Introduction
Juvenile xanthogranuloma (JXG) is the most common form of non-Langerhans cell histiocytosis in children, typically presenting as benign, self-limited papules during infancy or early childhood.1 A well-established association exists between JXG, neurofibromatosis type 1 (NF1), and juvenile myelomonocytic leukemia (JMML), a triad that confers an elevated leukemia risk, especially in children with eruptive JXG lesions.2, 3, 4 However, the relationship between JXG and other hematologic malignancies remains poorly defined.
A few case reports have documented the development of B-cell acute lymphoblastic leukemia (B-ALL) in children with a history of JXG, with some suggesting shared clonal or cytogenetic features between the 2 entities.5, 6, 7, 8 Recent reports have identified shared genetic alterations, including high hyperdiploidy and somatic mutations, in both JXG lesions and leukemic blasts in patients with coexisting disease, suggesting a potential clonal relationship or common hematopoietic progenitor origin.6,8
We present the case of a previously healthy male diagnosed with multifocal cutaneous JXG at age 6 months, who developed high hyperdiploid B-ALL at age 7. To our knowledge, this is one of the few reported cases of JXG preceding a diagnosis of B-ALL in a child without NF1 or known cancer predisposition syndrome, and the first case of such a presentation treated with the Children’s Oncology Group protocol AALL1731 protocol. This case contributes to the growing recognition of a potential association between JXG and B-ALL.
Case report
A 6-month-old male with no significant family or prenatal history presented to dermatology for evaluation of a dome-shaped, reddish-orange, hyperpigmented papule on the eyelid, noted since 3 months of age. Over the subsequent months, additional similar lesions developed on the forehead and bilateral cheeks (Fig 1). The child was otherwise healthy, meeting all developmental milestones, with no café-au-lait macules, axillary freckling, or family history of NF1. A skin biopsy was performed, and was consistent with JXG. Due to the eruptive cutaneous presentation, the patient underwent annual ophthalmologic examinations and quarterly hematology-oncology monitoring, which revealed no ocular or systemic involvement.
Fig 1.
Juvenile xanthogranuloma presenting as numerous smooth, firm, dome-shaped, reddish-orange, and hyperpigmented papules are scattered across the bilateral malar cheeks, temple, left upper and lower eyelids, and forehead.
At 7 years of age, the patient developed persistent daily fevers and progressive bone pain. A complete blood count obtained by the pediatrician revealed pancytopenia, and he was admitted to the hospital for further evaluation. Core biopsy revealed hypercellular marrow (98% cellularity) with diffuse sheets of lymphoblasts, complete effacement of normal hematopoiesis, and marked depletion of megakaryocytes. Flow cytometry of the marrow showed a 73% population of B-lymphoblasts expressing cluster of differentiation (CD)19, CD20, and CD22, consistent with B-ALL. Cytogenetic analysis revealed a high hyperdiploid karyotype, and fluorescence in situ hybridization confirmed multiple extra copies of chromosomes 4, 10, 12, 17, and 21, consistent with high hyperdiploid ALL. No abnormalities were detected on Philadelphia chromosome-like acute lymphoblastic leukemia fluorescence in situ hybridization testing, and no rearrangements involving cyclin-dependent kinase inhibitor 2A, breakpoint cluster region/Abelson murine leukemia viral oncogene homolog 1 fusion gene, lysine methyltransferase 2A, ETS variant 6, or transcription factor 3 were identified. These findings confirmed a diagnosis of standard-risk favorable B-ALL.
The patient was initiated on the Children’s Oncology Group AALL1731 protocol for standard-risk favorable B-ALL, which includes multiagent chemotherapy delivered across phases. Induction therapy involved intrathecal and systemic agents, including vincristine, dexamethasone, pegaspargase, cytarabine, and methotrexate. He achieved minimal residual disease-negative status at both interim and end-of-induction evaluations. Flow cytometry performed at an outside hospital identified no phenotypically aberrant lymphoblasts, confirming minimal residual disease negativity. No residual leukemic population was detected on corresponding clot sections or aspirate material. He proceeded through consolidation and interim maintenance without complications. He continues protocol-directed therapy, with maintenance treatment expected to continue for 2 years from the start of interim maintenance.
Discussion
Though the most well-documented association involving JXG is with NF1 and JMML, a growing body of literature suggests that JXG may also occur alongside lymphoid malignancies such as B-ALL.4 In a recent study of 1652 JXG cases, 25 patients developed hematologic malignancies, 59% of which were lymphoid in origin, including several cases of B-ALL.9
A review of 9 published cases (Table I) illustrates the broad clinical spectrum of JXG-B-ALL associations; 3 additional reports were excluded due to lack of full text or English translation. In several reports, JXG emerged concurrently with active leukemia or soon after the initiation of chemotherapy.3,6,8 This temporal relationship raises the possibility of JXG as a reactive process or secondary histiocytic proliferation triggered by leukemic inflammation or immunologic shifts during therapy.
Table I.
Demographics, clinical features, and outcomes of reported cases involving juvenile xanthogranuloma and B-cell acute lymphoblastic leukemia
| Study name | Patient age and sex | JXG presentation | Hematologic malignancy | Temporal relationship between JXG and malignancy | Treatment | Outcome |
|---|---|---|---|---|---|---|
| Aparicio et al.8 | 3-y-old male | Eruptive cutaneous JXG with ∼100 firm yellow-brown papules/nodules on scalp, face, trunk, extremities, palms, soles | Pre-B acute lymphoblastic leukemia (ALL) | JXG appeared concurrently with first relapse of ALL | Chemotherapy for relapsed ALL; supportive management of JXG (no specific JXG-directed therapy mentioned) | Second leukemia relapse 6 mo later with no response to treatment; JXGs darkened and flattened but did not fully regress |
| Cheng et al.6 | 12-y-old Hispanic male | Numerous reddish nodules on his face and scalp; biopsy demonstrated histiocytic proliferations consistent with JXG | Philadelphia chromosome–like B-ALL with CRLF2::IGH and KRAS G12D mutation | JXG developed during consolidation chemotherapy after initial induction remission | MEK inhibitor (trametinib), blinatumomab, total body irradiation, thiotepa, cyclophosphamide, antithymocyte globulin | Achieved remission; died 300 d post-HCT from multiorgan failure and infection due to steroid-refractory GVHD |
| Cheon et al.1 | 16-y-old male | JXG of bone marrow and bones; no cutaneous lesions | Pre-B ALL in remission state | Developed systemic JXG while receiving interim maintenance chemotherapy; active leukemia in remission | Continued standard ALL chemo (vincristine, dexamethasone, 6-mercaptopurine, methotrexate) without alteration | Fever and bone pain resolved during induction-like chemo; later a scalp skin lesion appeared and then spontaneously regressed over ∼2 mo |
| Llanes et al.3 | 17-y-old male | Multiple nodular, coalescing, dark brown, molluscoid lesions on face, neck, head, trunk, upper and lower extremities; biopsy consistent with JXG | B-cell acute lymphoblastic leukemia (ALL) | JXG developed 1 mo after induction phase of ALL chemotherapy | Standard ALL induction chemo (prednisone, vincristine, daunorubicin, L-asparaginase, cyclophosphamide, cytarabine) | Lesions emerged during chemotherapy; histopathologic diagnosis confirmed JXG; no indication of disease progression reported |
| Maly et al.4 | 11-mo-old male | Brownish nodules on head, trunk, and back | No confirmed leukemia at time of report, but bone marrow showed clonal cytogenetic abnormalities associated with B-ALL | JXG diagnosed at 6 mo; clonal proliferation detected at 11 mo; no overt leukemia at time of treatment | Vinblastine + prednisone per LCH 2009 protocol; later Cladribine due to disease progression | Initial regression of skin lesions and hematologic improvement; relapse after 6 mo; allogeneic stem cell transplant under consideration |
| Mundada et al.2 | 14-y-old male | Papular skin lesions on chest and abdomen, and JXG of bone marrow | B-cell lymphoblastic leukemia (B-LL) | JXG diagnosed 4 mo after initial B-LL diagnosis, during consolidation chemotherapy | Chemotherapy for B-LL (BFM-ALL protocol); antifungals; later vinblastine and prednisone for JXG | Skin lesions responded to treatment; persistent cytopenias and refractory thrombocytopenia; patient lost to follow-up as family pursued alternative therapy |
| Newman et al.5 | 7-y-old Hispanic female | Intraparenchymal JXG | B-cell acute lymphoblastic leukemia (B-ALL), hyperdiploid karyotype | B-ALL at age 7 → relapse at age 9 → JXG diagnosed at age 15 (6 y after initial B-ALL diagnosis) | B-ALL: COG AALL0932 → relapse therapy with AALL1331 + blinatumomab + whole brain radiation therapy. JXG: Larotrectinib (TRK inhibitor), dose adjusted for tolerability | B-ALL: In remission; JXG: Symptom and radiologic improvement after 10 mo of larotrectinib; ongoing surveillance for ETV6 mutation |
| Pawińska-Wa Sikowska et al.7 | 15-y-old male | Disseminated, single, pearly yellow nodules localized on the face, trunk, and extremities; biopsy confirmed JXG | Precursor B-cell ALL (pre-B-ALL) | JXG developed 3 mo after ALL diagnosis, during remission and consolidation | B-ALL: IC-BFM 2009 protocol → Protocol IB → allogeneic HSCT (treosulfan, fludarabine, thiotepa, alemtuzumab). JXG: tocilizumab (anti-IL-6R) × 5 doses → partial response → allogeneic HSCT → empiric anti-TB therapy (isoniazid + rifampin × 6 mo) | 2-y follow-up: remission of ALL and JXG; good general health |
| Sanchez-Petitto et al.10 | 21-y-old male | Disseminated flesh-colored dermal nodules on forehead, back, arms | B-cell acute lymphoblastic leukemia (B-ALL) | JXG developed during remission after second cycle of chemotherapy for B-ALL | Clofarabine; antifungals for candidemia | Death due to Candida krusei fungemia and multiorgan failure |
COG AALL0932, Children’s Oncology Group protocol AALL0932; ETV6, ETS variant 6; GVHD, graft-versus-host disease; HSCT, hematopoietic stem cell transplantation; IC-BFM 2009, Intercontinental Berlin-Frankfurt-Münster 2009; JXG, juvenile xanthogranuloma; KRAS, Kirsten rat sarcoma viral oncogene homolog; LCH, Langerhans cell histiocytosis.
In contrast, other reports suggest that JXG may predate leukemia by months or years, aligning more closely with our patient’s presentation.4,5 These cases raise the possibility of a shared hematopoietic progenitor harboring latent genetic abnormalities that give rise to both histiocytic and lymphoid neoplasms over time.
Further, cytogenetic overlap has been reported in several instances, including 1 patient with Philadelphia chromosome-like B-ALL and JXG harboring a shared Kirsten rat sarcoma viral oncogene homolog mutation, and co-occurrence of high hyperdiploid B-ALL and JXG in another patient with a pathogenic germline ETS variant 6 mutation.5,6 Although no clonal or germline alterations were identified in our case, the shared high hyperdiploidy raises the question of whether hyperdiploidy itself may represent a predisposing event shared between hematopoietic lineages.5
Notably, our patient’s JXG diagnosis occurred in infancy, consistent with typical JXG epidemiology, while leukemia emerged at age 7, making this one of the few documented cases in which JXG clearly preceded B-ALL in a child without NF1 or known cancer predisposition. His long latency interval, absence of NF1, and lack of systemic JXG features further distinguish this case from others in the literature.
While the overall number of reported cases remains small, these observations may reflect several mechanistic hypotheses that could play a role in the association between JXG and B-ALL. One possibility is that a shared hematopoietic progenitor may give rise to both JXG and B-ALL through lineage divergence. Alternatively, certain germline or somatic mutations may predispose to both histiocytic and lymphoid neoplasms. A third possibility is that immune dysregulation during leukemia or in the setting of chemotherapy may trigger histiocytic proliferation in susceptible individuals.1, 2, 3, 4, 5, 6, 7, 8,10
Ultimately, this case contributes to the evolving recognition that while JXG is typically benign, in rare circumstances it may precede or coexist with B-ALL, even in children without NF1 or JMML. Dermatologists and pediatricians should maintain a high index of suspicion in patients with eruptive JXGs or evolving systemic manifestations.
Conflicts of interest
None disclosed.
Footnotes
Funding sources: This research was supported (in whole or in part) by HCA Healthcare and/or an HCA Healthcare affiliated entity. The views expressed in this publication represent those of the author(s) and do not necessarily represent the official views of HCA Healthcare or any of its affiliated entities.
Disclaimer: The views expressed in this publication represent those of the author(s) and do not necessarily represent the official views of HCA Healthcare or any of its affiliated entities.
Patient consent: The authors obtained written consent from patients for their photographs and medical information to be published in print and online and with the understanding that this information may be publicly available. Patient consent forms were not provided to the journal but are retained by the authors.
IRB approval status: For this type of study, formal IRB approval is not required.
Ethics statement: All procedures performed in this case report were conducted in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
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