The histiocytoses comprise a diverse group of proliferative disorders characterized by the infiltration and accumulation of histiocytes and other immune effector cells within various tissues. The generic term “histiocyte” refers to several types of cells including: monocytes/macrophages, dermal/interstitial dendritic cells and Langerhans cells (LC). While the exact ontogeny is not completely understood, histiocytes are hypothesized to arise from a common CD-34 positive progenitor cell within bone marrow, and, depending upon the cytokine milieu, they will differentiate along two major pathways, namely into CD-14 positive cells or CD-14 negative cells. CD-14 positive cells further differentiate either into tissue macrophages or dermal/interstitial cells, whereas CD-14 negative cells become LC (1,2). Even after a cell has differentiated, an intimate interrelationship among this group of cells remains, often with functional, morphologic, or phenotypical overlap (1–4).
Abstract: Langerhans cell histiocytosis is a rare proliferative disorder where pathologic Langerhans cells accumulate in a variety of organs. Historically, the nomenclature regarding this entity has been confusing because the disease had been subcategorized simply based upon the different clinical manifestations. In the following article, we summarize the current recommendation of the Histiocyte Society regarding the classification, evaluation, prognosis, and treatment of Langerhans cell histiocytosis.
Current Classification of the Histiocytic Disorders
With the advent of ultrastructural studies and immunohistochemical staining, the Histocyte Society proposed reclassification of the histiocytoses based upon the predominant cell type within the infiltrate. This initial classification system included Langerhans histiocytosis (Class I), non-LC histiocytosis (Class II), and malignant histiocytosis (Class III) (5). More recently, a revised classification schema included division into (1) dendritic cell disorders: Langerhans cell histiocytosis (LCH), secondary dendritic cell processes, juvenile xanthogranuloma, and solitary histiocytomas with a dendritic phenotype; (2) macrophage-related disorders: primary and secondary hemophagocytic syndromes, Rosai-Dorfman disease, and solitary histiocytoma with a macrophage phenotype; and (3) malignant histiocytic disorders: monocyte-related leukemias, extramedullary monocytic tumor, and dendritic cell or macrophage-related histiocytic sarcoma (4).
Diagnostic Criteria for Langerhans Cell Histiocytosis
The cornerstone of diagnosis in LCH includes identification of the characteristic clinical features, but also corroboration of histopathologic and immunohistochemical results (5,6). As 50% to 80% of those affected manifest cutaneous involvement, a skin biopsy provides a rapid and accessible means to secure the diagnosis. A presumptive diagnosis of LCH may be made based upon light microscopic findings and a compatible clinical picture, but a definitive diagnosis, requires that lesional cells exhibit positive staining with S-100 and CD1a, and the sine quá non is identification of Birbeck granules upon electron microscopy (4,5). Although, the “gold standard” for identification of LC has been detection of Birbeck granules by transmission electron microscopy, this technique is rarely performed today. Furthermore, the number of LC with identifiable Birbeck granules can vary in different lesions, with limited numbers seen in tissue taken from the liver, spleen, gastrointestinal or central nervous systems. Therefore, other pathognomonic surface markers are being sought (7). Langerin (CD 207) is a relative new monoclonal antibody directed against a type II transmembrane protein associated with Birbeck granules (8,9). It appears to be more sensitive and specific for LC than CD1a, and, in the future it may be a key component of an immunocytochemical panel to diagnose LCH (9–12).
The Histiocyte Society has established guidelines to assist in the diagnosis and evaluation of LCH (6). All patients with suspected LCH must undergo a thorough physical examination, inclusive of height and weight measurements. Laboratory evaluation should include a complete hematologic panel and coagulation studies, liver function tests, and urine osmolality. In addition to the laboratory evaluation, the patient must have a complete skeletal radiographic survey and chest radiography. Patients who have positive findings on baseline evaluation, will require more specific studies, such as a bone marrow examination, although some authorities advocate that this should be included in every baseline examination. Pulmonary function tests and lung biopsy, small bowel series, liver biopsy, panoramic dental films, computerized tomography or magnetic resonance imaging of the brain with particular attention paid to the hypothalamic-pituitary axis, endocrine evaluation, and otolaryngology consultation with an audiogram represent ancillary studies that should be considered on a case by case basis.
The practitioner must be aware that LCH may involve almost any organ system, but the frequency of involvement, as well as the extent of the disease, is often age dependent. Several large retrospective studies consisting of neonates and children under the age of 4 years, have shown that 51% to 71% of children with LCH present with multiorgan disease (13–17). In comparison, most retrospective studies in adult patients have shown that 69% to 72% of adults have involvement of only a single organ system; most often the bones (52%), lungs (40%), or less frequently, the skin (7%) (13–21) (Table 1). However, a recent large retrospective study of 274 adult patients from 13 countries contradicts previous reports, and showed that 68.9% of the adults evaluated presented at the onset with multiorgan disease (21). This study attributes the higher observed systemic disease in these adults to improved recognition and diagnosis.
|Unifocal bone||Cutaneous only||Isolated pulmonary||Multifocal bone||Multi-system low-risk patients||Multi-system high-risk patients (under age 2 organ dysfunction)|
|Approximate incidence*||28–83%||Overall 10%, Neonates 33–37%||Overall 27%, 96% of which are adults||19–28%||39%||11%|
|Relapse||10%||5%||3% had progression||76%||55–61%||95%|
It has been shown that prognosis is dependent upon the number of organs involved, as well as the presence of organ dysfunction, and to a lesser degree, the age of the patient at the onset of the disease (22). In general, patients who present at a younger age and those with widely disseminated disease and organ dysfunction have the highest mortality. Yet, neonates with isolated cutaneous lesions often do exceptionally well. Therefore, the age of the patient is only important when multiorgan involvement is present (14,18,23–26). Involvement of the spleen, lung, liver or hematopoietic system also portends a poor prognosis (12,23). In one large study of 101 children with LCH, the overall survival rate for all was 79% at 1 year, 74% at 3 years, and 71% at 5 years; however, in patients with liver or spleen involvement 1-year survival was 33% and 5-year survival was just 25% (18).
Based upon the results of several large multi-center therapeutic trials, it has been shown that the single best prognostic indicator is a patient’s response to chemotherapy during the 6-week induction phase (13,23,27–32). Patients who respond to chemotherapy have a 88% to 91% survival rate, but for patients who do not demonstrate an early response the survival rate drops to 17% to 34%. Therefore, it has been advocated that these nonresponders be identified early so that more aggressive therapy may be employed (23,28,33,34).
To aptly determine a patient’s treatment protocol, it has been suggested that patients should be stratified based upon specific risk factors. The first step is to determine the number of organ systems involved. Then patients who have single system involvement should be further subcategorized based upon the number of sites involved (unifocal or multifocal). Whereas patients determined to have multiorgan disease should be further subcategorized based upon whether or not organ dysfunction is present. These latter patients can be additionally stratified based upon which organ systems are involved (4,9,22,34) (Table 2).
|Single organ system disease||Multi-organ disease|
|Unifocal||Multi-focal||No organ dysfunction||Organ dysfunction|
|Low risk (skin, bone, lymph node pituitary)|
|High risk (lung, liver, spleen, hematopoietic)|
In the past, treatment for LCH was anecdotal and sporadic; however, within the last 20 years several multi-center, randomized chemotherapeutic trials have contributed to a more unified therapeutic approach. Patients with limited cutaneous disease typically require no therapy; but, topical steroids may be utilized. Topical nitrogen mustard or PUVA represent viable second-line options (14,35). For patients with localized bone lesions, curettage is generally sufficient for both diagnosis and therapy; however, intralesional steroids or low dose radiation may be employed (36,37). Treatment of multi-organ disease is controversial, with some advocating high-dose prednisone as the first-line therapy, whereas others suggest use of single-agent chemotherapy (19,24,34,38). Several large cooperative studies have shown that multi-agent chemotherapy, sustained over a longer duration, resulted in a greater response rate with fewer recurrences (11,24,37). Currently, the LCHIII treatment protocol is probably the most common therapeutic strategy used for patients with multiorgan involvement. This protocol has several treatment arms dependent upon the number and type of organ systems involved, as well as whether organ dysfunction is present. Other therapies currently being investigated include monoclonal antibodies that target CD1a or CD207, specific cytokine inhibitors, and a relatively new agent, 2-chlorodeoxyadenosine (9,34).
Monitoring Disease Activity
Disease activity may be assessed based upon criteria established by the Histiocyte Society. Under this scale, patients are placed into one of four subcategories: nonactive disease, evidence of disease with regression, stable disease, and progressive disease. A more objective assessment of disease activity has recently been proposed (39). This methodology is based upon a score derived from three primary parameters; clinical examination, laboratory evaluation, and radiologic findings (Table 3). Patients with abnormal findings receive a higher score and thereby are at greater risk for disease progression and demise. Patients with a score >7 are considered high risk and generally have poor outcome.
|Clinical findings (Maximum score in this category is 17)|
|Fever (0–1), cutaneous eruption (0–2), and bone involvement causing obstruction (0–1) and/or pain (0–1)|
|Lymphadenopathy (0–1), hepatomegaly (0–2), splenomegaly (0–2), soft tissue tumor (0–2)|
|Respiratory dysfunction (0–5)|
|Laboratory evaluation (Maximum score in this category is 15)|
|Abnormal liver function tests; AST and ALT (0–2), GGT (0–2), and albumin (0–3)|
|Red blood cell count, with the score dependent upon units needed to be transfused (0–3)|
|Platelet counts, with the score dependent upon units needed to be transfused (0–4)|
|Radiological studies (chest radiograph or CT) (Maximum score in this category is 3)|
|If a pneumothorax is present the score is 2|
|If there are lung infiltrates the score is 1|
Despite adequate treatment, survivors of LCH in childhood may have long-term sequelae, some of which may not become apparent until many years later (40) (Table 4). One retrospective study of patients with a history of multi-organ system LCH found that 75% had detectable long-term sequelae with hypothalamic-pituitary dysfunction (50%), cognitive dysfunction (20%), and cerebellar involvement (17.5%) (41). Other sequelae may be multifactorial, such as growth retardation. Growth retardation can arise from gastrointestinal involvement resulting in malabsorption, dysfunction of the anterior pituitary resulting in deficiencies in growth hormone, or the residua of chemotherapy. Not only patients with multisystem disease are at risk for long-term complications, but also approximately 25% of patients with single-system disease may experience permanent sequelae (37). Even those patients diagnosed with congenital self-healing LCH may have late relapse or progression to systemic involvement. Consequently, all patients with LCH require long-term follow-up to identify disease recurrence or late-stage complications (15). Lastly caregivers should be cognizant that patients with LCH are at risk for second malignancies, including solid tumors and hematopoietic malignancies.
|Central nervous system|
|Neurodegenerative changes: gait disturbance, ataxia, dysarthria, intellectual impairment|
|Hypothalamic-pituitary dysfunction: growth hormone, thyroid stimulating hormone, and vasopressin deficiencies|
|Fractures or vertebral collapse|
|Orthopedic deformities: scoliosis, facial asymmetry, limb asymmetry|
|Visual disturbance from proptosis|
In sum, LCH represents a disease with a diverse spectrum of clinical manifestations. A definitive diagnosis is made upon biopsy, yielding cells that are morphologically and immunohistochemically compatible with LC. Proposals by the Histiocyte Society assist in the classification and treatment through risk stratification. The prognosis in individual patients depends chiefly upon involvement of multiple organ systems, and also upon the response to chemotherapy during the initial 6 weeks of treatment.
The authors thank the Histiocyte Society for providing protocol information.