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The histiocytoses are rare disorders characterized by the accumulation of macrophage, dendritic cell, or monocyte-derived cells in various tissues and organs of children and adults. More than 100 different subtypes have been described, with a wide range of clinical manifestations, presentations, and histologies. Since the first classification in 1987, a number of new findings regarding the cellular origins, molecular pathology, and clinical features of histiocytic disorders have been identified. We propose herein a revision of the classification of histiocytoses based on histology, phenotype, molecular alterations, and clinical and imaging characteristics. This revised classification system consists of 5 groups of diseases: (1) Langerhans-related, (2) cutaneous and mucocutaneous, and (3) malignant histiocytoses as well as (4) Rosai-Dorfman disease and (5) hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Herein, we provide guidelines and recommendations for diagnoses of these disorders.

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The histiocytoses are rare disorders characterized by the accumulation of cells thought to be derived from dendritic cells (DCs) or macrophages. Their clinical behavior ranges from mild to disseminated and, sometimes, life-threatening forms. The first classification of histiocytosis, published in 1987 by the Working Group of the Histiocyte Society (HS),1 consisted of 3 categories: Langerhans cell (LC) or non-LC-related, and malignant histiocytoses (MH). In light of recent insights, we propose to parsimoniously gather the large number of categories of histiocytic disorders into 5 groups (Figure 1; supplemental Methods, available on the Blood Web site) based on clinical, radiographic, pathological, phenotypic, genetic, and/or molecular features.

Histology and somatic mutations of histiocytoses of group L, C, R, M, and H. (A) L group: Histology of LCH (skin [i-ii] and bone [iii]) and of ECD (perirenal [iv-v]). Pie chart of relative frequencies of activating kinase mutations in LCH (vi) and ECD (vii). (B) C group: Histology of JXG (i-ii). (C) R group: Histology of RDD (meningeal with high IgG4+ plasma cell infiltration [i-ii]). (D) M group: Histology of MH (i-ii). (E) H group: Histology of inherited HLH (liver [i-ii]). Staining with CD1a (Lii in red), IgG4 (Rii in brown), CD163 (Hii in brown), or hematoxylin and eosin (all others). NOS, not otherwise specified.

The Langerhans/non-Langerhans dichotomy noted in prior classification of histiocytoses has become questionable as nearly 20% of patients with Erdheim-Chester disease (ECD) also have LC histiocytosis (LCH) lesions.4 Furthermore, both diseases have clonal mutations involving genes of the MAPK pathway in >80% of cases.5-8 Blood monocytes harboring the same mutations as pathological histiocytes have been reported in both diseases.7,8 In addition, both conditions may be associated with similar clinical complications such as diabetes insipidus and/or neurodegenerative disease. Thus, we propose to include LCH, ECD, and extracutaneous juvenile xanthogranuloma (JXG) in a single group (Table 1).

An important issue concerns extracutaneous or disseminated JXG. Indeed, histopathology and phenotype are not different from ECD, and some ECD patients may not have typical bilateral and symmetric involvement of long bones. Thus, we recommend performing molecular analysis of these cases, and to consider as ECD all extracutaneous or disseminated JXG with gain-of-function mutation of BRAF, NRAS, KRAS, or MAP2K1 (grade D2). A few cases of histiocytosis for which differential diagnosis of anaplastic lymphoma was excluded have strong expression of ALK,32 some of which have translocation involving ALK.8,32 Some of these cases had histology and clinical characteristics of ECD. Thus, we recommend performing ALK immunohistochemistry screening for all clinically progressive histiocytoses lacking BRAF and MAP2K1 mutations (grade D2).

RDD has to be distinguished from LCH; however, negativity for CD1a, as well as the presence of large CD1a-negative histiocytes with emperipolesis are in favor of RDD. Other histiocytoses, including LC sarcomas and histiocytic sarcomas, may harbor some RDD-like cells with emperipolesis, but usually are not predominant. In skin lesions, histopathological differential diagnosis with JXG may be difficult as RDD histiocytes may have a foamy aspect and be multinucleate, and emperipolesis, which is a useful criterion is not specific for diagnosing RDD.75

Herein, we have provided an overview of histiocytoses with a revised proposed grouping of >100 subtypes of these rare entities in 5 groups based on clinical and/or molecular relevance. Most cases of L group diseases have clonal mutations activating MAPK pathways5-8,33-35,37 and are considered by some as inflammatory myeloid neoplasms.34 Major clinical responses have been obtained with MAPK inhibitors for patients of this group.48-51 Several patients have histiocytoses limited to skin, the hallmark of which is solitary cutaneous JXG. Pathogenesis of most cutaneous histiocytoses is still unknown. MH may be primitive cancers or secondary to other hematologic neoplasia, and may be subclassified based on primitive localization, and/or the expression of macrophage and DC markers. RDD has characteristic histologic features, but corresponds to several different inherited or sporadic conditions, often associated with IgG4+ plasma cell infiltration. Finally, histiocyte infiltration that is frequently but not always observed in HLH has been shown to be reactive to an abnormal immune activation.

Possible differential diagnoses of LCH are other cutaneous histiocytoses such as xanthogranulomas, normolipemic granulomas, histiocytomas or haemophagocytic lymphohistiocytosis and should be considered [8]. In the present case the clinical presentation is difficult to be distinguished from medication related osteonecrosis of the jaw (MRONJ) or possible neoplastic lesions. Definite diagnosis will be achieved by the histopathological examination [9].

Sinus histiocytosis with massive lymphadenopathy (SHML) or Rosai-Dorfman Disease (RDD) was first described in 1969 [1], since then >400 cases have been reported in the RDD registry [2, 3]. This disease usually affects individuals in childhood and early adulthood but has a predilection for males of Caucasian and African descent in their twenties [2, 3]. It is generally considered a benign histiocytic disorder. Other disorders in this group include dendritic cell-related histiocytoses (like Langerhans cell histiocytosis), macrophage-related histiocytoses (like hemophagocytic lymphohistiocytosis), and histiocytosis from underlying malignancy or infection. However, this entity has a unique histopathologic appearance that distinguishes it from other processes in this group. RDD is diagnosed on histologic or cytologic basis, when evidence of abnormal amounts of histiocytes infiltrating lymph tissue is observed [2, 3]. The lymphoid tissue has massively engorged sinuses and/or interfollicular areas with infiltrating cells, which stain positive for S-100 protein [4, 5]. Immunohistochemical staining studies clearly identify RDD histiocytes as a separate process from T or B lymphoid population [4]. These cells are described as having abundant pale cytoplasm, round-to-oval nuclei with a single nucleolus and with evidence of lymphocytophagocytosis or emperipolesis. The etiology of RDD is still unknown. It has been noted to occur sporadically, with occasional clustering, which suggests a genetic or an infectious component [2]. It has been suggested that this disease is linked to a reactive disorder since it arises from circulating mononuclear cells and there is an increase in auto-immune antibodies in some affected individuals [2, 3]. Epstein-Bar virus and human herpes virus 6 has been purposed as the infectious agent and recently other diseases has been implicated like varicella zoster virus, cytomegalovirus, Brucella, and Klebsiella [2]. It has also been postulated that the development of RDD may be driven by disregulated cytokine expression [2].

Much has been learned about the molecular genetics of histiocytoses/histiocytic neoplasms in recent years. These neoplasms, in particular Langerhans cell histiocytosis/sarcoma, Erdheim-Chester disease, juvenile xanthogranuloma, RDD and histiocytic sarcoma, commonly show mutations in genes of the MAPK pathway, such as BRAF, ARAF, MAP2K1, NRAS and KRAS, albeit with highly variable frequencies, indicating a unifying genetic landscape for diverse histiocytoses and histiocytic neoplasms. ALK-positive histiocytosis furthermore converges on the MAPK pathway, which is one of the signaling pathways mediating ALK activation [87, 88]. Insights on genetic alterations have significant treatment implications, because of availability of highly effective therapy targeting components of the activated signaling pathway, such as BRAF and MEK inhibitors [88,89,90,91,92].

RDD lesions are FDG avid, presumably because of the cellular proliferation and inflammation [12, 13]. Diagnostic and staging evaluation of RDD is done by 18F-FDG PET/CT, similar to other histiocytoses such as Erdheim-Chester disease and Langerhans-cell histiocytosis [1, 5]. In children, judicious use of PET/CT is recommended, to minimize radiation exposure and the need for anesthesia. Whole-body PET scan should include distal extremities to evaluate osseous lesions, such as in this case. Whole-body contrast-enhanced MRI is an alternative for staging, especially to evaluate extranodal lesions such as brain, orbit, gastrointestinal or genitourinary lesion which are less favorably evaluated by FDG PET [1, 14]. 041b061a72

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