B-cell acute lymphoblastic leukemia and juvenile xanthogranuloma in a patient with ETV6 thrombocytopenia and leukemia predisposition syndrome: novel clinical presentation and perspective

ETV6-thrombocytopenia predisposition syndrome is a rare cancer predisposition with varying penetrance, which portends increased risk of hematologic malignancy. Here we present the unusual case of a patient with a novel pathogenic variant in ETV6 who developed both B-cell acute lymphoblastic leukemia (B-ALL) and an intracranial non-Langerhans cell histiocytic neoplasm.

Case

A 7-year-old Hispanic girl with fever and leg pain was diagnosed with standard-risk B-ALL. Diagnostic leukemia karyotype revealed hyperdiploid ALL with favorable trisomies (55, XX, +X, +4, +10, del(12)(p11.2), +add(12)(p13),+14, +add(17)(q25),+18,+20,+21[4]/46,XX[18]). She was treated on the Children’s Oncology Group (COG) clinical trial AALL0932¹ with negative minimal residual disease (MRD) at the end of induction. Unfortunately, 10 months off therapy she experienced a combined bone marrow and central nervous system relapse. Chromosomal microarray redemonstrated hyperdiploid ALL with similar trisomies as observed at diagnosis. She was subsequently treated on COG AALL1331,² randomized to the low-risk arm with blinatumomab.³ She underwent whole brain radiation therapy (1,800 cGY) administered in ten fractions at month 12, with total duration of relapsed ALL therapy of 2 years.

At age 15, she presented to our Emergency Department with 2 weeks of headache and right eye pain, as well as fever and myalgias. Her vital signs and physical exam were reassuring, notable only for a baseline non-reactive right pupil and disconjugate gaze. Laboratory studies revealed a normal complete blood count, including normal platelet count of 180x10⁹/L. A head computerized tomography scan and subsequent magnetic resonance imaging (MRI) demonstrated a well-circumscribed area of hyperattenuation within the left temporal lobe (1.7x1.4x1.4 cm) with surrounding edema and regional mass effect (Figure 1A). The patient subsequently underwent a bone marrow biopsy and lumbar puncture, revealing no evidence of recurrent leukemia. Temporal lobe biopsy demonstrated sheets of histiocytic cells, including frequent giant cell forms with occasional Touton-type giant cells. Immunohistochemical stains showed that the histiocytic cells expressed CD68, CD163 and Factor XIII and were associated with a low Ki67 proliferation index (<5%). A diagnosis of intraparenchymal juvenile xanthogranuloma (JXG) was rendered. Next-generation sequencing (NGS) analysis of the tumor detected ARHGEF2::NTRK1 fusion (Figure 2), which has been previously reported in other central nervous system (CNS) tumors.⁴ A skeletal survey revealed no bony disease. Tumor/normal (blood) NGS panel of 238 cancer genes⁵ demonstrated a germline pathogenic nonsense variant in both tumor and blood specimens: ETV6 c.1062C>A (p.Tyr354*) with variant allele frequencies of 0.49 and 0.40, respectively.

Figure 1.Magnetic resonance imaging of patient’s intraparenchymal juvenile xanthogranuloma before and after initiation of larotrectinib. (A) Magnetic resonance imaging at time of diagnosis. (B) Follow-up magnetic resonance imaging 10 months after initiation of larotrectinib.

Given the targetable NTRK1 fusion, the patient was initiated on larotrectinib for JXG therapy given data on rapid, durable responses and safety of larotrectinib in TRK fusion-positive CNS tumors.⁶ She was initiated on standard adult dosing (100 mg twice daily), but due to a common side effect of generalized body aches was transitioned to three times daily dosing (75/50/75 mg) which was well tolerated. Within 2 months she had improvement in headaches and on follow-up MRI 10 months after drug initiation there was significant decrease in mass size with reduction of surrounding signal abnormality (Figure 1B). The patient had no known family history of hematologic malignancies, thrombocytopenia, immune dysregulation, or other childhood cancers. However, cascade testing was performed for the identified pathogenic ETV6 variant and revealed that this variant was inherited from her father and is also carried by her younger sister, neither of whom have been diagnosed with cancer or experienced bleeding symptoms.

Germline pathogenic variants in ETV6 have been described in multiple kindreds of patients with ALL.⁷, ⁸ The ETV6 gene is located on chromosome 12p13.2 and encodes the essential hematopoietic transcriptional repressor erythroblast transformation specific variant 6 (ETV6) protein, which functions primarily as a transcriptional repressor and is essential for bone marrow hematopoiesis and thrombopoiesis.⁹ The ETV6 protein has two highly conserved DNA-binding domains, PNT and ETS, and the majority of reported germline variants are missense mutations within these domains, although nonsense and frameshift variants are also observed. This patient’s nonsense variant in exon 6 results in a premature stop codon predicted to cause an absent or truncated protein product, indicating pathogenicity. Many ETV6 pathogenic variants are thought to exhibit dominant-negative activity by dimerizing with wild-type ETV6 and sequestering in the cytoplasm;⁸ however, some experiments have demonstrated truncating and missense variants lose transcriptional repressor function, but have minimal dimerization effect.¹⁰ To our knowledge, the specific alteration in our patient has not been previously reported.

ETV6-related predisposition was initially recognized in pedigrees as an autosomal-dominant condition of thrombocytopenia and leukemia preponderance.⁷ Many families demonstrate complete penetrance of thrombocytopenia, although individuals with normal platelet counts have been reported, as seen in our patient. Among individuals with ETV6 variants with associated thrombocytopenia, bleeding phenotype is variable; some patients experiencing bleeding even with normal platelet counts and others have no bleeding despite thrombocytopenia.¹¹

Approximately 30% of individuals with ETV6 germline pathogenic variants will develop hematologic malignancy, with B-ALL being the most common.¹¹ Other malignancies include myelodysplastic syndrome and acute myeloid leukemia. There are also case reports of individuals developing solid tumors under age 50.

Unselected analysis of pooled pediatric ALL cohorts demonstrated approximately 0.5-1% incidence of germline pathogenic ETV6 variants.^10,12 Affected children are generally older at the time of diagnosis compared to children without germline ETV6 predisposition, and demonstrate an overrepresentation of hyperdiploid karyotype which was observed in this patient. There is no observed association with end-induction MRD or relapse risk, although further research is warranted.

Figure 2.Schematic of ARHGEF2::NTRK1 fusion. Top: local inversion or inverted fusion event resulted in the ARHGEF2::NTRK1 fusion. Dashed lines represent possible alternative inverted fusion events. A portion of intron 11 sequence was included in the fusion product (red star). Bottom: Sanger sequencing confirmation results on cDNA showing the fusion gene sequence near the junction point. The red arrows indicate the junction point.

To our knowledge, this is the first case report of a patient with a pathogenic germline ETV6 variant presenting with a xanthogranulomatous neoplasm. There is a single case report of a patient with disseminated JXG involving skin and bone marrow, concurrent with severe hemophagocytic lymphohistiocytosis during therapy for B-ALL; however, this patient had no identified germline predisposition.¹³

JXG are rare, benign tumors composed of non-Langerhans cell histiocytes. They often manifest as cutaneous lesions but can involve any organ system. Intracranial disease is only observed in about 7% of cases.¹⁴ JXG have previously been described in patients with Noonan Syndrome with PTPN11 pathogenic variants, and in Neurofibromatosis Type 1. Additionally, there are reports of histiocytic tumors co-occurring with B-ALL and T-ALL with shared B-cell and/or T-cell receptor gene rearrangements, suggesting a shared clonal cell of origin.¹⁵ There was insufficient tissue available on our patient’s JXG to perform gene rearrangement studies. It is possible the pathogenic ETV6 variant described may contribute to JXG pathogenesis, and this risk may have been amplified by exposure to whole brain radiation 3.5 years prior to JXG presentation. However, the JXG may also be unrelated to her cancer predisposition syndrome.

This case adds to the growing literature describing leukemia predisposition in children with ETV6 predisposition syndrome. We add the unique finding of intracranial non-Langerhans cell histiocytic neoplasm with NTRK1 fusion in a patient with a prior history of B-ALL. Germline predisposition is thought to account for approximately 10-15% of childhood cancers. As paired tumor/normal testing with NGS becomes more prevalent, this percentage is likely to increase over time. Here we highlight a patient whose predisposition went undiagnosed with somatic testing alone and required paired diagnostics. Providers should have a particularly high index of suspicion and consider germline testing in children and adolescents presenting with multiple independent neoplasms.

Footnotes

• Received August 23, 2023
• Accepted November 22, 2023

Correspondence

H. NEWMAN - newmanh@chop.edu

Disclosures

No conflicts of interest to disclose.

Contributions

All authors contributed to the writing and editing of this case report.