Overview
Histiocytic neoplasms represent hematologic disorders characterized by the accumulation of myeloid-dendritic cell-derived neoplastic cells with an accompanying inflammatory infiltrate.1,2 They are rare, accounting for less than 1% of cancers of the soft tissue and lymph nodes.2 Histiocytic neoplasms are heterogeneous, and presentation varies from localized and mild to disseminated and lethal.1 Initial presentation is often nonspecific, which can lead to a significant delay in the diagnosis and treatment of histiocytic disorders,3 and these patients should ideally be evaluated and treated at centers of expertise.
There are over 100 subtypes of histiocytoses.1 The original classification of histiocytic neoplasms by the Working Group of the Histiocyte Society, which was published in 1987, categorized these disorders as follows: Langerhans cell, non-Langerhans cell, and malignant histiocytoses.4 However, the categorization of histiocytic neoplasms as Langerhans/non-Langerhans may not be appropriate, because neoplasms classified as Langerhans cell histiocytosis (LCH) were discovered to share many of the same molecular features as those classified as Erdheim-Chester disease (ECD), following emerging deep sequencing diagnostic methods.1,2 For example, clonal mutations of genes in the MAPK pathway have been found in the majority of Langerhans and non-Langerhans histiocytoses.5–8 In 2016, the Histiocyte Society published a revised classification based on clinical, radiographic, histologic, phenotypic, and other molecular features, further dividing them into 5 groups of diseases: (1) Langerhans-related; (2) cutaneous and mucocutaneous; (3) malignant histiocytoses; (4) Rosai-Dorfman disease (RDD); and (5) hemophagocytic lymphohistiocytosis and macrophage activation syndrome.1
The NCCN Guidelines for Histiocytic Neoplasms include recommendations for diagnosis and treatment of adults with LCH, ECD, and RDD (though the WHO does not yet officially recognize RDD as a neoplasm). The evidence supporting the management of histiocytic neoplasms in adults is largely based on small retrospective studies, case series, and case reports, due to the paucity of prospective studies in adults. In addition, some of the diagnostic and treatment recommendations for adults with histiocytic neoplasms are, of necessity, extrapolated from prospective studies in children and young adults, except when stated otherwise.
Pathologic Analysis of Histiocytic Neoplasms
Immunohistochemical (IHC) analysis plays an important role in the diagnosis and should be performed when a histiocytic neoplasm is suspected. The basic IHC panel should include CD163/CD68, S100, CD1a, langerin/CD207, cyclin D1, and factor XIIIa as indicated.3 BRAF V600E (VE1) IHC is recommended for LCH and ECD. Anaplastic lymphoma kinase (ALK) may also be included as clinically indicated to identify ALK-rearranged histiocytoses.9 IHC analysis can be helpful in the broad differential diagnosis of histiocytosis, including varied entities such as composite IgG4-related disease and B-cell lymphoma, as well as infection, fat necrosis, and idiopathic retroperitoneal fibrosis.3
Next-generation sequencing (NGS) of tumor tissue for identification of mutations in the RAS/RAF/MAPK/ERK and PI3K/AKT pathway genes can be instrumental in the diagnosis of histiocytic neoplasms and can also inform systemic therapy decision-making.3 Additionally, fusion testing should include BRAF, ALK, and NTRK1 rearrangements. A complete list of fusions and rearrangements to include in the evaluation can be found in the “Summary of Pathologic and Molecular Features of Histiocytic Neoplasms” in the algorithm (HIST-A; page 1290). If fusion panel testing is unavailable, then IHC or fluorescence in situ hybridization may be used to evaluate for ALK rearrangements. Molecular testing can be done either in a stepwise fashion or in parallel, depending on clinical indication and institutional protocols. If a specific histiocytic disorder is suspected, then stepwise testing should be tailored based on the mutations known to be associated with that disorder. FDG-PET/CT may be useful for determining the extent of the disease and for guiding biopsies. Details regarding recommendations for pathologic analysis related to LCH, ECD, and RDD are detailed in subsequent sections and in the algorithm (HIST-A; page 1290).
Langerhans Cell Histiocytosis
LCH is the most common histiocytic disorder. It is more common in children than adults, with 5 to 9 cases per 1 million in children (>15 years) and 1 case per 1 million in adults (>15 years).10,11 Though many cases are mild and asymptomatic, rapidly progressing and/or disseminated life-threatening disease that is resistant to treatment may also occur. Common sites of involvement of LCH include bone, skin, pituitary gland, liver, spleen, bone marrow, lungs, and lymph nodes.12 A pulmonary form of LCH can occur in adults and is associated with smoking.13–15 Multifocal bone lesions without the involvement of other organs may also be observed in some cases, and bone mineral density may be lower than the expected range in adults with LCH.16 Permanent endocrinopathy is common in LCH, such as diabetes insipidus, which more commonly occurs with multisystem disease.14,17,18 Though there are cases of solitary central nervous system (CNS)-involved LCH, CNS involvement is most often accompanied with multisystem disease.12 There is a high prevalence of concomitant and subsequent malignancies, especially solid tumors or myeloid malignancies, in adults with LCH.19,20
CNS-involved LCH can present as space-occupying granulomatous tumors, frequently in the hypothalamic-pituitary region but also involving the choroid plexus, meninges, gray or white matter, or as neurodegenerative LCH (ND-LCH) lesions in the cerebellum and brain stem.21 The bone lesions in the mastoid, sphenoid, orbit, temporal bone, and clivus represent CNS-risk lesions, indicating increased risk of developing CNS LCH.21 ND-LCH is frequent in patients with pituitary, skin, and base-of-skull bone involvement. A study of children and young adults with LCH (n=1,897) showed that a BRAF mutation was present in 93.7% of patients with ND-LCH, compared with 54.1% in patients without ND-LCH.22 The 10-year risk of developing neurodegenerative disease is 33.1% in patients with a BRAF mutation, compared with 2.9% in patients without a BRAF mutation (P=.002).
The Histiocyte Society’s initial 1987 classification categorized LCH as an immunologic inflammatory disease but not as a neoplasm.4 However, presence of clonal histiocytes supports the neoplastic origin of LCH.14,23 Recurrent activating mutations in the MAPK pathway are found in the vast majority of cases.8,24 These discoveries support the WHO’s classification of histiocytic disorders, particularly LCH as a neoplastic process.25 In the Histiocyte Society’s revised classification, 4 categories of LCH are identified: single system, pulmonary-involved, multisystem with risk organ involvement, and multisystem without risk organ involvement.1
Diagnosis of LCH
Diagnosis of LCH is based on clinical and radiologic findings, though biopsy of tumor tissue is also recommended (see “Histopathologic Characterization of LCH,” page 1283).14 Initial diagnostic testing is dependent on clinical presentation. A detailed review of symptoms and comprehensive physical examination of the skin; head, eyes, ears, nose, and throat (HEENT); and cardiovascular, pulmonary, musculoskeletal, lymphatic, gastrointestinal, endocrine, and neurologic systems should be performed.14 Comprehensive neurocognitive and psychological assessments are also recommended in select patients.14
PET/CT is recommended for the staging of LCH. FDG-PET/CT is superior to other cross-sectional imaging techniques for detection of sites of active LCH, with the exception of pulmonary lesions.26–28 Bone involvement, which may appear as aggressive cortically based lytic lesions, is best detected using full-body (vertex-to-toes) FDG-PET/CT.3 It is controversial whether whole-body imaging is required for every patient with LCH, such as those presenting only with skin involvement, or those with symptoms limited to the lungs. However, whether a patient’s LCH is single or multisystem is unknown in the absence of staging. Therefore, whole-body PET/CT should be considered for patients with suspected multisystem disease.
Abnormal brain MRI is often observed in LCH, even in the absence of neurologic symptoms.12 Findings on brain MRI can mimic primary CNS tumors, brain metastases, or inflammatory granulomatous diseases.12 In ND-LCH, signal changes in white and deep gray matter with cortical atrophy may be observed with MRI.21 In cases that manifest with diabetes insipidus, the earliest change seen on MRI may be an enlargement of the pituitary stalk, and later the space-occupying tumors extending to the pituitary gland and hypothalamus. There is typically a ‘‘loss of bright spot’’ (ie, the lack of the physiologic hyperintense signal in the posterior pituitary on T1-weighted images), which is secondary to the loss of antidiuretic hormone-containing granules. Not all patients with diabetes insipidus will have an abnormal MRI.
Ultrasound of the abdomen and neck can discover hepatic and thyroid involvement, respectively.14 However, ultrasound is probably not needed if a PET has been performed. Other imaging techniques (eg, endoscopic retrograde cholangiopancreatography; CT of chest, abdomen, and pelvis; and panorex X-ray) may be performed as clinically indicated.
High-resolution chest CT may detect nodules 2 mm or less in the early stages of pulmonary LCH, and irregular cysts in the lungs may be observed in advanced disease.3,14 Pulmonary function testing should be considered to evaluate obstructive airway disease, air trapping, and carbon monoxide diffusing capacity.13,14 Echocardiogram is also recommended to screen for pulmonary hyper-tension.3
Laboratory tests should include complete blood count (CBC), blood chemistry, coagulation studies, thyroid-stimulating hormone, free T4, urine analysis, C-reactive protein, and morning serum cortisol with adrenocorticotropic hormone.14 Prolactin and insulin-like growth factor-1 level should be considered in select patients, as well as FSH/LH with testosterone and estradiol as clinically indicated. Bone marrow evaluation should be performed in all patients with abnormal CBC to rule out marrow involvement of LCH and a concomitant myeloid neoplasm. Biopsy of tumor tissue is recommended in all cases. BRAF V600E (VE1) IHC is recommended on all tissue biopsy samples, and NGS of tumor tissue for somatic variants in the MAPK pathway genes, as well gene fusion assay, is recommended in patients with BRAF V600E wild-type or equivocal disease. NGS of the peripheral blood is an alternative if biopsy is not feasible due to tumor location or other reasons (see “Pathologic Analysis of Histiocytic Neoplasms” [page 1279] and “Histopathologic Characterization of LCH” [page 1283]).
Because LCH frequently presents with lytic bone lesions, differential diagnosis may include multiple myeloma and metastatic bone involvement from other cancers. Skin involvement may be mistaken for seborrheic dermatitis, eczema, psoriasis, Candida infection, intertrigo, and lichen planus.14 Langerhans cell hyperplasia can be associated with mycosis fungoides, which could be misinterpreted as a composite LCH.29 Differential diagnosis for single-system pulmonary LCH includes hypersensitivity pneumonitis, interstitial pneumonia, pulmonary lymphangioleiomyomatosis, and sarcoidosis.
The complete recommendations for evaluation of LCH are provided in the algorithm and are adapted from recommendations in the consensus statement by the Mayo Clinic Histiocytosis Working Group3 (see “Langerhans Cell Histiocytosis: Workup/Evaluation” in the algorithm, page 1279 [LCH-1]). Subspecialty consultations (eg, pulmonary and smoking cessation, neurology, endocrinology) should be carried out as clinically indicated. Dermatology consultation is recommended for patients treated with certain targeted therapies (ie, BRAF and MEK inhibitors) for diagnosis and treatment of skin-related toxicities.30 Retinal evaluation may be considered due to the high incidence of serous retinopathy with MEK inhibitors.31,32
Histopathologic Characterization of LCH
LCH tumors often demonstrate neoplastic histiocytes admixed with marked inflammatory cell infiltration. On hematoxylin and eosin (H&E) stain, neoplastic LCH cells are mononucleated, typically with a coffee bean-shaped nucleus.1,24,33 Abundant eosinophils and multinucleated giant cells are frequently observed.1–3 Fibrosis may be present, particularly in bone lesions.3 IHC analysis of the LCH tumors shows abundant CD1a- and CD207- (langerin) positive neoplastic histiocytes and can also be positive for S100.3,24,33 Pathology of lesions from LCH-associated abnormal CNS imaging and LCH-associated abnormal CNS symptoms show infiltrating CD8+ lymphocytes, and, unlike other LCH tumors, lack CD1a-positive histiocytes.34 Cyclin D1 can be helpful for differentiating neoplastic Langerhans cells from reactive Langerhans cell proliferation.35,36 Birbeck granules can be identified by electron microscope, which is, however, now not commonly performed.
Activation of RAS-RAF-MAPK pathway is universal in all patients with LCH.5,37 BRAF V600E activating mutation is present in 38% to 64% of LCH cases,5,6,38–42 and this mutation is more frequent in mixed LCH/ECD, when compared with isolated LCH or ECD.43 Mutations in MAP2K1 are also prevalent in LCH (∼20%).8,38,42,44 BRAF V600E and MAP2K1 mutations are mutually exclusive in LCH.44 KRAS, NRAS, ARAF, and CSF1R mutations are less frequently observed in LCH.45,46
BRAF V600E (VE1) should be evaluated using IHC. However, studies evaluating IHC versus PCR testing of BRAF V600E mutations in pediatric patients with LCH (using stringent scoring criteria47) showed sensitivity values ranging from 35.6% to 80%; specificity values ranged from 75.5% to 100%.48,49 BRAF V600E allele-specific PCR is recommended if IHC is unavailable or when BRAF V600E (VE1) IHC results are equivocal or negative. A comprehensive NGS panel including other genes in the MAPK pathway (ie, ARAF, NRAS, KRAS, MAP21K, PIK3CA) should be performed in patients with BRAF wild-type disease.
For complete recommendations regarding pathologic analysis of LCH cases, see the “Principles of Pathology” in the algorithm (HIST-A; page 1290).
Treatment of LCH
Much of the evidence for treatment of LCH is extrapolated from prospective studies of children and adolescents. Studies of adults with LCH are limited to case series and retrospective studies. Treatment decisions of LCH should be made based on sites and extent of disease.14
Unifocal and Single System Disease With No Critical Organ Involvement
For patients with single system disease and no involvement of critical organs (ie, CNS, liver spleen, heart), treatment is limited to local therapy and observation (watch and wait).14
Limited curettage is recommended for patients with isolated bone lesions,50 but complete resection of bone lesions is not recommended, as this may result in an increase in the size of the bony defect and permanent skeletal defects.14 Steroid injection may facilitate healing after limited curettage.14 Radiation therapy for treatment of bone-involved LCH is associated with excellent local disease control.51,52 For patients with single system bone disease, radiation therapy may be used for some patients with limited sites of disease, specifically in cases with impending neurologic dysfunction and if surgical risk is high.14 “Limited” sites of disease is generally defined as 1 to 2 lesions in this context, though radiation therapy may be considered for up to 3 bone lesions as clinically indicated. The recommended radiation dose for treatment of bone-involved LCH in adults is 10 to 20 Gy.14,51 Watch and wait is also reasonable for asymptomatic and isolated bone lesions.
For patients with single system isolated skin disease, topical therapies may be used.50 Case reports describing treatment of older adults with cutaneous LCH support the use of psoralen with ultraviolet A and narrow band ultraviolet B.53,54 Other topical therapies such as nitrogen mustard (eg, mechlorethamine) and steroids are alternative options that have been shown to be effective in children with cutaneous LCH,55,56 though there are no published data in adults with LCH. Surgery should only be done for solitary skin lesions, and only for those in which surgery will not result in disfigurement. Systemic therapy may be used for symptomatic disease including pain, secondary infection, or if there are complications from skin lesions.50 Isolated skin-involved LCH has been reported to resolve spontaneously,57 so watch and wait is also an option for these patients.
Multifocal or Multisystem Disease or Unifocal Disease With Critical Organ Involvement
Systemic therapy is often required for the treatment of multisystem LCH, multifocal single system, or unifocal but involving a critical organ such as CNS, liver, spleen, or heart (see “Systemic Therapy,” subsequent section). However, if asymptomatic or if there is no impending organ dysfunction, watch and wait may be considered. Imaging changes precede clinical progression in ND-LCH, warranting consideration of early treatment.
Because pulmonary LCH is associated with smoking, treatment should include smoking cessation (see the NCCN Guidelines for Smoking Cessation, available at NCCN.org). Pulmonary LCH could resolve with smoking cessation alone.50 Therefore, watch and wait is an option, particularly in patients with asymptomatic disease or who have minor symptoms. Systemic therapy can be considered in patients with symptomatic and/or progressive pulmonary LCH, as well as in patients with persistent disease despite smoking cessation (see “Systemic Therapy,” next section). High-dose prednisone (1 mg/kg/day for 1 month, followed by a slow taper) can also be effective in treatment of pulmonary LCH.14 Steroid treatment is often associated with radiographic improvements in pulmonary LCH but may not improve the respiratory function.58 Lung transplant should be considered only in select patients with highly refractory and severe disease.50
Bisphosphonates (eg, zoledronic acid or pamidronate) for treatment of multifocal bone disease is supported by small retrospective studies and case series.59,60 In the absence of disease response after treatment with a bisphosphonate, other systemic therapy regimens may be considered (see “Systemic Therapy,” next section). Radiation therapy can also be considered in patients with persistent disease with limited disease sites after systemic treatment.14 Systemic treatment with indomethacin was reported as a successful alternative therapeutic approach for some patients with primary and recurrent bone LCH.61
Systemic Therapy
Systemic therapy is the standard treatment for multisystem and/or multifocal LCH, but responses to commonly used regimens in adults with LCH tend to be less robust compared with children.14 Evidence supporting use of chemotherapy in adults with LCH is based on small nonrandomized studies. Vinblastine and prednisone is the preferred chemotherapy-based treatment for LCH in the pediatric setting.24 In a retrospective study conducted at a single center including 58 adults with bone-involved LCH, use of vinblastine and prednisone was associated with worse outcomes. In this study, 84% of patients who received vinblastine and prednisone developed progressive disease within the first year, compared with 21% of patients who received cytarabine (odds ratio [OR], 20.3; 95% CI, 4.20–98.20; P<.001).62 For patients who received cladribine, 59% did not respond to treatment or relapsed in the first year. Cytarabine was the least toxic of the 3 regimens, with grade 3 to 4 adverse events being reported in 20% of patients who received cytarabine, compared with 37% and 75% who received cladribine and vinblastine/prednisone, respectively. Low-dose cytarabine is better tolerated in adults, but higher doses should be used for patients with CNS lesions.
Cladribine is another chemotherapy option that has been shown to be active in adults with LCH (overall response rate [ORR], 75%), based on results from a small phase II trial.63 A more recent retrospective study conducted at an NCCN Member Institution also showed a high ORR (79%) in adults with multifocal LCH (n=38; 82% multisystem) who were treated with cladribine, with complete response (CR) and partial response (PR) observed in 26% and 53% of patients, respectively.64 Five-year overall survival (OS), progression-free survival (PFS), and duration of response (DOR) for the sample was 75%, 58%, and 70%, respectively. There is also evidence supporting clofarabine for relapsed/refractory LCH in the pediatric setting, with disease improvement observed in 73% of 11 patients.65 Neutropenia occurred in all patients.
A prospective single-center phase II trial from China examined combination of cytarabine (100 mg/m2) and methotrexate (1 g/m2) as treatment of adults with multisystem or single system multifocal LCH (n=83). ORR, 3-year OS, and 3-year event-free survival were 87.9%, 97.7%, and 68.0%, respectively.66 A retrospective study conducted at a hospital in China examined cytarabine and methotrexate combination in adults with multisystem pulmonary-involved LCH (n=29). Pulmonary function was stable in 72.4% (n=24), improved in 13.8% (n=4), and deteriorated in 13.8% (n=4) of patients.67 Since both cytarabine and methotrexate cross the blood-brain barrier, this combination regimen may be ideal for treatment of CNS-involved LCH.66 High-dose methotrexate is also an option for CNS-involved LCH, based on a case report of a patient with CNS-involved ECD.68 In addition, cytarabine in combination with intravenous immunoglobulin or vincristine demonstrated therapeutic potential in children and young adults with CNS-LCH and ND-LCH.69,70
Multifocal skin disease may respond to systemic therapy treatment for multisystem LCH in general.14 However, small retrospective studies and case reports also support use of specific chemotherapy options for multifocal skin-involved LCH. A single-center retrospective study evaluated hydroxyurea monotherapy and in combination with oral methotrexate in 15 patients with relapsed/refractory LCH (mostly skin-involved) with a median age of 41.2 years (range, 2–73 years).71 An ORR of 80.0% was observed, and symptom progression or relapse after initial response was observed in 40%, with median time to progression of 5.7 months. Grade 3 to 4 adverse events were reported in only 2 patients. Retrospective data also support use of oral methotrexate combined with prednisone in children with low-risk LCH (ie, no bone marrow involvement or organ dysfunction) that was mostly bone- and/or skin-involved.72
Immunomodulating agents may also be used to treat multifocal skin disease. Thalidomide was evaluated in a phase II study including 12 children and 4 adults with LCH.73 Among 10 patients with low-risk disease (involvement of skin, lungs, and lymph nodes), an ORR of 70% was observed (4 CRs, 3 PRs). All of the patients but one who had low-risk disease had skin involvement. Administration of this drug was associated with significant toxicity and should be avoided in patients with critical organ involvement, for whom this drug was not effective. A case report also describes a CR from lenalidomide in an adult with relapsed/refractory multisystem LCH (involvement of skin, lungs, and lymph nodes).74
Targeted Therapies
Before 2012, there were relatively few effective treatment options for histiocytic neoplasms. The discovery of BRAF V600E and other gene mutations resulting in overactive MAPK pathway in histiocytic neoplasms led to a promising avenue of targeted therapies for patients with these rare cancers. The phase II VE-BASKET study evaluated the efficacy of BRAF inhibitor vemurafenib.75 The final efficacy and safety analysis included 26 adults with BRAF V600E-mutated LCH or ECD (85% ECD) and showed an ORR of 61.5% (95% CI, 40.6%–79.8%).76 Two-year PFS and OS rates were 86% (95% CI, 72%–100%) and 96% (95% CI, 87%–100%), respectively. Median PFS and OS were not reached. A metabolic response as measured with FDG-PET/CT was achieved in all of the patients who were evaluated (n=15; 80% CR, 20% PR). The most common grade 3 to 4 adverse events were hypertension (27%), maculopapular rash (23%), increased lipase (15%), arthralgia (12%), hyperkeratosis (8%), and actinic keratosis (8%). All patients required dose reduction due to toxicities. Encouraging results from a case series also support the use of dabrafenib, a second-generation BRAF inhibitor, in adults with LCH. Dabrafenib may be better tolerated than vemurafenib based on this case series, although there was no prospective head-to-head comparison.77 Use of dabrafenib in patients with ND-LCH led to rapid symptomatic and radiographic improvement.
There is also evidence supporting the use of MEK inhibitors for treatment of histiocytic neoplasms. The MEK inhibitor cobimetinib was evaluated in a phase II trial including 18 adult patients diagnosed with a histiocytic neoplasm (67% ECD, 11% LCH, 11% RDD, and 11% mixed histiocytosis).31 The ORR was 89% (one-sided 90% CI, 73%–100%), with a CR having been observed in 72% of patients. Median DOR and PFS were not reached after a median follow-up of 11.9 months. The most common adverse events that led to a dose reduction were ejection fraction decrease (27.8%), rash (11.1%), and diarrhea (11.1%). Though a mutation in the MAPK pathway was detected in 83% of patients, the efficacy of cobimetinib was not limited to these patients, indicating that cobimetinib can be used in any patient with a histiocytic disorder for whom systemic therapy is indicated.
Use of the MEK inhibitor trametinib for treatment of LCH is supported by case series and case reports.78–80 In one case report, a combination of dabrafenib and trametinib demonstrated a sustained response in an adult woman with BRAF V600E-mutated LCH.81
Adverse events in patients with histiocytic disorders treated with BRAF and MEK inhibitors are consistent with those observed in previously published studies (eg, rash, pyrexia),24 but the VE-BASKET trial showed that rates of hypertension and skin-related adverse events were higher in histiocytic neoplasms than previously observed in patients with metastatic melanoma.76
Activating mutations in CSF-1R and rearrangements involving RET and ALK in rare cases of LCH highlight the potential clinical benefit of other kinase inhibitors and should be considered in select cases with such alterations.46 Since NTRK fusions can occur in histiocytic disorders,82 the TRK inhibitors larotrectinib83 and entrectinib84 may also be used as indicated. Sirolimus and everolimus can be effective for PIK3CA-mutated LCH, based on extrapolation of data from ECD patients (see “Treatment of ECD,” page 1293).7,85
Follow-up
Imaging (PET/CT [preferred], CT, or MRI) of involved sites to evaluate treatment response should be done after 2 to 3 cycles of systemic therapy and after completion of treatment. LCH may relapse or reactivate after systemic therapy, which most commonly occurs in the first 2 years following treatment.50 Development of diabetes insipidus after treatment may be a sign of disease reactivation.50 Follow-up assessment depends on extent of disease and organ involvement, and a complete list of recommendations for surveillance following treatment of LCH can be found in the algorithm (see “Langerhans Cell Histiocytosis: Follow-up” in the algorithm [LCH-5, page 1283]).
Relapsed/Refractory Disease
In relapsed and refractory LCH, an alternate systemic therapy regimen other than the one used in the first line may be considered. However, if DOR to the first-line regimen was greater than 1 year, repeating the same treatment may also be considered.14
Erdheim-Chester Disease
ECD is a rare histiocytic neoplasm, with approximately 800 cases having been reported as of May 2020.45 An increase in detection of cases has been observed more recently, potentially due to improved recognition of this disease through imaging and pathology.12,45,86 ECD predominantly affects adults, with a median age of approximately 45 years in the United States, and is more common in men than women.12,45,86 ECD is rarely observed in children. Mixed ECD/LCH is fairly common, with LCH lesions reported in 20% of patients with ECD.43
Similar to LCH, ECD presentation can range from single system and asymptomatic disease to severe multisystem and life-threatening disease. Prognosis is predominantly influenced by specific organ involvement.86 Bone involvement affects almost all patients with ECD, with lower extremity bone pain being an especially common initial presenting symptom. Cardiovascular involvement, including pericardial disease, is reported to occur in about half of all patients87–89 and is associated with poor prognosis.90 Other affected organs/systems include the lungs, endocrine system, skin, and kidneys.12,91 Periarterial fibrosis of the thoracic and/or abdominal aorta, referred to as “coated aorta,” is also commonly obseved.86,88,90,92–95 Retroperitoneal involvement tends to be asymptomatic, but extension to the renal sinus or middle to distal ureters may result in hydronephrosis.96–98 CNS involvement occurs in 15% to 55% of cases12,86,99 and is associated with worse prognosis.100 Some ECD-related CNS lesions cause intracranial vascular infiltration, putting these patients at risk for ischemic stroke. Diabetes insipidus is the most common endocrine disorder in ECD, affecting about 25% to 50% of patients.3,86,101 Other commonly observed endocrine manifestations of ECD include hyperprolactinemia, hypogonadism, adrenal insufficiency, and hypothyroidism.3,101 Exophthalmos is also fairly common in ECD, and xanthelasma of the eyelids and periorbital spaces is a common cutaneous manifestation of ECD.1,86 Involvement of the facial bones and maxillary sinuses has also been observed.92
Two retrospective studies demonstrated that a concomitant myeloid neoplasm can occur in 3%–10% of ECD102,103; the higher rate (10%) in one study is likely due to inclusion of patients with mixed LCH/ECD.102 In one case series, median age of patients with ECD and a concomitant myeloid neoplasm was 65.4 years and tended to affect more men than women (male:female ratio = 2:1).104
Diagnosis of ECD
The diagnosis of ECD is largely made based on characteristic clinical and radiographic abnormalities. Evaluation of tumor tissue for molecular alterations should be performed, where available, as this would aid both in the diagnosis of ECD and treatment decision-making.45 Com-prehensive physical examination of the skin; HEENT; and cardiovascular, pulmonary, musculoskeletal, lymphatic, gastrointestinal, endocrine, neurologic systems should be performed. Neurocognitive and psychological assessments are also recommended in select patients. FDG-PET scan or bone scan should be used to evaluate bone involvement. Full-body (vertex-to-toes) FDG-PET is preferred to bone scan, as it allows for evaluation of metadiaphyseal osteosclerosis of the knees as well as other organ involvement.3,45 Bilateral, symmetric diaphyseal, and metaphyseal osteosclerosis of the long bones of lower extremities is a characteristic finding of ECD.2,3,12,45 CNS involvement may be detected using brain MRI with gadolinium contrast, and common findings include cerebellar and brain stem hyperintensities, cerebral white matter enhancement, and thickening of the pituitary stalk.3,12 “Coated aorta” may be detected with CT, and arterial lesions characterized by circumferential thickening may be observed.3,12,86,97 “Hairy kidney” detected on abdominal CT is characteristic of ECD (rarely seen in RDD and not seen in LCH) due to diffuse bilateral infiltration leading to stellate pattern of perinephric soft tissue thickening.3,97 Adrenal hypertrophy may be observed if the perirenal infiltration extends to the adrenal gland.97 In ECD with pulmonary involvement, chest CT may demonstrate mediastinal infiltration, pleural thickening, pleural effusion, and other pulmonary parenchymal abnormalities.3 Cardiac involvement should be evaluated with echocardiography and/or cardiac MRI. Findings and radiographic abnormalities include pericardial thickening, pericardial effusion, and myocardial infiltration, which, if present, most often involve the right atrioventricular groove and right atrial wall.3
Similar to LCH, laboratory evaluation for ECD should include CBC, blood chemistry, coagulation studies, thyroid-stimulating hormone, free T4, morning urine and serum osmolality, morning serum cortisol with adrenocorticotropic hormone, prolactin, insulin-like growth factor-1, follicle-stimulating hormone/luteinizing hormone with testosterone, and estradiol. C-reactive protein should be evaluated, as it is often elevated in patients with ECD.12 BRAF V600E (VE1) IHC is recommended on the tissue biopsy, and NGS of tumor tissue for mutations in the MAPK pathway in cases that are BRAF V600E wild-type or equivocal, as well as gene fusion assay, is also recommended (see “Pathologic Analysis of Histiocytic Neoplasms,” page 1279, and “Histopathologic Characterization of ECD,” page 1283). A biopsy of tumor tissue is recommended, but analysis of the peripheral blood for NGS may be done if biopsy is not feasible, and bone marrow evaluation should be performed in patients with abnormal CBC. Differential diagnosis should include evaluation for IgG4-related disease, which has a clinical presentation similar to that for ECD.12
The complete recommendations for evaluation of ECD are provided in the algorithm and are adapted from recommendations from an expert consensus group45 (see ECD-1 in the algorithm [page 1284]). Subspecialty consultations (eg, neurology, endocrinology, nephrology, urology) should be carried out as clinically indicated. As with LCH, dermatology and ophthalmology evaluations may be considered for management of toxicities associated with BRAF and MEK inhibitors.30–32
Histopathologic Characterization of ECD
On H&E stain, ECD tumor tissue often demonstrates foamy mononucleated histiocytes with a small nucleus, surrounding fibrosis, xanthogranulomatosis, and Touton giant cells.2,3,12 On IHC, neoplastic histiocytes are typically CD68-positive, CD163-positive, CD14-positive, factor XIIIa-positive, CD1a-negative, and CD207 (langerin)-negative.2,12,86 Typical features of stroma and histiocytic and reactive infiltrate have been found to vary depending on disease location (ie, bone, CNS, lung, skin, orbit, retroperitoneum, cardiac tissue).105 CD1a-positive, S100-positive, and langerin-positive findings can help distinguish LCH from ECD.1,86 The possible presence of S100-positive cells with emperipolesis may lead to challenges in distinguishing ECD from RDD.1
Somatic mutations contributing to ECD partially overlap with that of LCH.2 BRAF V600E activating mutations are present in 38% to 68% of ECD cases.6,7,86,92,105,106 Other prevalent gene mutations in ECD include MAP2K1, ARAF, NRAS, KRAS, and PIK3CA.7,8,105,106 CSF1R mutations and BRAF, ALK, and NTRK1 fusions are found in a small number of ECD cases.8,46,106 ECD co-occurring with RDD is most commonly driven by mutations in MAP2K1.105,107 Extracutaneous or disseminated juvenile xanthogranuloma with mutations in the MAPK pathway has similar histopathology and phenotype to ECD and thus may be considered ECD.1 BRAF V600E (VE1) should be evaluated using IHC, but allele-specific PCR for BRAF V600E may be considered (see “Histopathologic Characterization of LCH,” page 1283). As with LCH, panel testing should include other mutations in the MAPK pathway.
For complete recommendations regarding pathologic analysis of ECD cases, see the “Principles of Pathology” in the algorithm (HIST-A, page 1290).
Treatment of ECD
Treatment of ECD mainly consists of systemic therapy, though watch and wait may be considered for patients with asymptomatic disease not involving critical organs such as the heart, brain, and CNS.
As discussed in the LCH section (see “Targeted Therapies,” page 1288), the phase II VE-BASKET study showed that vemurafenib is highly effective in patients with BRAF V600E-mutated ECD that is associated with near universal responses.76 Results from the VE-BASKET study led to the FDA approval of vemurafenib for treatment of ECD. However, the FDA-approved dose (960 mg twice daily) is associated with significant toxicity that very often results in discontinuation, dose interruption, or dose modification.76 A retrospective study performed at an NCCN Member Institution including 23 patients with BRAF V600E-mutated ECD showed that progressive disease did not occur in patients (n=14) who received vemurafenib administered at half the FDA-approved dose (ie, 480 mg twice daily), though half of these patients still required further dose reduction, with 29% discontinuing vemurafenib treatment due to adverse events.108
The efficacy of dabrafenib for BRAF V600E-mutated ECD is supported by a retrospective single-center French study109 and a multicenter case series.110 As with LCH, dabrafenib appears to be less toxic than vemurafenib.110 As described previously for LCH (see “Targeted Therapies,” page 1288), in a phase II trial in which 67% of patients were diagnosed with ECD, a 72% CR rate was shown for cobimetinib.31 These promising results were not limited to patients with a mutation in the MAPK pathway. A small study supports use of the MEK inhibitor trametinib for treatment of non-LCH histiocytic neoplasms, regardless of molecular profile.111
Before the availability of targeted therapy for ECD, the largest body of evidence supported the use of interferon alpha-2a and pegylated interferon alpha for the treatment of ECD.86 In a multicenter, prospective, nonrandomized study conducted in Europe (n=53), interferon alpha or pegylated interferon alpha treatment was associated with improved survival (hazard ratio [HR], 0.32; 95% CI, 0.14–0.70; P=.006).100 A single-center report from France (n=8) showed that interferon alpha was most effective for relieving exophthalmos, bilateral hydronephrosis, and xanthelasma related to ECD, and was associated with a decrease in C-reactive protein.112 This report cautioned against the use of interferon alpha in patients with ECD involving the CNS and/or cardiovascular system. However, a more recent single-center study from France reported outcomes of a larger cohort (n=24) that high-dose interferon alpha was associated with a clinical and/or radiologic improvement in 46% of patients, including those with severe ECD with CNS or cardiovascular involvement.113 Interferon alpha as a treatment option for ECD is also supported by several case reports.114,115 Interferon alpha has been discontinued in the United States and is therefore not recommended in the NCCN Guidelines. Pegylated interferon alpha, which has a favorable toxicity profile compared with interferon alpha, is recommended as a substitute based on evidence discussed previously.
Evidence supporting other systemic therapy options for treatment of ECD is primarily based on retrospective single-center studies and case series. A retrospective study conducted at an NCCN Member Institution evaluated the efficacy of cladribine as first- or subsequent-line treatment of ECD (n=21).116 The clinical ORR was 52%, with CR and PR seen in 4% and 46% of patients, respectively. Progressive disease was seen in 30% of patients. The response was durable, with the median DOR of 9 months in the patients with response. Toxicities associated with cladribine were relatively minimal. In a single-center study from Italy including 10 patients with ECD, sirolimus combined with prednisone was associated with an ORR of 60% (all PRs).117 Oral methotrexate as first- or subsequent-line treatment of ECD was evaluated in a retrospective study conducted at an NCCN Member Institution (n=13).118 Oral methotrexate was administered either alone or in combination with prednisone or infliximab and was associated with a clinical ORR of 23% (all PRs). Progressive disease occurred in 70%. Despite the low ORR, methotrexate-based treatment was well-tolerated, and response was durable in some of those who responded to the treatment, especially those with ocular ECD. Finally, 2 small single-center studies showed good efficacy with the IL-1 receptor antagonist anakinra as a treatment option for ECD.119,120
As with LCH, a targeted therapy can be selected based on the respective molecular alteration. Crizotinib and selpercatinib for ECD with rearrangements in ALK and RET, respectively, as well as pexidartinib for ECD with activating mutations in CSF-1R, and larotrectinib and entrectinib for ECD with NTRK fusions, are all reasonable systemic therapy options when clinically indicated.46,82–84 Because mutations in PIK3CA are fairly common in ECD,7 mTOR inhibitors such as sirolimus and everolimus should also be considered when clinically indicated.85
Follow-up
As with LCH, follow-up assessment for patients with ECD depends on extent of disease and organ involvement. FDG-PET/CT should be used to monitor disease response once treatment is initiated. Organ-specific cross-sectional imaging (CT or MRI) may also be used as needed. Regular skin examination and ECG is recommended for patients treated with BRAF inhibitors, as well as ongoing evaluation for pituitary hormone abnormalities.
Rosai-Dorfman Disease
RDD is another rare histiocytic disorder that mainly affects children but is also diagnosed in adults. In RDD, accumulation of abnormal histiocytes in lymph node sinuses, lymphatic vessels of internal organs, and other extranodal sites is observed. This disease is more common in men than in women and often affects individuals of African ancestry.12,121 Cause is unknown but may be associated with familial, autoimmune, and/or malignant processes. It is a heterogeneous condition with a presentation that may be classified as single or regional lymph node-involved or localized to the skin and other organs. Prognosis is generally very good but becomes worse as the number of involved nodal groups increases.121 Recurrent disease is reported to occur in about one in three patients with RDD.122
Extranodal involvement occurs often in RDD, with common sites of involvement including the skin, soft tissue, upper respiratory tract, multifocal bone (mostly osteolytic lesions), retroperitoneum, and eye/retro-orbital tissue with lymphadenopathy.3,121,122 Bilateral massive cervical lymphadenopathy also commonly occurs and is often painless, though involvement of the mediastinal, inguinal, and axillary lymph nodes may also occur.121 Skin involved-RDD often presents as subcutaneous masses and, less often, as cutaneous lesions.122 Involvement of the nasal cavity, paranasal sinuses, and parotid gland have also been reported.12,121,123 CNS involvement may also occur but is generally rare.121,122,124,125 CNS-involved RDD may mimic meningioma.121
RDD may co-occur with Hodgkin and non-Hodgkin lymphoma, other histiocytic disorders, cutaneous clear-cell sarcoma, and following myelodysplastic syndrome and allogeneic stem transplant for precursor B-cell acute lymphoblastic leukemia.12,121,122 Germline mutations in SLC29A3, which is associated with Faisalabad histiocytosis, H syndrome, and pigmented hypertrichotic dermatosis with insulin-dependent diabetes, have been found in cases of familial RDD.121 About 20% of patients with H syndrome also have RDD.126 Germline mutation in the FAS gene TNFRSF, which is associated with autoimmune lymphoproliferative syndrome (ALPS) type I, has also been found in RDD cases.121 Immunologic diseases associated with RDD include systemic lupus erythematous, idiopathic juvenile arthritis, and autoimmune hemolytic anemia.121
Diagnosis of RDD
Diagnosis of RDD should include a clinical and radiologic examination, as well as histopathologic analysis. Comprehensive physical examination should include evaluation of the HEENT, endocrine system, and intrathoracic/pulmonary, cardiovascular, gastrointestinal, musculoskeletal genital, renal, and cutaneous symptoms. Neurologic and psychological assessment are also recommended. History of inherited conditions predisposing to RDD (eg, ALPS), malignancies and other neoplasia associated with RDD (eg, Hodgkin and non-Hodgkin lymphoma, other histiocytic disorders), and other autoimmune disorders (eg, systemic lupus erythematous, idiopathic juvenile arthritis) should be evaluated based on clinical symptoms and family history.
Full-body FDG-PET/CT is recommended as part of the baseline evaluation of RDD. A single-center retrospective study including 109 FDG-PET/CT scans in 27 patients with RDD showed that PET/CT detected lesions not recognized by anatomic cross-sectional imaging in 30% of patients with available prior CT or MRI (n=20).127 Results of PET/CT scans also led to changes in treatment in 41% of patients. Cross-sectional imaging can reveal dermatologic involvement in the form of lobular soft tissue lesions in the subcutaneous space.3 Pulmonary involvement in RDD tends to manifest as mediastinal lymphadenopathy, airway disease, pleural effusion, and cystic and interstitial lung disease.128 Extranodal retroperitoneal involvement, if present, would appear in radiologic findings as wispy infiltration and/or renal hilar masses.3 MRI of the head tends to be superior for evaluation of the sinuses and orbits, compared with PET/CT.3 MRI of the brain and spine is useful for identification of asymptomatic neurologic involvement.121
Laboratory evaluation should include CBC, comprehensive metabolic panel, coagulation studies, and an evaluation of C-reactive protein, uric acid, LDH, and serum immunoglobulins.121 If autoimmune disease is suspected based on clinical examination, then laboratory evaluation should include antinuclear antigen, antineutrophil cytoplasmic antibodies, rheumatoid factor, and HLA-B27. The ALPS panel is clinically indicated in patients with autoimmunity and lymphadenopathy. Laboratory evaluation in patients with anemia should include a Coombs test, haptoglobin, reticulocyte count, and blood smear. Lumbar puncture should be carried out if there are brain lesions that cannot be biopsied due to location. Bone marrow aspirate and biopsy are recommended for patients with unexplained cytopenias or abnormal CBC.121 As with LCH and ECD, biopsy of tumor tissue is recommended for diagnosis and NGS testing. If biopsy is not feasible, then peripheral blood analysis is reasonable. NGS of tumor tissue should include mutations in the MAPK pathway, and gene fusion assay (see “Pathologic Analysis of Histiocytic Neoplasms,” page 1279, and “Histopathologic Characterization of RDD,” next section).
The complete recommendations for evaluation of RDD are provided in the algorithm and are adapted from recommendations from an expert consensus group121 (see Rosai-Dorfman Disease: Workup/Evaluation in the algorithm [RDD-1, page 1287]). Like LCH and ECD, dermatology and ophthalmology evaluations may be considered due to toxicities associated with BRAF and MEK inhibitors.30–32
Histopathologic Characterization of RDD
Compared with LCH and ECD, histopathologic analysis of RDD can be challenging, because RDD tissue tends to contain relatively few lesional cells.122 Large histiocytic cells with hypochromatic nuclei and an abundant amount of pale cytoplasm are required for diagnosis or RDD.1 Emperipolesis, specifically intracytoplasmic leukocytes, is a frequently observed feature of RDD.1–3,12,121,122 However, emperipolesis may be observed less often in extranodal lesion tissue.121 Abundant plasma cells in the medullary cords and around the venules is a hallmark of nodal RDD.121 Other pathologic hallmarks include the accumulation of CD68-positive, CD163-positive, CD14-positive, and S100-positive histiocytic cells.1–3,121,122 RDD histiocytes tend to be CD1a- and CD207-negative, which helps to distinguish from LCH.121 Cyclin D1 expression by the abnormal histiocytes, and increased IgG4-positive plasma cells in the background inflammatory infiltrate, may also be found.129,130
Unlike LCH and ECD, BRAF V600E activating mutations are not commonly seen in patients with RDD.3,12,121 KRAS, MAP21K, ARAF, and NRAS mutations have been found in patients with RDD.8,121,131 Though the WHO does not classify RDD as a neoplasm, the presence of mutations in the MAPK/ERK pathway in about 1 in 3 patients and supports the categorization of RDD as a neoplasm.122,131 As with LCH and ECD, NGS panel testing should include mutations in the MAPK pathway. Even though some of these mutations (eg, BRAF V600E) are less common in RDD, a comprehensive panel test is helpful for distinguishing RDD from other histiocytic neoplasms. Germline testing for SLC29A3, if familial RDD is suspected, and TNFRSF may be considered if clinically indicated.
For complete recommendations regarding pathologic analysis of RDD cases, see “Principles of Pathology” in the algorithm (HIST-A, page 1290).
Treatment of RDD
Watch and wait is a reasonable treatment strategy for patients with asymptomatic and mild disease, as spontaneous remission has been reported to occur 40% of these patients.121,122 Surgery is also a reasonable curative option for those with isolated disease or for debulking of symptomatic disease of the CNS, sinuses, or airways.121,122 Patients with extranodal disease impacting critical organs and those with serious RDD-related complications require treatment. Radiation therapy (RT) should only be used for palliative purposes in patients with multifocal symptomatic disease.121 Case reports have shown some efficacy for RT when used to treat refractory disease in the eyelid and soft tissue of the cheek,132 as well as RDD lesions causing airway obstruction.133 RT dosing for RDD is not well-established, but 30 to 50 Gy may be used.121,133
Systemic Therapy
Systemic therapy is recommended for first-line treatment of symptomatic unresectable or multifocal disease and for treatment of relapsed/refractory disease. There is a dearth of research in this area, and some systemic therapy options that may be used for treating RDD are extrapolated from ECD.122 The strongest evidence supporting systemic therapy options for adults with RDD comes from two single-center retrospective studies, both conducted at NCCN Member Institutions. The first study, conducted at Mayo Clinic (n=57), showed that corticosteroid treatment (most often prednisone) was associated with a 56% ORR in the first-line setting, with relapse occurring in 53% of patients, and a 67% ORR in the subsequent-line setting.122 This study also showed that cladribine was the most commonly used systemic therapy for treatment of recurrent disease and was associated with a 67% ORR.122 In the second study, which was conducted at the University of Pennsylvania and included patients with massive lymphadenopathy (n=15), rituximab treatment was associated with a 64% PFS at 24 months (n=7) and a 40% ORR (PRs only), with complete resolution of symptoms when administered in the first-line setting (n=5).134 This drug was generally well-tolerated.
Case reports support use of cytarabine and oral methotrexate for treatment of RDD, as well as thalidomide for cutaneous RDD.135–138 A case report describing treatment of a pediatric patient with RDD supports use of methotrexate delivered intravenously,139 although oral administration is generally used. Use of sirolimus, which has demonstrated efficacy in patients with ALPS,140 is supported for treatment of RDD by a case report describing treatment of a pediatric patient with RDD and severe autoimmunity.141
Steroids may be used to treat patients with symptomatic nodal or cutaneous disease, for unresectable or multifocal extranodal disease, and/or for relief of symptoms from CNS- or orbit-involved disease.121,122 As described previously, the Mayo Clinic study supports use of prednisone for treatment of RDD, both in the first- and subsequent-line settings.122 This study showed that prednisone combined with 6-mercaptopurine and either methotrexate or azathioprine was also associated with disease response in the subsequent-line setting in patients with subcutaneous and lymph node involvement, and a PR was achieved in one patient who was treated with cyclophosphamide, vincristine, and prednisone. Prednisone combined with vinblastine is also supported by a case report describing treatment of a pediatric patient with RDD,142 but this regimen is associated with increased risk of neuropathy in adults.62 Optimal duration of steroid treatment is unknown at this time; treating to optimal response, followed by a slow taper, is a reasonable strategy.121 Adverse effects from steroids should be carefully monitored, though these are generally well-tolerated.122
Evidence supporting use of targeted agents for RDD is evolving, particularly for MEK inhibitors, and some options may be used based on extrapolation of evidence for use in ECD and LCH. In a retrospective multicenter French study of lung-involved RDD, cobimetinib was associated with decreased lung infiltration and SUVmax values.143 Cobimetinib is also supported by a case report describing treatment of a patient with RDD and a KRAS activating mutation.144 The MEK inhibitor trametinib is also an option, regardless of molecular profile.111 Just as with LCH and ECD, targeted systemic therapy options (ie, crizotinib for ALK rearrangements, selpercatinib for RET rearrangements, pexidartinib for activating mutations in CSF-1R, larotrectinib and entrectinib for NTRK fusions) may be recommended as clinically indicated.46,82–84
Follow-up
As with LCH and ECD, follow-up assessment for patients with RDD depends on extent of disease and organ involvement. A complete list of recommendations for surveillance after treatment of RDD can be found in the algorithm (see “Rosai-Dorfman Disease: Follow-up” in the algorithm [RDD-3, page 1289]).
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NCCN CATEGORIES OF EVIDENCE AND CONSENSUS
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
PLEASE NOTE
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application and disclaims any responsibility for their application or use in any way.
The complete NCCN Guidelines for Histiocytic Neoplasms are not printed in this issue of JNCCN but can be accessed online at NCCN.org.
© National Comprehensive Cancer Network, Inc. 2021. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.
Disclosures for the NCCN Histiocytic Neoplasms Panel
At the beginning of each NCCN Guidelines Panel meeting, panel members review all potential conflicts of interest. NCCN, in keeping with its commitment to public transparency, publishes these disclosures for panel members, staff, and NCCN itself.
Individual disclosures for the NCCN Histiocytic Neoplasms Panel members can be found on page 1303. (The most recent version of these guidelines and accompanying disclosures are available at NCCN.org.)
The complete and most recent version of these guidelines is available free of charge at NCCN.org.
