Pediatric and Adult Histiocytic Disorders

The histiocytic disorders comprise a broad grouping of hematologic and immunologic diseases united by aberrant function, differentiation, and/or proliferation of cells of the mononuclear phagocyte system. The term histiocyte historically referred to tissue phagocytes but now more precisely defines cells of the monocyte/macrophage lineage ( Fig. 53.1 ). The ontogeny of these cells and their role(s) in pathogenesis continue to be studied and refined. In the 1970s, Steinman and Cohn distinguished dendritic cells (DCs) from macrophages based on specific morphologic features of DC and superior antigen-presenting capacity. The characteristic cells seen in various histiocytic lesions can, in general, be differentiated by a variety of functional and phenotypic markers. The current classification of the histiocytoses is based on histological comparisons to physiologic “histiocytes” ( Table 53.1 ; Fig. 53.2 ). Updated classification including features of differentiation, genetic lesions, and tissue involvement has been proposed ( Table 53.2 ). Although malignant disorders involving monocyte/macrophages or dendritic cells are included in this classification, this chapter focuses solely on non-malignant histiocytic disorders.

Table 53.1

Historical Classification of Histiocytic Disorders

A.Dendritic cell−relatedLangerhans cell histiocytosisJuvenile xanthogranuloma and related disorders including:

Erdheim-Chester disease
Solitary histiocytomas with juvenile xanthogranuloma phenotype
Secondary dendritic cell disorders

B.Monocyte/macrophage−relatedHemophagocytic lymphohistiocytosis: familial and sporadicSecondary hemophagocytic syndromes

Infection-associated
Malignancy-associated
Autoimmune-associated

Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease)Solitary histiocytoma of macrophage phenotype

Adapted from Jaffe R. Histiocytic and dendritic cell neoplasms. In: Swerdlow SH, ed. WHO Calssification of Tumours of Hematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2008;353–357.

Table 53.2

Proposed Revised Classification of Histiocytoses

L Group	LCH Intermediate-cell histiocytosis (ICH) Erdheim-Chester disease (ECD) Mixed LCH/ECD
C Group	Cutaneous non-LCH Xanthomatous granuloma (XG) family: includes JXG Non-XG family: includes cutaneous RDD Cutaneous non-LCH with major systemic component XG family: xanthoma disseminatum Non-XG: multicentric reticulohistiocytosis
R Group	Familial RDD Sporadic RDD Classic RDD Extranodal RDD RDD with neoplasia or immune disease Unclassified
M Group	Primary malignant histiocytosis Secondary malignant histiocytosis
H Group	Primary HLH Secondary HLH (non-Mendelian) HLH of unknown/uncertain origin

ECD, Erdheim-Chester disease; HLH, hemophagocytic lymphohistiocytosis; JXG, juvenile xanthogranuloma; LCH, Langerhans cell histiocytosis; RDD, Rosai-Dorfman disease.

Adapted from Emile JF, Abla O, Fraitag S, et al. Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood . 2016;127(22):2672–2681.

Of the dendritic cell-related histiocytoses, the most clinically common and prominent one is Langerhans cell histiocytosis (LCH). This chapter also briefly discusses related histiocytic disorders, including juvenile xanthogranuloma (JXG); Erdheim-Chester disease (ECD); and sinus histiocytosis with massive lymphadenopathy (SHML), also referred to as Rosai-Dorfman disease (RDD). These conditions are now recognized as myeloid neoplastic disorders characterized by recurrent mitogen-activated protein kinase (MAPK) pathway–activating mutations.

Unlike LCH and related disorders, hemophagocytic lymphohistiocytosis (HLH) is a reactive immune disorder where activated macrophages observed in tissue biopsies reflect coordinated immune dysfunction of interactive partners including activated T cells and defective natural killer (NK) cells.

Table 53.1 lists a currently accepted classification of histiocytic disorders, and Table 53.2 outlines a proposed revision. These disorders are a diverse grouping ranging from benign skin lesions to rapidly life-threatening systemic disorders. Tables 53.3 and 53.4 outline clinical features and commonly used histologic markers or pathologic features that may be used to help distinguish some of these disorders. The clinical diversity of histiocytic disorders is underscored by recent discoveries related to their pathogenesis.

Table 53.3

Clinical Features of the Non-Langerhans Cell Histiocytosis, Non-Hemophagocytic Lymphohistiocytoses

Diagnosis	Ages	Lesions ( n )	Appearance	Common Sites	Natural History
JXG	0–18 years (median, 2 years)	Single: multiple 9 : 1 (disseminated in <6 months)	Reddish progressing to yellow brown	Head and neck	Gradual involution
Giant JXG	Young	Single	>2 cm	Upper extremity or back	Involution
Systemic JXG	(3 months ^a )	Single-multiple	Almost 50% have no skin lesions	Subcutis, liver, spleen, lung, CNS, iris	May involute (4%–10% fatal)
Adult XG	18–80 (35 years ^a )	Single	Same as JXG	Upper body	No involution
BCH	Young child	Few-multiple	Reddish-tan papules	Head and neck	Involution or progression to XG
GEH	Young adult	Disseminated	Reddish-tan papules in crops	Face, trunk, arms	Involution or progression
XD	Young adult	Disseminated	Yellow/reddish-brown plaques and nodules	Eyelids, mucosae, viscerae, CNS	Slow involution or progression
PNH	40–60 years	Disseminated	Xanthoma, nodules	Skin, subcutis	Progression to disfigurement
MRH	>40 years	Multiple	Pink/reddish-brown or yellow	Head, extremities with erosive polyarthritis	Progression
SHML	Wide age range (20 years ^a )	Mainly systemic	Firm indurated papules	Cervical adenopathy, 80% “B” symptoms, extranodal (43%)	Exacerbations and remissions (5%–11% fatal)
ECD	7–84 years (53 years ^a )	Mainly systemic	Xanthelasma, xanthoma	Long-bone sclerosis, retroperitoneal fibrosis	Highly fatal

BCH , Benign cephalic histiocytosis; CNS , central nervous system; DI , diabetes insipidus; ECD , Erdheim-Chester disease; GEH , generalized eruptive histiocytosis; JXG , juvenile xanthogranuloma; MRH , multicentric reticulohistiocytosis; PNH , progressive nodular histiocytosis; SHML , sinus histiocytosis with massive lymphadenopathy; XD , xanthoma disseminatum.

Adapted from Weitzman S, Jaffe R. Uncommon histiocytic disorders: the non-Langerhans cell histiocytoses. Pediatr Blood Cancer . 2005;45:256–264.

a Approximate median age of presentation.

Table 53.4

Histologic Features of Histiocytic Disorders

Clinical Entity	LCH	ECD/JXG	HLH	SHML
CD1a	++	−	−	−
CD14	−	++	++	++
CD68	+/−	++	++	++
CD163	−	++	++	++
Factor XIIIa	−	++	−	−
Langerin	++	−	−	−
Fascin	−	++	+/−	+
S100	+	−	+/−	+
Lysozyme	−	−	++	++
Birbeck granules	+	−	−	−
Hemophagocytosis			+/−
Emperipolesis				+

ECD, Erdheim-Chester disease; HLH, hemophagocytic lymphohistiocytosis; JXG, juvenile xanthogranuloma; LCH, Langerhans cell histiocytosis; SHML, sinus histiocytosis with massive lymphadenopathy.

Adapted from Weitzman S, Egeler RM. Histiocytic Disorders of Children and Adults . Cambridge: Cambridge University Press; 2005.

Langerhans Cell Histiocytosis

LCH is the most common histiocytic disorder. The physiologic epidermal Langerhans cell was first described in 1868 by 21-year-old medical student Paul Langerhans, though he initially described it as a nerve cell. In the early 1900s, Hand, Schüller, and Christian described the various presentations of LCH, which include lytic bone lesions, skin rash, and central diabetes insipidus (DI). Letterer and Siwe described more severe aggressive and rapidly fatal cases with liver and spleen involvement in young children. These disorders were later grouped under the term histiocytosis X by Lichtenstein based on common histologic appearance and uncertain cell of origin. Nezelof subsequently theorized that histiocytosis X was caused by a proliferation of pathologic Langerhans cells (LC) due to a common feature of Birbeck granules identified by electron microscopy. At present, “Langerhans cell histiocytosis” is typically accepted as the universal terminology replacing all previous nomenclature to refer to all varied clinical presentations of this protean disorder, though recent discoveries identify cells of origin as myeloid precursor cells rather than differentiated epidermal LC. LCH can present at any time in life from the neonatal period to old age. LCH lesions may spontaneously regress or repeatedly “reactivate,” contributing to long-term disabilities such as endocrinopathies or a neurodegenerative disease.

Epidemiology

The incidence of LCH has been estimated to be between 5 and 10 cases per million children, per year. While the incidence of LCH in adults is thought to be lower and estimated at 1 case per million adults per year, it is likely underdiagnosed in adults due to the under-recognition of LCH in adult medicine. Recent registry studies suggest an increased incidence in Hispanic populations and a significantly lower incidence in African Americans. Further, a genome-wide association study (GWAS) trio study identified an increased risk of LCH in patients with a SMAD6 variant that is enriched in Hispanic populations. Although families with multiple cases of LCH have been reported, these events are extremely rare. LCH may rarely arise as a shared clone with other hematologic malignancies, most notably in adults with myeloid histiocytic disorders as part of myeloid neoplasias associated with clonal hematopoiesis.

Pathophysiology

Over the past decade, there has been a significant evolution in the scientific understanding of the biologic mechanisms leading to LCH, driven by new insights in both normal epidermal and disease-associated LC. Prior to these more recent discoveries, LCH was variably classified as a neoplasm, a reactive disorder, or an aberrant immune response and thought to arise from transformed or pathologically activated epidermal LC. Like epidermal LC, LCH lesion LC express CD1a and CD207 (langerin) surface markers. The frequency of LC within LCH lesions is highly variable, with a median of about 8%. The balance of this granulomatous lesion includes lymphocytes (primarily T cells), eosinophils, and macrophages.

Two studies demonstrated that pathologic LCH cells have clonal properties based on clonal X-chromosome inactivation. Additionally, expression studies of pathologic LCH cells from lesions and epidermal Langerhans cells found in skin have demonstrated that pathologic LCH cells have relatively increased expression of immature myeloid dendritic-cell precursors and are therefore likely to derive from abnormal bone-marrow precursor cells or their differentiated ontogeny. Further, several recent studies demonstrated that the expression of langerin/CD207 is not exclusive to epidermal LC but rather that it can be induced in cells from multiple hematopoietic lineages.

The discovery of recurrent BRAF V600E somatic mutations in LCH lesions supports a neoplastic etiology for LCH. BRAFV600E is observed in ~8% of all human cancers and also in benign neoplastic conditions such as melanocytic nevi. Constitutive activation of a MAPK pathway leads to activation of the terminal extracellular signal-related kinase (ERK). Several groups have confirmed recurrent BRAF V600E in 50% to 64% of LCH cases as well as mutually exclusive activating mutations in MAPK pathway genes (primarily alternative BRAF mutations or mutations in MAP2K1 [encodes MEK1]) ( Fig. 53.3 ).

Figure 53.3, MAPK PATHWAY MUTATIONS IN HISTIOCYTIC DISORDERS.

Taking advantage of the BRAF V600E discovery in LCH lesions, subsequent studies identified BRAF V600E in hematopoietic stem cells from bone-marrow aspirate and myeloid precursors from peripheral blood of patients with disseminated LCH. Interestingly, BRAFV600E+ peripheral blood mononuclear cells were rarely observed in patients with more limited “low risk” LCH. A pathogenic role for BRAFV600E in myeloid precursors is further supported by recapitulation of an LCH-like phenotype in mice in which BRAF V600E expression was enforced in CD11c+ cells. The “Misguided Myeloid Differentiation” model suggests that the stage of myeloid precursor in which this mutation develops is related to the differentiation potential of the pathologic cell that determines the extent and severity of disease. These observations support the reclassification of LCH as an inflammatory myeloid neoplastic disorder.

Clinical Presentations

The clinical manifestations of LCH can be highly variable, with bony lesions (~80% of cases) as the most common site of disease ( Fig. 53.4 ). Skin involvement is highly pleiotropic and can mimic many common infant skin rashes. Soft tissue swelling, often in proximity to bony lesions, external ear drainage, enlargement of lymph nodes and thymus, and gum hypertrophy with premature eruption of baby teeth are also typical manifestations. More serious systemic involvement occurs when there is hepatosplenomegaly, liver dysfunction, and hematopoietic failure, typical of the widely disseminated form of LCH seen in young infants, and is associated with a high mortality rate.

Bony Involvement

Solitary or multifocal bone lesions are found predominantly in older children and young adults, usually within the first three decades of life. Such lytic bone lesions have commonly been referred to as eosinophilic granuloma because of their pathologic appearance, though we prefer consistent nomenclature of isolated , multifocal , or multisystem LCH of bone. The incidence of bone lesions peaks between 5 and 10 years of age. Solitary or multifocal LCH bone lesions (with or without the involvement of other organ systems) represent approximately 60% to 80% of all instances of LCH. These bone lesions often cause abnormal gait or inability to bear weight and may have tender swelling caused by soft tissue infiltrates overlying the bone lesions.

The most frequent sites of skeletal involvement include the flat bones of the skull, ribs, pelvis, and scapula (see Fig. 53.3H ). There may be extensive involvement of the skull, with multiple irregularly shaped, lucent lesions giving rise to the so-called geographic skull . Involvement of the vertebral bodies may lead to collapse ( vertebra plana ) as the principal or only presenting manifestation. In such cases, the diagnosis may be problematic, although biopsy is typically not advisable unless a soft tissue mass is present. In long bones, growth of lesions in the medullary cavity leads to pressure that may result in erosion through the cortex, stimulating the formation of periosteal new bone accompanied by soft tissue extension. The differential diagnosis includes Ewing and osteogenic sarcoma, bone lymphoma, benign bone tumor and cyst, and infection. Involvement of distal bones such as the wrists, hands, or feet is less common. Orbital involvement may result in vision loss or strabismus caused by optic nerve or orbital muscle involvement, respectively, and may mimic pre-septal cellulitis. Signs and symptoms may include bony defects with exophthalmos, with a characteristic tumor mass in the orbital cavity related to disease arising from the roof and lateral wall of the orbital bone. Oral involvement commonly affects the gums, palate, or both. In addition, teeth may be lost due to maxillary or mandibular involvement with or without oral mucosal gum infiltration. Erosion of the lamina dura gives rise to the characteristic “floating tooth” seen on dental radiographs. Erosion of gingival tissue causes premature eruption, decay, and tooth loss. Parents of affected children, particularly infants, frequently report precocious eruption of teeth when, in fact, the gums are receding, leading to the exposure of immature dentition. Chronic otitis media is caused by involvement of the mastoid and petrous portion of the temporal bone, leading to otitis externa manifesting as chronic otorrhea is common (see Fig. 53.3J ).

Cutaneous Involvement

Cutaneous involvement by LCH is both common (occurring in 20% to 40% of patients) and highly variable and can mimic more common skin conditions of children. The rash is typically a scaly seborrheic, eczematoid, sometimes purpuric rash involving the scalp, ear canals, abdomen, and intertriginous areas of the neck, face, trunk, and groin (see Fig. 53.4C–F ). Ulceration may result, especially in intertriginous areas, and may be painful. Mild, isolated cutaneous involvement is relatively common in young infants. Rarely, LCH may present only as subcutaneous skin nodules (formerly described as Hashimoto–Pritzker syndrome ), most often in young infants. In many cases of skin-limited neonatal LCH, the lesions may spontaneously resolve.

Involvement of Other Organ Systems

A subset of infants and toddlers with LCH have spleen, liver, or bone-marrow (BM) involvement, often in addition to prominent skin involvement and variable bony disease. This potentially fatal clinical phenotype is the most severe manifestation of LCH. Liver involvement may be clinically problematic, leading to significant cholestasis, hypoproteinemia, diminished synthesis of clotting factors, and ultimately sclerosing cholangitis.

LCH can rarely present with lymph node-limited disease that may be difficult to distinguish SHML, also known as RDD. This presentation is characterized by significant enlargement of multiple lymph node groups with little or no other signs of disease. Thymic involvement is relatively common in children with multisystem involvement but can also be isolated. Gastrointestinal tract disease is rare but is sometimes associated with severe symptoms of diarrhea, hematochezia, malabsorption, and hypoproteinemia. Pancreatic, thyroid, and thymus disease has also been reported.

Isolated pulmonary involvement is usually seen in young adults in their third or fourth decades of life, and occasionally in children and adolescents. It may follow a severe and often chronic debilitating course and patients may often present with spontaneous pneumothorax. Cigarette smoking has been strongly implicated in primary pulmonary histiocytosis. Findings on chest radiographs vary from a diffuse infiltrate consistent with bilateral interstitial pneumonia to a “honeycomb lung” appearance with nodules and cysts (see Fig. 53.4G ).

Other Clinical Features

Central DI affects 5% to 40% of patients with LCH. Most instances of DI occur in children who present with systemic disease and involvement of the orbit and skull. DI is caused by infiltration by LC and immune infiltrate into the hypothalamus with or without the involvement of the posterior pituitary gland (see Fig. 53.4K ). Most cases of DI present within the first 4 years of diagnosis, although it may occur at any time during the course of LCH. Definitive documentation of DI with measurement of serum and urine electrolytes and osmolality before and after a several-hour water deprivation period should be performed, usually in consultation with an endocrinologist. Antidiuretic hormone (ADH) levels can also be measured to document deficiency, although they are not required for diagnosis. DI typically persists beyond successful LCH therapy, requiring life-long management with desmopressin.

Short stature has been found in up to 40% of children with systemic LCH. Chronic illness and steroid therapy are believed to play an important role in this phenomenon. However, short stature also may be a consequence of anterior pituitary involvement and growth hormone deficiency, which can occur in up to half of patients with initial anterior pituitary dysfunction. Other endocrine manifestations associated with LCH may include adrenal insufficiency, hyperprolactinemia, or hypogonadism caused by hypothalamic infiltration.

One of the most severe complications of LCH is the development of a progressive central nervous system (CNS) neurodegenerative syndrome (LCH-ND). This syndrome may develop with the onset of LCH or more typically years after the patient is presumed to be cured. Increased risk of LCH-ND has been associated with “CNS-risk” bone lesions (orbit, mastoid, maxilla, temporal, sphenoid, zygomatic, clivus), pituitary lesions, and BRAF V600E mutations. Delayed CNS involvement is typically diagnosed after a prolonged, sometimes insidious, decrease in cognitive abilities/school function. Magnetic resonance imaging (MRI) characteristically reveals diffuse or polymorphic lesions involving the white matter of the cerebellum, pons, basal ganglia, and less often the cerebral hemispheres with T2 hyperintensity (see Fig. 53.4L ). Limited biopsy studies have previously revealed an inflammatory infiltrate, dominated by CD8 ⁺ T cells, initially suggestive of a paraneoplastic or autoimmune phenomenon. More recently, analysis of brain biopsy and autopsy specimens showed perivascular infiltrates of BRAFV600E+ monocytes and microglia-like cells at sites of neurodegeneration, suggesting that neurodegenerative disease likely represents an active form of LCH rather than an autoimmune or paraneoplastic phenomenon. Of note, although abnormal MRI findings (with white matter lesions) may precede clinical manifestations, such findings do not always correlate with clinical disease (even in retrospect) and do not always progress. Therapy for LCH-ND is controversial. Reports suggest the potential for responses in early disease with LCH-directed chemotherapy and/or MAPK pathway inhibitors.

Laboratory Manifestations

Tables 53.3 and 53.4 list the clinical and pathologic features that help to describe and distinguish LCH from other, much rarer, histiocytic disorders. The CD1a+/CD207+ LC is the essential diagnostic feature in the histology of LCH. Mitoses are rare. Multinucleated giant cells may be present. Other inflammatory cells, such as granulocytes, eosinophils, macrophages, and lymphocytes, are also present in variable numbers. The diagnosis of LCH relies on the immunohistochemical identification of the presence of LC by characteristic appearance with reniform nuclei and CD1a+/CD207+ by immunohistochemistry (see Fig. 53.2A–E ). Electron microscopy can identify Birbeck granules but is currently rarely used. Notably, CD207 expression levels may be variable within lesions and may be absent from liver, brain, or BM lesions. There are no predictive pathologic features that may define “favorable” or “unfavorable” histology. Immunohistochemistry, qualitative or quantitative PCR, and/or targeted sequencing may be used to identify BRAF V600E to support the diagnosis of LCH and also for risk-stratification. Additionally, high-sensitivity PCR of peripheral blood or BM mononuclear cells can identify BRAFV600E+ hematopoietic precursors, and the presence of which is associated with disseminated disease.

Patients who are suspected to have LCH or who have a new biopsy-proven diagnosis of LCH should have imaging to determine the extent of disease. Positron emission (PET) scanning is highly sensitive for LCH. Initial studies including a complete blood count, chemistries including liver function tests, coagulation workup, and urine osmolality are also warranted. Dental examination and radiographs should also be considered depending on clinical history and exam. The occurrence of cytopenias, particularly thrombocytopenia, in the presence of liver or spleen involvement may suggest BM involvement. We typically perform BM studies for all patients under the age of two years old and patients with liver or spleen disease, regardless of complete blood count (CBC) results.

Differential Diagnosis

The differential diagnosis of LCH depends on the clinical presentation and is typically elucidated with a tissue biopsy. Skin involvement may mimic seborrheic dermatitis, albeit with a severe or refractory course. Immunodeficiency syndromes or viral infection must be considered as well. The differential diagnosis of bony lesions, although typically quite distinctive, may include bone cyst, non-ossifying fibroma, lymphoma, sarcoma, or metastatic solid tumor. Chronic otorrhea due to temporal bone involvement is often initially misdiagnosed as chronic otitis media. Liver and spleen involvement must be distinguished from leukemia, infection, and metabolic storage diseases. The new onset of DI may also arise from germinoma or pituitary hypophysitis.

Prognosis

The prognosis of patients with LCH is largely determined by the extent of disease and response to initial therapies. In general, the population with the highest risk of mortality includes patients with visceral, or so-called “high risk organ” involvement (e.g., liver, spleen, and/or BM). Furthermore, the International Histiocyte Society conducted a clinical trial (LCH-II) that identified the response after an initial 6 weeks of therapy with weekly vinblastine and daily prednisolone as a risk factor in predicting mortality in patients with risk organ involvement. Of the approximately 79% of patients who responded to initial therapy, 94% were alive at 5 years, but only 11% of the non-responders survived. These important data suggest that alternative therapies should be tested early during the course of therapy for patients with poor early responses. Additionally, BRAF V600E mutation is associated with increased risk of refractory disease/relapse and LCH-ND.

Therapy

A generally accepted standard for the initial treatment of patients with LCH is the use of an appropriate amount of the least toxic therapy to treat the disease. Isolated skin lesions may spontaneously resolve or respond to topical therapies. Single bone lesions may be treated with curettage and/or steroid injection, with exceptions for functionally critical lesions that are not amenable to surgery and sites of disease that are considered CNS-risk. Patients with multifocal and multisystem disease typically require systemic therapy.

Surgery and Radiotherapy

Patients with disease involving a single bone can usually be managed with local therapy in consultation with surgical subspecialists. This most often involves surgical curettage or intralesional steroid injection for patients whose lesions are in easily accessible and non-CNS risk locations. Overly aggressive complete “cancer operation” resections are contraindicated and may impair remodeling that typically occurs if margins remain intact. Limited local radiotherapy may be indicated for rare circumstances where an isolated lesion is inaccessible.

Chemotherapy

Historically, systemic treatment of LCH has used chemotherapy drugs classically used for malignant diseases. Therapeutic advances for LCH in recent years have largely come from international cooperative trials testing empiric chemotherapeutic strategies conducted by the Histiocyte Society. LCH-III demonstrated lower relapse rates in patients treated with 1 year versus 6 months of vinblastine/prednisone. Further, the addition of methotrexate to patients with high-risk LCH was not beneficial. Therefore, the current standard of care for patients requiring chemotherapy for LCH includes vinblastine/prednisone for 1 year (with mercaptopurine added for high-risk LCH). The Histiocyte Society is currently testing the impact of further treatment prolongation (2 vs. 1 year) with vinblastine/prednisone/(mercaptopurine for high-risk) for frontline therapy (clinicaltrials.gov: NCT02205762). Based on responses to cytarabine monotherapy in an institutional series, another phase III trial is currently testing 1 year of vinblastine/prednisone/mercaptopurine versus cytarabine for frontline LCH (clinicaltrials.gov: NCT00276757).

Alternative treatment has not been standardized for patients with recurrent or refractory disease. Patients with recurrent disease (i.e., disease that reappears after a period of remission) may respond to re-initiation of the drugs with which they were initially treated. Several studies, including an international phase II trial, have demonstrated significant activity of nucleoside analogs (2-chlorodeoxyadenosine [2-CdA], cytarabine, and clofarabine) against recurrent and refractory LCH. The combination of 2-CdA and high-dose cytarabine has high response rates, but also notable treatment-related mortality. Moderate dose cytarabine and clofarabine have been reported as effective in institutional series. Prospective trials are required to determine the optimal agents and doses. Hematopoietic cell transplant has also been reported as successful in some extreme cases of disseminated LCH.

Since the discovery of the central pathologic role of MAPK pathway activation, BRAF-V600E and MEK inhibitors have been utilized primarily as salvage therapies with extremely high response rates. However, disease typically recurs with cessation of therapy and the toxicity profiles are not ideal for life-long use. Pre-clinical studies and clinical trials are required to determine optimal timing, duration, and potential combination therapies with MAPK inhibitors.

Long-Term Follow-Up

Over 50% of LCH survivors experience at least one permanent consequence, with more frequent long-term effects in patients with multisystem disease and multiple relapses. The most commonly reported late effects are DI and orthopedic abnormalities. Complications of developing DI include a significant incidence of anterior pituitary hormone deficiencies and an associated risk for later developing neurodegenerative syndrome. Patients with LCH-ND typically present with ataxia, dysarthria, dysmetria, and learning and behavior difficulties. The diagnosis may be aided by brain MRI, in which T2 hyperintense signals in the cerebellum, basal ganglia, or pons may be present, although such abnormalities do not always correlate with clinical disease and vice versa is also true (see Fig. 53.4 ). Treatment with low-dose cytarabine or MAPK inhibition has anecdotally resulted in stabilization or improvement of these symptoms.

The small but real risk of secondary malignancy in patients with LCH undergoing radiation and chemotherapy is well documented. Thus, judicious use of radiotherapy, avoidance of potentially carcinogenic chemotherapeutic agents, and good supportive care are recommended. Because etoposide was not shown to be any more effective than vinblastine in both the LCH-I and LCH-II trials for patients without risk of organ involvement, there does not appear to be compelling reasons to include this leukemogenic agent in the treatment of patients with newly diagnosed LCH. Rarely LCH can occur along with other hematologic malignancies that share a common origin.

Another serious late effect of LCH is sclerosing cholangitis, which may lead to secondary biliary cirrhosis and liver failure. Sclerosing cholangitis may develop years after successful therapy for LCH and does not typically signify disease recurrence. The only successful treatment of sclerosing cholangitis has been liver transplantation, although anecdotal reports with clofarabine and MAPK inhibitors have also shown promise in at least stabilizing this process.

Other late complications of LCH include pulmonary cyst formation, fibrosis, and chronic pneumothoraces, and progression to cor pulmonale and respiratory failure may occur. Lung transplantation has been used for the treatment of such patients. Consequently, all patients with LCH require long-term follow-up.

Future Directions

Frontline vinblastine/prednisone, the current standard of care for systemic LCH, cures fewer than 50% of patients. More effective therapy that minimizes toxicity and the risks of late consequences is clearly needed. With the recent insights into the pathophysiology of LCH, including a central role for MAPK activation in myeloid precursors, new possibilities for rationale, targeted therapies being explored. Ideally, future trials will lead to precision strategies to determine optimal therapy for patients based on features of the patient and disease.

Juvenile Xanthogranulomatous Disease

JXG (or more broadly, the full spectrum of juvenile xanthogranulomatous diseases) is a histiocytic disorder with features of macrophage histology. JXG most commonly affects infants and young children, with a slight male predominance and presents as a solitary or a few “fleshy nodules.” The most common sites are the skin of the frontal trunk, head, and neck, but they can occur at any site on the body. These red-yellowish, benign-appearing lesions are sometimes mistaken for molluscum. However, when biopsied, these lesions reveal a distinctive pathology (see Fig. 53.2F–H ). Multinucleated, Touton giant cells are usually found, and lesional histiocytes are positive for CD14, CD68, CD163, factor XIIIa, and fascin, historically compared to dermal dendrocytes. The cells are usually negative for CD1a, CD207, S100, plasmacytoid monocyte antigen CD123, and absent Birbeck granules. Lesions may vary significantly in size and number but are often several millimeters to 1 cm in size and solitary. However, in some patients, the lesions become widespread and quite disfiguring ( Fig. 53.5 ). Furthermore, JXG may be systemic (<5% pediatric cases) involving multiple organs, including deeper soft tissue, central nervous system, bone, lung, liver, spleen, pancreas, adrenal glands, intestines, kidneys, lymph nodes, BM, orbit, and heart. CNS involvement can present with seizures, hemiplegia, and increased intracranial pressure. Patients diagnosed with JXG, particularly multifocal JXG, may benefit from screening computed tomography (CT) or MRI scans to rule out disseminated involvement. Ophthalmologic examination may be helpful to rule out anterior chamber involvement and prevent potentially blinding complications.

The etiology of JXG and the basis for prevalence in children and tissue distribution is not well defined. Several cases suggesting an association between JXG, neurofibromatosis (types 1 and 2), and juvenile chronic myelogenous leukemia that potentially implicates MAPK pathway hyperactivity as shared pathogenesis have been reported. Additionally, molecular alteration in the MAPK pathway such as CSF1R , KRAS, NRAS , and MAP2K1 (rarely BRAF V600E) and PI3K pathway mutations have been identified (see Fig. 53.3 ).

Cutaneous JXG lesions usually resolve over several months and require no treatment. Of note, residual pigmented areas may persist indefinitely even after lesions have regressed. In patients in whom JXG becomes systemic and involves multiple organs, LCH-based systemic chemotherapy regimens such as vinblastine and steroids, cladribine, and clofarabine has led to responses in some case reports and series.

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