunologic produce IL-2 and IFN-g, leading to the induction of a diseases. nonspecific inflammatory response and subsequent granuloma 1 1 formation.9 Several studies also implicate the role of the same G Schiller Department of , University of J Said2 California at Los Angeles, Los Angeles, CA, USA in the development of HCL. More specifically, 2 S Pal3 Department of Pathology, University of activation of hairy cells involves expression of the autoregulated California at Los Angeles, Los Angeles, CA, USA IL-2 receptor (the CD25 surface antigen represents the a- 3Department of Medicine, University of chain).10 Thus, alteration of the cellular microenvironment by California at Los Angeles, Los Angeles, CA, USA the defective T-cells of sarcoidosis may lead to development of HCL. The presence of an as yet unexplained oligoclonal T-cell proliferation in HCL also bears resemblance to sarcoidosis. In References sarcoidosis, patients possess a wide variety of oligoclonal T-cell lines, theoretically representing responses to separate epitopes.9 1 Staines A, Cartwright RA. Hairy-cell leukemia: descriptive This scenario gives rise to the possibility that certain epitopes epidemiology and a case–control study. Br J Haematol 1993; 85: that trigger the inflammatory changes of sarcoidosis may serve 714. 2 Lauria F, Rondelli D, Zinzani PL, Bocchia M, Marotta G, Salvucci as exogenous stimuli for hairy cell activation. More likely, the M et al. Long-lasting complete remission in patients with hairy cell presence of oligoclonal T cells in both diseases supports the role leukemia treated with 2-CdA: a 5-year survey. Leukemia 1997; 11: of local cytokine mediators released in sarcoidosis in the 629–632. activation of hairy cells, as previously described. 3 Federico M, Zinzani PL, Frassoldati A, Vinceti M, Mode A, Annino Alhough not concordant with the temporal pattern described L et al. Risk of second cancer in patients with hairy cell leukemia: long-term follow-up. J Clin Oncol 2002; 20: 638–646. in one of the case studies referenced, the development of 4 Carpenter MT, West SG. Polyarteritis nodosa in hairy cell sarcoidosis as a sequela of HCL could also be considered. leukemia: treatment with -alpha. J Rheumatol 1994; 21: Several of the antigens restricted to hairy cells, such as CD11c 1150–1152. and CD103, have been associated with the activation of both 5 Blanche P, Bachmeyer C, Mikdame M, Dreyfus F, Sicard D. lymphoid and nonlymphoid cell types.8 This serves as a Scleroderma, polymyositis, and hairy cell leukemia. J Rheumatol rationale for the frequently reported association of non- 1995; 22: 1384–1385. Hodgkin’s lymphoma and HCL. Among the nonlymphoid 6 Berthiot G. Hairy-cell leukaemia and sarcoidosis. Eur J Med 1993; 2: 61. lineages activated are natural killer (NK) cells, which participate 7 Myers TJ, Granville NB, Witter BA. Hairy cell leukemia and directly in the nonspecific inflammatory response triggered by T sarcoid. Cancer 1979; 43: 1777–1781. cells.8 Thus, sarcoidosis may be induced either directly through 8 Pettitt AR, Zuzel M, Cawley JC. Hairy-cell leukaemia: biology and hairy cell antigen-mediated activation of T cells or indirectly management. Br J Haematol 1999; 106: 2–8. through promotion of the nonspecific inflammatory response. 9 Newman LS, Rose CS, Maier LA. Sarcoidosis. N Engl J Med 1997; A more concrete association of sarcoidosis and HCL will 336: 1224–1234. 10 de Totero D, Carbone A, Tazzari PL, Raspadori D, Ventura A, require examination of a larger number of patients. However, Reato G et al. Expression of the IL2 receptor alpha, beta and the interplay of these two disorders with respect to T-cell gamma chains in hairy cell leukemia. Leuk Lymphoma 1994; 14: function and subsequent cytokine-mediated responses does 27–32.

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