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Histiocytic lesions involving the bone marrow
Histiocytic Lesions Involving the Bone Marrow Karen L. Chang, MD, Karl K. Gaal, MD, Qin Huang, MD, and Lawrence M. Weiss, MD ● Histiocytic lesions involving the bone marrow include a number of reactive and neoplastic disorders. This article discusses the morphologic, immunophenotypic, and genotypic features of a variety of diseases associated with histiocytes and/or monocytes. Lysosomal storage disorders and hemophagocytic syndromes are often first diagnosed by bone marrow examination. Granulomas involving the bone marrow may also be the first indication of a systemic disorder. Apart from acute and chronic monocytic leukemias, the bone marrow is rarely involved by malignant histiocytic disorders, of which Langerhans cell histiocytosis is the most common. INDEX WORDS: Bone marrow, histiocytosis, Langerhans cell histiocytosis, granulomas, hemophagocytic syndrome, lysosomal storage diseases, acute leukemia, chronic myeloid leukemia, benign erythrophagocytosis © 2003 Elsevier Inc. All rights reserved.
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ISORDERS OF HISTIOCYTES involving the bone marrow are predominantly quantitative in nature and can be divided into neoplastic and nonneoplastic proliferations. The non-neoplastic diseases include granulomatous infections, storage disorders, hemophagocytic syndromes, and sinus histiocytosis with massive lymphadenopathy (SHML). Postchemotherapy/radiotherapy bone marrows may also exhibit a histiocytosis. Neoplastic diseases associated with bone marrow histiocytosis include Langerhans cell histiocytosis, acute and chronic myeloid leukemias, chronic myeloproliferative disorders, non-Hodgkin’s lymphomas (including histiocytic sarcoma/true histiocytic lymphoma), and Hodgkin’s disease. GRANULOMAS IN THE BONE MARROW Because granulomas are manifestations of a systemic chronic inflammatory reaction, they may be associated with a variety of diseases (Figs 1A and 1B).1-7 Table 1 lists conditions associated with bone marrow granulomas. Bone marrow granulomas are not infrequently seen in patients with Hodgkin’s disease, non-Hodgkin’s lymphoma, or post-bone marrow transplantation and do not necessarily represent involvement by malignancy. Granulomas in the bone marrow are similar to those appearing in other organs. They are composed of aggregates of histiocytes, which are typically surrounded by lymphocytes, plasma cells, and eosinophils (Fig 2).
From the Department of Pathology, City of Hope National Medical Center, Duarte, CA. Address reprint requests to Karen L. Chang, MD, City of Hope National Medical Center, 1500 East Duarte Rd, Duarte, CA 91010; e-mail: [email protected]. © 2003 Elsevier Inc. All rights reserved. 0740-2570/03/2003-0007$30.00/0 doi:10.1053/S0740-2570(03)00029-7 226
Lipogranulomas also have admixed adipocytes and are usually not associated with disease (Fig 3). Epithelioid granulomas do not contain adipose tissue. The epithelioid granulomas of immunocompromised patients are often loosely formed, and may be so dispersed that no granuloma is apparent (Fig 4). In these cases, special stains for mycobacteria and fungi should be performed (Figs 5A and B). Epithelioid granulomas associated with multinucleated giant cells or areas of necrosis may be seen in patients with mycobacterial or fungal infections. Q-fever granulomas have a characteristic central clearing surrounded by fibrin and may easily be mistaken for a lipogranuloma “Fibrin ring” granulomas have also been described in patients with cytomegalovirus infection (Fig 6). Granulomas are difficult to find in bone marrow smears and are most easily detected in bone marrow biopsy or clot sections. The differential diagnosis of bone marrow granulomas includes mast cell disease, large cell lymphoma, histiocyte/T-cell rich B-cell lymphoma, and metastatic clear cell carcinomas. These can be distinguished by the presence of malignant cytologic features and by different immunohistochemical profiles in the lymphomas and carcinomas. Mast cell disease has a characteristic immunostaining pattern (positive for tryptase) not seen in granulomas.8 LYSOSOMAL STORAGE DISEASES The histiocytes of storage diseases are qualitatively and quantitatively affected by an accumulation of proteins.9-14 The lysosomal storage diseases are rare hereditary deficiencies of one of the lysosomal enzymes necessary for glycolipid and glycoprotein degradation. Without the necessary enzymes, the cell lysosomes accumulate glycolipid or glycoprotein substrates. These disorders are subdivided based on the accumulated
Seminars in Diagnostic Pathology, VOL 20, NO 3 (AUGUST), 2003: pp 226-236
HISTIOCYTIC LESIONS Table 1.
Diseases Associated With Bone Marrow Granulomas
Caseating granulomas Tuberculosis Histoplasmosis Noncaseating granulomas Viral (Cytomegalovirus, Herpes zoster virus) Mycobacterium avium intracellulare Other infections (Brucellosis, rickettsial infections, Q-fever, typhoid fever, leprosy, tularemia, mycoplasma) Sarcoidosis Non-Hodgkin’s lymphoma Hodgkin’s disease Multiple myeloma Posttherapy Autoimmune disorders Drug-associated (phenytoin, chlorpropamide) Idiopathic
substrates and include sphingolipidosis, glycoproteinosis, mucolipidosis, and mucopolysaccharidosis. All of the storage diseases may contain histiocytes with characteristic lysosomal overload, which typically manifests as cytoplasmic vacuolation. The histiocyte morphology and extent of marrow involvement varies with the different lysosomal storage disorders. The lysosomal storage disorders most commonly associated with significant bone marrow pathology include two variants of sphingolipidosis, Gaucher’s disease and NiemannPick disease, as well as a variant of Niemann-Pick disease known as “sea-blue histiocytosis.” Gaucher’s disease, the prototypic sphingolipidosis, is caused by an accumulation of glucosylcerebroside. These patients most commonly present with splenomegaly, but may also have symptoms related to an accumulation of pathologic Gaucher cells in liver, bones, lungs, and brain.9 On aspirate smears, Gaucher cells are large with small inconspicuous nuclei and abundant light blue crinkled cytoplasm. The latter has been described as having the appearance of “skeins of yarn.” Their appearance on tissue sections is similar, with small bland nuclei and abundant slightly eosinophilic cytoplasm with a striated appearance (Fig 7). The cells may have a patchy distribution or may diffusely replace the normal marrow (Fig 8). The bony trabeculae are normal and necrosis is uncommon. Mimics of Gaucher cells include macrophages that are replete with lipid products derived from cellular destruction/high turnover, as seen in acute and chronic myeloid leukemias, congenital dyserythropoietic anemias, thalassemia major, and plasma cell dyscrasia. In these cases, the Gaucher-like cells are not due to the absence of the
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enzyme, but rather that the enzyme is overwhelmed. Therefore, the diagnosis of Gaucher’s disease must be corroborated by enzyme assay (measuring glucosyl cerebrosidase in the peripheral blood white cells). Niemann-Pick disease also typically presents with splenomegaly and is characterized by an absence of sphingomyelinase. As with other lysosomal clinical disorders, the disease exists in several clinical forms, which vary in severity. The histiocytes of NiemannPick disease are enlarged and have foamy cytoplasm, which results from numerous tiny vacuoles loaded with lipid products. Such histiocytes may also be seen in patients with hypercholesterolemia, Langerhans cell histiocytosis, Wolman’s disease, and Tangier disease (familial high density lipoprotein deficiency). A form of Niemann-Pick disease associated with splenomegaly, neurologic disorders, and thrombocytopenia is known as “sea-blue histiocytosis.”13 Sea blue histiocytes are slightly smaller than Niemann-Pick histiocytes and have cytoplasm loaded with coarse basophilic ceroid-containing granules that stain sea blue or blue green with a Romanowsky stain. The granules, which vary in size, stain with Sudan Black B and Oil Red O.15 They are seen in numerous hematologic diseases including Niemann-Pick disease, chronic myleogenous leukemia (CML), polycythemia vera, hematolytic anemia, and other conditions. The lysosomal storage disorders discussed above affect histiocytes far more often and more severely than other cell types. However, lymphocytes may also be affected in the storage disorders and may also be abnormal in patients with mucopolysaccharide accumulation.12 In fact, Alder-Reilly bodies, which are dense azurophilic granular inclusions composed of glycosaminoglycan in lysosomes, may be seen in lymphocytes and less frequently, monocytes of patients with inherited mucopolysaccharidosis. HEMOPHAGOCYTIC SYNDROMES A variety of neoplastic and non-neoplastic conditions contain macrophages that phagocytose hematopoietic cells, most commonly associated with erythroid precursors. Erythrophagocytosis is often accompanied by ingestion of other elements including platelets and neutrophils. The phagocytosing histiocytes usually contain abundant vacuolated cytoplasm, with one or several red blood cells or remnants, and containing round to oval nuclei with lacy bland chromatin and inconspicuous nucleoli.
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Infection-Associated Hemophagocytic Syndrome
Familial Hemophagocytic Lymphohistiocytosis
Infection-associated hemophagocytic syndrome is a non-neoplastic, systemic proliferation of benign-appearing histiocytes affecting almost every organ, including the bone marrow.16-22 Almost any infectious agent may be involved, but acute viral infections account for the majority of cases. This syndrome usually occurs in patients who have a documented primary or iatrogenic (eg, organ-transplant-related) immunodeficiency. Patients usually present with fever and other constitutional symptoms, and have hepatosplenomegaly, generalized lymphadenopathy, and less frequently, a skin rash and bilateral pulmonary infiltrates. Pancytopenia and liver function abnormalities are often present. Infection-associated hemophagocytic syndrome is a benign, self-limiting condition. However, affected patients may die during the acute disease episode due to multisystem failure or later due to infectious complications exacerbated by their underlying immunodeficiency. Epstein-Barr-associated hemophagocytic syndrome appears to be a particularly virulent form of this syndrome, affecting young children and leading rapidly to death.23,24 The pathologic features vary with the time that biopsies are performed. Early in the disease, the bone marrow may only partially be involved by a small number of histiocytes. Later in the disease, one may see massive infiltration by benign-appearing histiocytes (Fig 9). The histiocytes may show prominent hemophagocytosis and platelet phagocytosis. The bone marrow may also be cell-poor, with marked myeloid and erythroid hypoplasia. Other manifestations of infection, such as left-shifted granulopoiesis, mild lymphocytosis, and plasmacytosis, and granulomas, may also be present. The differential diagnosis of infection-associated hemophagocytic syndrome includes familial hemophagocytic lymphohistiocytosis and malignant lymphomas associated with benign hemophagocytosis, both of which are discussed below.
Familial hemophagocytic lymphohistiocytosis is a rare and usually fatal disease that is also characterized by marked lymphohistiocytic infiltration in multiple organs.25-27 Most patients are infants, and approximately three fourths of cases are familial, with an autosomal recessive mode of inheritance. The infants usually present with fevers, hepatosplenomegaly, pulmonary effusions, and a skin rash. Pancytopenia and a severe hypofibrinogenemia without abnormalities of other clotting factors are typical laboratory findings. Impaired cellular and humoral immunity are features of this disorder. The disease is usually rapidly fatal (within weeks), with death due to sepsis or bleeding. The lymph nodes and bone marrow are the most frequently involved organs, followed by the spleen, liver, and the central nervous system.28 The bone marrow in patients with familial hemophagocytic lymphohistiocytosis is partially to completely effaced by a loose infiltrate of benign-appearing histiocytes, lymphocytes and plasma cells. The histiocytosis is quite pronounced and is accompanied by prominent erythrophagocytosis as well as phagocytosis of lymphocytes and other cellular debris. Other organs of the reticuloendothelial system may also contain large numbers of hemophagocytic histiocytes. Familial hemophagocytic lymphohistiocytosis and infection-associated hemophagocytic syndrome may be clinically and morphologically similar. In fact, they may represent the same disease, with familial hemophagocytic lymphohistiocytosis presenting as infection-associated hemophagocytic syndrome in individuals with familial immunodeficiencies. Importantly, one must distinguish these morphologically benign diseases from the histiocytosis accompanying malignant disorders such as non-Hodgkin’s lymphomas. Sinus Histiocytosis with Massive Lymphadenopathy Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) is a rare idiopathic disease of
Š Fig 1. (A) Granulomas in the bone marrow may be in a paratrabecular or interstitial location. (B) This is a case of granulomas associated with regeneration following bone marrow transplantation. Fig 2. A tight epithelioid granuloma is typical of sarcoidosis, which is a multisystemic disease. Fig 3. Lipogranulomas have various amounts of lipid inclusions. This case contains finely vacuolated cytoplasm. Fig 4. These histiocytes are interspersed with other chronic inflammatory cells and do not form a true granuloma. Fig 6. This ring granuloma was found in a post-bone marrow transplantation patient, who was infected with cytomegalovirus. Fig 5. (A) The aspirate smear from this case shows histiocytes with 3 prominent clear vacuoles as well as several other vacuoles. (B) GMS stain from the tissue section of this case shows histoplasmosis. Fig 7. The bone marrow aspirate smear of a patient with Gaucher’s disease contains histiocytes with granular and striated cytoplasm.
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proliferating histiocytes.29-31 Approximately 90% of patients present with massive, painless, bilateral cervical lymphadenopathy. Extranodal sites are involved in approximately 40% of cases, but bone marrow involvement is extraordinarily rare and has been described as patchy paratrabecular and non-paratrabecular foci of foamy histiocytes.31 Despite lack of extensive bone marrow involvement, patients may develop hemolytic anemia, idiopathic hypereosinophilic syndrome and malignant lymphoma. Sinus histiocytosis with massive lymphadenopathy involving bone marrow has histiocytes with the distinctive nuclear features of SHML in other organs (Fig 10). Paraffin immunohistochemical studies show staining with antibodies to S100 protein and other macrophageassociated antigens.32 The cells do not express the CD1 antigen found on Langerhans cells, and also lack expression of R4/23, a monoclonal antibody with high specificity for follicular dendritic cells. Molecular studies show a germline configuration for both the immunoglobulin heavy chain gene and the -T cell receptor gene.33 The differential diagnosis includes reactive sinus histiocytosis and Langerhans cell histiocytosis (Fig 11). Reactive histiocytes should not stain with S100, unlike the histiocytes of SHML. The cytologic characteristics of Langerhans cells and the presence of eosinophils helps to separate Langerhans cell histiocytosis from SHML. CD1 expression, the presence of Birbeck granules, and lack of emperipolesis in Langerhans cell histiocytosis also help differentiate Langerhans cell histiocytosis from SHML. POST-BONE MARROW TRANSPLANTATION HISTIOCYTIC PROLIFERATION Radiation or chemotherapy may result in severe bone marrow damage.34-37 Hematopoiesis is essentially ab-
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sent, there is a proliferation of stromal cells and possibly plasma cells, and there may be interstitial edema and hemorrhage. There is marked predominance of adipocytes (sometimes fat necrosis) and hemosiderinladen macrophages. In the resolution stage, one may see an abundance of histiocytes. The clinical setting makes iatrogenic histiocytosis easy to separate from other forms of histiocytosis. MALIGNANCIES ASSOCIATED WITH HISTIOCYTES/MONOCYTES While not strictly a histiocytic disorder, monocytic proliferations share common ontogeny with histiocytic lesions and are therefore included in this review.38 Apart from subtypes of acute and chronic leukemias, malignancies of histiocyte/monocyte origin involving the bone marrow are extremely rare. Langerhans Cell Histiocytosis (Histiocytosis X) Langerhans cell histiocytosis is a term that comprises a group of closely related clinicopathologic disorders with a common neoplastic proliferating element, the Langerhans cell.39-41 Historically, the entity was also known as histiocytosis X and Langerhans cell granulomatosis. Generally there are 3 main and sometimes overlapping clinical syndromes. Unifocal disease (solitary eosinophilic granuloma) accounts for approximately two thirds of cases. Multifocal unisystem disease (Hand-Schuller-Christian syndrome), and multifocal multisystem disease (Letterer-Siwe syndrome) are the other 2 common syndromes. The bone is involved in all three clinical presentations and the bone marrow may be involved by extension. The bone marrow is only rarely the sole site of involvement. Bone marrow involvement is more easily seen in biopsies than aspirate smears because the characteristic nuclear features are not present in air-dried preparations.
Š Fig 8. This trephine biopsy section shows a paratrabecular and patchy interstitial infiltrate of Gaucher histiocytes. Fig 9. This histiocyte from a patient with viral-associated hemophagocytic syndrome is phagocytosing red blood cells and other nuclear debris. Fig 10. This bone marrow from a patient with SHML shows paratrabecular fibrosis and a proliferation of histiocytes with somewhat vesicular nuclear chromatin and abundant cytoplasm. Fig 11. This bone marrow is hypercelluar and contain numerous histiocytes admixed with lymphocytes, eosinophils, and other chronic inflammatory cells. Special stains for microorganisms and paraffin immunohistochemical studies failed to reveal an infectious or malignant etiology. No specific cause was ever found in this patient. Fig 12. A bone marrow trephine biopsy section from a patient with Langerhans cell histiocytosis shows prominent interstitial involvement. Fig 13. One prominent promonocyte is admixed with monoblasts in this aspirate smear from a patient with AML M5 b. Fig 14. These monoblasts have blastic chromatin, and very little nuclear or cytoplasmic maturation. Fig 15. Butyrate esterase activity in monoblasts is strong and diffusely cytoplasmic. Fig 16. Pseudo-Gaucher cells are often seen in patients with chronic myelogenous leukemia.
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The diagnosis is easily made by observing a proliferation of Langerhans cells in the appropriate cellular background. Langerhans cells have a single large nucleus with a characteristic folded or grooved nucleus (so-called “coffee-bean” appearance) with small inconspicuous nucleoli. The nuclear chromatin is usually bland. Slight cytologic atypia may be seen. The cells are approximately 12 to 15 in diameter, with a moderate amount of eosinophilic cytoplasm. Mitotic activity varies from lesion to lesion, but is generally low. The background cells include mononuclear and multinucleated histiocytes, abundant eosinophils, neutrophils, and small lymphocytes. Small clusters of eosinophils may be associated with necrosis, forming so-called eosinophilic microabscesses. Marrow fibrosis may be extensive. Plasma cells are rarely, if ever, seen. Involvement may be patchy or diffuse (Fig 12). Cases in which the Langerhans cells have unequivocally malignant cytologic features have been called malignant histiocytosis X or malignant Langerhans cell histiocytosis, but these have not been described in the bone marrow.42 The ultrastructural, enzyme histochemical, and immunohistochemical features of Langerhans cells of Langerhans cell histiocytosis are virtually identical to those of normal Langerhans cells. By immunohistochemistry, Langerhans cells virtually always express CD1 and S100 protein, and a portion of the neoplastic cells express CD68 and anti-placental alkaline phosphatase.43-45 CD1 staining has the greatest diagnostic utility, because CD1 expression is limited to reactive and neoplastic Langerhans cells, immature thymocytes, and T-lineage lymphoblastic neoplasms. Other histiocytic and dendritic cells lack CD1 expression.46 CD30 and CD15 expression are not found in Langerhans cells. Electron microscopy of Langerhans cells shows characteristic Birbeck granules, which are racket-shaped organelles approximately 200 to 400 nm long and 33-nm wide, with an osmiophilic core and a double outer sheath.47 Langerhans cell histiocytosis has been shown to be a monoclonal proliferation, as evidenced by its pattern of X-chromosome inactivation in the X-linked human androgen-receptor gene.48 Molecular hybridization studies show a germline configuration for the immunoglobulin heavy chain gene as well as for the beta, gamma, and delta chains of the T cell receptor genes.48,49 Bone marrow involvement by Langerhans cell histiocytosis should be distinguished from other more common large cell proliferations involving the bone mar-
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row, including granulomatous disease, metastatic adenocarcinoma, metastatic malignant melanoma, and large cell lymphoma, as well as the even less common SHML involving the bone marrow. Identification of the characteristic Langerhans cell cleaved nucleus, as well as the characteristic cellular milieu, helps to establish the diagnosis of Langerhans cell histiocytosis. Large cell lymphomas lack the unique grooved nucleus and show reactivity for B-cell or T-cell antigens. The malignant cytology of cells of the metastatic malignancies and sinusoidal malignant lymphoma contrasts with the bland cytology of Langerhans cell histiocytosis. The cells of SHML have rounded nuclei with vesicular chromatin and prominent nucleoli and abundant cytoplasm, which differs from the folded, grooved nuclei of Langerhans cell histiocytosis. One reported case of Erdheim-Chester disease, a multiorgan infiltration of fibrosing xanthogranulomas, presented with diffuse bone marrow infiltration by foamy histiocytes, Toutontype giant cells, and fibroblastic cells associated with extensive coagulative necrosis.50 Paraffin immunohistochemistry showed positivity for CD68 and rare cells for S100. Clinical and radiologic correlation helped establish a diagnosis of Erdheim-Chester disease. Acute Myeloid Leukemia Acute myelogenous leukemia accounts for more than 50% of leukemias in adult and approximately 20% of leukemias in children. The myeloid leukemias with cytologic and cytochemical features of monocytic/histiocytic differentiation fall into the category of “acute myeloid leukemia, not otherwise categorized,” in the WHO classification, and corresponds to “acute myelomonocytic leukemia,” “acute monoblastic leukemia,” and “acute monocytic leukemia” (FAB-M4, FAB-M5a, and FAB-M5b, respectively) in the FrenchAmerican-British Classification. These monocytoid/ monocytic subtypes of acute leukemia are far more common than the other neoplastic histiocytic disorders discussed elsewhere in this review. These leukemias differ solely in the percentage of immature cells showing cytochemical evidence of monocytic differentiation, and whether those immature cells are more or less mature.51 Monoblasts and promonocytes are most easily distinguished from one another in bone marrow aspirate smears, and not in fixed bone marrow biopsy sections. Both cell types are large with large nuclei. Promonocytes have irregular, folded and convoluted nuclear contours, with a moderate amount of cytoplasm that may be vacuolated but not granulated (Fig 13). In other words, they appear just slightly less mature than
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mature monocytes. In contrast, monoblasts lack the folded nuclei and abundant vacuolated cytoplasm of a promonocyte. Instead, monoblasts usually have round to oval nuclei with delicate chromatin, prominent nucleoli, and abundant cytoplasm (Fig 14). Some authors have described the monoblasts as appearing amoeboid. The authors consider the distinction between the two to be merely academic, as promonocytes and monoblasts are both counted as “blasts” in assessing for AML. The cytochemical stains most specific for monocytes are alpha-naphthyl butyrate as substrate and hexa-azotized pararosaniline as coupler (monocyte-specific non-specific esterase activity) (Fig 15).52 Alpha-naphthyl acetate and naphthol AS-D acetate are also reactive substrates for monocytes, but specificity for monocytes must be validated by showing fluoride inhibition, which is a unique feature of monocyte esterases. One distinct subtype of acute myeloid leukemia, AML M5b, shows monocytoid blasts with abundant intracytoplasmic granules and prominent erythrophagocytosis by the leukemic cells.53 This subtype of acute monocytic leukemia is associated with t(8;16)(p11; p13), disseminated intravascular coagulation, and prominent central nervous system and extramedullary involvement. Chronic Myeloid Leukemia Chronic myeloid leukemia, a clonal myeloproliferative disorder characterized by a reciprocal translocation between chromosomes 9 and 22, affects mostly adults in their sixth decade or older.54,55 The bone marrow is hypercellular and usually shows marked myeloid and megakaryocytic hyperplasia. There is high cell turnover, manifesting as lipid-filled macrophages resembling Gaucher cells and sea-blue histiocytes (Fig 16). The presence of marrow fibrosis and the demonstration of the characteristic cytogenetic finding, as well as the BCR-ABL (breakpoint cluster region gene of chromosome 22 and ABL gene of chromosome 9) gene rearrangement, establishes the diagnosis of CML and helps exclude storage disorders and other forms of myeloproliferative disorder, which may also be associated with Gaucher-like macrophages.
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characterized by at least 10% monocytes in the peripheral blood white blood cell count differential, less than 20% blasts, and lack of BCR-ABL gene rearrangement. The bone marrow is usually hypercellular and contains a proliferation of mature monocytes, which are often dysplastic. The peripheral blood monocytosis is also mature, but is not reliable by itself for the diagnosis of chronic myelomonocytic leukemia, because mature monocytes may also be seen in the peripheral blood of patients with acute myelomonocytic leukemia or acute monocytic leukemia. Malignant Lymphoma With Benign Erythrophagocytosis T-cell lymphomas, and less often other lymphomas, may induce a marked hyperplasia of cytologically benign hemophagocytosing histiocytes.58,59 Malignant lymphoma with benign erythrophagocytosis is a condition in which lymphoma is associated with a reactive hemophagocytic disorder and may present in two different ways. In the first presentation, patients with known lymphoma develop a syndrome mimicking infection-associated hemophagocytic syndrome. In these cases, malignant lymphoma cells are found in the bone marrow often without the histiocytic proliferation. In the second clinical presentation, the hemophagocytic syndrome occurs in the absence of any previously diagnosed malignancy and usually prompts a search for malignancy. In this setting, benign hemophagocytizing histiocytes are intimately interspersed with lymphoma cells. Paraffin and frozen section immunophenotyping studies usually demonstrate a T-cell lineage. Malignant lymphoma with benign erythrophagocytosis may be confused with infection-associated hemophagocytic syndrome. Identification of the lymphoma cells distinguishes the malignancy from infection-associated hemophagocytic syndrome. Also, the lymphomas are usually not associated with a systemic infection, as is infection-associated hemophagocytic syndrome. Biopsies of other organs may be needed for cases in which this distinction may be difficult.
Mixed Myeloproliferative/Myelodysplastic Syndrome
Histiocytic Sarcoma
Patients with chronic myelomonocytic leukemia often present with splenomegaly, abnormal white blood cell counts, and trilineage dysplasia.56,57 The patient’s WBC count serves to separate the entity into myelodysplastic subtype (⬍13,000/uL) and myeloproliferative subtypes (ⱖ13,000/uL). Both of these subtypes are
True histiocytic lymphoma, malignant histiocytosis, and histiocytic sarcoma are synonymous terms for a rare neoplasm in which the malignant cells show lineage consistent with histiocytes.60-68 This tumor is extremely rare, accounting for ⬍ 0.5% of all hematolymphoid neoplasms. Lymph nodes are commonly
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involved but bone marrow involvement is extremely rare. The bone marrow spaces may be partially or completely effaced by a proliferation of cytologically malignant cells that resemble histiocytes. The neoplastic cells are variable in size and have a large, eccentric oval nucleus with a prominent irregular nucleolus and abundant eosinophilic cytoplasm. Histiocytic sarcomas may also contain bizarre multinucleated tumor cells, multiple nucleoli, vacuolated cytoplasm, and hemophagocytosing tumor cells. Spindle cell sarcoma-like areas may also be present. Mitotic activity is usually quite high. The tumor cells have no unique morphologic characteristics and thus, immunophenotypic and molecular studies are absolutely essential for diagnosis. As in other organs, the diagnosis of histiocytic sarcoma in the bone marrow is based on strong immunologic evidence of histiocytic lineage, with complete absence of specific T and B lineage markers. In addition, the tumor must have molecular evidence of a germline configuration for the T-cell receptor and immunoglobulin genes.69-72 The tumor cells show paraffin immunohistochemical staining with CD68, lysozyme, and alpha-1-antitrypsin, and they should not stain with CD30, CD1a, any B-lineage or T-lineage-specific antibodies, any of the anti-keratin antibodies, or HMB45.60-68 The differential diagnosis of histiocytic sarcoma includes anaplastic large cell lymphoma, B-cell sinusoidal large cell lymphoma, anaplastic carcinomas showing hemophagocytosis, malignant lymphomas associated with benign erythrophagocytosis, follicular dendritic cell neoplasms, hepatosplenic T-cell lymphoma, infection-associated hemophagocytic syndrome, storage diseases such as Gauchers disease and Niemann-Pick disease, and familial hemophagocytic lymphohistiocytosis. In fact, the early reports of malignant histiocytosis have since been reclassified as anaplastic large cell lymphoma, B- or T-cell lymphomas, or infection-associated hemophagocytic syndrome.60-68 The strict morphologic, phenotypic, and molecular criteria of histiocytic sarcoma, along with clinical presentation, help separate histiocytic sarcoma from the other malignant entities in the differential diagnosis. Unlike the reactive processes, the phagocytic histiocytes of histiocytic sarcoma have highly atypical, hyperchromatic, and often multinucleated nuclei.
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REFERENCES 1. Bodem C, Hamory B, Taylor H, et al: Granulomatous bone marrow disease: A review of the literature and clinicopathologic analysis of 58 cases. Medicine 62:372-383, 1983 2. Bhargava V, Farhi D: Bone marrow granulomas: Clinicopathologic findings in 72 cases and review of the literature. Hematol Pathol 21:43-50, 1988 3. Vilalta-Castel E, Valdes-Sanchez M, Teno-Esteban C, et al: Significance of granulomas in bone marrow: A study of 40 cases. Eur J Haematol 41:12-16, 1988 4. Srigley J, Geddie W, Vellend H, et al: The liver and bone marrow pathology. Am J Surg Pathol 9:752-758, 1985 5. Young J, Goulian M: Bone marrow fibrin ring granulomas and cytomegalovirus infection. Am J Clin Pathol 99:65-68, 1993 6. Yu H, Rywlin A: Granulomatous lesions of the bone marrow in non-Hodgkin’s lymphoma. Hum Pathol 13:905-910, 1982 7. O’Brien D, Boon A, Boughton B: Bone marrow granulomas in acute myeloid leukemia following interleukin-2 and lymphokineactivated killer cells. Histopathology 20:271-272, 1992 8. Horny H, Sillaber C, Menke D, et al: Diagnostic value of immunostaining for tryptase in patients with mastocytosis. Am J Surg Pathol 22:1132-1140, 1998 9. Beutler E: Gaucher disease. Blood Rev 2:59-70, 1988 10. Landas S, Foucar K, Sando G, et al: Adult Niemann-Pick disease masquerading as sea blue histiocyte syndrome: Report of a case confirmed by lipid analysis and enzyme assays. Am J Hematol 20:391-400, 1985 11. Lee R: Histiocytic diseases of bone marrow. Hematol Oncol Clin North Am 2:657-667, 1988 12. Peterson L, Parkin J, Nelson A: Mucopolysaccharidosis type VII: A morphologic, cytochemical, and ultrastructural study of the blood and bone marrow. Am J Clin Pathol 78:544-548, 1982 13. Silverstein M, Ellefson R: The syndrome of the sea-blue histiocyte. Semin Hematol 9:293-307, 1972 14. Brunning R: Morphologic alterations in nucleated blood and marrow cells in genetic disorders. Hum Pathol 1:99-124, 1970 15. Sawitsky A, Rosner F, Chosky S: The sea-blue histiocyte syndrome, a review: Genetic and biochemical studies. Semin Hematol 9:285, 1972 16. Risdall R, McKenna R, Nesbit M, et al: Virus-associated hemophagocytic syndrome: A benign histiocytic proliferation distinct from malignant histiocytosis. Cancer 44:993, 1979 17. Risdall R, Brunning R, Hernandez J, et al: Bacteria-associated hemophagocytic syndrome. Cancer 54:2968, 1984 18. McKenna RW, Risdall RJ, Brunning RD: Virus associated hemophagocytic syndrome. Hum Pathol 12:395, 1981 19. Gaffey M, Frierson H, Medeiros L, et al: The relationship of Epstein-Barr virus to infection-related (sporadic) and familial hemophagocytic syndrome and secondary (lymphoma-related) hemophagocytosis: An in situ hybridization study. Hum Pathol 24:657, 1993 20. Wong KF, Chan JK: Reactive hemophagocytic syndrome: a clinicopathologic study of 40 patients in an Oriental population. Am J Med 93:177-180, 1992 21. Henter J, Elinder G, Ost A: FHL Study Group of the Histiocyte Society. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. Semin Oncol 18:29-33, 1991 22. Woda B, Sullivan J: Reactive histiocytic disorders. Am J Clin Pathol 99:459-463, 1993 23. Chen R-L, Su I-J, Lin K-H, et al: Fulminant childhood he-
HISTIOCYTIC LESIONS mophagocytic syndrome mimicking histiocytic medullary reticulosis: An atypical form of Epstein-Barr virus infection. Am J Clin Pathol 96:171-176, 1991 24. Kikuta H, Sakiyama T, Matsumoto S, et al: Fatal Epstein-Barr virus-associated hemophagocytic syndrome. Blood 82:3259-3264, 1993 25. Favara BE: Hemophagocytic lymphohistiocytosis: A hemophagocytic syndrome. Semin Diagn Pathol 9:63-74, 1992 26. Janka GE: Familial hemophagocytic lymphohistiocytosis: Review. Eur J Pediatr 140:221-230, 1983 27. Wieczorek R, Greco A, McCarthy K, et al: Familial erythrophagocytic lymphohistiocytosis; immunophenotypic, immunohistochemical and ultrastructural demonstration of the relation to sinus histiocyutes. Hum Pathol 17:55-63, 1986 28. Soffer D, Okon E, Rosen N, et al: Familial hemophagocytic lymphyhistiocytosis in Israel: II: Pathologic findings. Cancer 54: 2423-2431, 1984 29. Rosai J, Dorfman RF: Sinus histiocytosis with massive lymphadenopathy: A newly recognized benign clinicopathologic entity. Arch Pathol 87:63-70, 1969 30. Rosai J, Dorfman RF: Sinus histiocytosis with massive lymphadenopathy: A pseudolymphomatous benign disorder. Analysis of 34 cases. Cancer 30:1174-1188, 1972 31. Foucar E, Rosai J, Dorfman RF: Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): Review of the entity. Semin Diagn Pathol 7:19, 1990 32. Eisen R, Buckley P, Rosai J: Immunophenotypic characterization of sinus histiocytosis with massive lymphadenopathy (RosaiDorfman disease). Semin Diagn Pathol 7:74-82, 1990 33. Copie-Bergman C, Wotherspoon A, Norton A, et al: True histiocytic lymphoma: A morphologic, immunohistochemical, and molecular genetic study of 13 cases. Am J Surg Pathol 22:1386-1392, 1988 34. Adelstein D, Hines J: Bone marrow morphologic changes after combination chemotherapy including VP-16. Cancer 61:467-471, 1985 35. Chang J, Geary C, Testa N: Long-term bone marrow damage after chemotherapy for acute myeloid leukaemia does not improve with time. Br J Haematol 75:68-72, 1990 36. Dalal B, Freier L, Johnston J, et al: Peripheral blood and bone marrow changes following 2’deoxycoformycin therapy in hairy cell leukemia. Cancer 63:14-22, 1989 37. Wittels B: Bone marrow biopsy changes following chemotherapy for acute leukemia. Am J Surg Pathol 4:135-142, 1980 38. Foucar K, Foucar E: The mononuclear phagocyte and immunoregulatory effector (M-PIRE) system: Evolving concepts. Sem Diagn Pathol 7:4-18, 1990 39. Lichtenstein L, Lichtenstein L, Histiocytosis X: integration of eosinophilic granuloma of bone, Letterer-Siwe disease and Schu¨ llerChristian disease as related manifestations of a single nosologic entity. Arch Pathol 56:84-102, 1953 40. Favara BE: Langerhans cell histiocytosis: Pathobiology and pathogenesis. Semin Oncol 18:3, 1991 41. Pileri SA, Grogan TM, Harris NL, et al: Tumours of histiocytes and accessory dendritic cells: An immunohistochemical approach to classification from the International Lymphoma Study Group based on 61 cases. Histopathology 41:1-29, 2002 42. Ben-Ezra J, Bailey A, Azumi N, et al: Malignant histiocytosis X: A distinct clinicopathologic entity. Cancer 68:1050-1060, 1991 43. Azumi N, Sheibani K, Swartz WG, et al: Antigenic phenotype of Langerhans cell histiocytosis: An immunohistochemical study
235 demonstrating the value of LN-2, LN-3 and vimentin. Hum Pathol 19:1376-1382, 1988 44. Hage C, Willman CL, Isaacson PG: Langerhans’ cell histiocytosis (histiocytosis X): immunophenotype and growth fraction. Hum Pathol 24:840-845, 1993 45. Ruco LP, Pulford KAF, Mason D: Expression of macrophageassociated antigens in tissues involved by Langerhans’ cell histiocytosis (histiocytosis X). Am J Clin Pathol 92:273-279, 1989 46. Krenacs L, Tiszlavicz L, Krenacs T, et al: Immunohistochemical detection of CD1a antigen in formalin-fixed and paraffin-embedded tissue sections with monoclonal antibody O10. J Pathol 171:99104, 1993 47. Mierau GW, Favara BE, Brenman JM: Electron microscopy in histiocytosis X. Ultrastr Pathol 3:137-142, 1982 48. Willman CL, Busque L, Griffith BB, et al: Langerhans’-cell histiocytosis (Histiocytosis X): A clonal proliferative disease. N Engl J Med 331:154-160, 1994 49. Yu RC, Chu AC: Lack of T-cell receptor gene rearrangements in cells involved in Langerhans cell histiocytosis. Cancer 75:11621166, 1995 50. Kim NR, Ko YH, Choe YH, et al: Erdheim-Chester disease with extensive marrow necrosis: A case report and literature review. Int J Surg Pathol 9:73-79, 2001 51. Milligan D, Roberts B, Limbert H, et al: Cytochemical and immunological characteristics of acute monocytic leukaemia. Br J Haematol 58:391-397, 1985 52. Wrotnowski U, Innes DJ, Hobson A: Nonspecific esterase staining patterns in acute monocytic leukemia. Am J Clin Pathol 87:515-518, 1987 53. Hanslip J, Swansbury G, Pinkerton R, et al: The translocation t(8;16)(p11;p13) defines an AML subtype with distinct cytology and clinical features. Leuk Lymphoma 6:479-486, 1992 54. Sawyers CL: Chronic myeloid leukemia. N Engl J Med 340: 1330-1340, 1999 55. Faderl S, Talpaz M, Estrov Z, et al: The biology of chronic myeloid leukemia. N Engl J Med 341:164-172, 1999 56. Solal-Celigny P, Desaint B, Herrera A, et al: Chronic myelomonocytic leukemia according to FAB classification: analysis of 35 cases. Blood 63:634-638, 1984 57. Storniolo AM, Moloney WC, Rosenthal DS, et al: Chronic myelomonocytic leukemia. Leukemia 4:766-770, 1990 58. Falini B, Pileri S, DeSolas I, et al: Peripheral T-cell lymphoma associated with hemophagocytic syndrome. Blood 75:434-444, 1990 59. Boyd A, Ellis D, Kannourakis G, et al: Activated killer cell lymphoma: an erythrophagocytic syndrome simulating histiocytic medullary reticulosis. Pathology 20:265, 1988 60. Isaacson P, Wright DH, Jones DB: Malignant lymphoma of true histiocytic (monocyte-macrophage) origin. Cancer 51:80, 1983 61. Wilson MS, Weiss LM, Gatter KC, et al: Malignant histiocytosis: A reassessment of cases previously reported in 1975 based upon paraffin section immunophenotyping studies. Cancer 66:530536, 1990 62. Egeler RM, Schmitz L: Malignant histiocytosis: a reassessment of cases formerly classified as histiocytic neoplasms and review of the literature. Med Pediatr Oncol 25:1-7, 1995 63. Cattoretti G, Villa A, Vezzoni P, et al: Malignant histiocytosis: A phenotypic and genotypic investigation. Am J Pathol 136:10091019, 1990 64. Hsu SM, Ho YS, Hsu PL: Lymphomas of true histiocytic origin: Expression of different phenotypes in so-called true histio-
236 cytic lymphoma and malignant histiocytosis. Am J Pathol 138:13891404, 1991 65. Hanson CA, Jaszcz W, Kersey JH, et al: True histocytic lymphoma: histopathologic, immunophenotypic and genotypic analysis. Brit J Haematol 73:187-198, 1989 66. Ralfkiaer E, Delsol G, O’Connor NTJ, et al: Malignant lymphomas of true histiocytic origin: A clinical, histological, immunophenotypic and genotypic study. J Pathol 160:9-17, 1990 67. Milchgrub S, Kamel OW, Wiley E, et al: Malignant histiocytic neoplasms of the small intestine. Am J Surg Pathol 16:11, 1992 68. Kamel OW, Gocke CD, Kell DL, et al: True histiocytic lymphoma: A study of 12 cases based on current definition. Leuk Lymphoma 18:81-86, 1995
CHANG ET AL 69. Weiss LM, Crabtree GS, Rouse RV, et al: Morphologic and immunologic characterization of 50 peripheral T-cell lymphomas. Am J Pathol 118:316-324, 1985 70. Picker LJ, Weiss LM, Medeiros LJ, et al: Immunophenotypic criteria for the diagnosis of non-Hodgkin’s lymphoma. Am J Pathol 128:181, 1987 71. Weiss LM, Picker LJ, Grogan TM, et al: Absence of clonal beta and gamma T-cell receptor gene rearrangements in a subset of peripheral T: cell lymphomas [published erratum appears in]. Am J Pathol 130:436-442, 1998 72. Weiss LM, Picker LJ, Copenhaver CM, et al: Large-cell hematolymphoid neoplasms of uncertain lineage. Hum Pathol 19:967973, 1988
D
ISORDERS OF HISTIOCYTES involving the bone marrow are predominantly quantitative in nature and can be divided into neoplastic and nonneoplastic proliferations. The non-neoplastic diseases include granulomatous infections, storage disorders, hemophagocytic syndromes, and sinus histiocytosis with massive lymphadenopathy (SHML). Postchemotherapy/radiotherapy bone marrows may also exhibit a histiocytosis. Neoplastic diseases associated with bone marrow histiocytosis include Langerhans cell histiocytosis, acute and chronic myeloid leukemias, chronic myeloproliferative disorders, non-Hodgkin’s lymphomas (including histiocytic sarcoma/true histiocytic lymphoma), and Hodgkin’s disease. GRANULOMAS IN THE BONE MARROW Because granulomas are manifestations of a systemic chronic inflammatory reaction, they may be associated with a variety of diseases (Figs 1A and 1B).1-7 Table 1 lists conditions associated with bone marrow granulomas. Bone marrow granulomas are not infrequently seen in patients with Hodgkin’s disease, non-Hodgkin’s lymphoma, or post-bone marrow transplantation and do not necessarily represent involvement by malignancy. Granulomas in the bone marrow are similar to those appearing in other organs. They are composed of aggregates of histiocytes, which are typically surrounded by lymphocytes, plasma cells, and eosinophils (Fig 2).
From the Department of Pathology, City of Hope National Medical Center, Duarte, CA. Address reprint requests to Karen L. Chang, MD, City of Hope National Medical Center, 1500 East Duarte Rd, Duarte, CA 91010; e-mail: [email protected]. © 2003 Elsevier Inc. All rights reserved. 0740-2570/03/2003-0007$30.00/0 doi:10.1053/S0740-2570(03)00029-7 226
Lipogranulomas also have admixed adipocytes and are usually not associated with disease (Fig 3). Epithelioid granulomas do not contain adipose tissue. The epithelioid granulomas of immunocompromised patients are often loosely formed, and may be so dispersed that no granuloma is apparent (Fig 4). In these cases, special stains for mycobacteria and fungi should be performed (Figs 5A and B). Epithelioid granulomas associated with multinucleated giant cells or areas of necrosis may be seen in patients with mycobacterial or fungal infections. Q-fever granulomas have a characteristic central clearing surrounded by fibrin and may easily be mistaken for a lipogranuloma “Fibrin ring” granulomas have also been described in patients with cytomegalovirus infection (Fig 6). Granulomas are difficult to find in bone marrow smears and are most easily detected in bone marrow biopsy or clot sections. The differential diagnosis of bone marrow granulomas includes mast cell disease, large cell lymphoma, histiocyte/T-cell rich B-cell lymphoma, and metastatic clear cell carcinomas. These can be distinguished by the presence of malignant cytologic features and by different immunohistochemical profiles in the lymphomas and carcinomas. Mast cell disease has a characteristic immunostaining pattern (positive for tryptase) not seen in granulomas.8 LYSOSOMAL STORAGE DISEASES The histiocytes of storage diseases are qualitatively and quantitatively affected by an accumulation of proteins.9-14 The lysosomal storage diseases are rare hereditary deficiencies of one of the lysosomal enzymes necessary for glycolipid and glycoprotein degradation. Without the necessary enzymes, the cell lysosomes accumulate glycolipid or glycoprotein substrates. These disorders are subdivided based on the accumulated
Seminars in Diagnostic Pathology, VOL 20, NO 3 (AUGUST), 2003: pp 226-236
HISTIOCYTIC LESIONS Table 1.
Diseases Associated With Bone Marrow Granulomas
Caseating granulomas Tuberculosis Histoplasmosis Noncaseating granulomas Viral (Cytomegalovirus, Herpes zoster virus) Mycobacterium avium intracellulare Other infections (Brucellosis, rickettsial infections, Q-fever, typhoid fever, leprosy, tularemia, mycoplasma) Sarcoidosis Non-Hodgkin’s lymphoma Hodgkin’s disease Multiple myeloma Posttherapy Autoimmune disorders Drug-associated (phenytoin, chlorpropamide) Idiopathic
substrates and include sphingolipidosis, glycoproteinosis, mucolipidosis, and mucopolysaccharidosis. All of the storage diseases may contain histiocytes with characteristic lysosomal overload, which typically manifests as cytoplasmic vacuolation. The histiocyte morphology and extent of marrow involvement varies with the different lysosomal storage disorders. The lysosomal storage disorders most commonly associated with significant bone marrow pathology include two variants of sphingolipidosis, Gaucher’s disease and NiemannPick disease, as well as a variant of Niemann-Pick disease known as “sea-blue histiocytosis.” Gaucher’s disease, the prototypic sphingolipidosis, is caused by an accumulation of glucosylcerebroside. These patients most commonly present with splenomegaly, but may also have symptoms related to an accumulation of pathologic Gaucher cells in liver, bones, lungs, and brain.9 On aspirate smears, Gaucher cells are large with small inconspicuous nuclei and abundant light blue crinkled cytoplasm. The latter has been described as having the appearance of “skeins of yarn.” Their appearance on tissue sections is similar, with small bland nuclei and abundant slightly eosinophilic cytoplasm with a striated appearance (Fig 7). The cells may have a patchy distribution or may diffusely replace the normal marrow (Fig 8). The bony trabeculae are normal and necrosis is uncommon. Mimics of Gaucher cells include macrophages that are replete with lipid products derived from cellular destruction/high turnover, as seen in acute and chronic myeloid leukemias, congenital dyserythropoietic anemias, thalassemia major, and plasma cell dyscrasia. In these cases, the Gaucher-like cells are not due to the absence of the
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enzyme, but rather that the enzyme is overwhelmed. Therefore, the diagnosis of Gaucher’s disease must be corroborated by enzyme assay (measuring glucosyl cerebrosidase in the peripheral blood white cells). Niemann-Pick disease also typically presents with splenomegaly and is characterized by an absence of sphingomyelinase. As with other lysosomal clinical disorders, the disease exists in several clinical forms, which vary in severity. The histiocytes of NiemannPick disease are enlarged and have foamy cytoplasm, which results from numerous tiny vacuoles loaded with lipid products. Such histiocytes may also be seen in patients with hypercholesterolemia, Langerhans cell histiocytosis, Wolman’s disease, and Tangier disease (familial high density lipoprotein deficiency). A form of Niemann-Pick disease associated with splenomegaly, neurologic disorders, and thrombocytopenia is known as “sea-blue histiocytosis.”13 Sea blue histiocytes are slightly smaller than Niemann-Pick histiocytes and have cytoplasm loaded with coarse basophilic ceroid-containing granules that stain sea blue or blue green with a Romanowsky stain. The granules, which vary in size, stain with Sudan Black B and Oil Red O.15 They are seen in numerous hematologic diseases including Niemann-Pick disease, chronic myleogenous leukemia (CML), polycythemia vera, hematolytic anemia, and other conditions. The lysosomal storage disorders discussed above affect histiocytes far more often and more severely than other cell types. However, lymphocytes may also be affected in the storage disorders and may also be abnormal in patients with mucopolysaccharide accumulation.12 In fact, Alder-Reilly bodies, which are dense azurophilic granular inclusions composed of glycosaminoglycan in lysosomes, may be seen in lymphocytes and less frequently, monocytes of patients with inherited mucopolysaccharidosis. HEMOPHAGOCYTIC SYNDROMES A variety of neoplastic and non-neoplastic conditions contain macrophages that phagocytose hematopoietic cells, most commonly associated with erythroid precursors. Erythrophagocytosis is often accompanied by ingestion of other elements including platelets and neutrophils. The phagocytosing histiocytes usually contain abundant vacuolated cytoplasm, with one or several red blood cells or remnants, and containing round to oval nuclei with lacy bland chromatin and inconspicuous nucleoli.
HISTIOCYTIC LESIONS
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Infection-Associated Hemophagocytic Syndrome
Familial Hemophagocytic Lymphohistiocytosis
Infection-associated hemophagocytic syndrome is a non-neoplastic, systemic proliferation of benign-appearing histiocytes affecting almost every organ, including the bone marrow.16-22 Almost any infectious agent may be involved, but acute viral infections account for the majority of cases. This syndrome usually occurs in patients who have a documented primary or iatrogenic (eg, organ-transplant-related) immunodeficiency. Patients usually present with fever and other constitutional symptoms, and have hepatosplenomegaly, generalized lymphadenopathy, and less frequently, a skin rash and bilateral pulmonary infiltrates. Pancytopenia and liver function abnormalities are often present. Infection-associated hemophagocytic syndrome is a benign, self-limiting condition. However, affected patients may die during the acute disease episode due to multisystem failure or later due to infectious complications exacerbated by their underlying immunodeficiency. Epstein-Barr-associated hemophagocytic syndrome appears to be a particularly virulent form of this syndrome, affecting young children and leading rapidly to death.23,24 The pathologic features vary with the time that biopsies are performed. Early in the disease, the bone marrow may only partially be involved by a small number of histiocytes. Later in the disease, one may see massive infiltration by benign-appearing histiocytes (Fig 9). The histiocytes may show prominent hemophagocytosis and platelet phagocytosis. The bone marrow may also be cell-poor, with marked myeloid and erythroid hypoplasia. Other manifestations of infection, such as left-shifted granulopoiesis, mild lymphocytosis, and plasmacytosis, and granulomas, may also be present. The differential diagnosis of infection-associated hemophagocytic syndrome includes familial hemophagocytic lymphohistiocytosis and malignant lymphomas associated with benign hemophagocytosis, both of which are discussed below.
Familial hemophagocytic lymphohistiocytosis is a rare and usually fatal disease that is also characterized by marked lymphohistiocytic infiltration in multiple organs.25-27 Most patients are infants, and approximately three fourths of cases are familial, with an autosomal recessive mode of inheritance. The infants usually present with fevers, hepatosplenomegaly, pulmonary effusions, and a skin rash. Pancytopenia and a severe hypofibrinogenemia without abnormalities of other clotting factors are typical laboratory findings. Impaired cellular and humoral immunity are features of this disorder. The disease is usually rapidly fatal (within weeks), with death due to sepsis or bleeding. The lymph nodes and bone marrow are the most frequently involved organs, followed by the spleen, liver, and the central nervous system.28 The bone marrow in patients with familial hemophagocytic lymphohistiocytosis is partially to completely effaced by a loose infiltrate of benign-appearing histiocytes, lymphocytes and plasma cells. The histiocytosis is quite pronounced and is accompanied by prominent erythrophagocytosis as well as phagocytosis of lymphocytes and other cellular debris. Other organs of the reticuloendothelial system may also contain large numbers of hemophagocytic histiocytes. Familial hemophagocytic lymphohistiocytosis and infection-associated hemophagocytic syndrome may be clinically and morphologically similar. In fact, they may represent the same disease, with familial hemophagocytic lymphohistiocytosis presenting as infection-associated hemophagocytic syndrome in individuals with familial immunodeficiencies. Importantly, one must distinguish these morphologically benign diseases from the histiocytosis accompanying malignant disorders such as non-Hodgkin’s lymphomas. Sinus Histiocytosis with Massive Lymphadenopathy Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) is a rare idiopathic disease of
Š Fig 1. (A) Granulomas in the bone marrow may be in a paratrabecular or interstitial location. (B) This is a case of granulomas associated with regeneration following bone marrow transplantation. Fig 2. A tight epithelioid granuloma is typical of sarcoidosis, which is a multisystemic disease. Fig 3. Lipogranulomas have various amounts of lipid inclusions. This case contains finely vacuolated cytoplasm. Fig 4. These histiocytes are interspersed with other chronic inflammatory cells and do not form a true granuloma. Fig 6. This ring granuloma was found in a post-bone marrow transplantation patient, who was infected with cytomegalovirus. Fig 5. (A) The aspirate smear from this case shows histiocytes with 3 prominent clear vacuoles as well as several other vacuoles. (B) GMS stain from the tissue section of this case shows histoplasmosis. Fig 7. The bone marrow aspirate smear of a patient with Gaucher’s disease contains histiocytes with granular and striated cytoplasm.
HISTIOCYTIC LESIONS
proliferating histiocytes.29-31 Approximately 90% of patients present with massive, painless, bilateral cervical lymphadenopathy. Extranodal sites are involved in approximately 40% of cases, but bone marrow involvement is extraordinarily rare and has been described as patchy paratrabecular and non-paratrabecular foci of foamy histiocytes.31 Despite lack of extensive bone marrow involvement, patients may develop hemolytic anemia, idiopathic hypereosinophilic syndrome and malignant lymphoma. Sinus histiocytosis with massive lymphadenopathy involving bone marrow has histiocytes with the distinctive nuclear features of SHML in other organs (Fig 10). Paraffin immunohistochemical studies show staining with antibodies to S100 protein and other macrophageassociated antigens.32 The cells do not express the CD1 antigen found on Langerhans cells, and also lack expression of R4/23, a monoclonal antibody with high specificity for follicular dendritic cells. Molecular studies show a germline configuration for both the immunoglobulin heavy chain gene and the -T cell receptor gene.33 The differential diagnosis includes reactive sinus histiocytosis and Langerhans cell histiocytosis (Fig 11). Reactive histiocytes should not stain with S100, unlike the histiocytes of SHML. The cytologic characteristics of Langerhans cells and the presence of eosinophils helps to separate Langerhans cell histiocytosis from SHML. CD1 expression, the presence of Birbeck granules, and lack of emperipolesis in Langerhans cell histiocytosis also help differentiate Langerhans cell histiocytosis from SHML. POST-BONE MARROW TRANSPLANTATION HISTIOCYTIC PROLIFERATION Radiation or chemotherapy may result in severe bone marrow damage.34-37 Hematopoiesis is essentially ab-
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sent, there is a proliferation of stromal cells and possibly plasma cells, and there may be interstitial edema and hemorrhage. There is marked predominance of adipocytes (sometimes fat necrosis) and hemosiderinladen macrophages. In the resolution stage, one may see an abundance of histiocytes. The clinical setting makes iatrogenic histiocytosis easy to separate from other forms of histiocytosis. MALIGNANCIES ASSOCIATED WITH HISTIOCYTES/MONOCYTES While not strictly a histiocytic disorder, monocytic proliferations share common ontogeny with histiocytic lesions and are therefore included in this review.38 Apart from subtypes of acute and chronic leukemias, malignancies of histiocyte/monocyte origin involving the bone marrow are extremely rare. Langerhans Cell Histiocytosis (Histiocytosis X) Langerhans cell histiocytosis is a term that comprises a group of closely related clinicopathologic disorders with a common neoplastic proliferating element, the Langerhans cell.39-41 Historically, the entity was also known as histiocytosis X and Langerhans cell granulomatosis. Generally there are 3 main and sometimes overlapping clinical syndromes. Unifocal disease (solitary eosinophilic granuloma) accounts for approximately two thirds of cases. Multifocal unisystem disease (Hand-Schuller-Christian syndrome), and multifocal multisystem disease (Letterer-Siwe syndrome) are the other 2 common syndromes. The bone is involved in all three clinical presentations and the bone marrow may be involved by extension. The bone marrow is only rarely the sole site of involvement. Bone marrow involvement is more easily seen in biopsies than aspirate smears because the characteristic nuclear features are not present in air-dried preparations.
Š Fig 8. This trephine biopsy section shows a paratrabecular and patchy interstitial infiltrate of Gaucher histiocytes. Fig 9. This histiocyte from a patient with viral-associated hemophagocytic syndrome is phagocytosing red blood cells and other nuclear debris. Fig 10. This bone marrow from a patient with SHML shows paratrabecular fibrosis and a proliferation of histiocytes with somewhat vesicular nuclear chromatin and abundant cytoplasm. Fig 11. This bone marrow is hypercelluar and contain numerous histiocytes admixed with lymphocytes, eosinophils, and other chronic inflammatory cells. Special stains for microorganisms and paraffin immunohistochemical studies failed to reveal an infectious or malignant etiology. No specific cause was ever found in this patient. Fig 12. A bone marrow trephine biopsy section from a patient with Langerhans cell histiocytosis shows prominent interstitial involvement. Fig 13. One prominent promonocyte is admixed with monoblasts in this aspirate smear from a patient with AML M5 b. Fig 14. These monoblasts have blastic chromatin, and very little nuclear or cytoplasmic maturation. Fig 15. Butyrate esterase activity in monoblasts is strong and diffusely cytoplasmic. Fig 16. Pseudo-Gaucher cells are often seen in patients with chronic myelogenous leukemia.
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The diagnosis is easily made by observing a proliferation of Langerhans cells in the appropriate cellular background. Langerhans cells have a single large nucleus with a characteristic folded or grooved nucleus (so-called “coffee-bean” appearance) with small inconspicuous nucleoli. The nuclear chromatin is usually bland. Slight cytologic atypia may be seen. The cells are approximately 12 to 15 in diameter, with a moderate amount of eosinophilic cytoplasm. Mitotic activity varies from lesion to lesion, but is generally low. The background cells include mononuclear and multinucleated histiocytes, abundant eosinophils, neutrophils, and small lymphocytes. Small clusters of eosinophils may be associated with necrosis, forming so-called eosinophilic microabscesses. Marrow fibrosis may be extensive. Plasma cells are rarely, if ever, seen. Involvement may be patchy or diffuse (Fig 12). Cases in which the Langerhans cells have unequivocally malignant cytologic features have been called malignant histiocytosis X or malignant Langerhans cell histiocytosis, but these have not been described in the bone marrow.42 The ultrastructural, enzyme histochemical, and immunohistochemical features of Langerhans cells of Langerhans cell histiocytosis are virtually identical to those of normal Langerhans cells. By immunohistochemistry, Langerhans cells virtually always express CD1 and S100 protein, and a portion of the neoplastic cells express CD68 and anti-placental alkaline phosphatase.43-45 CD1 staining has the greatest diagnostic utility, because CD1 expression is limited to reactive and neoplastic Langerhans cells, immature thymocytes, and T-lineage lymphoblastic neoplasms. Other histiocytic and dendritic cells lack CD1 expression.46 CD30 and CD15 expression are not found in Langerhans cells. Electron microscopy of Langerhans cells shows characteristic Birbeck granules, which are racket-shaped organelles approximately 200 to 400 nm long and 33-nm wide, with an osmiophilic core and a double outer sheath.47 Langerhans cell histiocytosis has been shown to be a monoclonal proliferation, as evidenced by its pattern of X-chromosome inactivation in the X-linked human androgen-receptor gene.48 Molecular hybridization studies show a germline configuration for the immunoglobulin heavy chain gene as well as for the beta, gamma, and delta chains of the T cell receptor genes.48,49 Bone marrow involvement by Langerhans cell histiocytosis should be distinguished from other more common large cell proliferations involving the bone mar-
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row, including granulomatous disease, metastatic adenocarcinoma, metastatic malignant melanoma, and large cell lymphoma, as well as the even less common SHML involving the bone marrow. Identification of the characteristic Langerhans cell cleaved nucleus, as well as the characteristic cellular milieu, helps to establish the diagnosis of Langerhans cell histiocytosis. Large cell lymphomas lack the unique grooved nucleus and show reactivity for B-cell or T-cell antigens. The malignant cytology of cells of the metastatic malignancies and sinusoidal malignant lymphoma contrasts with the bland cytology of Langerhans cell histiocytosis. The cells of SHML have rounded nuclei with vesicular chromatin and prominent nucleoli and abundant cytoplasm, which differs from the folded, grooved nuclei of Langerhans cell histiocytosis. One reported case of Erdheim-Chester disease, a multiorgan infiltration of fibrosing xanthogranulomas, presented with diffuse bone marrow infiltration by foamy histiocytes, Toutontype giant cells, and fibroblastic cells associated with extensive coagulative necrosis.50 Paraffin immunohistochemistry showed positivity for CD68 and rare cells for S100. Clinical and radiologic correlation helped establish a diagnosis of Erdheim-Chester disease. Acute Myeloid Leukemia Acute myelogenous leukemia accounts for more than 50% of leukemias in adult and approximately 20% of leukemias in children. The myeloid leukemias with cytologic and cytochemical features of monocytic/histiocytic differentiation fall into the category of “acute myeloid leukemia, not otherwise categorized,” in the WHO classification, and corresponds to “acute myelomonocytic leukemia,” “acute monoblastic leukemia,” and “acute monocytic leukemia” (FAB-M4, FAB-M5a, and FAB-M5b, respectively) in the FrenchAmerican-British Classification. These monocytoid/ monocytic subtypes of acute leukemia are far more common than the other neoplastic histiocytic disorders discussed elsewhere in this review. These leukemias differ solely in the percentage of immature cells showing cytochemical evidence of monocytic differentiation, and whether those immature cells are more or less mature.51 Monoblasts and promonocytes are most easily distinguished from one another in bone marrow aspirate smears, and not in fixed bone marrow biopsy sections. Both cell types are large with large nuclei. Promonocytes have irregular, folded and convoluted nuclear contours, with a moderate amount of cytoplasm that may be vacuolated but not granulated (Fig 13). In other words, they appear just slightly less mature than
HISTIOCYTIC LESIONS
mature monocytes. In contrast, monoblasts lack the folded nuclei and abundant vacuolated cytoplasm of a promonocyte. Instead, monoblasts usually have round to oval nuclei with delicate chromatin, prominent nucleoli, and abundant cytoplasm (Fig 14). Some authors have described the monoblasts as appearing amoeboid. The authors consider the distinction between the two to be merely academic, as promonocytes and monoblasts are both counted as “blasts” in assessing for AML. The cytochemical stains most specific for monocytes are alpha-naphthyl butyrate as substrate and hexa-azotized pararosaniline as coupler (monocyte-specific non-specific esterase activity) (Fig 15).52 Alpha-naphthyl acetate and naphthol AS-D acetate are also reactive substrates for monocytes, but specificity for monocytes must be validated by showing fluoride inhibition, which is a unique feature of monocyte esterases. One distinct subtype of acute myeloid leukemia, AML M5b, shows monocytoid blasts with abundant intracytoplasmic granules and prominent erythrophagocytosis by the leukemic cells.53 This subtype of acute monocytic leukemia is associated with t(8;16)(p11; p13), disseminated intravascular coagulation, and prominent central nervous system and extramedullary involvement. Chronic Myeloid Leukemia Chronic myeloid leukemia, a clonal myeloproliferative disorder characterized by a reciprocal translocation between chromosomes 9 and 22, affects mostly adults in their sixth decade or older.54,55 The bone marrow is hypercellular and usually shows marked myeloid and megakaryocytic hyperplasia. There is high cell turnover, manifesting as lipid-filled macrophages resembling Gaucher cells and sea-blue histiocytes (Fig 16). The presence of marrow fibrosis and the demonstration of the characteristic cytogenetic finding, as well as the BCR-ABL (breakpoint cluster region gene of chromosome 22 and ABL gene of chromosome 9) gene rearrangement, establishes the diagnosis of CML and helps exclude storage disorders and other forms of myeloproliferative disorder, which may also be associated with Gaucher-like macrophages.
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characterized by at least 10% monocytes in the peripheral blood white blood cell count differential, less than 20% blasts, and lack of BCR-ABL gene rearrangement. The bone marrow is usually hypercellular and contains a proliferation of mature monocytes, which are often dysplastic. The peripheral blood monocytosis is also mature, but is not reliable by itself for the diagnosis of chronic myelomonocytic leukemia, because mature monocytes may also be seen in the peripheral blood of patients with acute myelomonocytic leukemia or acute monocytic leukemia. Malignant Lymphoma With Benign Erythrophagocytosis T-cell lymphomas, and less often other lymphomas, may induce a marked hyperplasia of cytologically benign hemophagocytosing histiocytes.58,59 Malignant lymphoma with benign erythrophagocytosis is a condition in which lymphoma is associated with a reactive hemophagocytic disorder and may present in two different ways. In the first presentation, patients with known lymphoma develop a syndrome mimicking infection-associated hemophagocytic syndrome. In these cases, malignant lymphoma cells are found in the bone marrow often without the histiocytic proliferation. In the second clinical presentation, the hemophagocytic syndrome occurs in the absence of any previously diagnosed malignancy and usually prompts a search for malignancy. In this setting, benign hemophagocytizing histiocytes are intimately interspersed with lymphoma cells. Paraffin and frozen section immunophenotyping studies usually demonstrate a T-cell lineage. Malignant lymphoma with benign erythrophagocytosis may be confused with infection-associated hemophagocytic syndrome. Identification of the lymphoma cells distinguishes the malignancy from infection-associated hemophagocytic syndrome. Also, the lymphomas are usually not associated with a systemic infection, as is infection-associated hemophagocytic syndrome. Biopsies of other organs may be needed for cases in which this distinction may be difficult.
Mixed Myeloproliferative/Myelodysplastic Syndrome
Histiocytic Sarcoma
Patients with chronic myelomonocytic leukemia often present with splenomegaly, abnormal white blood cell counts, and trilineage dysplasia.56,57 The patient’s WBC count serves to separate the entity into myelodysplastic subtype (⬍13,000/uL) and myeloproliferative subtypes (ⱖ13,000/uL). Both of these subtypes are
True histiocytic lymphoma, malignant histiocytosis, and histiocytic sarcoma are synonymous terms for a rare neoplasm in which the malignant cells show lineage consistent with histiocytes.60-68 This tumor is extremely rare, accounting for ⬍ 0.5% of all hematolymphoid neoplasms. Lymph nodes are commonly
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involved but bone marrow involvement is extremely rare. The bone marrow spaces may be partially or completely effaced by a proliferation of cytologically malignant cells that resemble histiocytes. The neoplastic cells are variable in size and have a large, eccentric oval nucleus with a prominent irregular nucleolus and abundant eosinophilic cytoplasm. Histiocytic sarcomas may also contain bizarre multinucleated tumor cells, multiple nucleoli, vacuolated cytoplasm, and hemophagocytosing tumor cells. Spindle cell sarcoma-like areas may also be present. Mitotic activity is usually quite high. The tumor cells have no unique morphologic characteristics and thus, immunophenotypic and molecular studies are absolutely essential for diagnosis. As in other organs, the diagnosis of histiocytic sarcoma in the bone marrow is based on strong immunologic evidence of histiocytic lineage, with complete absence of specific T and B lineage markers. In addition, the tumor must have molecular evidence of a germline configuration for the T-cell receptor and immunoglobulin genes.69-72 The tumor cells show paraffin immunohistochemical staining with CD68, lysozyme, and alpha-1-antitrypsin, and they should not stain with CD30, CD1a, any B-lineage or T-lineage-specific antibodies, any of the anti-keratin antibodies, or HMB45.60-68 The differential diagnosis of histiocytic sarcoma includes anaplastic large cell lymphoma, B-cell sinusoidal large cell lymphoma, anaplastic carcinomas showing hemophagocytosis, malignant lymphomas associated with benign erythrophagocytosis, follicular dendritic cell neoplasms, hepatosplenic T-cell lymphoma, infection-associated hemophagocytic syndrome, storage diseases such as Gauchers disease and Niemann-Pick disease, and familial hemophagocytic lymphohistiocytosis. In fact, the early reports of malignant histiocytosis have since been reclassified as anaplastic large cell lymphoma, B- or T-cell lymphomas, or infection-associated hemophagocytic syndrome.60-68 The strict morphologic, phenotypic, and molecular criteria of histiocytic sarcoma, along with clinical presentation, help separate histiocytic sarcoma from the other malignant entities in the differential diagnosis. Unlike the reactive processes, the phagocytic histiocytes of histiocytic sarcoma have highly atypical, hyperchromatic, and often multinucleated nuclei.
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