Histiocytic disorders arise from abnormal development or function of histiocytes, which literally means “tissue cells.” However, we remain loyal to the archaic nomenclature for histiocytosis that is meant to encompass all cells of the mononuclear phagocytic system. The histiocytic umbrella therefore covers a wide range of disorders, from physiologic reaction to inflammatory stimuli to dysregulated differentiation and proliferation. This chapter will focus on the most common histiocytic disorders in children, including Langerhans cell histiocytosis (LCH), juvenile xanthogranuloma (JXG), Rosai-Dorfman disease, and hemophagocytic lymphohistiocytosis (HLH).
LANGERHANS CELL HISTIOCYTOSIS
Historical diagnoses of Hand-Schüller-Christian disease (pituitary and bone lesions), Letterer-Siwe disease (disseminated disease), or eosinophilic granuloma (bone lesions) are now collectively classified as LCH. While LCH is often thought of as a rare disease, it is actually as common as pediatric rhabdomyosarcoma and pediatric Hodgkin lymphoma, with an estimated 5 cases per 1 million children. The median age at diagnosis is 1.8 years, although it can present at any age. Males are affected slightly more than females by a 1.3-to-1 ratio. No inherited risk factors have been identified, though LCH arises more frequently in people with Hispanic ethnicity and is relatively rare in people with African ancestry.
PATHOGENESIS AND GENETICS
Langerhans cell histiocytosis lesions have a characteristic appearance on hematoxylin and eosin (H&E) stain, with the histiocytes having coffee-bean–shaped nuclei surrounded by an inflammatory infiltrate (Fig. 459-1A). The pathologic dendritic cells in LCH lesions have a shared histology with epidermal Langerhans cells, which stain with CD1a+/CD207 (Fig. 459-1B). Based on shared histology, LCH was initially hypothesized to arise from abnormally activated or transformed epidermal Langerhans cells.
Langerhans cell histiocytosis (LCH) lesion histology. A: LCH lesion demonstrating foamy histiocytes with grooved nuclei on a polymorphous inflammatory infiltrate background composed of abundant eosinophils, lymphocytes, neutrophils. B: CD207+ (langerin) antibody stain on an LCH lesion demonstrating strong positivity with associated multinucleated giant cells from an LCH lesion. C: Juvenile xanthogranuloma lesion demonstrating multinucleated Touton giant cells and xanthomatous cells in background. D: Biopsy of an enlarged lymph node from a child with significant bilateral cervical lymphadenopathy. This image demonstrates emperipolesis, a characteristic of Rosai-Dorfaman disease, where viable lymphocytes traffic through with histiocytes (clear background). E: Bone marrow aspirate from a patient with hemophagocytic lymphohistiocytosis, demonstrating characteristic vacuolated macrophages engulfing red blood cells (hemophagocytosis) and lymphocytes.
Multiple studies have identified specific clonal LCH histiocytes within LCH lesions. Additionally, recent discoveries of somatic mutations in LCH lesion histiocytes have advanced our understanding of the pathogenesis of LCH. Approximately 60% of LCH biopsy samples are found to have a recurrent mutation in BRAF V600E, an oncogene that constitutively activates the mitogen-activated protein kinase (MAPK) signal transduction pathway (Fig. 459-2). In patients without BRAF V600E, recurrent mutations have been identified in other MAPK pathway genes. An institutional series suggested that relapse was significantly more common in patients with BRAF V600E than in patients with other mutations.
Somatic mutations in MAPK pathway in Langerhans cell histiocytosis (LCH). Pathways to LCH demonstrating known recurrent activating MAPK mutations leading to ERK activation. Mutually exclusive recurrent mutations in BRAF-V600E and MAP2K1 have been reported. (*) indicates genes with case reports of activating somatic mutations.
The BRAF V600E mutation was identified in hematopoietic stem cells and myeloid precursors in patients with high-risk disease (liver, spleen, bone marrow involvement) and is generally not detectable with low-risk LCH (sites other than liver, spleen, bone marrow), suggesting the cell of origin in high-risk LCH may be a less differentiated cell (eg, CD34+ hematopoietic stem cell) compared to low-risk LCH myeloid precursor cells. The model of LCH arising as a result of abnormal growth signals at specific stages of differentiation supports classification of LCH as an inflammatory myeloid neoplasia, and it is now recognized by the National Cancer Institute as a malignancy. This evolving understanding of LCH pathogenesis has provided new insight into new targets for treatment.
CLASSIFICATION AND PROGNOSTIC FACTORS
The age of the patient at diagnosis of LCH correlates with extent of disease, as those less than 2 years of age are more likely to have multisystem high-risk disease compared to older patients, but age itself is not an adverse prognostic factor. Langerhans cell histiocytosis lesions in liver, spleen, or bone marrow are considered high risk due to the increased risk of death in these patients. The lungs were previously considered a high risk organ, but clinical studies have demonstrated that lung lesions do not significantly impact risk of recurrence or death.
Patients with lesions in the facial bones or skull base (mastoid, temporal, maxillary sinus, orbital, sphenoid, zygomatic arch, ethmoid, clivus), pituitary, or brain parenchyma are considered “CNS-risk” (central nervous system-risk) lesions based on increased probability of developing pituitary involvement or LCH-related neurodegeneration.
Langerhans cell histiocytosis is a classic “morning report” disease with a wide spectrum of clinical presentations. It can involve only a single site or multiple organ systems (Fig. 459-3) and may be associated with serious systemic symptoms at the time of initial presentation. The diagnosis of LCH is often challenging because the symptoms may mimic other more common pediatric disorders
Clinical spectrum of Langerhans cell histiocytosis (LCH). A: Osteolytic LCH bone lesion in humerus. B: Parietal LCH skull lesion. C: Chest CT in a patient with LCH, demonstrating multiple pulmonary nodules and associated cysts throughout the lung parenchyma. D: Scaly erythematous rash with papules, erosions, and crusting in a patient with skin LCH. E: Brain MRI demonstrates classic findings in neurodegenerative LCH with abnormal T2-weighted signal in brainstem and cerebellum. F: Large erosive orbital LCH lesion. CT, computed tomography; MRI, magnetic resonance imaging.
Osteolytic bone lesions, the most frequent finding in patients with LCH, most commonly occur in the skull, pelvis, long bones, and ribs. Clinical signs and symptoms include bone pain, headaches, palpable indentations or swelling, or gait abnormalities. Vertebral compression can also cause acute back pain. The lesions are readily identified on plain radiographs.
Cutaneous lesions are present in up to 50% of patients at diagnosis. They are usually scaly, waxy, seborrhea-like brown-to-red papules that are especially pronounced in intertriginous zones. Langerhans cell histiocytosis is often misdiagnosed initially as a common diaper rash or eczema. On the scalp, LCH may be mistaken for common cradle cap. Any rash that does not respond to common topical treatments or persists longer than expected should be referred for skin biopsy. Patients can be born with single or multiple lesions and are often first evaluated for infections until definitive tissue diagnosis is made. While skin-limited LCH may occasionally resolve spontaneously, approximately half of patients will have multifocal lesions with more complete examinations.
Langerhans cell histiocytosis may present with an inflamed ear canal, otorrhea, cysts, or adjacent rash. Otitis externa that does not respond to standard treatment should be referred for evaluation.
Cytopenias caused by bone marrow dysfunction secondary to LCH infiltration are often also associated with hepatosplenomegaly and confer a poor prognosis. Approximately 30% of patients under 2 years of age will have bone marrow involvement. Despite a histologically normal bone marrow aspirate, evidence of involvement may be present in as many as 50% of cases using molecular assays for BRAF V600E mutated cells. The enlargement of the spleen with the accumulation of pathologic Langerhans cells may also be a contributing cause of cytopenias. Lymph node involvement in LCH is often seen with bone or skin involvement, but it may also be isolated and is not associated with a worse prognosis.
Gastrointestinal Tract and Liver
Failure to thrive or weight loss caused by malabsorption is the most common sign of LCH gastrointestinal tract involvement. Other symptoms include vomiting, diarrhea (with or without blood), and protein-losing enteropathy. Liver dysfunction can lead to ascites, hypoalbuminemia, coagulopathy, and jaundice. Sclerosing cholangitis can be found in the final stage of liver involvement.
Patients may have pain or swelling of the face, gingival hyperplasia, or mucosal lesions. Younger children who present with early tooth eruption should be examined closely for signs of gingival hyperplasia. In addition, any patient who is found to have “floating teeth” on dental radiographs should be evaluated for LCH.
Tachypnea and chest retractions are often symptoms of lung involvement. Pulmonary LCH has a diffuse micronodular appearance on chest radiographs or computed tomography (CT) scan and develops cystic changes if progressive. Increasing numbers of cysts form “honeycomb lungs” and, in later stages, large bullae that may lead to a spontaneous pneumothorax. Emphysematous changes along with pulmonary fibrosis can be found in advanced stages of LCH lung involvement.
An isolated pituitary mass with diabetes insipidus (DI) is a clinical challenge with a differential diagnosis that includes LCH, germinoma, lymphoma, sarcoid, or hypophysitis. More extensive imaging can facilitate a diagnosis of LCH if there are other sites of disease. Diabetes insipidus can occur initially as an isolated finding, during active disease in other sites, or several years after the resolution of disease at other sites. Patients present with excessive thirst and urination, often waking multiple times at night to drink water or with new onset of nocturnal enuresis. Clinical assessment for polyuria and polydipsia is therefore important in all patients currently or previously affected by LCH, as it can develop at any time and has been found in up to 20% of all patients with LCH and 50% of patients with CNS-risk lesions. If clinical history suggests the possibility of diabetes insipidus, screening labs with urine specific gravity, urine osmolality, and serum osmolality should be obtained as well as brain magnetic resonance imaging (MRI). In addition to diabetes insipidus, other central endocrinopathies such as adrenal insufficiency, thyroid dysfunction, and growth hormone deficiency may occur. Growth retardation resulting from anterior pituitary involvement affects approximately 50% of children who have diabetes insipidus.
Acute signs of central nervous system (CNS) involvement, such as intracranial hypertension or seizures, are very rare. Some patients may have meningeal enhancement and mass lesions that can be located anywhere in the CNS. Patients with parenchymal brain lesions, pituitary involvement, or CNS-risk lesions have a significantly increased risk of developing a CNS LCH neurodegenerative disease (LCH-ND) that can arise acutely or years after presumed cure. MRI (T2 with axial flair) of the brain typically demonstrates bilateral symmetric lesions in the basal ganglia, pons, and deep cerebellar nuclei. Patients with LCH-ND exhibit a continuum of clinical findings, and abnormalities on imaging may occur in the absence of clinical manifestations. Behavioral and cognitive dysfunction may be subtle, and motor findings can be as simple as a fine tremor. Neurodegenerative disease can also progress to more severe symptoms with progressive ataxia, dysarthria, nystagmus, hyperreflexia, dysdiadochokinesia, dysphagia, blurred vision, cranial nerve palsies, and muscle weakness resulting in severe disabilities. These symptoms can be caused by active LCH lesions in the brain or by a neurodegenerative condition that shows a lymphocytic infiltration, resulting in gliosis and neuronal death, rather than a mass lesion.
Once LCH is considered, the diagnosis is relatively straightforward with tissue biopsy. Standard H&E staining identify characteristic histiocytes with coffee-bean nuclei and immunostains identify surface expression of CD1a and CD207 (langerin). Additional immunostains for factor XIIIa, CD163, and fascin differentiate LCH from other histiocytic disorders such as juvenile xanthogranuloma. Molecular analysis for BRAF V600E with high-sensitivity assays may also be informative. In cases where lesions are inaccessible for biopsy, testing peripheral blood mononuclear cells or plasma for BRAF V600E may support a diagnosis of LCH, if positive.
In order to determine the extent and severity of disease, additional laboratory and imaging evaluation is needed. All patients should be evaluated with a complete blood count and differential, liver function tests, and sedimentation rate to assess for cytopenias, liver dysfunction, and baseline level of inflammation, respectively. If the clinical history is concerning for diabetes insipidus, serum sodium and osmolality, urine osmolality, and urine specific gravity should be obtained as screening tools; however, a definitive diagnosis of diabetes insipidus requires a water deprivation test, typically administered by a pediatric endocrinologist. Short stature, growth failure, diabetes insipidus, hypothalamic syndromes, galactorrhea, and precocious or delayed puberty are all indications for an endocrine evaluation. Patients with endocrinopathies or CNS lesions should all undergo brain MRI with contrast and dedicated pituitary imaging. Thickening of the hypothalamic-pituitary stalk region and absence of the posterior pituitary bright spot are frequently seen.
Baseline radiographic evaluations on all patients should include a chest radiograph and skeletal survey, including dedicated skull series (4 views). A fluorodeoxyglucose positron emission tomography (FDG-PET) scan should be considered in all patients as it is more sensitive than other imaging modalities (except for the CNS/spinal cord where MRI may be more appropriate), it can identify occult lesions, and it can identify metabolically active hepatic and splenic involvement important for risk assessment. If pulmonary involvement is suspected, CT of the chest and pulmonary function tests should be obtained. Evaluation with panoramic dental radiographs of the mandible and maxilla is warranted if oral involvement is suspected and may reveal the almost pathognomonic finding of floating teeth. Patients should be referred to a pediatric otolaryngologist for complete evaluation including audiogram if otorrhea or hearing loss is identified. Bilateral bone marrow aspirate and biopsy are indicated for patients with unexplained cytopenias and in all patients under 2 years old, as these younger patients are more likely to have high-risk organ involvement and may not present with cytopenias in the same manner as older patients. As discussed above, molecular assays for BRAF V600E may increase sensitivity of morphologic assays to identify bone marrow involvement. Langerhans cell histiocytosis involvement of the intestines may lead to chronic diarrhea or failure to thrive, and may be localized with endoscopic biopsies. Additional studies should be guided by suspected organ involvement if not already identified on standard evaluations.
Treatment of patients with LCH depends on the extent and anatomic site of involvement. If complete baseline evaluation identifies LCH limited to a single bone site (other than CNS-risk bones), treatment can be conservative with biopsy/curettage and intralesional steroid injection. However, these patients will need to be followed closely, as many will develop recurrent lesions. It is critical to note that clean margins of a cancer surgery approach are not indicated and will impair ability of bone to remodel.
Skin-limited LCH in infants may occasionally regress spontaneously, but if rash is severe or persistent, treatment with oral chemotherapy has been successfully used with few adverse effects.
Patients with more than 1 site of disease, a CNS-risk lesion, or high-risk organ involvement should be treated with systemic chemotherapy, ideally on a clinical trial. The current standard of care is generally considered to be LCHIII, a 1-year course of vinblastine and prednisone, with addition of mercaptopurine for high-risk patients. Overall survival for children with high-risk LCH is approximately 85%, and nearly 100% for children with low-risk disease. Despite excellent survival, the relapse rate with this approach is very high (> 50%). Patients with refractory disease or relapse have demonstrated good response to monotherapy or multiagent myeloid directed chemotherapy, such as cytarabine, clofarabine, or cladribine. Chronic active disease and treatment failures are associated with increased risk of long-term complications. Treatment approaches for patients with resistant or chronically relapsing disease include newer biologically targeted agents (BRAF inhibitors and other drugs directed at the MAPK pathway). In extreme cases, hematopoietic stem cell transplantation may be curative.
There is no established treatment for isolated diabetes insipidus secondary to LCH. However, some reports suggest that early treatment of CNS-risk bone lesions with chemotherapy may decrease the frequency of diabetes insipidus. Similarly, treatment of neurodegenerative disease has yielded mixed results with standard LCH chemotherapy and immunomodulatory approaches. Patients with isolated pituitary disease or CNS-risk lesions should be monitored at least annually with a detailed neurological exam and brain MRI; approximately half of these patients will develop radiologic changes in the cerebellum, pons, or basal ganglia, within 3 years from initial diagnosis. MAPK pathway inhibitors remain to be tested in patients with CNS disease.
COMPLICATIONS AND LATE EFFECTS
Results of the Late Effects Study of the Histiocyte Society suggest that at least 1 adverse, permanent sequela occurs in most patients within a 3-year follow-up period. The most commonly reported complications were diabetes insipidus (25%), orthopedic problems (20%), hearing loss (13%), neurologic consequences (11%), and growth retardation (9%). Most of the serious adverse sequelae, such as endocrine and CNS complications, occur in patients who have extensive risk organ disease or CNS-risk lesions.
NON-LANGERHANS CELL HISTIOCYTIC DISORDERS
While JXG occurs primarily in infants and young children, patients of all ages can be affected. The typical presentation is a single or sometimes multiple cutaneous, nodular papules of yellow to reddish-purple color involving the scalp, extremities, or trunk. These papules may range in size from just a few millimeters to several centimeters. Histologic findings demonstrate a mixture of foamy macrophages, lymphocytes, and scattered multinucleated Touton giant cells (Fig. 459-1C). The histiocytes in these lesions characteristically express factor XIIIa and fascin. In addition to cutaneous forms of JXG, the disease can be systemic and involve multiple organs, including the liver, lungs, testes, pericardium, eyes, pituitary gland, and brain. Extensive skin involvement may increase the risk for developing other organ involvement. Patients with systemic or organ involvement with JXG often require treatment with chemotherapeutic agents similar to the treatment for refractory LCH. MAPK-activating mutations have been identified in JXG, and there is increased risk of JXG in children with neurofibromatosis.
SINUS HISTIOCYTOSIS WITH MASSIVE LYMPHADENOPATHY (ROSAI-DORFMAN DISEASE)
Sinus histiocytosis with massive lymphadenopathy (SHML), also called Rosai-Dorfman disease, is a histiocytic disorder characterized by massive, usually nonpainful cervical adenopathy, although any lymph nodes can be involved. Extranodal involvement can also occur, particularly in the salivary glands, retro-orbital area, skeleton, skin, testis, and CNS. SHML frequently presents with recurrent fevers, elevated inflammatory markers and hypergammaglobulinemia. Biopsies reveal sinusoidal dilatation with increased numbers of histiocytes and activated lymphocytes. Lesional histiocytes may be multinucleated and demonstrate a large amount of foamy cytoplasm (Mikulicz cells). Emperipolesis, trafficking of viable lymphocytes through the cytoplasm of histiocytes, is a classic feature of SHML (Fig. 459-1D). While SHML may spontaneously regress over weeks to months, patients with unresectable disease, systemic disease, or critical organ involvement may require treatment. Steroids will temporarily reduce lesion size in cases where rapid decompression is required, and chemotherapy with agents similar to those used for refractory LCH has cured some patients. It should be noted that patients with reactive lymphadenitis from any cause may have histiocytes without emperiopolesis in the spaces (sinuses) between lymphoid follicles. These sinus histiocytes are a normal histiologic findings and do not mean the patient has Rosai-Dorfman disease.
HLH is a syndrome of uncontrolled immune activation with clinical manifestations of extreme inflammation. Pathologic inflammation is the result of some combination of inherited immune defects and immunogenic challenges. It is becoming increasingly clear that HLH represents a wide spectrum of conditions that arrive at a common endpoint of multisystem organ failure mediated by pathologic inflammation.
Children with proven defects in immune function or a family history consistent with inherited disease are considered to have primary or familial HLH. Children and adults with HLH associated with immune activation including autoimmune disease, malignancy, or infection are often categorized as secondary HLH. In reality, most primary HLH is triggered by infection, and the genetics of immune dysregulation is becoming increasingly complex. In the HLH-94 study, survival was similar for both primary and presumed secondary HLH patients. A key point is that HLH has significant clinical overlap with sepsis; thus, considering HLH in the differential diagnosis is essential to identify patients who may benefit from (sometimes counterintuitive) immune suppression. The distinction of “primary” versus “secondary” HLH becomes important once life-threatening inflammation has been controlled since inherited defects leading to “primary” HLH require replacement hematopoietic stem cell transplant to replace the patient’s dysfunctional immune system. Secondary HLH may be controlled with antigen-directed therapy (eg, chronic immune suppression for auto-immune disease or chemotherapy for malignancy); although these strategies are only effective in some cases.
HLH has an incidence of approximately 1 per 1.5 million live births, but may account for 1 in 3000 tertiary pediatric hospital admissions. The incidence is likely higher as this disorder is probably underdiagnosed due to vague clinical symptoms that overlap with other more common disorders. Familial HLH typically presents during the first 2 years of life and is often associated with parental consanguinity. However, hypomorphic or incompletely penetrant mutations have been identified in older children and even older adults who develop HLH. Secondary HLH can occur at any age but is more frequent in older cohorts, and is frequently associated with malignancy in adults.
PATHOLOGY AND PATHOGENESIS
HLH can be viewed as the loss of immune homeostasis leading to amplified inflammation.
There is a spectrum of genotype-phenotype presentations, and severity of disease has been proven to correlate with the underlying cytotoxic defect. Several underlying gene defects have thus far been identified, many affecting the function of the cytolytic perforin granule pathway of cytotoxic T cells and natural killer (NK) cells. Perforin is either not synthesized normally because of mutations in the perforin gene (PRF1), or perforin is not properly released from cytotoxic lymphocytes because of mutations in the genes-presenting cells. Failure to prune antigen-presenting cells results in unchecked T-cell expansion and activation, which then systemically activates lymphocytes and macrophages (Table 459-1).
TABLE 459-1GENETIC SYNDROMES ASSOCIATED WITH PREDISPOSITION TO HEREDITARY HLH ||Download (.pdf) TABLE 459-1GENETIC SYNDROMES ASSOCIATED WITH PREDISPOSITION TO HEREDITARY HLH
|FAMILIAL HEMOPHAGOCYTOSIS |
|Affected Gene(s) ||Biologic Correlate ||Associated Syndrome ||Clinical Features ||Typical Mode of Inheritance |
|PRF1/Perforin ||Perforin expression (forms pores in membranes of target cells) ||Familial hemophagocytosis ||Life-threatening HLH ||Autosomal recessive |
|UNC13D/Munc 13-4 ||Unc family of proteins (regulate maturation of cytolytic granules) ||Familial hemophagocytosis ||Life-threatening HLH ||Autosomal recessive |
|STX11/Syntaxin 11 ||Control of granule exocytosis ||Familial hemophagocytosis ||Life-threatening HLH ||Autosomal recessive |
|STXBP2/Munc18-2 ||Interacts with Syntaxin 11; defective erythropoiesis resulting in hemolysis ||Familial hemophagocytosis ||Life-threatening HLH ||Autosomal recessive |
|IMMUNODEFICIENCY SYNDROMES ASSOCIATED WITH INCREASED RISK OF DEVELOPING HLH |
|Affected Gene(s) ||Biologic Correlate ||Associated Syndrome ||Clinical Features ||Typical Mode of Inheritance |
|CHS1/LYST ||Regulation of lysosomal trafficking ||Chediak-Higashi syndrome ||Recurrent bacterial and fungal infections ||Autosomal recessive |
|RAB27A ||GTP binding protein ||Griscelli syndrome ||Hypopigmentation, thrombocytopenia, neurologic issues ||Autosomal recessive |
|SH2D1A/SAP ||Activates NK and T cells ||X-linked lymphoproliferative disease 1 ||Chronic and abnormal EBV infection ||X-linked recessive |
|XIAP/BIRC4 ||Protects cells from apoptosis ||X-linked lymphoproliferative disease 2 ||Chronic and abnormal EBV infection ||X-linked recessive |
|MAGT1 ||Magnesium transporter ||XMEN disease ||Chronic EBV infection and EBV-associated malignancies ||X-linked recessive |
|ITK ||Deficient interleukin-2-inducible T-cell kinase ||ITK deficiency ||Lymphoproliferative disease, lymphomatoid granulomatosis, dysgammaglobulinemia ||Autosomal recessive |
|HPS1, AP3B1 (HPS2), HPS3, HPS4, HPS5, HPS6, DTNBP1(HPS7), BLOC1S3 (HPS8), BLOC1S6 (PLDN) ||Cytotoxic defect ||Hermansky-Pudlak syndrome ||Oculocutaneous albinism, platelet storage pool deficiency ||Autosomal recessive |
|Genetically heterogeneous ||Defective production of free radicals leading to impaired phagocytosis ||Chronic granulomatous disease (CGD) ||Recurrent bacterial and fungal infections || |
|SLC7A7/y+LAT1 ||Defective cationic amino acid transporter in epithelial cells ||Lysinuric protein intolerance ||Hematologic abnormalities, lung disease ||Autosomal recessive |
Antigen Challenges and HLH
Infection is associated with almost all cases of HLH. Epstein-Barr virus (EBV) infection is the most common infectious cause of HLH and has a specific association with an expanding number of gene mutations that lead to impaired T immune function including SH2D1A/BIRC4 (X-linked lymphoproliferative disease), XMEN, IKT, and TNFRSF7. In each of these cases, EBV infection cannot be controlled by the patient's cytotoxic T or NK cells leading to uncontrolled T stimulation and cytokine release, which induces HLH (Table 459-1).
Malignancy can also drive HLH by direct immune activation, transformation of functional lymphocytes, or loss of inhibitory immune function with chemotherapy or hematopoietic stem cell transplantation. Many HLH-associated genes are also associated with increased risks of malignancy.
Iatrogenic HLH is a new phenomenon observed in patients with malignancies treated with immunotherapy that results in extreme immune activation.
Autoimmune disease, most commonly juvenile idiopathic arthritis or systemic lupus erythematosus, may also induce HLH. In the setting of autoimmune disease, rheumatologists sometimes prefer naming it macrophage activation syndrome (MAS) versus HLH. Given the clinical overlap in diagnostic criteria, it is important to consider HLH in patients who fail to respond to typical autoimmune-disease–directed therapy. Additionally, many children ultimately diagnosed with inherited HLH were first thought to have Kawasaki disease.
The clinical features of HLH reflect the predisposing immunodeficiency, immune activation, and resulting end-organ damage from uncontrolled inflammation. The initial presentation almost always includes fever and hepatosplenomegaly (> 90%), and is sometimes associated with neurologic symptoms, lymphadenopathy, or a nonspecific rash. Pallor, petechiae, or purpura due to cytopenias are also frequently observed.
CNS involvement at the time of diagnosis, manifested by meningeal signs, altered mental status, and/or seizures, may also be present in many patients. Increased intracranial pressure, subdural hemorrhages and effusions, ataxia, and brain-stem–related signs and symptoms may be present. Cerebrospinal fluid studies may reveal an elevated protein concentration, moderate pleocytosis, and occasionally hemophagocytosis on cytologic evaluation.
Cytopenias (particularly thrombocytopenia and anemia), hypertriglyceridemia, hypofibrinogenemia, and hyperferritinemia are typical laboratory abnormalities, but not all of these are universally present, which adds to the challenge of recognizing the diagnosis. Elevated serum transaminases and bilirubin levels indicate hepatic involvement. Laboratory abnormalities should normalize when remission is achieved.
The HLH-2004 clinical trial criteria generally serve as the de facto clinical evaluation for HLH. The diagnosis can be established if (1) there is a molecular diagnosis (ie, identification of biallelic disease-causing mutations consistent with primary HLH), or (2) if 5 of the 8 diagnostic criteria in Table 459-2 are fulfilled. A ferritin over 3000 ng/mL has been found to be highly associated with the diagnosis of HLH.
TABLE 459-2DIAGNOSTIC CRITERIA FOR HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH) ||Download (.pdf) TABLE 459-2DIAGNOSTIC CRITERIA FOR HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH)
|Diagnostic Criteria (At Least 5) ||Specifications |
|Fever ||≥ 38.5°C |
|Splenomegaly ||On exam or abdominal ultrasound |
|Cytopenias involving 2 or more cell lines ||Hemoglobin < 9 g/dL; platelets < 100,000/μL; absolute neutrophil count < 1000/μL |
|Hypertriglyceridemia and/or hypofibrinogenemia ||Fasting triglycerides > 265 mg/dL and/or hypofibrinogenemia (fibrinogen < 150 mg/dL) |
|Hemophagocytosis on pathologic examination ||Bone marrow, spleen, lymph node, or cerebrospinal fluid |
|Low or absent natural killer cell activity || |
|Hyperferritinemia ||> 500 mg/L (authors recommend a level > 3000 mg/L) |
|Elevated soluble CD25 (soluble IL-2 receptor alpha) ||> 2400 units/mL, or 2 standard deviations > normal limit for age |
Bilateral bone marrow biopsies should be obtained in all patients, in part to look for hemophagocytosis, but also to rule out any underlying malignancy or infection affecting the bone marrow. It should be noted that hemophagocytosis is neither sensitive nor specific for HLH (Fig. 459-1E). Bone marrow aspirate or biopsies often demonstrate an increased number of activated CD163+ macrophages. Lumbar puncture should be performed at diagnosis (if clinically safe) to assess for the presence of CNS inflammation as reflected by pleocytosis and CSF protein levels. Additionally, brain MRI may show subdural effusions or hemorrhages, parameningeal infiltration, or areas of hypodensity or necrosis.
HLH is typically fatal if untreated, and the risk of mortality increases if there are delays in initiation of therapy. Prior to treating primary HLH patients with current strategies of immune suppression, median survival was less than 2 months. In patients who are promptly diagnosed and treated, survival ranges from 50% to 80%. Several strategies of immune suppression have been successful in prolonging survival for patients with primary (familial) or secondary HLH. The only current curative treatment for inherited defects that lead to HLH is hematopoietic stem cell transplant (HSCT).
For stable patients with MAS, a trial of disease-directed therapy is appropriate. However, if patients deteriorate or are clinically unstable, HLH-directed therapy may be required to control pathologic inflammation.
The standard approach to treatment of HLH, derived from protocol HLH-94, includes dexamethasone and etoposide (along with intrathecal steroids and chemotherapy in patients with CNS inflammation) for 8 weeks. Although therapy with etoposide may seem unusual, since it is best known as a chemotherapy agent, it is known to have specific activity against activated T cells that likely explains its benefit for patients with HLH. Early initiation of etoposide is correlated with improved outcomes, even in some cases of secondary HLH. Supportive care and treatment aimed at possible underlying triggers (such as antimicrobials or chemotherapy) are also critical.
Following initial immune suppression, observation or more disease-directed therapy (as in the case of autoimmune disease) is appropriate. However, these patients need to be followed very closely due to the risk of infection following therapy and long-term risks of recurrent HLH. Patients with proven HLH-associated gene defects, CNS involvement, persistent immune dysfunction, or persistent/relapsing disease require HSCT. For patients with uncontrolled disease despite etoposide/dexamethasone, alemtuzumab, an antibody directed against the CD52 antigen present on most leukocytes, is usually effective. The therapeutic potential of an antibody directed against interferon-γ is also being tested. The historic 5-year survival in primary HLH is currently around 50% to 60%, though this is improving with reduced-intensity conditioning HSCT strategies.
HLH is a syndrome that is likely under-recognized, leading to suboptimal outcomes. While the criteria for diagnosis of HLH may appear nonspecific, clinical outcomes data provide strong evidence that patients meeting these criteria are at very high risk for mortality, and that early initiation of immune-chemotherapy results in improved outcomes. Future work may improve outcomes by identifying specific host factors and immune challenges that result in HLH to identify the optimal graded and personalized therapies. We propose a shift in emphasis from counting diagnostic criteria to determining the “pathologic inflammation due to X,” then solving for X (inherited or acquired immune dysfunction, autoimmune disease; malignancy; specific infection; or combination). The most significant factor for survival in a patient with HLH, however, remains consideration of the diagnosis by the treating team.
Histiocytic disorders are a heterogeneous group of diseases with a broad spectrum of clinical manifestations as well as severity; the common feature of a dysfunctional mononuclear phagocytic cell is at the center of its pathogenesis. Recent scientific inquiries into the genetic and biologic origins of these diseases offer hope for new understanding, increased recognition, and improved therapies for these challenging disorders.
KL. How I treat Langerhans cell histiocytosis. Blood. 2015;126(1):26–35.
et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood
et al. BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups. J Exp Med
CE. Progress in understanding the pathogenesis of Langerhans cell histiocytosis: back to Histiocytosis X? Br J Haematol
CE. Cell(s) of origin of Langerhans cell histiocytosis. Hematol Oncol Clin North Am
et al. Diverse and targetable kinase alterations drive histiocytic neoplasms. Cancer Discov
et al. Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood
LP. Juvenile xanthogranuloma: forms of systemic disease and their clinical implications. J Pediatr
et al. Therapy prolongation improves outcome in multi-system Langerhans cell histiocytosis. Blood
et al. Permanent consequences in Langerhans cell histiocytosis patients: a pilot study from the Histiocyte Society-Late Effects Study Group. Pediatr Blood Cancer
et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer
D. Juvenile xanthogranuloma in childhood and adolescence: a clinicopathologic study of 129 patients from the Kiel Pediatric Tumor Registry. Am J Surg Pathol
W. Extranodal Rosai-Dorfman disease in children. J Pediatr Hematol Oncol
et al. Langerhans'-cell histiocytosis (histiocytosis X)—a clonal proliferative disease. N Engl J Med