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Adult Langerhans cell histiocytosis presenting with multisystem involvement and sarcomatoid features: a case report



Langerhans cell tumors are rare clonal disorders characterized by neoplastic proliferation of dendritic cells that can be further classified into the subtypes Langerhans cell histiocytosis and Langerhans cell sarcoma, which are rare neoplasms exhibiting aggressive features and a poor prognosis. In addition to illustrating the refractoriness and poor outcomes of multisystem Langerhans cell histiocytosis in adults, specific events in this case highlight important characteristics of disease biology that warrant detailed discussion and exposition to a wider audience.

Case presentation

We describe the case of a 42-year-old Caucasian man with Langerhans cell histiocytosis diagnosed from a lesion on the left arm that presented with constitutional symptoms, early satiety, and weight loss. Esophagogastroduodenoscopy showed extensive esophageal and duodenal involvement by Langerhans cell histiocytosis with features of Langerhans cell sarcoma. He was initially treated for Langerhans cell histiocytosis with low doses of cytarabine until he eventually presented clear transformation to acute monoblastic leukemia with complex karyotype that could not be properly controlled, leading eventually to death.


Langerhans cell histiocytosis remains an exceedingly rare entity in adults, frequently presenting as multisystem disease with risk organ involvement. Langerhans cell sarcoma represents an aggressive subtype with extremely poor prognosis for which intensive acute myeloid leukemia induction should be strongly considered.

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Langerhans cell tumors are rare clonal disorders characterized by neoplastic proliferation of dendritic cells with distinctive protein expression (CD1a/langerin/S100) and ultrastructural features (Birbeck granules) with Langerhans cell histiocytosis (LCH) and Langerhans cell sarcoma (LCS) subtypes [1,2,3]. Historically, LCH has been classified as a unifocal disease, multifocal unisystem disease, or multifocal multisystem disease [2]. LCS is a rare neoplasm exhibiting aggressive features that carries a poor prognosis. We report a case of a patient with a presentation with symptomatic multisystem multifocal LCH disease with early suggestion of leukemic transformation with particular sensitivity to growth factors. In addition to illustrating the refractoriness and poor outcomes of multisystem LCH in adults, specific events in this case highlight important characteristics of disease biology that warrant detailed discussion and exposition to a wider audience to raise awareness of this unusual entity and aid in the earlier identification of its potential complications.

Case presentation

A 42-year-old Caucasian man presented to our hospital with acute onset of fatigue, nausea, vomiting, early satiety, diarrhea, and weight loss 3 months after LCH had been diagnosed on the basis of biopsy of an asymptomatic lesion on the left arm. His physical examination was pertinent for tender hepatosplenomegaly and multiple eczematous papular lesions on the trunk and extremities. His complete blood count (CBC) results and lactate dehydrogenase (LDH) level were normal. Esophagogastroduodenoscopy (EGD) demonstrated herpes esophagitis and Helicobacter pylori gastritis. Biopsies of the duodenum and esophagus showed involvement by LCH with features suggestive of LCS (Fig. 1). The BRAF V600E mutation was not detected. Imaging did not demonstrate any suspicious bone or central nervous system (CNS) involvement. His bone marrow biopsy (BMBx) showed no LCH or acute myeloid leukemia (AML). He was started on intravenous cytarabine 100 mg/m2 daily for 5 days every 4 weeks, which led to improvement but no resolution of his skin lesions or gastrointestinal (GI) symptoms. After four cycles, his therapy was adjusted to every 2 weeks in view of kinetic failure. This adjustment led to clinical improvement, but his LDH level continued to rise, leading to repeat BMBx performed after cycle 8, which showed no evidence of AML.

Fig. 1
figure 1

Langerhans cell histiocytosis with progression to Langerhans cell sarcoma involving gastric and small intestine mucosa. Endoscopically derived biopsies of gastric and small intestine mucosa showed involvement by Langerhans cell histiocytosis. Pronounced pleomorphism, apoptosis, and mitotic figures were frequent, consistent with progression to Langerhans cell sarcoma (a; H&E stain, 1000× magnification). Neoplastic cells expressed langerin protein (b; 400× magnification), and a subset showed preserved expression of CD1a (c; 400× magnification). Langerhans cells were negative for S100. Ki67-based proliferative rate was estimated at 85% (d; 400× magnification). Although objective distinction between involvement by systemic Langerhans cell histiocytosis and Langerhans cell sarcoma is difficult, the pleomorphic features of the neoplastic cells, aberrant diminished expression of CD1a and S100, and high proliferative rate support designation as Langerhans cell sarcoma. The result of B-RAF testing was negative

Three weeks later, he presented with acute left hemianopia resulting from an ischemic cerebrovascular accident. Workup demonstrated circulating blasts, spontaneous tumor lysis syndrome, and disseminated intravascular coagulation (DIC). BMBx confirmed acute monoblastic leukemia with a complex karyotype. Next-generation sequencing (NGS) showed no additional mutations. The patient was started on induction 7 + 3 (daunorubicin/cytarabine), which led to transient resolution of skin lesions that quickly worsened by day 15. The lesions appeared as multiple erythematous papules and nodules throughout the back. Histological sections showed heavily epidermotropic and bandlike dermal infiltrates of leukemic cells in the dermis with pseudo-blisters formed by tumor necrosis (Fig. 2a). A subset of tumor cells showed features of Langerhans cells, including reniform nuclei and atypical large and hyperchromic nuclei (Fig. 2b). Immunophenotyping revealed that the tumor cells were positive for langerin, S100, and CD1a with intratumoral heterogeneity and a Ki67 showing a nearly 80% cell proliferation rate (Fig. 2c, d). The tumor cells were also positive for CD56, CD117, and CD123 in a subset of cells. The immunophenotype supported both myelomonoblastic and Langerhans cell differentiation. Marrow cytogenetics detected t(13:14) in all tumor cells and additional structural abnormalities involving chromosomes 1, 8, 9, 10, and Y. In this particular context, the cutaneous lesions were best classified as cutaneous involvement of leukemia. Cytogenetic profiling with NGS showed nonsynonymous mutation p.E69K affecting the PTPN11 gene (SHP2), homozygous loss of CDKN2A at 9p21, and a tumor mutational burden of 26%.

Fig. 2
figure 2

Punch biopsy of the skin showing superficial epidermal involvement by a hematopoietic neoplasm. Epidermal erosion and ulceration with underlying hematopoietic infiltrate involving epidermis and upper dermis (a; H&E stain, 100× magnification). The hematopoietic neoplasm is poorly differentiated with blastic nuclear features and round to reniform nuclei. Cellular apoptosis is increased. Numerous small reactive lymphoid cells are also present (b; 500× magnification). The majority of the blastic cells express CD1a by immunohistochemistry (c; 500× magnification) and coexpress langerin (d; 500× magnification). The findings are those of acute monoblastic leukemia with Langerhans cell differentiation involving skin

He was started on salvage therapy with CLAG-M (cladribine 5 g/m2, cytarabine 2 g/m2, granulocyte colony-stimulating factor (G-CSF), mitoxantrone 10 g/m2), and after the first dose of filgrastim (G-CSF), he developed acute diplopia with leptomeningeal involvement by AML as identified by brain magnetic resonance imaging and lumbar puncture (Fig. 3). Intensive intrathecal therapy with methotrexate (MTX) was initiated twice per week for six cycles. The patient’s skin lesions and neurologic symptoms resolved with restaging consistent with complete remission. However, 1 week later, his skin lesions recurred, followed by recurrence of neurologic deficits that responded poorly to salvage therapy, including high-dose cytarabine, further intrathecal therapy, and CNS radiation. The patient died 1 year after diagnosis of LCH while undergoing treatment with MTX and cytarabine as a bridge to marrow transplant. Table 1 summarizes the cardinal features associated with this case.

Fig. 3
figure 3

T1-weighted magnetic resonance imaging (MRI) of the brain with contrast enhancement (sagittal view) and cerebrospinal fluid analysis. Leptomeningeal involvement by acute myeloid leukemia demonstrated by brain MRI with contrast (a) with diffuse pachymeningeal thickening and enhancement overlying the bilateral cerebral hemispheres (white arrows) and cerebrospinal fluid showing abnormal hypercellularity due to the presence of monoblasts (b and c; Wright Giemsa stain at 200× and 1000× magnification, respectively)

Table 1 Oncologic history/summary

Discussion and conclusions

LCH is a rare entity that results from atypical clonal proliferation of a subset of mononuclear dendritic cells closely resembling Langerhans cells that derive from myeloid progenitor cells. Somatic mutations activating the MAPK (mitogen-activated protein kinase) signaling pathway are commonly observed in LCH, with BRAF V600E mutation identified in over half cases [6, 7]. LCH is mostly described and studied in children [1]. Median age at the time of diagnosis is 1–3 years with an annual incidence of 3-5 cases per million persons per year in children and 1-2 cases per million persons per year in adults [2, 3] LCH is further stratified into single-system disease with unifocal or multifocal involvement or multifocal multisystem disease with or without risk organ (marrow, liver, or spleen) involvement [1,2,3]. The majority of adults present with multisystem involvement mostly characterized by osteolytic lesions, skin or mucocutaneous involvement, diabetes insipidus, and hepatosplenomegaly. CNS or GI compromise is uncommon [8,9,10]. Prognosis correlates with extent of disease and degree of organ dysfunction, with more than half presentations with multisystem disease dying of LCH [4, 11]. LCS, reported mainly in adults, is extremely rare. Differentiation from LCH is challenging because immunophenotype is identical and diagnosis is based on overtly malignant pleomorphic appearance [11,12,13,14,15].

Therapy is extrapolated from pediatric studies and single-institution experiences because clinical trials in adults are lacking [16]. Although the commonly used pediatric approach with vinblastine and prednisone is acceptable, single-agent cytarabine or cladribine has been the preferred first-line option, mostly to minimize steroid-induced toxicity and neuropathy [17]. A review of the management of 58 adults with LCH demonstrated significantly higher response with cytarabine than with vinblastine/prednisone, which also presented worse toxicity with 75% grade 3–4 neuropathy [18]. Recurrences in adults are common. Besides the use of other cytotoxic agents such as clofarabine, the BRAF inhibitor vemurafenib has demonstrated excellent, albeit transient, responses in patients with BRAF V600E mutation [19]. The role of consolidation with allogeneic stem cell transplant is unclear. A review of 87 patients with high-risk LCH who underwent allogeneic transplant demonstrated greater than 70% long-term survival with higher relapse rates with reduced-intensity conditioning [12, 20]. A literature review of LCS described dramatic variation in management from chemotherapy to surgery, radiation, or a combination of them. Chemotherapy regimens were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-based with mixed results. Survival was overall poor, 58% at 1 year, and outcomes were poorer in disseminated presentations [12].

Our case highlights the refractoriness of LCH in adults. Agents known to have activity in LCH demonstrated suboptimal responses. Attention to specific events during our patient’s presentation highlight important biologic characteristics of LCH. Molecular therapy was not possible, because no targetable mutation was identified. One central finding was the detection of LCS by EGD biopsy. Although our patient presented with symptomatic multisystem disease that required systemic therapy, the LCS component was minute. A more intensive first-line therapy was contemplated but was believed not to be indicated, considering that the presentation was mostly of LCH with a negligible LCS component with normal CBC, LDH, and BMBx. The best response was achieved after an AML induction/salvage regimen (cladribine, cytarabine, and filgrastim with idarubicin [CLAG-Ida]) that was intentionally chosen in view of the described activity of cladribine in LCH [5, 21]. One is left to wonder if our patient’s outcome would have been different had he received intensive induction chemotherapy for what was ultimately a presentation of myeloid sarcoma.

CNS involvement was another critical event. Although our patient had no suggestion of CNS involvement at initial staging, an ischemic cerebrovascular accident believed to be closely related to the DIC was the hallmark of presentation at disease progression/transformation to AML. Nonetheless, the most intriguing aspect of CNS involvement was the acute development of diplopia after the first dose of G-CSF administered as part of CLAG-Ida. The potential relationship between CNS involvement and G-CSF was highlighted during salvage, when the resolved diplopia recurred after a dose of pegfilgrastim. Numerous serum cytokines, including G-CSF, have been associated with the pathogenesis of LCH [22, 23]. The timing between growth factor injection and development of neurologic deficits implies a potential correlation.

The homozygous loss of CDKN2A at 9p21 was also an interesting finding when analyzing the cytogenetic profile of our patient’s tumor. In contrast to its counterpart of LCH, a recent study demonstrated frequent homozygous loss of CDKN2A/B locus (9p21) and both MAP2K1 and NRAS genes mutations in LCS, which may provide a future basis for potential targeted therapy [24].

In summary, LCH remains an exceedingly rare entity in adults, frequently presenting as multisystem disease with risk organ involvement. Although therapeutic targets such as BRAF V600E mutations have been identified, therapeutic options remain limited. An intensive AML induction regimen should be strongly considered for LCH presentations with suggestion of an LCS component with cautious use of growth factors and particular attention to CNS involvement. In view of the limited number of effective therapeutic interventions, patients with refractory cases or atypical presentations of LCH and LCH-related disorders should be encouraged to enroll in one of multiple active clinical trials (Table 2).

Table 2 Active clinical trials recruiting patients with Langerhans cell histiocytosis and related disorders

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Authors and Affiliations



LEA and IS were involved in data collection, designed the case report protocol, reviewed the existing literature, and drafted the paper. AA and MFL were involved in the care of the patient, designed the treatment protocol, and supervised the data collection. JC analyzed the pathology slides and submitted the figures and footnotes. AA codrafted, reviewed, and approved the final manuscript. All authors read and approved the final manuscript.

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LEA and IS are resident physicians at the Department of Internal Medicine at the University of Miami and Jackson Memorial Hospital. MFL works as assistant professor of gastroenterology and is the medical director of the Gastrointestinal Endoscopy Unit at Jackson Memorial Hospital and at the University of Miami Miller School of Medicine. JC works as associate professor of pathology at the University of Miami. She is the director of the Immunohistochemistry Laboratory and associate program director at the Department of Pathology and Laboratory Medicine at the University of Miami and Jackson Memorial Hospital. AA works as assistant professor of medicine at the University of Miami and is a member of the lymphoma program at the University of Miami Sylvester Comprehensive Cancer Center.

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Correspondence to Alvaro Alencar.

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Aguirre, L.E., Schwartz, I., Chapman, J. et al. Adult Langerhans cell histiocytosis presenting with multisystem involvement and sarcomatoid features: a case report. J Med Case Reports 14, 169 (2020).

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