International expert consensus recommendations for the diagnosis and treatment of Langerhans cell histiocytosis in adults

Diagnostic approach

The diagnosis of LCH usually relies on a histopathologic review of lesional tissue. All attempts should be made to obtain a tissue biopsy, not only to achieve a diagnosis but also for mutational analysis that can direct therapy; however, in instances without classic pathologic findings or inaccessible/insufficient tissue specimen, a presumptive diagnosis can be made based on characteristic clinical, radiographic, or molecular features (Table 4; CS#1-2). Definitive diagnosis of single-system PLCH may be obtained through transbronchial, transthoracic, or, more commonly, by surgical lung biopsy.^{82, 83} In cases where a lung biopsy is not considered safe, a diagnosis of single-system PLCH can be rendered in the presence of typical radiologic findings on high-resolution computed tomography (HRCT) of the chest in a smoker after careful ruling out of other etiologies (Table 4; CS#1).^{83, 84} In such cases, circulating DNA analysis for MAPK-ERK mutations may help solidify the diagnosis. Among patients who have undergone FDG-PET/CT, the safely accessible sites of greatest FDG hypermetabolism should be targeted for biopsy. We recommend acquiring multiple (5-10) core biopsies (16-18 gauge) instead of fine-needle aspiration, given the variable cellularity of lesions. Bone specimens present unique challenges, including crushed samples and interference with mutational analysis from decalcification, including false-negative immunohistochemistry (IHC) results for BRAF-V600E. To circumvent this issue, it is recommended to either preserve a fragment of tissue without acid decalcification or use ethylenediaminetetraacetic acid (EDTA)-based decalcification to maintain DNA integrity.

Histopathologic features and differential diagnosis

On tissue biopsy, the LCH infiltrate is characterized by clusters of intermediate-sized cells with reniform nuclei, frequent longitudinal nuclear grooves, dispersed chromatin, and abundant eosinophilic cytoplasm.^{3, 48, 70} Occasional multinucleated giant cells may be present. A reactive inflammatory cell background is common and includes eosinophils, small lymphocytes, and macrophages (Figure 2). In PLCH, the neoplastic LCs are preferentially located in and destroy the walls of distal bronchioles.⁸⁴ In certain anatomic sites, in particular bone and lung, there is an evolution of the lesions over time from cellular infiltrates to “burned-out” lesions with patchy cellularity, increased fibrosis, and foamy histiocytes.^{3, 85} Within skin lesions, the neoplastic cells of LCH are distinguished from reactive LC populations by their enlarged nuclei, sheet-like collections with involvement of the epidermis, and lack of dendritic processes.⁸⁶ In lymph nodes, LCH involves and expands the sinuses, with their microanatomic location being a critical distinction from the reactive LCs that are present in the paracortex of lymph nodes with dermatopathic change.⁷²

The phenotype of LCH is similar to that of benign LCs, with the expression of CD68 (Golgi dot-like staining), S100 (nuclear and cytoplasmic), CD1a (surface), langerin/CD207 (cytoplasmic), and ZBTB46 (a marker of classical dendritic cells).⁸⁷ They are commonly negative for monocyte-macrophage markers CD14, CD163, and OCT2.⁸⁸ In contrast to reactive LCs, the neoplastic cells of LCH show more diffuse expression of cyclin D1.⁸⁶ To diagnose LCH, the minimal panel of antibodies should include CD1a and langerin/CD207, with the correct pathologic pattern and correlating clinical/radiographic findings.⁷⁰ In cases where BRAF-V600E is the driver mutation, this can be identified by IHC using a mutant-specific antibody clone VE1 with moderate to strong cytoplasmic staining (Figure 2).^{89, 90}

LCH can be distinguished from other histiocytic neoplasms such as ECD and RDD by morphologic and immunophenotypic features (Table 5).^{13, 48} On morphology, ECD shows bland xanthogranulomatous inflammation and variable degrees of fibrosis,⁹¹ and RDD shows enlarged histiocytes with abundant pale-staining cytoplasm and emperipolesis. In contrast to LCH, the histiocytes of ECD and RDD express CD163 and lack expression of CD1a, langerin, and ZBTB46. ECD usually shows strong expression of factor XIIIa, and RDD is characteristically positive for S100, fascin, and OCT2.⁸⁸ Mixed histiocytoses can occur with both LCH and either ECD or RDD components present within the same biopsy or involving different sites in the same patient.⁹² Another rare differential diagnosis to consider is indeterminate cell histiocytosis, which is likely a distinct neoplasm with the absence of langerin/CD207 expression and primarily cutaneous involvement.⁹³ Recently, ETV3-NCOA2 translocations have been identified as a unique driver of this disease entity.⁹⁴

The distinction between LCH and Langerhans cell sarcoma (LCS) is currently based on morphologic criteria, with the WHO classification defining LCS as having “overtly malignant cytologic features,”^{3, 95} which may be subjective in some cases. Chromosome and molecular genetic studies may be helpful, as LCH generally has a normal karyotype and <5 somatic mutations,⁸ whereas malignant histiocytic neoplasms like LCS typically have frequent chromosomal gains or losses.⁹⁶

Unifocal LCH

Unifocal LCH is often curable in adults, and local therapies may be sufficient in many cases (CS#20).¹⁰³ Surgical resection may be preferred depending on the disease location but should only be attempted if not heroic or mutilating. Most skull lesions can resolve after limited curettage without the need for prostheses. If surgical resection is successful, there is no established role for adjuvant treatments. Depending on the location, intralesional corticosteroid therapy (eg, methylprednisone or triamcinolone)¹⁰⁴ or, especially in the case of an accompanying soft tissue component, radiation therapy (eg, 10-20 Gy)^{105, 106} may offer an excellent and durable response. If symptoms disappear quickly after diagnostic biopsy, remission can occur even without further therapy.¹⁰⁷ Hence, in these cases, careful observation is an appropriate approach. Isolated skin nodules, lymph nodes, oral mucosal lesions, and isolated polyps of the gastrointestinal tract are usually completely resectable and require no further therapy; however, for anogenital and gingival lesions, oral methotrexate or hydroxyurea may be favored.^{77, 108, 109, 110} Symptomatic cutaneous LCH is generally treated with topical or oral therapy. The choice of therapy depends on the severity of the disease and patient/physician preference. Topical triamcinolone can be used for disease involving small areas of the skin. Locally extensive LCH of the skin is usually less sensitive to topical or systemic steroid therapy but usually responds to treatment with hydroxyurea or low-dose methotrexate.^{110, 111} In refractory cases, local therapy with imiquimod, 20% N-mustard, or irradiation can be effective.^{47, 105, 112, 113} The treatment of unifocal LCH involving sites that are not easily amenable to local therapies (nervous system, pituitary, liver, spleen, heart, etc) is not well defined and likely warrants systemic therapies similar to multisystem disease (CS#21).

Single-system pulmonary LCH

Management of patients with single-system PLCH should be individualized and take into consideration respiratory symptoms, the degree of lung function impairment, and the radiologic extent of disease. In all cases, smoking cessation (all forms, including marijuana and vaping) is mandatory, which remains difficult to achieve in practice (CS#23). It is often the only required intervention that results in complete remission.¹¹⁴ Combined inhaled corticosteroid and long-acting β2-agonist therapy may provide benefit to patients with wheezing and moderate obstructive lung disease. Pneumothorax management may be particularly difficult as it may recur in half of the patients.¹¹⁵ Surgical pleurodesis should ideally be avoided in these young patients who may need lung transplantation in the future. Lower respiratory tract infection is a common cause of deterioration for PLCH and should be promptly treated. Seasonal influenza, pneumococcal, and COVID-19 vaccinations are recommended for all patients barring contraindications. Systemic therapy should be instituted for patients with persistent or worsening symptoms who do not respond to smoking cessation or are unable to quit smoking (CS#24). Vinblastine has limited efficacy in PLCH.¹¹⁶ Cladribine (2-chlorodeoxyadenosine) use was associated with improved lung function in multiple studies and is the preferred systemic therapy.^{117, 118, 119, 120} Its long-term effects and tolerance are being evaluated in an uncontrolled phase 2 study (NCT01473797). The role of vasodilator therapy in severe PLCH with pulmonary hypertension is not well established and should be reserved for centers with expertise.¹²¹ Patients with advanced single-system PLCH may be candidates for lung transplantation, although the disease may relapse in the transplanted lungs (CS#25).¹²² The role of MAPK pathway inhibition in single-system PLCH warrants further exploration; review of existing literature showed a single case report of successful treatment using a MEK inhibitor, trametinib.¹²³

Multifocal and multisystem LCH

Long-term remissions can be achieved with multifocal and multisystem disease, and several therapeutic principles generally apply. For patients with multisystem LCH that is asymptomatic and without critical organ involvement (eg, brain, liver, lung) or end-organ dysfunction, an initial period of careful observation and surveillance is reasonable to determine the tempo of the disease. Treatment should be initiated when symptoms ensue or if there is impending organ compromise. The optimal treatment of single-system multifocal and multisystem disease remains undefined in adult LCH because of a paucity of prospective studies. Most retrospective studies have used chemotherapy regimens adopted from the pediatric LCH experience, and some existing treatment guidelines embody this approach. However, pediatric regimens may cause greater toxicities in adults, leading to discontinuation and subsequently diminished efficacy. Moreover, the codified risk stratification system¹²⁴ has not been fully validated in adults. Therefore, it is unclear whether the risk-based treatment strategy implemented in the pediatric setting can be applied to adults.

Treatment regimens that have been published in a series of ≥10 patients are listed in Table 6.^{110, 116, 120, 125, 126, 127, 128, 129, 130} In general, these can be categorized into 2 groups, vinca alkaloid/steroid-based and antimetabolite-based (cladribine, cytarabine) regimens. The vinca alkaloid/steroid-based regimens are similar to or adaptations of pediatric regimens. Although the response rates are generally high, between 70% and 80%, this treatment has been associated with high failure/relapse rates (40% to 80%).^{116, 126} While 2-drug regimens are relatively well tolerated, the more complex regimens with ≥4 or more drugs have, as expected, a higher toxicity profile. The only prospective trials available are for antimetabolite-based regimens. The largest trial investigated the methotrexate + cytarabine regimen, with a response rate of 88% and a 3-year progression rate of 32%. However, almost half (48%) developed febrile neutropenia while a third (33%) developed grade 3/4 thrombocytopenia.⁴⁴ The only other prospective trial used cladribine and showed a response rate of 75% with a median duration of 3 years and febrile neutropenia rate of 15%.¹²⁵ Recent retrospective studies have confirmed the high response rates (79% to 90%) among patients who received cladribine as frontline or at disease relapse.^{120, 127} Limiting cladribine treatment to 4 cycles may reduce the rate of severe cytopenias, and maximum response is attained usually within 4 cycles of treatment.¹²⁰ Another nucleoside analog, clofarabine, has demonstrated efficacy in refractory pediatric LCH¹³¹ and is being evaluated in a clinical trial that includes adults (NCT02425904).

Other systemic treatments, including bisphosphonates for bone-predominant disease,¹³² immunomodulatory imide drugs (IMiDs),^{133, 134, 135} hydroxyurea, oral low-dose methotrexate, hematopoietic stem cell transplant (HSCT), and BRAF and MEK inhibitors, have been reported in smaller series or case reports. In a combined adult and pediatric series of patients with skeletal disease, the use of bisphosphonate therapy (alendronate, pamidronate, or zoledronate) was associated with durable resolution of bone pains as well as radiographic ossification and normalization of bone lesions in the majority of the cases (92%). About half of the patients received only 1 infusion of zoledronate, and the rest were treated over months to a few years.¹³² Of the IMiDs, both thalidomide and lenalidomide have been reported to elicit responses, with some lasting over a year. However, maintenance therapy was required, and relapses occurred almost uniformly after discontinuation of therapy.^{133, 134} Multifocal skin disease is usually responsive to hydroxyurea, IMiDs, oral low-dose methotrexate therapy with or without prednisone/6-mercaptopurine.^{110, 111, 133, 136} Patients with asymptomatic lymph node-only disease can be monitored closely without treatment and may result in spontaneous remissions, especially in the case of cervical lymphadenopathy.¹⁰⁹ There are 6 published cases of adults with refractory LCH (age range 21-35 years) who underwent HSCT, with most cases achieving sustained remissions.^{136, 137, 138, 139, 140, 141} Data on the efficacy of BRAF and MEK inhibitors in frontline and relapsed setting are emerging with several published cases. The majority had BRAF-V600E mutation and received vemurafenib, although there are also reports using cobimetinib, trametinib, and dabrafenib + trametinib.^{9, 10, 136, 142, 143, 144, 145, 146} Responses were near-universal regardless of the site of involvement, and most had a sustained complete remission as long as treatment continued.

Suggested treatment approach

For unifocal disease, local therapy such as surgical excision may be curative if it can be safely undertaken. Unifocal disease not amenable to local therapies (pituitary, CNS, heart) should be treated similar to multisystem disease with systemic therapies (CS#21). Radiation therapy is an effective option for symptomatic bone-only disease with a limited number of lesions (<3). Other treatment options for multifocal cutaneous or bone disease include immunosuppressive agents like low-dose methotrexate, hydroxyurea, 6-mercaptopurine, or IMiDs. Bisphosphonates are an option for bone-only disease without the risk of structural compromise or instability (CS#26-27). For disease recurrence not amenable to local therapies or unresponsive to immunosuppressive agents, systemic chemotherapy is recommended (Table 6; CS#28). The treatment of single-system PLCH often requires collaboration between pulmonologists and oncologists. For multifocal and multisystem disease, we propose the treatment approach using the algorithm provided in Figure 4. Among systemic treatment options for LCH, chemotherapy using either cladribine or cytarabine is preferred because of relatively high overall response rates and the potential for long-term remissions with limited cycles of treatment (CS#28). Vinblastine + prednisone is a reasonable alternative, although it is not the preferred choice of therapy in adults given the high risk of relapse and potential for peripheral neuropathy. Data on BRAF and MEK inhibitors are still evolving, but advantages include near-universal and quick responses, making them a preferred treatment for patients who require a rapid reversal of organ compromise. Similar to the experience in ECD, discontinuation of these agents will likely result in disease relapse, necessitating prolonged therapy.¹⁴⁷ However, carefully selected patients may be good candidates for low-dose chronic administration or treatment breaks. Because most patients will require a dose reduction and lower doses of BRAF and MEK inhibitors are quite effective, it is reasonable to start at half of the dose currently used to treat patients with melanoma. With the advent of targeted inhibitors, the role of HSCT in adults with refractory LCH is unclear.

For patients with CNS disease, cladribine, higher doses of cytarabine, IV methotrexate-based regimens, or kinase inhibitors are preferred (CS#29,30). The treatment data on adults with neurodegenerative disease are lacking, but BRAF/MEK–inhibitor- or cytarabine-based chemotherapy may be preferred based on limited pediatric experience.^{148, 149} For LCH-associated sclerosing cholangitis, the optimum therapy is unknown. Due to poor outcomes with chemotherapy, targeted agents are preferable. Prolonged remissions following liver transplant have been reported^{50, 150, 151, 152}; therefore, early transplant referral should be undertaken in otherwise fit patients. In a study of mostly pediatric patients with LCH, disease relapse in the transplanted liver was seen in 8% of cases.¹⁵² For disease that is relapsed or refractory following chemotherapy, it is reasonable to consider an alternate chemotherapy agent or a kinase inhibitor based on patient-specific factors and drug availability (CS#30).