Chapter 36: Inflammatory and Malignant Histiocytosis

• The terms histiocyte and macrophage are synonyms for the mature cell of the monocyte-macrophage system. The latter is the preferred term in discussions of cell biology and immunology, but “histiocytosis” continues to be used by pathologists and in textbooks for diseases of macrophages because of its entrenchment in the medical literature.

• A classification of the histiocytoses most relevant to hematologists is shown in Table 36–1. They have been classified based on whether they are monocyte-derived dendritic cell–related, monocyte-macrophage–related, or neoplastic transformations of dendritic cells or macrophages.

• Distinctions among the diseases of macrophages are made based on clinical findings, histopathology, immunophenotyping of surface antigen, cytochemistry, and cytogenetic or genetic features (Table 36–2).

Langerhans Cell Histiocytosis

Definition and History

• The term Langerhans cell histiocytosis includes disorders previously called histiocytosis X (eosinophilic granuloma, Letterer-Siwe disease, Hand-Schüller-Christian disease), self-healing histiocytosis, and Langerhans cell granulomatosis.

• Langerhans cells are macrophages with irregularly shaped nuclei present in epidermis, mucosa, lymph nodes, thymus, and spleen.

• As all macrophages types, they originate in marrow from a multipotential hematopoietic cell.

• Identified by unique racquet-shaped ultrastructural inclusions (Birbeck bodies) and by immunoreactivity to neuroprotein S-100, neuronal specific enolase, and surface antigen CD1a and CD207 (Langerin). Birbeck bodies, CD1a expression, and strong CD207 expression are pathognomonic for Langerhans cells.

• The principal function of Langerhans cells is to process antigen and present it to T cells.

Etiology and Pathogenesis

• Although long thought to be an inflammatory or immunologic disorder, it is now known to be a clonal disease and, therefore, a neoplastic disorder with localized and disseminated forms.

• X chromosome–linked, DNA probes found clonal CD1a+ histiocytes in all lesions tested whether solitary or widespread and whether the lesional cells studied are in one organ or another. In contrast, the T lymphocytes are polyclonal.

• The disease simulates inflammation because the neoplastic Langerhans cells, a dendritic histiocytes, make up a very small fraction of most lesions (≤ 1%).

• The lesion is composed largely of accompanying inflammatory cells (eg, eosinophils, T lymphocytes, macrophages), and is often xanthomatous, fibrotic, or granulomatous, simulating inflammation or infection.

• The presence of BRAF^V600E mutations in approximately 35% of a small sample of patients may result in a new therapeutic target in these patients.

Epidemiology

• There are approximately 6 cases per million children younger than age 15 years.

• Disease appears before age 10 years in 75% and before age 30 years in 90% of patients.

• Median age of presentation is 30 months, but disease can present in adults of any age.

• Males frequently have localized disease; 90% of cases with multisystem involvement occur before age 20 years.

Pathogenesis

• Langerhans cell histiocytosis could be a neoplasm based on the compelling evidence in several laboratories for a monoclonal pattern. Studies of adult solitary pulmonary involvement have not found clonal Langerhans cells. Array comparative genomic hybridization did not identify gene mutations in CD207+ cells (presumptive Langerhans cells).

• The Langerhans cells in this disorder behave as an immature dendritic cell and do not stimulate primary T-cell responses effectively. They present antigen poorly and proliferate at a low rate.

Clinical Findings

• Patients may present with single or multiorgan involvement.

• Lesions often involve bone (especially skull and facial bones), skin, lungs, lymph nodes, spleen, thymus, pituitary, and hypothalamus.

• Disease may be localized to a bone or soft tissue site, multifocal in bone only, or multifocal in bone and other sites.

• The disease can occur in any bone. The skull, femurs, ribs, vertebrae (esp. cervical) and humeri are the most frequent sites involved.

• In children, the most frequent site is a lytic lesion of the skull, either painful or not.

• Bony involvement in the face bones has a several-fold risk of central nervous system involvement and diabetes insipidus.

• Diabetes insipidus may appear early or late in the course and is the most frequent sign of central nervous system involvement.

• Diabetes insipidus is the presenting symptom in approximately 4% of patients and 15% to 2% will develop diabetes insipidus during the course of the disease.

• Uncommonly, other central nervous system effects of the disease occur (eg, mass lesions in gray or white matter, neurodegeneration with dysarthria, ataxia, dysmetria). Magnetic resonance imaging may show significant brain changes years before onset of clinical manifestations.

• Cervical lymph nodes most common lymphatic site involved. The thymus and mediastinal nodes may be enlarged.

• Infants may have fever, otitis media, or mastoiditis, with enlargement of liver, spleen, and lymph nodes, or self-limited skin lesions of head and neck.

• Skin lesions can have seborrheic or eczematoid features, and in infants, can be mistaken as prolonged “cradle cap” and in adults as dandruff.

• Skin lesions commonly affect skin flexures in groin, perianal area, the ears, the neck, the armpits, and below the breasts.

• Skin lesions in older children and adults may appear as red papules. Lesions may ulcerate.

• Skin lesions may precede more diffuse disease.

• Oral mucosal lesions may include ulcers on the soft or hard palate, tongue, or lips. There may be gingival hypertrophy.

• Children and adolescents often have pain, tenderness, swelling caused by lytic bone lesion(s); bleeding from gastrointestinal tract; polydipsia; and polyuria as a result of hypothalamic involvement.

• Adult males may have primary pulmonary involvement, causing chronic nonproductive cough, chest pain, dyspnea, wheezing, with a high frequency of associated lung cancer.

• Young women may have localized involvement of the genital tract or it may be part of multicentric involvement. Pregnancy is associated with exacerbation of diabetes insipidus.

• There is a high risk of severe disease in sites including the liver, spleen, lung, and marrow.

• Massive splenomegaly can result in cytopenias.

• Liver enlargement can lead to dysfunction with low albumin, hyperbilirubinemia, and clotting factor deficiencies. Sclerosing cholangitis as a result of bile duct injury is a very serious complication.

• Lung involvement is far more common in adults than children and is associated with cigarette smoking. Chest radiographs show an interstitial infiltrate but computed tomography uncovers cystic and nodular pattern characteristic of Langerhans cell histiocytosis. Later fibrosis can lead to severe pulmonary insufficiency.

• Marrow involvement may be associated with hemophagocytic macrophages as a result of cytokine activation but bone or skin involvement and biopsy results should discriminate between hemophagocytic lymphohistiocytosis and Langerhans cell histiocytosis.

• There is a low risk of severe disease in sites including the skin, bone, lymph nodes, and pituitary gland singly or in any combination.

Laboratory Findings

• Neutrophilia, increased erythrocyte sedimentation rate, increased serum alkaline phosphatase level, and other abnormalities are indicative of liver disease may occur.

• Biopsy of involved tissue demonstrates pathologic Langerhans cells: abundant in proliferative lesions, scarce in fibrotic lesions. Langerhans cells express CD1a and CD207.

• Radiographs, computed tomograms, or positron emission tomograms can identify bone lesions. The latter technique is useful to measure healing of bone after therapy.

Differential Diagnosis

• Depending on site of involvement, this includes chronic granulomatous infections, various infections, lymphoma, collagen vascular disease, pneumoconiosis, and amyloidosis.

• Reactive Langerhans cells may be present in biopsies of Hodgkin lymphoma, malignant lymphoma, and chronic lymphocytic leukemia.

Treatment

• Treatment of skin disease is dictated in part by extent of involvement. Topical glucocorticoids usually do not induce a satisfactory response. Oral methotrexate (20 mg/m²), once weekly, for 6 months or oral thalidomide, 50 to 200 mg, nightly, can be beneficial. Topical nitrogen mustard may benefit those not responding to oral agents, if the disease is not widespread. Psoralen with ultraviolet A light (PUVA) has been used.

• Patients with (1) single skull lesions of the frontal, parietal, or occipital regions or (2) single lesions of any other bone may be treated with curettage or curettage plus injections of methylprednisolone.

• Patients with skull lesions of mastoid, temporal, or orbital bones have a risk of developing diabetes insipidus (~35% of untreated patients) and should receive 12 months of treatment with vinblastine, 6 mg/m², intravenously, weekly for 7 weeks, and then every 3 weeks, if a good response, coupled with prednisone, 40 mg/m², orally, daily, for 4 weeks, then tapered to zero over next 2 weeks. Thereafter, prednisone is given at 40 mg/m², orally, daily for 5 days, every 3 weeks with vinblastine injections. If suboptimal response at 6 weeks, vinblastine is continued weekly for an additional 6 weeks before going to every 3 weeks.

• Patients with femoral or vertebral lesions at risk of collapse require orthopedic and neurosurgical evaluation. Radiation therapy and a stabilizing orthopedic or neurosurgical procedure, respectively, may be required.

• Patients with bone lesions or combinations of skin, lymph node, or pituitary gland involvement with or without bone lesions should receive 12 months of treatment with vinblastine, 6 mg/m², intravenously, weekly for 7 weeks, and then every 3 weeks, if a good response, coupled with prednisone, 40 mg/m², orally, daily, for 4 weeks, then tapered to zero over next 2 weeks. Thereafter, prednisone is given at 40 mg/m², orally, daily for 5 days, every 3 weeks with vinblastine injections. Single-drug treatment is insufficient in this setting and has a high relapse rate.

• Patients with spleen, liver, marrow, or lung (with or without skin, bone, lymph node, or pituitary gland involvement) should receive multidrug therapy as shown in Table 36–3.

• Patients with central nervous system mass lesions or leptomeningeal involvement have received intravenous cladribine in doses ranging from 5 to 13 mg/m² at various frequencies. Also, various other drug combinations have been reported for treatment of neurodegenerative disease associated with Langerhans cell histiocytosis.

• Optimal treatment of children with recurrent or refractory, or progressive disease has not been determined.

• Blood component therapy may be needed for severe cytopenias.

• Splenectomy may be warranted for massive symptomatic splenomegaly and transfusion dependence (hypersplenism).

• Allogeneic hematopoietic stem cell transplantation has been beneficial in some patients with multisystem disease who were refractory to multidrug regimens. Reduced-intensity conditioning can be curative and is associated with less toxicity.

• For isolated bone disease that recurs 6 months or more after the end of treatment, the same treatment program with vinblastine and prednisone can be reused (see above discussion on treatment of bone lesions).

• Recurrent high-risk organ involvement requires one of several multidrug regimens; there is in these cases relatively high treatment-related mortality. Specific approaches have not yet been developed in clinical trials and depend on the organ(s) involved and the duration of the prior remission.

• For high-risk organ disease, a multidrug program akin to that used for acute myelogenous leukemia or aggressive lymphoma, which includes cytarabine and cladribine, can be used. Allogeneic stem cell transplantation should be incorporated into the latter treatment plan in eligible patients.

• Cladribine and pentostatin have been used in relapsed patients and have frequent salutary effect in those with skin, bone, and lymph node involvement, but less so in patients with liver, marrow, spleen or lung involvement.

• Mutilating surgery of skin, teeth, or jaw bones should not be done as these problems can be managed by systemic chemotherapy, allowing bones to reform.

Course and Prognosis

• Good prognosis is associated with isolated bone lesions.

• Poor prognosis is associated with onset of disease during first 2 years of life, fever not explained by infection, blood cytopenias, and abnormal liver function or pulmonary function tests.

• Refractory multisystem disease is defined as progression on therapy during first 6 weeks or no response to therapy by 12 weeks. Children in this category have approximately a 10% chance of long-term survival.

• Long-term survival (cure) in patients treated with vinblastine and prednisone for low-risk disease is very high, if treatment extends well beyond 6 months.

• Long-term survival in high-risk patients is dependent on a multidrug regimen (see Table 36–3), but many can enter long-term remissions. Long-term remissions are in the range of 80% following allogeneic hematopoietic stem cell transplantation.

• About 25% of children with low-risk disease treated successfully have long-term sequelae of therapy. Those with diabetes insipidus are at risk for hypopituitarism (up to 55% with growth hormone deficiency at 10 years follow-up) and should be monitored carefully for growth and development.

• About 75% of patients treated for high-risk disease have long-term problems. Orthopedic problems, hearing loss, neurologic abnormalities, and cognitive defects are among the sequelae seen. Secondary malignancies after intensive multidrug therapy, pulmonary insufficiency, sclerosing cholangitis, and marrow insufficiency may develop.

Special Characteristics in Adults with Langerhans Cell Histiocytosis

• Manifestations very similar to childhood cases.

• The disease has a median age of presentation of approximately 45 years.

• Isolated adult pulmonary disease has an association with smoking.

• In adults, chest pain may indicate a pneumothorax, which can be the presenting sign of pulmonary disease.

• Long periods of symptoms and signs are often present before a diagnosis is made.

• Presenting symptoms in order of frequency are dyspnea or tachypnea, polydipsia and polyuria, bone pain, weight loss, masses in lymph node areas, fever, gum problems, ataxia, and memory problems.

• Presenting signs in order of frequency are skin rash, scalp nodules, soft-tissue swelling near bone lesions, lymphadenopathy, gingival hypertrophy, hepatosplenomegaly.

• Eighty percent of adult patients presenting with diabetes insipidus had other organ involvement develop over time (eg, bone, skin, lung, lymph nodes).

• Adults have more frequent involvement of the mandible than children (30% vs 7%) and less frequent involvement of the skull than children (21% vs 40%).

• Therapy for adult patients has not been studied in clinical trials.

• Cessation of smoking is very important.

• Adults have frequent severe neuropathic toxicity with vinblastine and do not tolerate prolonged high-dose regimens with glucocorticoids.

• Intravenous cytarabine or cladribine are alternative approaches. The former appears to have a better therapeutic-to-toxicity ratio, but clinical trials have not been done to verify these impressions.

• Oral thalidomide or oral methotrexate have been useful for skin lesions.

• Anecdotes have suggested that intravenous bisphosphonate pamidronate can suppress bone pain in patients with multiple osteolytic lesions.

• Mutilating surgery to remove skin, teeth, or jaw bones is not indicated. These lesions can be dealt with by systemic chemotherapy, allowing bones to reform.

• Lung transplantation has been successful in patients with intractable, disabling pulmonary disease.

Malignant Histiocytosis

Definition

• This rare, rapidly fatal disorder is associated with jaundice, lymphadenopathy, refractory anemia, leukopenia, and hepatosplenomegaly.

• Malignant histiocytosis has been confused with large cell lymphomas. The term malignant histiocytosis should be restricted to neoplasms in which the cells have the immunophenotype of histiocytes (see Diagnosis, below).

Clinical Features

• Median age of onset is 35 years.

• Fever, weakness, weight loss, malaise, and sweating are frequent if disease is widespread (see Table 36–4).

• Generalized lymphadenopathy, hepatomegaly, and splenomegaly are frequent.

• Skin, central nervous system, and lung involvement may be associated.

• Localized disease may appear in skin, intestines, or isolated lymph node group.

Laboratory Features

• Anemia and thrombocytopenia present at time of diagnosis in virtually all patients; leukopenia is frequent.

• Marrow examination occasionally shows hemophagocytic macrophages, which are not an important diagnostic feature.

• Increased levels of serum bilirubin and lactic acid dehydrogenase often present. Liver-derived enzymes usually not significantly elevated.

• Elevated serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1α receptor, α₁-antitrypsin, and lysozyme, and angiotensin-converting enzyme are often present.

Diagnosis

• Diagnosis requires lymph node biopsy, marrow aspiration/biopsy, or biopsy of another involved site and unequivocal demonstration of macrophage phenotype and exclusion of B- or T-lymphocyte immunophenotype and T-cell receptor gene rearrangement.

• Neoplastic histiocytes are positive for nonspecific esterase but not for peroxidase reactions, cytochemically.

• Usually can be distinguished by immunophenotype (Table 36–5). In addition, may variably express monocyte-macrophage surface antigens (eg, CD11b, CD11c, CD14, CD15, CD33, CD36).

Differential Diagnosis

• This includes anaplastic large cell lymphomas, which are usually positive for CD30 and may express T-cell or, less often, B-cell antigens; Hodgkin lymphoma; and malignant fibrous histiocytoma, a myofibroblastic tumor that had masqueraded as a histiocytoma on morphologic grounds before marker studies were available.

• This condition is related to other monocyte-macrophage neoplasms (monoblastic leukemia without maturation, if extramedullary involvement is present and marrow is only partially involved). Generally, marrow involvement becomes extensive and leukemia becomes obvious in a short time.

• Langerhans cell sarcoma and follicular dendritic cell tumors are rare malignancies that have been characterized as histiocytic tumors.

Treatment

• There have been no systematic drug trials because of the infrequency of this tumor.

• Multidrug regimens, similar to those used for large-cell lymphomas (eg, drugs such as cyclophosphamide, doxorubicin, vincristine, and prednisone; also bleomycin, teniposide, mechlorethamine hydrochloride, and procarbazine) given at monthly intervals for variable periods have largely been unsuccessful in stage III or IV cases.

• Occasional case reports of responses to oral thalidomide, intravenous alemtuzumab, or a multidrug regimen consisting of mesna, doxorubicin, ifosfamide, and dacarbazine have appeared.

• In some cases, surgical resection of a solitary mass followed by radiation therapy has been successful.

• Remissions are infrequent, but rare long responses (5–7 years) have been observed.

• Allogeneic hematopoietic stem cell transplantation should be considered in eligible patients.

Hemophagocytic Lymphohistiocytosis

Definition

• This progressive and potentially fatal syndrome results from inappropriate activation of lymphocytes and macrophages.

• The pathologic hallmark is macrophages engulfing all types of blood cells in marrow, lymph nodes, spleen, or liver.

• It is also known as autosomal recessive familial lymphohistiocytosis, familial erythrophagocytic lymphohistiocytosis, viral-associated hemophagocytic syndrome, or infection-related hemophagocytic syndrome.

• The designation primary hemophagocytic lymphohistiocytosis has been proposed for very young cases with known gene mutations or a family history and secondary or acquired hemophagocytic lymphohistiocytosis for older children, young adults, or those without known gene mutations or for infection-associated cases.

• The overarching term hemophagocytic lymphohistiocytosis has been proposed for all because (1) the same mutation may be seen in primary and secondary cases; (2) there is no rapid or definitive gene-testing diagnostic approach; (3) the clinical presentations are the same; and (4) in the acute setting, the distinction is not useful. Both forms should be diagnosed promptly and treated aggressively.

Epidemiology

• In Sweden, annual incidence is 0.12/100,000 children; it occur in 1/50,000 live births.

• In Texas Children’s Hospital, there has been 1 case in 3000 inpatient admissions over a 2-year period.

• Males and females are affected equally.

• The condition affects neonates and infants; 90% of cases are children younger than 2 years of age.

• Two-thirds of cases are in siblings; there is frequent parental consanguinity.

Pathogenesis

• Defects in natural killer (NK) and cytotoxic T-cell function lead to inappropriate activation of T cells and macrophages, which secrete proinflammatory cytokines: interferon-γ, TNF-α, IL-6, IL-10, IL-12, soluble IL-2R-α (sCD25).

• Hypercytokinemia (“cytokine storm”) results in potentially fatal, severe multiorgan dysfunction.

• Mutation in perforin gene (PRF1) leads to decreased perforin elaboration by NK cells and cytotoxic T-lymphocytes. This abnormality decreases apoptosis in target cells resulting in sustained inflammatory response.

• Mutations in other genes in NK and cytotoxic T cells act to decrease apoptosis of target cells, fostering failure to modulate inflammatory reactions.

• Syndromes with high frequency of hemophagocytic lymphohistiocytosis (eg, Chédiak-Higashi syndrome, Hermansky-Pudlak syndrome) have immune deficiencies associated with lysosomal trafficking.

• Epstein-Barr virus infection in setting of immune deficiency state (eg, X-linked lymphoproliferative disorder) can result in hemophagocytic syndrome, a common fatal complication in this circumstance.

Clinical Findings

• In infants, the following findings occur: fever (> 90%), anorexia, vomiting, irritability, and rash (43%).

• Enlarged liver (90%) and spleen (85%) are very common.

• Lymphadenopathy (42%), jaundice, ascites, and edema may occur with progression of disease.

• Meningitis, encephalitic features, seizures, hemiplegia, or coma may ensue.

Laboratory Findings

• Anemia, reticulocytopenia, and thrombocytopenia in most patients at onset; neutropenia less common but with progression of disease, pancytopenia is the rule (Table 36–6).

• Marrow eventually contains an increased number of macrophages with prominent phagocytosis of blood cells (hemophagocytic histiocytes). This finding is neither sufficient to make the diagnosis nor is it always present. It is absent in one-third of cases and, thus, is not required for the diagnosis (Table 36–6).

• Repeat marrow biopsies as disease progresses may be helpful in uncovering hemophagocytosis, if suspicion of this disease is high.

• Marrow may progress to be hypoplastic with few macrophages and little evident hemophagocytosis.

• The spleen contains swollen macrophages engorged principally with red cells and sometimes leukocytes and platelets.

• Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, lactic dehydrogenase, and triglyceride levels are often elevated.

• Coagulation assays (especially fibrinogen, partial thromboplastin time, and prothrombin time) should be performed and if abnormal further factor assays may be necessary.

• Increased serum concentrations of interferon-γ, TNF, soluble CD8, and IL-6 suggest relationship with cytotoxic T cells and inflammatory cytokines.

• Highly elevated soluble CD25 (soluble IL-2 receptor) greater than 2400 units/mL along with four other criteria shown in Table 36–6 can be used to make the diagnosis.

• Biopsy of liver or lymph nodes reveals lymphohistiocytic infiltrate with cytologically normal macrophages engorged with phagocytosed erythrocytes (and often leukocytes and platelets). Paracortical lymphoid depletion in lymph nodes is also present.

• Highly elevated serum ferritin (> 500 μg/L) virtually always present, and levels greater than 10,000 μg/L provide 90% sensitivity and 96% specificity for the diagnosis of hemophagocytic lymphohistiocytosis.

• Increasing serial serum ferritin levels are strongly suggestive of lymphohistiocytic hemophagocytic syndrome.

• Highly elevated ferritin (> 500 μg/L) along with four other criteria as shown in Table 36–6 can be used to make a diagnosis.

• Cerebrospinal fluid examination in patients with nervous system signs may reveal pleocytosis and elevated fluid protein, indicating central nervous system involvement.

• Perforin expression of NK and T cells is decreased.

Differential Diagnosis

• Moderate infections, sepsis, multiorgan dysfunction, hepatitis, other causes for anemia and thrombocytopenia, and autoimmune diseases such as disseminated lupus erythematosus or rheumatoid arthritis may present with features overlapping the diagnostic findings in hemophagocytic lymphohistiocytosis.

• Consider hemophagocytic lymphohistiocytosis if no clear diagnosis is established and the patient’s condition is deteriorating.

• Identification of an underlying immunodeficiency, such as X-linked lymphoproliferative disease, Chédiak-Higashi syndrome, or Griscelli syndrome should increase suspicion of hemophagocytic lymphohistiocytosis.

• Epstein-Barr virus, cytomegalovirus, and other herpes viruses are the most frequent causes of hemophagocytic lymphohistiocytosis. A wide variety of bacterial and fungal infections have been associated with hemophagocytic lymphohistiocytosis.

• The macrophage activation syndrome describes the signs and symptoms of hemophagocytic lymphohistiocytosis in patients with juvenile rheumatoid arthritis or systemic lupus erythematosus.

• The macrophage activation syndrome may include fever, hepatosplenomegaly, mental status changes, cytopenias, and coagulopathy with hypofibrinogenemia. Proliferation of T lymphocytes and macrophages occur and may include poor NK cell function and low perforin expression.

Treatment

• One useful regimen is induction therapy with etoposide and dexamethasone followed by continuous treatment with cyclosporine and pulses of dexamethasone and etoposide.

• Despite neutropenia, etoposide is important, if it can be continued, because it provides singular apoptotic effects on macrophages.

• Cyclosporine levels greater than 200 ng/mL in patients with hypertension or liver or renal disease are dangerous. Such patients may experience seizures and encephalopathy.

• Patients with central nervous system signs or cerebrospinal fluid abnormalities receive intrathecal methotrexate.

• A significant fraction of patients do not respond to initial therapy or have early recurrence. In such patients, while awaiting efforts to use allogeneic hematopoietic stem cell transplantation, escalation of dexamethasone and etoposide therapy or alemtuzumab therapy should be considered because of the high mortality rates associated with initial treatment failure or recurrence. Infliximab, daclizumab, anakinra, and other agents have also been used.

• Treatment is often less intense for patients with HIV-associated hemophagocytic lymphohistiocytosis and patients with juvenile rheumatoid arthritis or systemic lupus erythematosus with the macrophage activation syndrome.

• Anti-TNF-α agents (eg, infliximab or etanercept) can prove useful.

• In patients with the macrophage activation syndrome, therapy should start with cyclosporine and glucocorticoids but not etoposide. The latter should be added only if there is no evidence of improvement after 48 hours of therapy.

• Patients may require support with red cell and platelet transfusions and fresh frozen plasma.

• Prophylactic therapy for Pneumocystis jiroveci with sulfamethoxazole and fungi with fluconazole is usually administered.

• Newly diagnosed patients should have human leukocyte antigen typing and a search for a potential related or unrelated donor.

• Allogeneic hematopoietic stem cell transplantation from a histocompatible sibling or unrelated matched donor should be considered in any patient who has resistant disease, relapses, or who has familial hemophagocytic lymphohistiocytosis or a documented relevant gene mutation.

• Reduced–intensity conditioning with allogeneic hematopoietic stem cell transplantation coupled with inclusion of alemtuzumab has shown improved survival and decreased toxicity.

Course

• This syndrome can be rapidly fatal. With current therapy, 3-year survival is approximately 55%.

• Some patients have an initial good response but then relapse as indicated by increase in serum ferritin, coagulation abnormalities, respiratory insufficiency, hypotension, and deteriorating renal function.

• Death is from infection, hemorrhage, or central nervous system abnormalities.

Macrophage Activation Syndrome

• The term is applied to patients with juvenile rheumatoid arthritis or disseminated lupus erythematosus with signs and symptoms simulating hemophagocytic lymphohistiocytosis.

• Macrophage activation is characterized by proliferation of macrophages and T cells, defective NK cell function, and low perforin expression.

• Patients may present with fever, purpura, hepatosplenomegaly, mental status changes, cytopenias, coagulopathy, and hypofibrinogenemia.

• Patients may respond to primary treatment for the underlying autoimmune disease.

• If they do not improve, dexamethasone and etoposide therapy may be tried.

Infection-Induced, Disease-Induced, or Drug-Induced Hemophagocytic Histiocytosis

Etiology

• This condition is usually associated with systemic viral infection; occasionally with bacterial, fungal, or protozoal infections.

• It appears to be an unusual, exaggerated inflammatory reaction to infection.

• It also may occur in association with malignancies.

Clinical Findings

• Fever, severe malaise, myalgias, and lethargy occur.

• Enlargement of liver and spleen is frequent in children but less so in adults.

Laboratory Findings

• Severe anemia (< 90 g/L), leukopenia (< 2.5 × 10⁹/L), thrombocytopenia (< 50 × 10⁹/L), or combination of two cytopenias occur in nearly all cases.

• Interferon-γ, TNF-α, IL-6, and soluble IL-2 receptor plasma levels are markedly increased.

• Macrophages may be present in the blood film.

• Marrow may be hypocellular, with decreased erythropoiesis and granulopoiesis. Increased macrophages frequently contain phagocytosed erythrocytes and erythroblasts and occasionally platelets and neutrophils.

Treatment

• Stop or decrease immunosuppressive therapy in transplant patients.

• If underlying infection, administer appropriate antimicrobial agents.

• Cyclosporine A, antithymocyte globulin, gamma globulin, and etoposide use has been accompanied by improvement in Epstein-Barr virus–associated syndrome.

• In patients with Epstein-Barr virus, rituximab can be useful.

Course

• Patients are severely ill but often recover in weeks with complete disappearance of evidence of histiocytosis in months.

• Fatal outcome is frequent in immunosuppressed patients.

Sinus Histiocytosis with Massive Lymphadenopathy (Rosai-Dorfman Syndrome)

Definition

• This unique entity is characterized by polyclonal (nonmalignant) proliferation of histiocytes with massive lymphadenopathy. It is often self-limited.

Epidemiology

• The syndrome usually occurs in first three decades of life (median age 21 years) but may occur at any age.

• It often occurs in children with an immunologic disorder.

Clinical Findings

• Massive, painless, bilateral cervical lymphadenopathy is characteristic (90% of patients).

• Axillary and inguinal adenopathy develop in 50% of patients.

• Some patients may have fever, night sweats, malaise, and weight loss.

• Extranodal involvement in about 50% of patients. Virtually every tissue may be affected (eg, skin, sinuses, orbit, salivary glands, liver, kidney, bone, and others).

• Bilateral parotid or submandibular gland enlargement may be present.

• Approximately 20% of patients have a maculopapular rash, which can be reddish, bluish, or yellow as a result of xanthomatous involvement.

• Approximately 20% have nasal and paranasal sinus involvement with nasal airway obstruction, epistaxis, nasal septal displacement, or mass lesions invading sinuses.

• Approximately 10% have eyelid or orbital involvement with proptosis.

• Approximately 5% have central nervous system involvement, with intracranial, epidural, or dural masses, or nerve palsies.

Laboratory Findings

• Signs of chronic inflammation (ie, anemia, neutrophilia, elevated erythrocyte sedimentation rate, polyclonal hypergammaglobulinemia) occur.

• Pathologic features in lymph node include:

  — Marked capsular fibrosis and distention of sinuses by phagocytic macrophages are found. Plasma cells are plentiful.

  — Macrophages with ingested intact lymphocytes are virtually diagnostic. Erythrophagocytosis by macrophages is often present.

  — Numerous plasma cells may accompany the macrophages.

  — Macrophages are positive for CD14, CD68, CD163 but are negative for CD1a (Table 37–2).

  — Macrophages also express lysozyme, transferrin receptor, and IL-2 receptor.

  — The macrophage proliferation is polyclonal.

Treatment

• The majority of patients will gradually improve without specific treatment.

• Case reports have described improvement in patients with multiorgan involvement necessitating treatment after oral dexamethasone, oral methotrexate, oral 6-mercaptopurine, intravenous cladribine, or intravenous vinorelbine plus methotrexate.

• In patients with bone or central nervous system involvement, intravenous clofarabine has been used.

Course and Prognosis

• Lymph node enlargement usually progresses for weeks to months and then recedes, with no residual evidence of disease after 9 to 18 months.

• Some patients have persistent adenopathy; others may have a fatal outcome.

Erdheim-Chester Disease

Definition and Epidemiology

• This disease results from infiltration of lipid-laden histiocytes that infiltrate bones and viscera, causing a fibroblastic reaction and leading to organ failure.

• The disease affects individuals from childhood to old age and has a mean age of onset of 50 years.

• The etiology is unknown.

• Cells have been determined to be clonal in several cases and polyclonal in several others. Thus, its status as a neoplasm is uncertain.

• The presence of BRAF^V600E mutations in approximately 5% of a small sample of patients may result in a therapeutic target in these patients.

Clinical Findings

• Fever, weakness, and weight loss are common presenting complaints.

• Osteosclerosis of long bones is a principal feature.

• Extraosseous involvement occurs in 50% of patients.

• Encasing masses around various organs are characteristic.

• Retroperitoneal and renal involvement causes abdominal pain, dysuria, and hydronephrosis.

• Pulmonary involvement results in dyspnea and pulmonary insufficiency.

• Circumferential sheathing of aorta and coronary arteries may cause cardiac failure.

• Involvement of the pericardium can lead to effusions and effects on myocardial function.

• Diabetes insipidus is a very common presenting disorder.

• Some patients have focal neurologic signs, notably headaches, neuropsychiatric or cognitive difficulties, cranial nerve palsies, and cerebellar dysfunction.

• Bilateral painless exophthalmos may appear.

• Xanthomatous skin lesions may emerge appearing as reddish-brown papules.

Laboratory Findings

• There are no specific chemical findings.

• Radiographs show bilateral patchy osteosclerosis of the metaphysic and diaphysis of the femur, proximal tibia, and fibula in virtually all patients; lytic bone lesions occur in one-third of patients.

• Computed tomography may show perirenal infiltration extending through perirenal fat giving the appearance of “hair kidneys.”

• Computed tomography may show aortic and aortic branch vessel with circumferential encasement by fibrous tissue.

• Computed tomography may show diffuse interstitial infiltrates.

• The histopathology is distinctive: lipid laden histiocytes with foamy or eosinophilic cytoplasm infiltrating bone and other organs. A fibroblastic reaction is characteristic. The histiocytes express CD68 and factor XIIIa but do not express CD1a and lack Birbeck granules; the latter are specific for Langerhans cell histiocytosis.

Treatment and Course

• No specific regimen has been shown to be effective. Most series have relatively few patients.

• Interferon-α has resulted in significant improvement in some patients in small series and single case reports.

• Glucocorticoids (1 mg/kg per day) have decreased exophthalmos or constitutional symptoms in a small fraction of patients so treated.

• Sixty percent of patients die of their disease and about two-thirds do so within 6 months of diagnosis.

• Mean survival is less than 3 years.

• Cardiac, pulmonary, and renal failure are the principal causes of death.

Juvenile Xanthogranuloma

• This disease of children is usually seen in the first 5 years of life.

• This disorder of dermal dendrocytes forming multiple nodules affect principally the skin of the head, neck, and trunk.

• They are usually skin colored but may be erythematous or yellowish.

• Extracutaneous involvement is rare and systemic symptoms are present only if viscera are involved. Virtually any organ can be affected: nervous system, heart, lung, liver, spleen, intestines, and others. Marrow involvement may cause cytopenias. Pituitary involvement may cause diabetes insipidus.

• Histiocytes are CD14+CD68+ and express factor XIIIa (Table 36–2).

• In early disease, intermediate sized histiocytes in sheet-like infiltrations. These cells have small quantities of lipid in the cytoplasm and no Touton-type giant cells (lipid-laden histiocytes with multiple nuclei) with a small amount of centrally located cytoplasm.

• Established disease has abundant foamy histiocytes with Touton giant cells interspersed. Also, there are some lymphocytes and eosinophils.

• If single or few lesions, no therapy is usually needed. Excisional biopsy can be done, if disfiguring.

• In rare cases of systemic disease, a variety of multidrug programs have been used. Inclusion of a vinca alkaloid and a glucocorticoid is recommended.