Multiple facial neoplasms in a pediatric patient during treatment for B-lymphoblastic leukemia/lymphoma

Abstract

Histiocytoses encompass a group of rare mononuclear phagocytic cell proliferations with diverse presentations and overlapping features, making them at times difficult to classify. We present a unique case of one such histiocytic disorder, juvenile xanthogranuloma (JXG), in a 15-year-old patient who developed lesions shortly after initiation of chemotherapy for treatment of B-lymphoblastic leukemia/lymphoma and displayed genetic mutations not typically associated with JXG. Appropriate diagnosis and management of JXG requires an understanding of key features in clinical presentation and histopathology, associated conditions, and genetic mutations.

KEY POINTS

• Classifying histiocytoses may be difficult due to lack of precise diagnostic criteria and overlapping features and thus requires an understanding of clinical presentation, histopathology, and cell markers.

• Our patient displayed genetic mutations BRAF p.469E and KRAS p.G12V, which are rarely associated with juvenile xanthogranuloma.

• Our patient paradoxically developed histiocytic lesions after initiation of chemotherapy for treatment of B-lymphoblastic leukemia/lymphoma.

• Genomic studies can help guide effective treatment.

CASE SUMMARY

A 15-year-old male with a history of B-lymphoblastic leukemia/lymphoma (B-ALL) presented to our clinic with multiple new skin lesions that had diffusely erupted on his face after starting a new chemotherapy regimen of methotrexate, vincristine, and mercaptopurine. On initial physical examination, several pink to yellow-orange papules and plaques were scattered across the forehead, eyelids, temples, and cheeks (Figure 1). A shave biopsy was performed at the initial encounter, plus a few excisional biopsies of the large lesions at a subsequent visit. Histopathology of the initial biopsy revealed histiocytes with Touton giant cells consistent with juvenile xanthogranuloma (JXG); however, the excisional biopsy revealed more atypical cells with mitoses (Figure 2). Stains were negative for S100, CD1a, and CD207; positive for CD68; and weakly positive for CD45RB. Systemic involvement of histiocytosis was ruled out based on computed tomography of the chest, abdomen, and pelvis, as well as lactate dehydrogenase and erythrocyte sedimentation rate values, bone marrow biopsy studies, and ophthalmologic evaluation. Clonality studies, including IgH and IgK gene rearrangement studies, were negative for a suspected relationship between the lesions and the patient’s B-ALL. Genomic sequencing with next-generation sequencing listed the lesions as having BRAF p.469E and KRAS p.G12V mutations.

Figure 1.

Pink to yellow-orange papules and plaques scattered across the forehead, eyelids, temples, and cheeks at (a) initial visit and (b) a 4-month follow-up visit.

Figure 2.

Hematoxylin and eosin–stained histopathology slides of (a) a shave biopsy revealing histiocytes with Touton giant cells at 20× magnification and (b) an excisional biopsy revealing atypical cells with mitoses at 40× magnification.

Clinical Questions

1. What is the next step in management?

   1. Surgical removal of lesions

   2. Ophthalmology referral

   3. Increased dose of methotrexate

   4. No further intervention; monitor clinically

2. Which of the following conditions is associated with an increased risk of developing juvenile xanthogranulomas?

   1. Birt Hogg Dube

   2. Juvenile myelomonocytic leukemia

   3. Cowden syndrome

   4. Tuberous sclerosis

Answers are provided at the end of the article.

DISCUSSION

Histiocytoses are a group of rare proliferations of cells derived from macrophages or dendritic cells. Histiocytic disorders contain a wide range of clinical presentations, depending on the extent of organs affected, and presentations can overlap with one another. Multiple classification systems for histiocytoses have been suggested. Traditionally, they are divided into three categories: Langerhans cell, non-Langerhans cell, and malignant histiocytoses. JXG are the most common of the non-Langerhans cell histiocytoses.^1,2

JXG typically presents in early childhood as erythematous to yellow papules with a predilection for the head, neck, and trunk, which usually resolve spontaneously within months to years. Extracutaneous lesions may occur on the soft tissue, ocular region, liver, spleen, lung, kidney, and central nervous system (CNS), though systemic involvement is rare, occurring in <1% of cases. Those with systemic involvement tend to have multiple, multifocal, and/or larger cutaneous JXG compared to patients without systemic involvement.

Our patient’s initial biopsy revealed Touton giant cells and positive immunohistochemistry staining for CD68, with negative staining for S-100 and CD1a, supporting a diagnosis of JXG.¹ Due to the eruptive and diffuse clinical presentation of these lesions, systemic involvement was a concern. Ophthalmology evaluation and systemic workup were negative for extracutaneous involvement, as mentioned above. The atypical cytology and immunohistochemistry stains of the subsequent excisional biopsies were concerning for histiocytic sarcoma. However, given no systemic involvement, our patient’s clinical presentation was more consistent with banal JXG.

Serious complications are typically seen only with systemic involvement, with fatalities primarily due to progressive CNS disease and liver failure. Additional CNS complications may include seizures, increased intracranial pressure, diabetes insipidus, and developmental delay. Most lesions of JXG in childhood resolve spontaneously and do not require treatment, although symptomatic JXG may be treated with chemotherapy or radiotherapy.³ Intriguingly, our patient paradoxically developed diffuse facial lesions within several months after initiating chemotherapy treatment for B-ALL with methotrexate, vincristine, and mercaptopurine. Both methotrexate and mercaptopurine have been reported to be efficacious in treating histiocytic neoplasms.

Histiocytoses, including multiple JXGs and malignant histiocytoses, have been reported to occur after or simultaneously with hematologic neoplasms and lymphoproliferations such as B-ALL.^4–6 This case supports the increasing evidence of a possible relationship between lymphoid neoplasms and histiocytic neoplasms derived from hematopoietic stem cells. Notably, studies have shown that leukemic initiating cells in acute leukemias, while primarily committed to the T-cell lineage, can also exhibit features of myeloid or dendritic cell differentiation.⁷ This plasticity may help explain the emergence of lymphoid and histiocytic neoplasms in some patients with B-ALL.

Approximately 70% of JXG cases display driver mutations of mitogen-activated protein kinase (MAPK) and receptor tyrosine kinase (RTK), with MAP2K1, KRAS/NRAS, CSF1R, and NTRK1 fusion being particularly prevalent.¹ BRAF V600E mutations are also known to be reported in JXG lesions.³ Our patient’s JXGs were found to have BRAF p.469E and KRAS p.G12V mutations, atypical for JXG. Identification of the specific mutation allowed the treatment team to consider medications used to target KRAS p.G12V mutation, including binimetinib, cobimetinib, selumetinib, and trametinib, highlighting the importance of genomic sequencing in selecting effective targeted therapy. The results were discussed with the patient’s oncologist, who planned to initiate trametinib. Unfortunately, the patient was lost to follow up at the dermatology clinic.

While JXG has displayed distinct clinical presentations, histopathology, and associated genetic mutations, our case highlights the gaps in our understanding of the broad spectrum of these histiocytic neoplasms and how further genetic testing can guide treatment in complicated cases.

ANSWERS TO CLINICAL QUESTIONS

Question 1, b. Ophthalmology referral is the correct answer. Systemic involvement is seen in 4% of children, with a mortality rate of 5% to 10%, and thus must be ruled out. The eye is the most common presentation for extracutaneous JXG, making an ophthalmology referral the best next step in management. Additionally, morbidity due to ocular involvement includes hemorrhage, glaucoma, and blindness, further warranting ophthalmologic evaluation.³ Other workup to assess for systemic JXG, depending on clinical suspicion and severity of the initial presentation, may include computed tomography of the chest, abdomen, and pelvis, laboratory evaluation (lactate dehydrogenase, erythrocyte sedimentation rate), and a bone marrow biopsy. All of these were performed and were negative in our patient’s case.

Question 2, b. Juvenile myelomonocytic leukemia is the correct answer. The association between JXG and juvenile myelomonocytic leukemia has been established, as well as a “triple association” consisting of JXG, neurofibromatosis type 1, and juvenile myelomonocytic leukemia. To date, there is not an established association between JXG and acute lymphoblastic leukemia; however, JXG development in patients with B-ALL has been reported.^4–6 This case further highlights the potential association of the non-Langerhans histiocytoses like JXG and lymphoid malignancies.

Disclosure statement/Funding

The authors report no funding or conflicts of interest. The patient and family gave verbal permission for the images and case to be published in this academic journal.