Histiocytoses: A Review of the Most Recent Classification System

A look at the proposed new classification system, grouping the histiocytoses into five categories, with tabular summaries for differential diagnosis.

By Jolie Krooks, BS, Milen Minkov, MD, PhD, and Klemens Rappersberger, MD

Histiocytes are immune cells found in various tissues throughout the body whose functions are diverse and include housekeeping via phagocytosis, activating the immune system via antigen presentation to T cells, and promoting peripheral tolerance via proliferation of regulatory T cells.1,2 Histiocytes of the skin include the CD14+ dendritic cells and macrophages of the dermis and CD14- Langerhans cells of the epidermis and mucosa.3,4 Langerhans cells share unique properties with both macrophages and dendritic cells. Like dendritic cells, macrophages and Langerhans cells may be long-standing byproducts of fetal hematopoiesis in the yolk sac and liver or may be renewed by bone marrow myeloid precursor cells during severe inflammatory conditions. However, in contrast to dendritic cells, macrophages and Langerhans cells self-renew during stable conditions.5-7 Nevertheless, Langerhans cells more closely resemble dendritic cells than macrophages in their ability to migrate to lymph nodes in order to present antigens to and stimulate T lymphocytes.8

The pathologic propagation of histiocytic cells encompasses over 100 different subtypes of rare disorders collectively referred to as the histiocytoses.9 Of the histiocytoses, Langerhans cell histiocytoses (LCH) is the most common, affecting an estimated four to five per million children per year (age 0-15).10,11 LCH affects children in >90 percent of cases.12

The first classification of the histiocytoses, established by the Working Group of the Histiocyte Society in 1987, classified the histiocytoses as Langerhans cell-related, non-Langerhans cell-related, or malignant.13 The original classification was updated in 1997 by a joint effort of the Histiocyte Society and the WHO Committee on Histiocytic/Reticulum Cell Proliferations to “disorders of varied biological behavior” and malignant, which included further subdivision to dendritic cell-related, macrophage-related, and monocyte-related. “Disorders of varied biological behavior” represented non-malignant disorders of diverse clinical severities.14

Since then, there have been breakthroughs regarding the specific molecular mechanisms involved in the pathogenesis of many of the histiocytoses, especially those pertaining to LCH and Erdheim-Chester disease. The identification of specific mutations in the MAPK pathway, shared by both LCH and Erdheim-Chester disease, has shaped the way researchers regard these disorders in relation to each other, and there has been a shift in considering these disorders as neoplastic, rather than as simply inflammatory, conditions.15-20 Considering these new insights, Emile et al recently presented a new classification of the histiocytoses.9 Specifically, in this new classification, the histiocytic disorders are grouped into five categories based on clinical, genetic, and (immuno)-histologic features: Langerhans (L); cutaneous and mucocutaneous (C); malignant (M); Rosai-Dorfman disease (R); and hemophagocytic lymphohistiocytosis (H).9

Indicative of the relevance of the histiocytoses to dermatology is the fact that there is a distinct category for histiocytoses with predominantly cutaneous and mucocutaneous manifestations. Additionally, many of the systemic clinical forms (including the malignant entities) can also present with cutaneous manifestations. Other histiocytoses classification systems have also emphasized the dominating role of the skin.21 Accordingly, correct diagnosis may depend on the expertise of the dermatologist and dermatopathologist.

This review includes a discussion of the proposed classification system from Emile et al and the pathogenesis of the different histiocytic disorders, and provides tabular summaries of the clinical presentation, the cutaneous manifestations, and the characteristic immunohistochemical findings (Tables 1-6).

Histiocytoses groups

L group. The Langerhans (L) group consists of Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), Mixed LCH/ECD, and Indeterminate cell histiocytosis (ICH), grouped together due to similarities in both clinical presentation and disease pathogenesis. Specifically, activating mutations in the MAPK pathway are central to disease pathogenesis in this group; the MAPK pathway is essential for cell growth, differentiation, and apoptosis.15-17 Still, it is important to note that mutations in the MAPK pathway, i.e. BRAFV600E, MAP2K1, KRAS, are not specific to LCH, ECD, and ICH, as these mutations have been implicated in non-histiocytic tumors and in other histiocytoses, including histiocytic sarcoma, interdigitating dendritic cell sarcoma, dendritic cell sarcoma, follicular dendritic cell sarcoma, and Rosai-Dorfman disease.22

Emile et al consider ECD as a specific manifestation of extracutaneous/disseminated juvenile xanthogranuloma (JXG) with activating mutations in the MAPK pathway.9 Indeed, the co-existence of ECD and LCH lesions in the same patient is attributed to MAPK pathway activating mutations, particularly BRAF-V600E, in bone marrow progenitors, monocytes, and myeloid dendritic cells. Furthermore, the diseases are not distinguishable by a specific distribution of mutant cell involvement.23 Of the 19 percent of patients with ECD that have mixed LCH/ECD, 89 percent have BRAF mutations.18 Observations of BRAF-V600E mutations in 58 percent of ECD patients20 and 56 percent of LCH patients19 have been confirmed by other studies.24-29 Of note to dermatologists, BRAF-V600E mutation is significantly more prevalent in patients with cutaneous involvement (EDC: 76 percent;30 LCH: 77 percent31). In addition to BRAF-V600E, mutations in other genes activating the MAPK pathway, as well as additional mutations in BRAF, have also less frequently been observed.20,32-37

Due to the rarity of ICH, studies assessing BRAF-V600E mutation status have been limited to isolated case reports and case series.22,38,39 Nevertheless, considering ICH’s histologic and clinical overlap with LCH, a shared primary component of disease pathogenesis would be expected. Specifically, like the pathologic cells observed in LCH, those of ICH also express CD1a and S100, but are negative for CD207 (langerin), an antibody to Birbeck granules. Indeterminate cells are considered dermal dendritic precursors of Langerhans cells that have not been acted upon by TGF-Β, a cytokine that promotes migration from the dermis to the epidermis and the acquisition of Birbeck granules.40

Despite the overlap between ICH and LCH, recent report of a NCOA2-ETV3 gene fusion identified in three cases of ICH, but absent in 11 cases of LCH, may indicate that they are distinct clinical entities.41 However, more research is needed to possibly identify this mutation in isolated LCH cases, and further follow-up is needed to identify whether its presence in the three ICH cases will be associated with another malignancy (one patient had a history of breast cancer; follow-up for all cases was only four to five months). When identified in six children with acute lymphoblastic leukemia, NCOA2-ETV3 gene fusion was also associated with a significant number of NOTCH1 mutations.42 NOTCH1 pathway mutations have been implicated in upregulation of the MAPK pathway43 and have been identified in LCH patients with a history of T-cell acute lymphoblastic leukemia.44

C group. By Emile et al’s categorization, the cutaneous and mucocutaneous (C) group consists of non-LCHs primarily localized to the skin and/or mucosa, (though systemic involvement may also be observed), and is divided into the xanthogranuloma (XG) family and non-XG family. The XG family includes: juvenile xanthogranuloma (JXG); adult xanthogranuloma (AXG); solitary reticulohistiocytoma (SRH); benign cephalic histiocytosis (BCH); generalized eruptive histiocytosis (GEH); progressive nodular histiocytosis (PNH); and xanthoma disseminatum (XD). The non-XG family includes: cutaneous Rosai-Dorfman disease (RDD); necrobiotic xanthogranuloma (NXG); and multicentric reticulohistiocytosis (MRH).9 As noted, Emile et al adapted their classification system from Weitzman and Jaffe, who also distinguished cutaneous non-LCHs as either JXG or non-JXG.21 While disorders of the JXG family share the same immunophenotype, they vary in clinical presentation and histologic appearance (Table 2).

M group. The malignant histiocytoses (M) group is comprised of histiocytic sarcoma (HS); indeterminate cell sarcoma (ICS); Langerhans cell sarcoma (LCS); and follicular dendritic cell sarcoma (FDCS). Patients must present with rapidly progressing tumors for diagnosis. Tumor cells must also express at least two of the following macrophage/dendritic cell markers: CD68, CD163, CD4, and lysozyme. Malignant histiocytoses may be primary or secondary to another hematologic neoplasm.9

R group. Rosai-Dorfman disease (RDD), also referred to as sinus histiocytosis with massive lymphadenopathy, has an unknown etiology. Emile et al categorize classical RDD separately from RDD isolated to the skin into the R group and C group, respectively.9 RDD may be classical (nodal), extranodal, familial, neoplasia-associated, and immune disease-associated.9

Classical (nodal) RDD is a self-limited, benign disease that typically presents with bilateral painless cervical lymphadenopathy accompanied by systemic signs. Involvement of other lymph nodes is also commonly observed.45 Extranodal involvement has been observed in about 40 percent of cases, and the skin is the most frequent extranodal site (11 percent).46 Nevertheless, isolated cutaneous involvement (C group) is rare (three percent).46 Of note, in addition to distinct clinical presentations, epidemiologic factors regarding disease prevalence differs between classical RDD and RDD with isolated cutaneous involvement (Tables 3 and 5). Familial cases of RDD present in patients with the inherited conditions H syndrome and autoimmune lymphoproliferative syndrome.9 A discussion of these conditions is beyond the scope of this paper.

H group. Haemophagocytic lymphohistiocytosis (HLH), a disorder marked by excessive immune activation with resulting tissue damage,47 comprises the H group, and may be either inherited (primary) or acquired (secondary). HLH may be observed at any age, though generally patients presenting with primary disease are significantly younger than those presenting with secondary disease.48

Primary disease is either familial or attributed to an inherited immunodeficiency. Familial haemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive disorder occurring almost exclusively in infants49 that results from mutations in genes encoding proteins involved in granule-mediated cellular cytotoxicity,50-57 a means by which natural killer and T cells destroy infected or neoplastic cells. In addition to HLH inherited as an independent condition in the familial form, HLH may also develop secondary to an inherited immunodeficiency, such as Chédiak–Higashi syndrome,58,59 X-linked lymphoproliferative syndrome,60,61 Griscelli syndrome,62,63 and Hermansky-Pudlak syndrome.64,65 Secondary HLH develops in patients with acquired conditions that elicit excessive inflammation, such as those with autoimmune disease and/or other rheumatologic conditions,66-70 malignancy,71-75 organ or hematopoietic stem cell transplant,76-79 metabolic disorders,80-84 and infection.70,73,85-88 When secondary HLH occurs in patients with an underlying rheumatologic condition, the disease is referred to as “macrophage activation syndrome (MAS).”


Dermatologists are often essential in the diagnosis and management of histiocytic disorders due to the prevalence of cutaneous involvement, and should therefore be familiar with their unique clinical presentations, cutaneous manifestations, and immunohistochemical findings. Familiarity with Emile et al’s classification system will aid dermatologists in forming a differential diagnosis and in managing histiocytoses patients.

The authors are grateful to Prof Ronald Jaffe for his critical comments and suggestions concerning the pathology descriptions.

The authors did not receive funding and there are no conflicts of interest to report.

Jolie Krooks, BS is a pre-med student at Florida Atlantic University Charles E. Schmidt College of Medicine, Boca Raton, FL.

Milen Minkov, MD, PhD is at Medical University of Vienna, Rudolfstiftung Hospital, and Sigmund Freud Private University in Vienna, Austria.

Klemens Rappersberger, MD is at Rudolfstiftung Hospital and Sigmund Freud Private University in Vienna, Austria.

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About Practical Dermatology

Practical Dermatology is the monthly publication that provides coverage of medical care, cosmetic advancements, and practice management for clinicians in the field. With straight-forward, how-to advice from experts in various fields, we strive to enhance quality of care and improve the daily operation of dermatology practices.