LCH lesions include a median of 8% infiltrating pathologic DCs, but may be as low as 0.1%. The LCH DCs express high levels of T-cell costimulatory molecules and proinflammatory cytokines. The inflammatory infiltrate may include macrophages, eosinophils, and lymphocytes enriched for regulatory T cells.^6,7 Dozens of cytokines, chemokines, and cytokine/chemokine receptors that constitute the “cytokine storm” in LCH lesions have been hypothesized to play roles in LCH pathogenesis. However, the mechanisms through which pathologic DCs in LCH orchestrate inflammation remain to be defined.

Studies showing clonality in LCH were published in 1994 using polymorphisms of methylation-specific restriction enzyme sites on the X-chromosome regions coding for the human androgen receptor assay (HUMARA), as well as polymorphism for three other loci.⁸ Biopsies of lesions from both single system and multisystem disease were found to have a proliferation of LCs from a single clone. Despite clonality, pathologic DCs do not appear dysplastic, mitoses are rarely observed,⁷ and chromosomes are typically intact.⁹

A major discovery in 2010 described recurrent somatic mutations in the BRAF gene in 57% of LCH lesions.¹⁰ The BRAF-V600E mutation leads to constitutive activation of the downstream kinases, MEK and ERK, and is observed in a wide spectrum of human cancers (e.g., melanoma, thyroid carcinoma, and hairy cell leukemia), as well as many benign neoplasias (e.g., nevi, colon polyps).¹¹ In an institutional series, BRAF-V600E was associated with a twofold increase in risk of recurrence, but otherwise no clinical differences have been associated with the mutation, including age, survival, or clinical risk status.¹² The presence of circulating cells carrying the BRAF-V600E mutation was associated with high-risk clinical status (liver, bone marrow, spleen involvement) and localized to myelomonocytic lineage (CD11c⁺ and CD14⁺ fractions). Hematopoietic cell progenitors with the BRAF-V600E mutation were also identified in patients with high-risk LCH. Therefore, a proposed model of LCH pathogenesis is one in which high-risk LCH arises from pathologic activation of ERK in hematopoietic progenitor cells, and low-risk disease arises from ERK activation in tissue-restricted precursors. This model is supported by the ability of enforced expression of BRAF-V600E in early myeloid (CD11c⁺) cells to drive a LCH-like phenotype in mice.¹² The presence of BRAF-V600E in hematopoietic progenitor cells in bone marrow and myelomonocytic precursors in circulating blood in patients with high-risk LCH is also consistent with the classification of LCH as a myeloid neoplasia, and suggests that “histiocytosis X” may in fact be a more appropriate nomenclature than “Langerhans cell” histiocytosis.

Seborrheic scalp rash is a common presentation of LCH, which may be confused with cradle cap in infants or severe dandruff in older children and adults. Red papular lesions resembling candida may also develop in the scalp, groin, abdomen, back, or chest (Fig. 25.2A). Ulcerative lesions behind the ears or involving the scalp, axillae, genitalia, or perianal region are often misdiagnosed as bacterial or fungal infections. Patients may also present with brown-to-purplish papules over any part of their body. In some patients, LCH skin lesions may disappear during the first year of life with no therapy, while in others skin lesions may be the most clinically evident manifestation of disseminated disease.¹⁵ In a report of 61 neonatal LCH cases from 1,069 patients in the Histiocyte Society database, almost 60% of neonates had multisystem disease and 72% had risk organ involvement.¹⁶

Presenting symptoms of oral LCH include gingival hypertrophy and ulcers of the soft or hard palate, buccal mucosa, or on the tongue and lips. Early eruption of teeth occurs with LCH infiltration of the mandible or maxilla.¹⁷

The most frequent site of LCH is bone, usually a lytic lesion of the skull, which may be asymptomatic or painful (Fig. 25.2B).¹⁸ Other common sites of bone involvement include the femur, ribs, vertebra, and humerus. Proptosis from a LCH mass in the orbit may mimic rhabdomyosarcoma, leukemia, neuroblastoma, inflammatory pseudotumor, or benign fatty tumors of the eye. Some lytic skull lesions may have an accompanying soft tissue mass that impinges on the dura.

Central nervous system (CNS)-risk category of LCH bone lesions includes lesions of facial bones or anterior or middle cranial fossae (e.g., orbit, mastoid, temporal, sphenoid, ethmoid, or zygomatic). For reasons that remain to be defined, patients with lesions in these locations have a threefold increased risk for developing DI and an increased risk of LCH-associated neurodegenerative disease.

The cervical nodes are most frequently involved and may be soft or hard-matted groups with accompanying lymphedema. An enlarged thymus or involvement of the mediastinal nodes can mimic lymphoma or an infectious process and may cause asthma-like symptoms.¹⁹

The posterior pituitary gland can be affected in LCH patients, causing central DI (see section Endocrine System). Anterior pituitary involvement often results in the failure of growth and sexual maturation.

Hepatic involvement can cause hepatomegaly and liver dysfunction, leading to elevated liver enzymes, hypoalbuminemia with ascites, hyperbilirubinemia, and clotting factor deficiencies (Fig. 25.2D). Sonographic, computed tomographic (CT), or magnetic resonance images of the liver will show hypoechoic or low signal intensity along the portal veins or biliary tracts.²⁰ Two of the most serious complications of hepatic LCH are cholestasis and sclerosing cholangitis. Biopsies typically do not include histiocytes, but demonstrate periportal lymphocytic infiltrates, bile duct inflammation, and loss of bile ducts. Seventy-five percent of children with sclerosing cholangitis will not respond to chemotherapy, and all of these patients require liver transplantation.²¹ Massive splenomegaly may lead to cytopenias, because of hypersplenism and respiratory compromise, although splenectomy is rarely indicated.

The lung was once considered a high-risk organ and is less frequently involved in children than in adults, in whom smoking is a key etiologic factor. Children with pulmonary LCH plus low-risk organs have a 5-year survival of 91% compared with 94% for those with only low-risk organ involvement.²² Chest x-rays may show a nonspecific interstitial infiltrate. A high-resolution CT of the chest is needed to visualize the cystic/nodular pattern of LCH that leads to the destruction of lung tissue (Fig. 25.2C). A spontaneous pneumothorax may be the first sign of LCH in the lung, although patients may present with tachypnea or dyspnea from widespread fibrosis and destruction of lung tissue. Declining diffusion capacity may also herald the onset of pulmonary hypertension. In young children with diffuse disease, there is significant potential for pulmonary tissue recovery with resolution of LCH.

Bone marrow involvement occurs most frequently in young children who have diffuse disease involving the liver, spleen, lymph nodes, and skin, and may be associated with marked thrombocytopenia or neutropenia. Others have only mild cytopenias and are found to have marrow involvement with LCH by sensitive immunohistochemical or flow cytometric analysis of the bone marrow.²³ Of note, in many high-risk patients reported to have normal bone marrow by histology, BRAF-V600E mutations have been identified in hematopoietic precursor cells from bone marrow aspirate specimens.¹² LCH patients with very high-risk disease may present
with marrow hemophagocytosis that mimics hemophagocytic lymphohistiocytosis.²⁴

Diabetes insipidus (DI) is the most frequent endocrine manifestation of LCH. Some patients present with an apparent idiopathic presentation of DI before other lesions are identified. A review of such patients found that 51% would have other lesions diagnostic of LCH within a year of identifying DI symptoms.²⁵ A study of 589 LCH patients in France revealed that the 10-year risk of pituitary involvement was 24%.²⁶ These investigators did not see a decreased prevalence of DI in chemotherapy-treated patients. However, Grois et al.²⁷ reported a decline in the prevalence of DI from 40% to 20% with 6 months of treatment that included vinblastine and prednisone for patients with CNS-risk lesions (involvement of mastoid, orbit, temporal, or sphenoid bones).

A few patients with diarrhea, hematochezia, perianal fistulas, diarrhea, or malabsorption have been reported.²⁸ Diagnosing gastrointestinal lesions in symptomatic patients may be difficult due to patchy involvement. Endoscopic evaluation, including multiple biopsies, may be required to identify foci of disease, along with CD207 immunostaining of all biopsies.

Acute Manifestations of Diabetes Insipidus. DI caused by damage to the posterior pituitary is the most frequent initial sign of LCH (4%) in the CNS. Historically, DI was noted in 25% of all LCH patients, but in the LCH-III study the prevalence was 8% to 12%.²⁹ As noted earlier, treatment of patients with bone lesions in CNS-risk sites of the skull and facial bones has been observed to reduce risk of progression to pituitary involvement and development of DI.²⁷ Owing to the clinical risks, biopsies are rarely performed. Most often, the diagnosis is established by biopsy of skin, bone, or lymph node of a patient who also has pituitary imaging abnormalities or clinical signs and symptoms of DI. In the absence of additional LCH sites, and in the absence of clinical or laboratory evidence of an infectious etiology or alternative neoplastic disorder such as germinoma, one may consider a trial of empiric LCH therapy to minimize the potential for progressive pituitary damage.

Chronic Manifestations of Diabetes Insipidus. Fifty-six percent of LCH patients with DI will develop anterior pituitary hormone deficiencies (growth, thyroid, or gonadal-stimulating hormones) within 10 years of the onset of DI.³⁰

LCH patients may develop mass lesions of the choroid plexus, grey, or white matter containing CD1a-positive LCs as well as CD8⁺ lymphocytes.³¹ In 1% to 4% of LCH patients, a chronic neurodegenerative syndrome may develop with clinical symptoms of dysarthria, ataxia, dysmetria, and behavior changes. Magnetic resonance imaging (MRI) shows hyperintensity of the dentate nucleus and white matter of the cerebellum on T2-weighted images, or hyperintense lesions of the basal ganglia on T1-weighted images, and atrophy of the cerebellum³¹ (Fig. 25.2E). Diagnostic imaging findings may precede the onset of symptoms by many years or be concurrent. A study of 83 LCH patients, with at least two brain MRIs for evaluation of craniofacial lesions, DI, and/or other endocrine deficiencies or neuropsychological symptoms, was recently published. Forty-seven of 83 patients (57%) had radiological neurodegenerative changes at a median time of 34 months from diagnosis. Of the 47 patients, 12 (25%) had clinical neurological deficits that presented 3 to 15 years after LCH diagnosis.³²