COVER FOCUS 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

istiocytes are immune cells found in various tissues ior” and malignant, which included further subdivision to throughout the body whose functions are diverse and dendritic cell-related, macrophage-related, and monocyte- include housekeeping via phagocytosis, activating the related. “Disorders of varied biological behavior” represented immune system via antigen presentation to T cells, non-malignant disorders of diverse clinical severities.14 Hand promoting peripheral tolerance via proliferation of regula- Since then, there have been breakthroughs regarding the tory T cells.1,2 Histiocytes of the skin include the CD14+ dendrit- specific molecular mechanisms involved in the pathogenesis of ic cells and macrophages of the dermis and CD14- Langerhans many of the histiocytoses, especially those pertaining to LCH cells of the epidermis and mucosa.3,4 Langerhans cells share and Erdheim-Chester disease. The identification of specific unique properties with both macrophages and dendritic cells. mutations in the MAPK pathway, shared by both LCH and Like dendritic cells, macrophages and Langerhans cells may be Erdheim-Chester disease, has shaped the way researchers regard long-standing byproducts of fetal hematopoiesis in the yolk sac these disorders in relation to each other, and there has been a and liver or may be renewed by bone marrow myeloid precur- shift in considering these disorders as neoplastic, rather than sor cells during severe inflammatory conditions. However, in as simply inflammatory, conditions.15-20 Considering these new contrast to dendritic cells, macrophages and Langerhans cells insights, Emile et al recently presented a new classification of the self-renew during stable conditions.5-7 Nevertheless, Langerhans histiocytoses.9 Specifically, in this new classification, the histio- cells more closely resemble dendritic cells than macrophages in cytic disorders are grouped into five categories based on clinical, their ability to migrate to lymph nodes in order to present anti- genetic, and (immuno)-histologic features: Langerhans (L); cuta- gens to and stimulate T lymphocytes.8 neous and mucocutaneous (C); malignant (M); Rosai-Dorfman The pathologic propagation of histiocytic cells encompasses disease (R); and hemophagocytic lymphohistiocytosis (H).9 over 100 different subtypes of rare disorders collectively referred Indicative of the relevance of the histiocytoses to derma- to as the histiocytoses.9 Of the histiocytoses, Langerhans cell his- tology is the fact that there is a distinct category for histio- tiocytoses (LCH) is the most common, affecting an estimated cytoses with predominantly cutaneous and mucocutaneous four to five per million children per year (age 0-15).10,11 LCH manifestations. Additionally, many of the systemic clinical affects children in >90 percent of cases.12 forms (including the malignant entities) can also present The first classification of the histiocytoses, established by with cutaneous manifestations. Other histiocytoses classifi- the Working Group of the Histiocyte Society in 1987, classi- cation systems have also emphasized the dominating role of fied the histiocytoses as Langerhans cell-related, non-Lang- the skin.21 Accordingly, correct diagnosis may depend on the erhans cell-related, or malignant.13 The original classification expertise of the dermatologist and dermatopathologist. was updated in 1997 by a joint effort of the Histiocyte This review includes a discussion of the proposed classifica- Society and the WHO Committee on Histiocytic/Reticulum tion system from Emile et al and the pathogenesis of the dif- Cell Proliferations to “disorders of varied biological behav- ferent histiocytic disorders, and provides tabular summaries

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TABLE 1. IMMUNOHISTOCHEMICAL AND CLINICAL FINDINGS; L GROUP*

Disease Histology Clinical presentation Cutaneous manifestations

LCH LCH cells with “coffee-bean” Highest incidence before age 1, decreases thereafter Most commonly presents as cleaved nuclei, benign, round- Systemic involvement, with potential for multi- a seborrheic dermatitis-like or ed morphology, and eosino- organ failure, likely when patients present with eczematous rash on the trunk, philic cytoplasm cutaneous signs (87-93%) head, and/or face, though vari- CD1a+, CD207+, HLA-DR+ Bone (80%), skin (33%), pituitary (25%), liver (15%), ous lesions and sites of involve- cytoplasmic dot, Birbeck gran- spleen (15%), hematopoietic system (15%), lungs ment have been observed ules present (15%), lymph nodes (5–10%), and CNS excluding the pituitary (2–4%) are most commonly affected

ECD This entity represents an extra- Highest incidence in men age 40-70, Periorbital xanthelasmas cutaneous systemic form of Predominantly affects long bones, bilateral cortical increasing in size (33%); other JXG immunohistochemically. osteosclerosis (90%) skin lesions resemble either See XG family (Table 2) Cardiovascular (45%), especially aortic coating, those of JXG, diffuse , However, Emile et al empha- CNS (50%), pulmonary (20%), and endocrine (5%) , or LCH; size ECD’s molecular similarity involvement, hairy kidney (30%), exopthamos, dip- most commonly involves upper with LCH and co-occurrence lopia, and/or vision impairment (25%), and cutane- trunk and extremities in the same patients. ous lesions (30%) are common Most common initial findings are diabetes insipi- dus (25%) and bone pain (17%) Typically involves >1 organ system (90%) 60% mortality

Mixed Mimics LCH, ECD, or both In a report of 23 patients, average age of diagnosis LCH-like lesions more prevalent LCH/ECD was 43 years (range 2-75), 1 males:1.1 females (61%), though ECD-like lesions ECD either followed (52%, median interval also common (35%) between diagnoses 13.5 years) or presented at the same time as LCH (48%); ECD preceding LCH has rarely been reported in the literature Most prevalent lesions: LCH-type: bone (70%), skin (61%) • Nonspecific: CNS (48%), pituitary (57%) • ECD-type: bone lesions (91%), large vessel (65%), retroperitoneal (56%) • Equivalent mortal- ity rate as ECD, but significantly higher in patients diagnosed with both diseases concurrently

ICH Dermal inflammatory infiltrate Most commonly an isolated cutaneous disease in Presents with pleomorphic and foamy histiocytes with otherwise healthy adults, though bone and corneal pink-red papules or nodules liposomes involvement and cases in children have also been that are either single, multiple S100+, CD1a+ but CD207-, reported unifocal, or disseminated with- CD68+, Birbeck granules Typically has a benign course out accompanying pain, pruritis, absent or mucosal findings

Langerhans cell LCH, Erdheim-Chester disease ECD, Xanthogranuloma XG, JXG, Indeterminate cell histiocytosis ICH *Data from multiple sources.10,18,22,30,89-105

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TABLE 2. IMMUNOHISTOCHEMICAL AND CLINICAL FINDINGS; C GROUP; XG FAMILY*

Histology: Different histiocytic cell morphologies observed on histology include: vacuolated, spindle-shaped, xanthomatized, scal- loped, and/or oncocytic mononuclear cells or Touton, ground-glass appearing, Langhans, and/or foreign body multinuclear cells. CD68+, factor VIIIa+, CD163+, fascin+, S100-, CD1a-, CD207-, Birbeck granules absent

Disease Clinical presentation Cutaneous manifestations

JXG Typically, benign and self-limited in otherwise healthy children <2 years Most commonly a solitary (66%), asymptomatic 5% of patients present with an isolated extracutaneous lesion pink/yellow rubbery papule or nodule that progress- 4% have systemic involvement with multiple cutaneous lesions es to a yellow/brown color on the head and neck Eye involvement rare (0.3-0.5%) in patients with cutaneous disease, how- (42%) or trunk (20-40%) ever it is still the most common of the extracutaneous manifestations Other areas of involvement less common

AXG Extracutaneous disease is rare, but has been reported to affect the Compared to JXG, lesions are more often solitary spine, CNS, orbit, and heart. and larger. Spontaneous resolution is less common than in JXG Lesions are typically the same color as JXG and most Multiple lesions are associated with a higher rate of spontaneous commonly involve the head and neck resolution (50%) than solitary lesions, but with a greater prevalence Rare instances of multiple lesions have been of hematologic malignancy reported If BRAF+, must exclude ECD by clinical and imaging studies

SRH May occur in children but more commonly in adults (mean age 35 Solitary, asymptotic, cutaneous or mucosal nodule years) typically not larger than 1cm Benign with spontaneous resolution in otherwise healthy individuals Most commonly on the trunk (36%), lower extrem- ity (27%), head/neck (18%), upper extremity (14%)

BCH Isolated cutaneous disease in patients 2-66 months with spontane- Yellow and red-brown asymptotic macules and pap- ous resolution ules (1-8 mm) that first appear on the face and neck and may then spread caudally

GEH Benign Multiple self-limited, non-coalescing, red-brown or More prevalent in adults, but may also affect children blue-red symmetric papular lesions on the trunk and proximal extremities with sparing of the flexures Rare mucous membrane or visceral involvement

PNH Affects adults>children Multiple disseminated yellow-brown papules and red- No systemic involvement despite progression of cutaneous lesions brown dermal nodules are more prevalent than pap- ules; may cause disfigurement, particularly of the face Mucosal involvement possible Progressive course of cutaneous lesions

XD Non-malignant, chronic course Diffuse red-yellow to red-brown papules and nod- Most common in patients<25 years and men ules, most prevalent in the flexures and around the Affects mucosa of upper digestive/respiratory tracts (40%) leading eyes, that may become disfiguring to dysphagia, dyspnea, and potentially life-threatening obstruction Mucosal lesions also observed Osseous, ocular, hepatic, respiratory, CNS, cardiovascular, renal, gastroin- testinal, and muscular involvement and diabetes insipidus reported If BRAF+, must exclude ECD by clinical and imaging studies

Xanthogranuloma XG, Juvenile xanthogranuloma JXG, Adult xanthogranuloma AXG, Erdheim-Chester disease ECD, Solitary reticulo- histiocytoma SRH, Benign cephalic histiocytosis BCH, Generalized eruptive histiocytosis GEH, Progressive nodular histiocytosis PNH, XD; *Data from multiple sources.14,106-169

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of the clinical presentation, the cutaneous manifestations, and clinical entities.41 However, more research is needed to possibly the characteristic immunohistochemical findings (Tables 1-6). identify this mutation in isolated LCH cases, and further follow- up is needed to identify whether its presence in the three ICH HISTIOCYTOSES GROUPS cases will be associated with another malignancy (one patient L group. The Langerhans (L) group consists of Langerhans cell had a history of breast cancer; follow-up for all cases was only histiocytosis (LCH), Erdheim-Chester disease (ECD), Mixed four to five months). When identified in six children with acute LCH/ECD, and Indeterminate cell histiocytosis (ICH), grouped lymphoblastic leukemia, NCOA2-ETV3 gene fusion was also together due to similarities in both clinical presentation and associated with a significant number of NOTCH1 mutations.42 disease pathogenesis. Specifically, activating mutations in the NOTCH1 pathway mutations have been implicated in upregu- MAPK pathway are central to disease pathogenesis in this lation of the MAPK pathway43 and have been identified in LCH group; the MAPK pathway is essential for cell growth, differenti- patients with a history of T-cell acute lymphoblastic leukemia.44 ation, and apoptosis.15-17 Still, it is important to note that muta- C group. By Emile et al’s categorization, the cutaneous and tions in the MAPK pathway, i.e. BRAFV600E, MAP2K1, KRAS, mucocutaneous (C) group consists of non-LCHs primar- are not specific to LCH, ECD, and ICH, as these mutations have ily localized to the skin and/or mucosa, (though systemic been implicated in non-histiocytic tumors and in other histio- involvement may also be observed), and is divided into the cytoses, including histiocytic , interdigitating dendritic xanthogranuloma (XG) family and non-XG family. The XG cell sarcoma, dendritic cell sarcoma, follicular dendritic cell sar- family includes: juvenile xanthogranuloma (JXG); adult xan- coma, and Rosai-Dorfman disease.22 thogranuloma (AXG); solitary reticulohistiocytoma (SRH); Emile et al consider ECD as a specific manifestation of extra- benign cephalic histiocytosis (BCH); generalized eruptive his- cutaneous/disseminated juvenile xanthogranuloma (JXG) tiocytosis (GEH); progressive nodular histiocytosis (PNH); and with activating mutations in the MAPK pathway.9 Indeed, the xanthoma disseminatum (XD). The non-XG family includes: co-existence of ECD and LCH lesions in the same patient is cutaneous Rosai-Dorfman disease (RDD); necrobiotic xan- attributed to MAPK pathway activating mutations, particu- thogranuloma (NXG); and multicentric larly BRAF-V600E, in bone marrow progenitors, monocytes, (MRH).9 As noted, Emile et al adapted their classification sys- and myeloid dendritic cells. Furthermore, the diseases are tem from Weitzman and Jaffe, who also distinguished cutane- not distinguishable by a specific distribution of mutant cell ous non-LCHs as either JXG or non-JXG.21 While disorders of involvement.23 Of the 19 percent of patients with ECD that the JXG family share the same immunophenotype, they vary have mixed LCH/ECD, 89 percent have BRAF mutations.18 in clinical presentation and histologic appearance (Table 2). Observations of BRAF-V600E mutations in 58 percent of ECD M group. The malignant histiocytoses (M) group is comprised patients20 and 56 percent of LCH patients19 have been con- of (HS); indeterminate cell sarcoma (ICS); firmed by other studies.24-29 Of note to dermatologists, BRAF- (LCS); and follicular dendritic cell sar- V600E mutation is significantly more prevalent in patients coma (FDCS). Patients must present with rapidly progressing with cutaneous involvement (EDC: 76 percent;30 LCH: 77 per- tumors for diagnosis. Tumor cells must also express at least cent31). In addition to BRAF-V600E, mutations in other genes two of the following macrophage/dendritic cell markers: CD68, activating the MAPK pathway, as well as additional mutations CD163, CD4, and lysozyme. Malignant histiocytoses may be pri- in BRAF, have also less frequently been observed.20,32-37 mary or secondary to another hematologic neoplasm.9 Due to the rarity of ICH, studies assessing BRAF-V600E R group. Rosai-Dorfman disease (RDD), also referred to as sinus mutation status have been limited to isolated case reports histiocytosis with massive lymphadenopathy, has an unknown and case series.22,38,39 Nevertheless, considering ICH’s his- etiology. Emile et al categorize classical RDD separately from tologic and clinical overlap with LCH, a shared primary RDD isolated to the skin into the R group and C group, respec- component of disease pathogenesis would be expected. tively.9 RDD may be classical (nodal), extranodal, familial, neo- Specifically, like the pathologic cells observed in LCH, plasia-associated, and immune disease-associated.9 those of ICH also express CD1a and S100, but are nega- Classical (nodal) RDD is a self-limited, benign disease that tive for CD207 (langerin), an antibody to Birbeck granules. typically presents with bilateral painless cervical lymphade- Indeterminate cells are considered dermal dendritic precur- nopathy accompanied by systemic signs. Involvement of other sors of Langerhans cells that have not been acted upon by lymph nodes is also commonly observed.45 Extranodal involve- TGF-β, a cytokine that promotes migration from the dermis ment has been observed in about 40 percent of cases, and to the epidermis and the acquisition of Birbeck granules.40 the skin is the most frequent extranodal site (11 percent).46 Despite the overlap between ICH and LCH, recent report of Nevertheless, isolated cutaneous involvement (C group) is rare a NCOA2-ETV3 gene fusion identified in three cases of ICH, but (three percent).46 Of note, in addition to distinct clinical pre- absent in 11 cases of LCH, may indicate that they are distinct sentations, epidemiologic factors regarding disease prevalence

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TABLE 3. IMMUNOHISTOCHEMICAL AND CLINICAL FINDINGS; C GROUP; NON-XG FAMILY*

Disease Histology Clinical presentation Cutaneous manifestations

Cutaneous Florid, mixed inflamma- Predilection for Asians, Caucasians, and females; Lesions may be single or multiple and RDD tory infiltrate, very large mean age of onset 46 years may affect any site, most commonly the cells with abundant Rare presentation of RDD extremities, trunk, and face water-clear cytoplasm, No systemic signs Ovoid lesions on erythematous base with and emperipolesis Typically, self-limited and benign yellow satellite structures by dermoscopy S100+, CD68+, CD163+, 3 types of lesions: (1) Papu-lonodular CD1a- (80%): red-brown, red-yellow, or purple lesions, typically multiple, may coalesce to form papuloplaques and/or noduloplaques; (2) Indurated plaques (13%): hyperpig- mented with palpable edges, diffuse brown papules on/around plaque, extensive sub- cutaneous involvement; (3) Tumor type (8%): diverse presentation

NXG Granulomatous inflam- Mean age diagnosis: 53 Typically, multiple and multifocal indu- matory infiltrate with Systemic disease prevalent (95%), particularly rated papules, nodules, or plaques with necrobiosis, Touton involvement of the respiratory and CV systems a yellow hue (.3-20 cm diameter) with giant cells, foamy histio- Chronic and progressive with recurrence after ulceration, telangiectasia, and/or atrophy, cytes, lymphoid follicles, surgical removal most commonly involving, from most to and cholesterol clefts Ocular lesions may also cause photophobia, visual least prevalent, the periorbital area (95%), CD68+, CD1a-, S100- loss or complete blindness, dryness, epiphora, trunk, face besides the periorbital area, blurred vision, diplopia, cataracts, blepharoptosis, and extremities restricted ocular motility, inflammatory disease, Lesions may be asymptomatic or accom- glaucoma, proptosis, ptosis, exophthalmos panied by pain, tenderness, burning, and/ Comormid conditions include monoclonal gam- or pruritus mopathy (71%), plasmacytosis (53%), and cryo- globulinemia (6%)

MRH Multinucleated giant Mean age onset 43; female:male 3:1 Small pruritic (33%) yellow-red muco- cells and histiocytes with Predominantly affects Caucasians (88%) cutaneous nodules and/or xanthelasma ground glass cytoplasm Polyarthritis typically precedes cutaneous lesions most frequently on the face (94%), due to lipid accumula- (66%) especially behind the ears, and the hands tion, with numerous Presentation resembles rheumatoid arthritis, how- (91%), often with mucosal involvement lysosomes detected by ever the distal interphalangeal (DIP) joints are most (52%) electron microscopy commonly implicated Periungal “coral bead” papules (28%) TRAP+, CD68+, lyso- Weight loss (39%), weakness (24%), fever (18%), May present with lesions mimicking der- zyme+, HAM-56+, S100-, and concomitant malignancy (27%) common matomyositis CD1a-, factor XIIIa- Pulmonary, cardiac, and hepatic involvement and Several lesions may form a confluent concomitant autoimmune disease also reported mass and/or result in facial disfigurement Elevated ESR (48%), anemia (48%), hypercholester- olemia (33%), positive tuberculin skin test (56%)

Xanthogranuloma XG, Rosai-Dorfman disease RDD, Necrobiotic xanthogranuloma NXG, Multicentric reticulohistiocytosis MRH *Data from multiple sources.46,170-219

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TABLE 4. IMMUNOHISTOCHEMICAL AND CLINICAL FINDINGS; M GROUP*

Disease Histology Clinical presentation Cutaneous manifestations

HS Large, pleomorphic, polygonal, potentially Median age 55 years Soft tissue involvement typi- binucleate cells with eosinophilic cyto- Commonly affects lymph nodes, soft tis- cally presents as a painless mass plasm in discohesive sheets with an inflam- sue, and GI tract. Disease has also been (71%), but may be accompanied matory infiltrate Hemophagocytosis may reported involving the respiratory and with pain and fever. or may not be observed reproductive tracts and reticuloendo- CD68+, CD163+, CD4+, CD1a-, CD207- thelial system. GI involvement typically manifests with abdominal pain (80%), but may also present with obstruction, GI bleeding, and weight loss. Aggressive clinical course and high mor- tality (58%)

ICS Convoluted, pleomorphic multinucleated Data limited to case reports, therefore Single or multiple papules, cells with nuclear grooves, eosinophilic knowledge regarding median age and plaques, or nodules on the trunk, cytoplasm, and mitotic figures epidemiology limited face, neck, or extremities S100+, CD1a+, HLA-DR+ cytoplasmic dot, Typically, systemic with secondary cuta- CD30-, CD207-, Factor XIIIa-, Birbeck gran- neous disease ules absent

LCS Pleomorphic, high proliferative index, atyp- Median age diagnosis 50 years, 86%>age Cutaneous presentation diverse; ical mitosis, hyperchromatic nuclei 20 solitary or multiple tumors, nod- CD1a+, CD207+, HLA-DR+ cytoplasmic Most commonly aggressive course and ules, ulcers, and erythematous dot, S-100+, CD68- poor prognosis plaques have been described Lymph nodes (74%), skin (49%), lung (29%), liver (17%), and spleen (15%) involvement most commonly observed at diagnosis Disease may involve single or multiple sites

FDCS Typically, low-grade proliferation of spindle Most prevalent in adults, mean age 44 Cases of paraneoplastic pemphi- cells in storiform or whorled pattern years gus have been observed Eosinophilic tumor cells with indistinct Most commonly presents with asymp- borders, elongated nuclei, potentially with tomatic, insidious cervical lymphade- nuclear pseudoinclusions, and with promi- nopathy nent cellular atypia in high grade lesions Affects extranodal sites in 33% of cases, Lymphocitic infiltrate with scattered typically asymptomatic but may present Warthin-Finkeldey-like giant cells with disease-localized pain and systemic CD21+, CD23+, CD35+, clusterin+, signs Podoplanin+, c-Synuclein+, CD1a-, CD34-, May present with Castleman’s disease CD3-, CD30-, HMB-45-, Birbeck granules and/or myasthemia gravis, or associated absent with Epstein-Barr virus (note CD21+)

Histiocytic sarcoma HS, Indeterminate cell sarcoma ICS, Langerhans cell sarcoma LCS, Follicular dendritic cell sarcoma FDCS *Data from multiple sources.14,22,90,220-250

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TABLE 5. IMMUNOHISTOCHEMICAL AND CLINICAL FINDINGS; R GROUP* Disease Histology Clinical presentation Cutaneous manifestations RDD Large histiocytic cells with Most common in first and second decades, males, and African See cutaneous hypochromatic nuclei and descent RDD demonstrating emperipolesis Most commonly presents with bilateral painless lymphadenopathy, and numerous polyclonal typically cervical, with systemic signs and elevated ESR, anemia, leu- plasma cells kocytosis, and hypergammaglobulinemia S100+, fascin+, CD68+, Extranodal involvement (43%) typically involves the skin, nasal cav- CD14+, HLA-DR+, CD163+, ity, bone, soft tissue, and orbit CD1a-, CD207-, Birbeck gran- Usually benign and self-limited ules absent Some overlap with IgG4-related disease Rosai-Dorfman disease RDD ; *Data from multiple sources.9,251-254 TABLE 6. IMMUNOHISTOCHEMICAL AND CLINICAL FINDINGS; H GROUP* Disease Histology Clinical presentation Cutaneous manifestations HLH Hemophagocytosis Patients present with fever (91%), hepatomegaly (90%), splenomegaly (84%), Generalized, tran- in the spleen, bone neurological symptoms (47%), rash (43%), and lymph node enlargement sient, non-pruritic marrow, or (42%) maculopapular rash lymph nodes Diagnostic criteria: Molecular diagnosis consistent with HLH or 5/8: fever May have cutane- ≥38.5 °C; splenomegaly; cytopenias affecting at least 2 lineages (hemoglobin ous findings associ- <9 gms/dL, for infants <4 weeks: hemoglobin 10 gms/dL, platelets <100,000/ ated with bone μL, neutrophils <1,000/μL); hypertriglyceridemia (fasting >265 mg/dL) and/ marrow involve- or hypofibrinogenemia <150 mg/dL; hemophagocytosis; ferritin >500 ng/ ment (i.e. purpura, mL; low or absent NK cell activity; elevated soluble CD25 jaundice) Haemophagocytic lymphohistiocytosis HLH; *Data from multiple sources.255,256

differs between classical RDD and RDD with isolated cutaneous deficiency, such as Chédiak–Higashi syndrome,58,59 X-linked involvement (Tables 3 and 5). Familial cases of RDD present in lymphoproliferative syndrome,60,61 Griscelli syndrome,62,63 and patients with the inherited conditions H syndrome and auto- Hermansky-Pudlak syndrome.64,65 Secondary HLH develops in immune lymphoproliferative syndrome.9 A discussion of these patients with acquired conditions that elicit excessive inflam- conditions is beyond the scope of this paper. mation, such as those with autoimmune disease and/or other H group. Haemophagocytic lymphohistiocytosis (HLH), rheumatologic conditions,66-70 malignancy,71-75 organ or hema- a disorder marked by excessive immune activation with topoietic stem cell transplant,76-79 metabolic disorders,80-84 resulting tissue damage,47 comprises the H group, and may and infection.70,73,85-88 When secondary HLH occurs in patients be either inherited (primary) or acquired (secondary). HLH with an underlying rheumatologic condition, the disease is may be observed at any age, though generally patients pre- referred to as “macrophage activation syndrome (MAS).” senting with primary disease are significantly younger than those presenting with secondary disease.48 CONCLUSION Primary disease is either familial or attributed to an inher- Dermatologists are often essential in the diagnosis and ited immunodeficiency. Familial haemophagocytic lymphohis- management of histiocytic disorders due to the prevalence of tiocytosis (FHL) is an autosomal recessive disorder occurring cutaneous involvement, and should therefore be familiar with almost exclusively in infants49 that results from mutations in their unique clinical presentations, cutaneous manifestations, genes encoding proteins involved in granule-mediated cel- and immunohistochemical findings. Familiarity with Emile et lular cytotoxicity,50-57 a means by which natural killer and T al’s classification system will aid dermatologists in forming a dif- cells destroy infected or neoplastic cells. In addition to HLH ferential diagnosis and in managing histiocytoses patients. n inherited as an independent condition in the familial form, The authors are grateful to Prof Ronald Jaffe for his critical com- HLH may also develop secondary to an inherited immuno- ments and suggestions concerning the pathology descriptions.

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