Histiocytic Disorders

R. Maarten Egeler, Robert J. Arceci, and Jan-Inge Henter

Under the term histiocytoses, we consider a group of disorders that have in common the proliferation of cells of the mononuclear phagocytic system and the dendritic cell (DC) system. Normally, histiocytes (tissue macrophages) and DCs are involved in immune and inflammatory responses. The histiocytoses are each characterized by localized or generalized reactive or neoplastic proliferation of cells similar, if not identical, to one of these cell types. They are diagnosed on the basis of characteristic signs, symptoms, and laboratory findings that, in combination with specific histological features, satisfy diagnostic criteria. In the case of Langerhans cell histiocytosis (LCH), the proliferating cell is the Langerhans cell, and in hemophagocytic lymphohistiocytosis (HLH), the macrophage accumulates.

LANGERHANS CELL HISTIOCYTOSIS

PATHOPHYSIOLOGY AND GENETICS

The diagnosis of Langerhans cell histiocytosis (LCH) is based on hematologic and histological criteria established by the international Histiocyte Society and subsequently revised by Favara and colleagues.^1,2 They feature a monoclonal population of CD1a+ histiocytes with a phenotype akin to that of cells of the antigen-presenting Langerhans cell (LC) family. T lymphocytes, macrophages, eosinophils, together with multinucleated giant cells, are variably present. The CD1a+ LCH cells, required for a definitive diagnosis, in contrast to normal LC, are actively proliferating and have a round rather than dendritic shape. They have a moderate amount of homogeneous, pink, granular cytoplasm and distinct cell margins, and they express several distinctive antigenic markers. The nucleus is folded with indistinct nucleoli. Birbeck granules, typically rod- or racket-shaped intracytoplasmic granules demonstrable on electron microscopy, are only found in LC. High levels of Langerin/CD207 are expressed in the LCH cells in association with Birbeck granules.³

A central feature of normal immunological regulation involves the production and local action of cytokines. However, this action is normally short lived. In cases of immunologic dys-regulation, as is thought to occur in LCH, the overproduction of cytokines can lead to pathologic consequences. LCH is characterized by a lesional “cytokine storm,” so called because of the high level and diversity of cytokines produced locally.⁴ The inappropriate accumulation of LC at various anatomic sites in LCH, commonly including skin, bone, and lymph nodes as well as nearly all other organs, has shown that the LCH cells are likely to use chemokine-mediated mechanisms to traffic to aberrant anatomical sites or to maintain the persistence of LCH lesions. Chemokines function both by autocrine and paracrine mechanisms; they not only may cause the retention of lesional LCH cells but are also instrumental in the recruitment and retention of bystander cells such as eosinophils and activated T cells.⁵ The increased levels of cytokines probably reflect the immune activation of the various inflammatory cell types involved in LCH lesions. Although the increased levels of cytokines in LCH lesions might be a secondary phenomenon, it is highly likely that they play a fundamental role in propagating the inflammatory responses responsible for tissue damage. Coury and colleagues reported that the CD1a+ LCH cells spontaneously express the proinflammatory cytokine interlukein-17A, which can also induce dendritic cell fusion, resulting in multinucleated giant cells (MGCs), the size of which increased upon addition of interferon-γ.⁶ This may help to explain the presence of MGCs in the lesions and may further contribute to bone resorption observed in the majority of LCH patients with skeletal involvement by acting indirectly through enhancement of the osteoclast-inducing enzymes tumor necrosis factor-α, interlukein-1, and receptor activator of nuclear factor-κB ligand. This pathway targets immature dendritic cells and differentiates dendritic cell–derived effectors with aggressive tissue-destructive enzymatic activities. Understanding the role particular cytokines play in fibrosis and tissue destruction also helps us to use more specific anti-inflammatory therapy to prevent permanent consequences of LCH.

It is clear that the proliferation and survival of LCH Langerhans cells lie at the heart of the development and persistence of disease lesions. One requirement for such unlimited proliferation in normal cells is the maintenance of telomere length. Two studies have reported that LCH cells from lesions of multi-system patients expressed telomerase regardless of the lesional site. However, telomere shortening and clonality suggest that LCH cells may be similar to preneoplastic or neoplastic disorders in which the pathologic cells circumvent telomere shortening through alternative molecular pathways.^7,8 Several studies have raised the possibility of genetic mechanisms playing a role in LCH, although specific genetic defects or gene mutations have not yet been identified.

CLINICAL FEATURES

Langerhans cell histiocytosis (LCH) has a wide spectrum of clinical presentation and may occur at any age, with at least 50% diagnosed in children. Some forms are age dependent. For example, isolated bone lesions are often seen in children between 5 and 15 years old, and systemic LCH is more common in children ages 1 to 2 years. The age of the patient at diagnosis of LCH is a prognostic factor with the younger patient usually having a worse prognosis. Besides very young age and the number of organs involved, the involvement of risk organ, currently defined as hematopoietic, liver, spleen, and lung involvement, is also a poor prognostic factor.

Besides fever, weight loss, and fatigue, the following more specific signs and symptoms are also commonly observed. Cutaneous lesions are usually scaly, erythematous, seborrhealike brown to red papules, especially pronounced in intertriginous zones. Bone lesions are osteolytic and sometimes associated with painful swelling. Lymph node involvement in LCH may be seen in association with bone or skin involvement; however, it may also be present as a solitary lesion or part of systemic disease. Pancytopenia caused by bone marrow dysfunction is also usually associated with hepatosplenomegaly and a poor prognosis. Liver dysfunction can lead to ascites, hypoalbuminemia, and jaundice. Sclerosing cholangitis can be found in the final stage of liver involvement. The enlargement of the spleen with the accumulation of pathologic LCH Langerhans cells may also be a contributing cause to pancytopenia. Tachypnea and chest retractions are often symptoms of lung involvement. With time, increasing numbers of cysts form “honeycomb lungs” and, in later stages, large bullae, which may result in a spontaneous pneumothorax. Emphysematous changes along with pulmonary fibrosis can be found in advanced stages of LCH lung involvement. Failure to thrive is the most common sign of gastrointestinal tract involvement caused by malabsorption. Other symptoms include vomiting, diarrhea (with or without blood), and protein-losing enteropathy. Diabetes insipidus, the most common endocrinopathy observed in LCH, can occur initially as an isolated finding, during active disease in other sites, as well as after the resolution of disease at other sites. Growth retardation resulting from anterior pituitary involvement and growth hormone deficiency are seen in 50% to 60% of children who develop diabetes insipidus. Acute signs of central nervous system (CNS) involvement, such as intracranial hypertension or seizures, have been observed in up to 10% of patients. Chronic CNS symptoms may include progressive ataxia, dysarthria, nystagmus, hyperreflexia, dysdiadochokinesia, dysphagia, blurred vision, or cranial nerve palsies. Cognitive affection may also occur. These symptoms can be caused by active LCH in the brain or by a neurodegenerative condition that often does not show active LCH but instead a lymphocytic infiltration, gliosis, and neuronal death.

DIAGNOSTIC EVALUATIONS

A definitive diagnosis of Langerhans cell histiocytosis (LCH) requires a biopsy from an affected lesion revealing either CD1a antigen on lesional cells using antibodies directed against the CD1a antigen (nearly always currently possible on paraffin sections) or the demonstration of Birbeck granules by electron microscopy. To determine the extension and severity of the disease, additional laboratory evaluation is needed.¹ Besides white blood count and differential blood cell count, liver function and coagulation studies are usually obtained. Because of the possibility of diabetes insipidus, urine osmolality measurement after an overnight or several hour water deprivation is needed. In infants, such a period of water deprivation should be done under close medical supervision. A thorough medical history is also helpful in suspecting the presence of diabetes insipidus. Radiographic evaluations usually include a chest radiograph as well as a skeletal radiographic survey. On specific indications, based on history and/or physical examination, additional investigations should be carried out, such as a chest or abdominal computed tomography (CT) scan, pulmonary function tests, brain magnetic resonance imaging (MRI) with gadolinium contrast, as well as liver or gastrointestinal biopsy. For oral involvement, a panoramic dental radiograph of mandible and maxilla are useful. For aural discharge or deafness, an otolaryngology consultation and audiogram should be done. Otherwise unexplained anemia, leukopenia, or thrombocytopenia should prompt a bone marrow aspirate and trephine biopsy. In case of liver dysfunction, including hypoproteinemia not caused by protein-losing enteropathy, a liver biopsy may be considered.

Pulmonary LCH frequently presents with a diffuse micronodular pattern on chest radiographs or CT scan; CD1a immunohistochemical staining of alveolar fluid cells obtained by bronchoalveolar lavage or biopsy confirms diagnosis of LCH. In the case of an abnormal chest x-ray or tachypnea and intercostal retractions, besides pulmonary function tests, a CT scan of the chest is indicated. Unexplained chronic diarrhea or failure to thrive suggests the need for gastrointestinal biopsies. Short stature, growth failure, diabetes insipidus (DI), hypothalamic syndromes, galactorrhea, and precocious or delayed puberty are all indications for an endocrine evaluation. Confirmation of DI by an appropriate water deprivation test and by measurement of serum and urine electrolytes and osmolality as well as serum arginine vasopressin is essential because partial defects may occur and may spontaneously remit. Gadolinium-enhanced MRI is usually informative: thickening of the hypothalamic-pituitary stalk region and absence of the posterior pituitary “bright” signal are frequently seen. Besides all the typical signs and symptoms of LCH, a biopsy of the affected organ is required to make a definitive diagnosis. There is no established treatment of isolated DI secondary to LCH. However, some reports have suggested that early treatment with chemotherapy or radiation may reverse it. This remains a controversial area.

TREATMENT

Treatment of patients with Langerhans cell histiocytosis (LCH) depends on the extent of disease. The number of organs involved as well as organ dysfunction are critical in determining optimal treatment. Patients with restricted LCH need careful staging of their disease to ensure that the lesions are not part of a more extensive process. The clinical course is generally benign, and spontaneous remissions may occur. Initially, treatment of patients with LCH apparently localized to the skin may be unnecessary because in many cases, mainly in infants, the lesions regress spontaneously. When treatment is necessary, the application of topical steroids may be useful. A single bone lesion, especially after biopsy and/or curettage, may resolve spontaneously during a period of months to years. Criteria for additional treatment include persistent pain and radiographic progression as well as the threat of unacceptable deformity or disability. Intralesional injection of corticosteroids is an often effective and convenient treatment for accessible lesions.

Patients with extensive LCH involvement should be treated on clinical protocols, such as those of the Histiocyte Society. On such trials, patients with extensive disease but without involvement of the risk organs (ie, liver, spleen, lung, and hematopoietic system) have an excellent survival with relatively minimal therapy. Patients with extensive disease, including risk organ involvement, are routinely evaluated after 6 weeks of induction therapy according to the Histiocyte Society trials.⁹ Evaluation of response at 6 and 12 weeks allows allocation of patients to either a “responder” or “nonresponder” group. Nonresponse after 6 to 12 weeks of induction therapy portends a poor prognosis with a survival of less than 30%; such patients should be treated with alternative regimens, preferably on clinical trials. The combination of 2-CdA (2-chlorodeoxyadenosine) and cytosine arabinoside (ARA-C) is currently being examined in the LCH-S-2005 protocol by the Histiocyte Society. In addition to those patients whose disease does not respond after 6 to 12 weeks of chemotherapy, patients with chronically relapsing disease associated with good survival but significant long-term complications and patients with the late progressive involvement of liver, lung, and central nervous system may require alternative therapy. Treatment approaches for patients with resistant and/or chronically relapsing disease include chemotherapy, immunomodulatory approaches, and stem cell transplantation.

COMPLICATIONS AND LATE EFFECTS

Results of the late effects study of the Histiocyte Society suggest that at least 1 adverse, permanent sequela occurs in up to 75% of multisystem and 25% of single-system patients within a 3-year follow-up period. The most commonly reported complications were diabetes insipidus (25%), orthopedic problems (20%), hearing loss (13%), neurologic consequences (11%), and growth retardation (9%). From the point of view of therapeutic decision making, most of the serious adverse sequelae, such as endocrine and central nervous system complications, occur in patients with extensive disease and with lesions involving the facial bones and base of skull. Extensive surgical resections should be avoided, and the use of carcinogenic drugs and radiation therapy should be limited to life-threatening situations in order to reduce adverse sequelae as a consequence of treatment.

SUMMARY

The first major advance toward understanding Langerhans cell histiocytosis (LCH) was taken when ultrastructural studies identified the proliferating cells as Langerhans cells. Another step forward was the definition of the morphologic, immunohistochemical, and clinical criteria needed for the diagnosis of LCH. Such diagnostic criteria helped to standardize clinical management and to compare treatment and outcome data in a systematic fashion and formed the foundation upon which international clinical trials and laboratory research can be accomplished.¹⁰ The mechanisms of cytokine expression and function, leading to tissue damage, are now also better understood and should lead to more rational and effective treatment approaches.

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS

Hemophagocytic lymphohistiocytosis includes several entities with similar clinical features but distinct pathophysiologic triggers.¹¹ Primary HLH is an autosomal recessive disorder. Secondary HLH includes all other forms, such as virus-associated hemophagocytic syndrome, bacteria-associated hemophagocytic syndrome, malignancy-associated hemophagocytic syndrome, macrophage activation syndrome associated with autoimmune diseases, fulminant LCH, and fat-overload syndrome.^12,13

EPIDEMIOLOGY

Primary HLH has an annual incidence of approximately 1.2 children per 1 million, with an equal sex distribution. The disease most often affects preschool children, typically during the first 2 years of life; the disorder is frequently associated with parental consanguinity. However, recent advances in genetics have shown that primary HLH may also affect adolescents and young adults. Age at onset is often later for secondary forms of HLH, but these forms may also affect all ages. It is often not possible to distinguish primary and secondary HLH in an early phase of the disease, particularly because both may be triggered by infections. Viruses, especially Epstein-Barr, are the most common triggering factors, but bacterial infections may also trigger HLH development, as in premature infants, as can numerous other conditions.

PATHOLOGY AND PATHOGENESIS

The pathologic signature of the hyperinflammatory condition HLH is an accumulation of lymphocytes and macrophages, some with hemophagocytosis. The liver, spleen, lymph nodes, bone marrow, and central nervous system (CNS) are most commonly involved.¹⁴

The cause of primary HLH is impaired function of cytotoxic T cells and natural killer cells.¹⁵ Three underlying gene defects have thus far been identified, all affecting the function of the cytolytic perforin granule pathway. Perforin is either not synthesized normally because of mutations in the perforin gene (PRF1), or perforin is not properly released from cytotoxic lymphocytes because of mutations in the genes UNC13D and STX11 encoding the proteins Munc13-4 and syntaxin-11.^16-18 The deficient immune downregulation causes a polyclonal accumulation of lymphocytes and macrophages, particularly after strong immune activation, such as observed with certain viral infections. These abnormalities result in the pronounced and characteristic hypercytokinemia, which includes interleukin-2 (IL-2), IL-6, IL-10, IL-12, interferon-γ, and tumor necrosis factor-α.

CLINICAL MANIFESTATIONS

The typical initial presentation of HLH is fever and hepatosplenomegaly, sometimes associated with lymphadenopathy and a nonspecific rash. Pallor and purpura, due to cytopenias, are also frequent findings. One third of the patients already have CNS involvement at the time of diagnosis, especially aseptic meningitis and seizures.¹⁹ These CNS signs and symptoms can be meningeal, cortical, and cerebellar. Signs and symptoms of increased intracranial pressure can occur.

Cytopenias (particularly thrombocytopenia and anemia), hypertriglyceridemia, hypofibrinogenemia, and hyperferritinemia are typical laboratory abnormalities. The cerebrospinal fluid may have elevated protein content or moderate pleocytosis. Elevated serum transaminases and bilirubin levels indicate hepatic involvement. These laboratory values are all useful as indicators of HLH activity and normalize in remission.

DIAGNOSIS

According to the diagnostic guidelines for HLH by the Histiocyte Society, the diagnosis can be established if (1) there is a molecular diagnosis (ie, identification of biallelic disease-causing mutations consistent with primary HLH) or (2) if 5 of the 8 following diagnostic criteria are fulfilled:

1. fever

2. splenomegaly

3. peripheral blood cytopenia involving 2 or more lineages

4. hypertriglyceridemia or hypofibrinogenemia

5. hemophagocytosis (without evidence of malignancy) in bone marrow, spleen, or lymph nodes

6. low or absent natural killer cell activity

7. hyperferritinemia

8. elevated soluble IL-2 receptor levels¹⁴

Notably, a family history of HLH is not always present even in patients with the familial form. Hence, it is often difficult to distinguish primary and secondary forms, both of which can be triggered by infections.

TREATMENT AND PROGNOSIS

Without treatment, primary HLH is typically fatal within a few months. Several therapies, including chemotherapeutic and immunomodulatory agents, have been successful in prolonging survival, but ultimately, the only curative treatment is hematopoietic stem cell transplant (HSCT). In 1994, the Histiocyte Society consolidated these approaches into a clinical trial, HLH-94, that was revised in 2004 (HLH-2004). Initial therapy consists of immunochemotherapy for 8 weeks (etoposide, corticosteroids, and cyclosporin A).¹⁴ For patients with unresponsive CNS disease, intrathecal administration of methotrexate and corticosteroids is recommended. Patients with genetically verified or familial disease, as well as patients with persistent or relapsing disease, are treated by administration of continuation immunochemotherapy in order to obtain a remission of the disease prior to HSCT. Following HSCT, stable, mixed chimerism of the donor graft may be sufficient for durable remission in the treatment of patients with familial hemophagocytic lymphohistiocytosis. A key element in maintaining a disease remission is the level of cytotoxic T-lymphocyte and natural killer cell function.

For patients with severe, progressive, or relapsing secondary HLH, initial therapy with the HLH-2004 protocol approach is appropriate. For those who attain clinical remission, no further therapy is indicated unless a relapse of the disease occurs. In that instance, treatment as per the initial approach is usually given again, and HSCT should be considered. Intensive supportive care, including antimicrobial therapy, is suggested for all HLH patients.

The 5-year survival in primary HLH is currently around 50% to 60%, with deaths occurring pre-HSCT and post-HSCT.²⁰ The most frequent and most severe sequelae are caused by CNS involvement. To prevent permanent sequelae, it is suggested to initiate therapy early in the disease course. In certain cases, therapy may have to be initiated on the basis of strong clinical suspicion even if the diagnostic criteria have not been fulfilled.

MISCELLANEOUS NONLANGERHANS CELL HISTIOCYTIC DISORDERS

JUVENILE XANTHOGRANULOMATOUS DISEASE

While juvenile xanthogranulomatous disease (JXG) occurs primarily in infants and young children, patients of all ages can be affected. The usual presentation is with a single or sometimes multiple cutaneous, nodular papules of yellow to reddish-purple color involving the scalp, extremities, or trunk.²¹ These papules may range in size from just a few millimeters to several centimeters in size. Pathologic findings demonstrate a mixture of foamy macrophages, lymphocytes, and scattered Touton giant cells. The histiocytes in these lesions are characteristically positive for expression of factor XIIIa. In addition to cutaneous forms of JXG, the disease can also become systemic and involve multiple organs, including liver, lung, testis, pericardium, eyes, and brain. Children with extensive skin involvement appear more likely to develop other organ involvement. A related disorder, benign cephalic histiocytosis, also frequently presents in infancy and is characterized by small, reddish-brown macules, primarily involving the scalp, but also may extend to other areas of the body. These lesions slowly regress, like localized, cutaneous JXG. Thus, neither of these disorders requires treatment. Patients with systemic or organ involvement with JXG often require treatment with chemotherapeutic agents that include vinblastine plus steroids similar to the treatment for LCH; for patients with refractory disease, alternatives using etoposide, 2-chlorodeoxyadenosine, methotrexate along with other agents have been utilized with some success.^22-24

SINUS HISTIOCYTOSIS WITH MASSIVE LYMPHADENOPATHY

Sinus histiocytosis with massive lymphadenopathy (SHML), also called Rosai-Dorfman disease, is a nonclonal disorder characterized by massive, usually nonpainful cervical adenopathy, although any lymph nodes can be involved. Extranodal involvement can also occur, particularly of the salivary glands, retroorbital area, skeleton, skin, testis, and central nervous system.²⁵ SHML is also commonly associated with fevers, elevated erythrocyte sedimentation rate, or C-reactive protein and polyclonal hyper-gammaglobulinemia.^22-24 Biopsies reveal sinusoidal dilatation with increased numbers of histiocytes and activated lymphocytes. Lesional histiocytes may be multinucleated and demonstrate a large amount of foamy cytoplasm (called Mikulicz cells). Hemophagocytosis may be present, and at the electron microscopic level, the wrapping of histiocyte/macrophage membranes around lymphocytes and other blood derived cells is termed emperiopolesis.²⁶ While SHML may spontaneously regress over weeks to months, some patients require treatment, which usually includes steroids, sometimes with chemotherapeutic agents such as vinblastine, etoposide, methotrexate, or 2-chlorodeoxyadenosine.^21-28 The anti-CD20 monoclonal antibody Rituximab and the tyrosine kinase inhibitor imatinib have also been used as treatment in anecdotal cases.^29,30

REFERENCES

See references on DVD.

Stay updated, free articles. Join our Telegram channel

Join