This increased understanding of the pathophysiology of Langerhans cell histiocytosis should help guide treatment and therapies and provides the rationale for using agents effective against myeloid malignancies.
In 1868, a 21-year-old German medical student named Paul Langerhans published an article describing cells with stellate protrusions, or dendrites (hence the term “dendritic cells”), in the skin. These cells would come to bear his name, and today are referred to as Langerhans cells. Paul Langerhans became a prominent pathologist who also described the islet cells of the pancreas (islets of Langerhans). Disorders involving Langerhans cells have previously been known by other names, such as Hand-SchÃ¼ller-Christian disease, Letterer-Siwe disease, eosinophilic granuloma, Hashimoto-Pritzker disease, and histiocytosis X. With the recognition that all of these disorders involve abnormal collections of the same cell, the Langerhans cell, they now are all referred to as Langerhans cell histiocytosis, with an additional description that may refer to the system involved (eg, “skin only”), the number of lesions (eg, “bony single lesion”), or the number of systems involved (eg, “multisystem disease”). In recent years, there has been dramatic progress in our understanding of Langerhans cell histiocytosis and in the development of therapies. This progress has been supported by collaboration between the Histiocytosis Association, a patient-driven organization that has raised significant funding for research in this orphan disease, and the Histiocyte Society, a forum led by researchers and physicians devoted to improving our understanding of the histiocytic disorders and clinical care of patients.
Langerhans cell histiocytosis has long been considered a disease of childhood. The lesions of Langerhans cell histiocytosis, which contain inflammatory cells and Langerhans cells, typically develop in the bone and/or skin, but may involve the lung, bone marrow, liver, spleen, central nervous system, or gastrointestinal tract. Thus, depending on the location or organ system involvement of the Langerhans cell histiocytosis lesion(s), the clinical presentation can be different for each patient. Also, Langerhans cell histiocytosis may mimic other disorders. These tendencies create a high chance for misdiagnosis, which can result in some patients and families distrusting the medical profession, and the difficulty of correctly diagnosing Langerhans cell histiocytosis should be addressed in order to help them cope with this challenging medical situation. Drs. Zinn, Chakraborty, and Allen comprehensively review the epidemiology and the diagnostic and pathologic criteria of Langerhans cell histiocytosis. In particular, they review each organ system that may be involved, and for each system describe some of the possible clinical symptoms and features characteristic of Langerhans cell histiocytosis involvement. They also discuss the organ systems that have been associated with poor outcomes; these “risk organs” include the liver, spleen, lymph nodes, and bone marrow.
There has been longstanding controversy over the pathologic mechanism of disease for Langerhans cell histiocytosis. Some consider Langerhans cell histiocytosis an oncologic process, since there has been some evidence for clonality of the lesions, while others argue that Langerhans cell histiocytosis is caused by immune dysregulation leading to inflammation, which then promotes the formation of the histiocytic lesions. In their review, Zinn and colleagues make the argument that Langerhans cell histiocytosis is primarily a neoplasm of myeloid origin. They note its similarity to Hodgkin lymphoma, which may present with features of inflammation (B symptoms) and which on biopsy exhibits only a small number of the pathognomonic Reed-Sternberg cells, with a large component of the lesions consisting of reactive cells, such as histiocytes, lymphocytes, or eosinophils. In a similar manner, Langerhans cell histiocytosis may present with inflammatory-like symptoms, and on biopsy the Langerhans cell histiocytosis lesions exhibit some Langerhans cells, along with many reactive cells, such as eosinophils.
Zinn and colleagues outline three studies, which when taken together set forth the rationale for the “misguided myeloid differentiation” hypothesis, and thus for consideration of Langerhans cell histiocytosis as a myeloid neoplastic process. First, the discovery of a recurrent BRAF mutation, the V600E mutation, in a significant percentage of Langerhans cell histiocytosis lesions, reported by Rollins et al in 2010, has led to increased support for the notion that Langerhans cell histiocytosis is an oncologic process. Extracellular growth factors bind a transmembrane tyrosine kinase receptor that activates the Ras protein (a GTPase), which in turn activates a protein kinase cascade (Ras, Raf, MEK, ERK), and thus promotes cell proliferation. This is referred to as the mitogen-activated protein kinase (MAPK) signaling pathway. There are several forms of Raf, including ARAF, BRAF, and CRAF. BRAF is a serine-threonine kinase. Activating mutations in the BRAF gene have been associated with different cancers. The V600E mutation confers the change of valine to a glutamic acid at the 600 position in BRAF, resulting in constitutively increased activity of the serine-threonine kinase, and subsequently increased cell proliferation. BRAF mutations, in particular the V600E mutation, are commonly found in melanoma. Now, in recent reports, this same mutation has been found in over half of Langerhans cell histiocytosis lesions,[10,11] thus supporting the contention that Langerhans cell histiocytosis is a neoplastic process.
The second concept supporting the “misguided myeloid differentiation” hypothesis is the fact that the presence of a BRAF mutation in Langerhans cell histiocytosis lesions is not indicative of disease extent or response to therapy or risk level-however, the extent of disease is correlated with the ability to detect the mutation in circulating mononuclear cells. Thus, patients with multisystem disease likely acquire MAPK pathway mutations in more undifferentiated myeloid cells, while in those with more limited disease, MAPK mutations develop in more differentiated myeloid dendritic cells.
Finally, gene expression profiling has revealed that features of the aberrant Langerhans cells in patient samples are more similar to those of myeloid cells than to those of cells of epidermal origin. Thus, the era of genomics has helped establish that Langerhans cell histiocytosis is likely due to the acquisition of a mutation in a myeloid precursor cell, which leads to abnormal differentiation. In other words, the more immature the abnormal cell is at the time the mutation is acquired, the greater the chance for more extensive the disease: the “misguided myeloid differentiation” hypothesis.
This increased understanding of the pathophysiology of Langerhans cell histiocytosis should help guide treatment and therapies and provides the rationale for using agents effective against myeloid malignancies. The authors review the traditional treatment, which typically includes different courses involving vinblastine and corticosteroids; recent studies show that a longer duration of treatment results in less disease reactivation. Salvage therapy regimens, which are used when reactivations occur, are less well studied; these regimens include monotherapy or combination therapy with agents such as cladribine, clofarabine, methotrexate, 6-mercaptopurine, and/or cytarabine.[15,16] Increasing confirmation of the “misguided myeloid differentiation” hypothesis leads to consideration of treatment with the newly available inhibitors of the MAPK pathway and the development of personalized treatments based on individual mutation analysis.[17,18] However, equal attention must be given to the likely toxicities and pitfalls associated with inhibition of the MAPK pathway using these newly available agents. Zinn and colleagues do not skirt over these difficulties, even as they paint a hopeful picture of new therapeutic options-and thus they have painted a landscape of the direction that Langerhans cell histiocytosis therapy will likely take in the future.
Financial Disclosure:The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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