Leukemia (1997) 11, 762–764  1997 Stockton Press All rights reserved 0887-6924/97 $12.00

OPEN FORUM True histiocytic lymphoma: is it an entity? M Tarek Elghetany

Division of Hematopathology, Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA

Monocytes and macrophages are closely related in origin, Revised European American classification.13 Yet, THL is a structure and function. True histiocytic lymphoma is a neo- recognized entity in the classification of histiocytic dis- plasm of phagocytic histiocytes and is treated as non-Hodg- eases.1,14 Using retrospective studies, the incidence of THL kin’s lymphoma. Tissue involvement with myeloid leukemia, 15–17 including monocytic leukemia, is called extramedullary myeloid was less than 0.5% of all cases of NHL. cell tumor or granulocytic sarcoma and treated wtih antileu- A well-defined group of malignant histiocytic neoplasms is kemic chemotherapy. Differentiating true histiocytic lymphoma acute monocytic leukemia (AMoL).1,14 Acute myeloid leuke- from tissue involvement with monocytic leukemia is a rather mia (AML) including monocytic subtypes may present as impossible task using available morphologic, cytochemical, localized tumors of immature cells known as extramedullary immunocytochemical and molecular methods. The two entities need to be unified probably more appropriately as extramedul- myeloid cell tumors (EMCT) preceding or occurring during the lary myeloid cell tumor of monocytic origin, and should there- course of the disease. EMCT occurs in approximately 5% of fore be treated as such. AML patients. However the incidence is much higher in Keywords: myeloid leukemia; histiocytic lymphoma; granulocytic monocytic subtypes.18,19 Approximately 30% of EMCT at pres- sarcoma entation have normal peripheral blood counts with no leu- kemic blasts, normal bone marrow examination and no his- tory of preceding leukemia (primary EMCT).18 The most Monocytes and macrophages are part of the body defense sys- common sites for these primary EMCT are skin, lymph nodes, tem and are considered ‘professional phagocytes’.1 Their dis- soft tissues and small intestine.19 These sites are rather ident- tinctive phagocytic capability together with the absence of ical to those of THL.4 In fact, AMoL have been described as ultrastructural bodies, known as Birbeck granules, differentiate having a lymphoma-like presentation.20 New cases of myeloid them from the other members of the histiocytic group, namely leukemia in the USA are estimated at 12 800 for 1996 while Langerhans cells and dendritic cells.1 Monocytes arise in the those for NHL are estimated to be 52700.21 From the pre- bone marrow from a stem cell designated colony-forming unit viously mentioned incidences, if myeloid leukemias granulocyte–macrophage (CFU-GM). Monocytes briefly circu- presenting as EMCT represents 1.5%, this would result in late in the blood before entering the tissues to become macro- approximately 190 cases per year, the majority of which rep- phages.1 Therefore, both monocytes and macrophages are resent monocytic leukemias. For THL, if the incidence is 0.3% closely related in origin, structure and function. of all NHL, this would result in approximately 160 cases per True histiocytic lymphoma (THL) or histiocytic sarcoma is year which is rather similar to the incidence of primary EMCT. an uncommon type of non-Hodgkin’s lymphoma (NHL) com- The question now becomes if a patient presents with an posed of neoplastic phagocytic histiocytes.2 THL usually extramedullary tumor of monocyte/macrophage lineage at presents as localized tumors which may or may not progress these sites, is it feasible to differentiate between THL and to disseminated disease.3 The prefix ‘true’ was added to help extramedullary presentation of acute monocytic leukemia or differentiate this entity from ‘histiocytic lymphoma’, a term do we need to? Are there markers to help differentiate used in the Rappaport classification to describe large cell lym- between a neoplastic monocyte and a neoplastic macro- phoma of lymphoid origin.4 With the introduction of better phage? techniques for studying the lineage of different cell types, immunophenotyping of hematologic neoplasms on fixed Morphologic difference paraffin-embedded tissue has become a fairly reliable method which correlates well with genotypic analysis.5 These new The morphology of THL is highly variable. It varies from rather methods of phenotyping and genotyping has brought to ques- homogeneous cells with a large amount of cytoplasm and tion the existence of histiocytic neoplasia in general and THL indented nuclei to pleomorphic, bizarre shapes with multinu- in particular.6,7 THL is becoming more rare when retrospective cleation.4 However, even in recent reports, some cases of studies are performed on archival material using these new anti- CD30-positive anaplastic large cell lymphoma are included bodies. A high percentage of histiocytic neoplasms are reclassi- with THL.15,17 On the other hand, monoblasts may express fiedashighgradelymphomaofBorTlineage.8–10 This has variable morphology and prominent phagocytosis and have been reflected in different classification schemes of NHL. THL high incidence of extramedullary involvement, particularly in has been acknowledged in Lukes and Collin’s Classification association with translocation t(8;16).22 In fact, monocytic leu- and the Working Formulation.11 However, this entity was not kemia with translocation t(8;16) has been previously misdiag- clearly included in the Updated Kiel Classification12 or the nosed as malignant histiocytosis.23

Surface and cytoplasmic immunohistochemical marker Correspondence: M Tarek Elghetany, Division of Hematopathology, difference Department of Pathology, University of Texas Medical Branch, 301 University, Galveston, TX 77555-0743, USA It has been suggested that monocytes are positive for CD14, Received 28 November 1996; accepted 16 January 1997 CD13/33, and CD11b and negative for factor XIII while True histiocytic lymphoma M Tarek Elghetany 763 macrophages have the reverse pattern of reactivity.3,24,25 in childhood: a disease in quest of new nosological criteria. Med However, there is evidence for the presence of CD11b and Pediatr Oncol 1995; 25: 67–69. CD33 on macrophages.1 CD14 expression on macrophages is 8 Arai E, Su WPD, Roche PC, Li C-Y. Cutaneous histiocytic malig- nancy. Immunohistochemical re-examination of cases previously very variable depending on the location and the inflammatory diagnosed as cutaneous histiocytic lymphoma and malignant status of the tissue. Peritoneal and pleural macrophages are histiocytosis. J Cutan Pathol 1993; 20: 115–120. associated with high expression of CD14 while alveolar 9 Wilson MS, Weiss LM, Gatter KC, Mason DY, Dorfman RF, macrophages and microglial cells express CD14 at a much Warnke RA. Malignant histiocytosis. A reassessment of cases lower level.26 In the mucosa of normal bowel, only 4% of previously reported in 1975 based on paraffin section immuno- macrophages are CD14 positive. However, in inflammatory phenotyping studies. Cancer 1990; 66: 530–536. 10 van der Valk P, van Oosteveen JW, Stel HV, van der Kwast TH, bowel disease, 25% of macrophages become CD14 posi- Melief CJM, Meijer CJL. Phenotypic and genotypic analysis of 27 tive. There is ample evidence indicating that bone marrow large cell lymphomas, formerly classified as true histiocytic lym- and peripheral blood monocytes synthesize and contain phoma: identification of an unusual group of tumors. Leukemia factor XIII.28,29 Res 1990; 14: 337–346. 11 National Cancer Institute Sponsored Study of Classifications of non-Hodgkin’s Lymphoma. Summary and description of a work- ing formulation for clinical usage. Cancer 1982; 49: 2112–2135. Proliferative capacity 12 Stansfeld AG, Diebold J, Kapanci Y, Kelenyi G, Lennert K, Mioduszewska O, Noel H, Rilke F, Sundstrom C, van Unnik JAM, It has been suggested that the proliferative capacity of macro- Wright DH. Updated Kiel classification for lymphoma. Lancet phages is very limited. Yet, this capacity can be influenced by 1988; i: 292–293. the environment. For instance, alveolar macrophages nor- 13 Harris NL, Jaffe ES, Stain H, Banks PM, Chan JKC, Cleary ML, Delsol G, De Wolf-Peeters C, Falini B, Gatter KC, Grogan TM, mally have a very weak proliferative capacity. However, in Isaacson PG, Knowels DM, Mason DY, Muller-Hermelink H-K, sarcoidosis, their proliferative capacity increases several Pileri SA, Piris MA, Ralfkiaer E, Warnke RA. A revised European– fold.30 This physiologic change in proliferative capacity is not American classification of lymphoid neoplasms: a proposal from relevant to the diagnosis of AMoL and THL since both entities the International Lymphoma Study Group. Blood 1994; 84: usually have high mitotic activity. 1361–1392. 14 Komp DM, Perry MC. The histiocytic syndromes. Semin Oncol 1991; 18: 1–2. 15 Hanson CA, Jaszcz W, Kersey JH, Astorga MG, Peterson BA, Gail- Therapeutic outcome Peczalska KJ, Frizzera G. True histiocytic lymphoma: histologic, immunophenotypic and genotypic analysis. Br J Haematol 1989; Most THL have been treated as high-grade lymphoma with 73: 187–198. 16 Ralfkiaer E, Delsol G, O’Connor NTJ, Brandtzaeg P, Brousset P, overall poor response and short survival.15,16 Asimilar Vejlsgaard GL, Mason DY. Malignant lymphoma of true histiocytic scenario occurs for patients with EMCT who are treated origin. A clinical, histological, immunophenotypic and genotypic with local therapy alone or receive the chemotherapy study. J Pathol 1990; 160: 9–17. designed for high grade lymphoma.19 However, patients 17 Aozasa K, Ohsawa M, Saeki K, Horiuchi K, Tamai M, Kohro T, given multiagent chemotherapy for acute leukemia may show Kurata A. Histiocytic neoplasia: immunohistochemical evaluation a better response.20,31,32 of their frequencies among malignant lymphoma and related con- Differentiating so-called THL from EMCT of monocytic ditions in Japan. J Surg Oncol 1991; 47: 215–220. 18 Hutchison RE, Kurec AS, Davey FR. Granulocytic sarcoma. Clin origin is a difficult or impossible task using available morpho- Lab Med 1990; 10: 889–901. logic, cytochemical, immunocytochemical and molecular cri- 19 Byrd JC, Edenfield WJ, Shields DJ, Dawson NA. Extramedullary teria. 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