Diagnosis and Discussion - Case 1114

Final Diagnosis

B-cell Acute Lymphoblastic Leukemia (B-ALL) with t(12;21)(p13.2;q22.1)/ETV6::RUNX1 (by ICC – International Consensus Classification)2 or B-ALL with ETV6::RUNX1 fusion (by WHO 5th Ed. Classification)3.

Discussion

Pediatric B-ALL is the most common hematological malignancy in children, accounting for close to one-third of all childhood malignancies. Patients commonly present with signs and symptoms including pallor, fever, easy bruising, hepatosplenomegaly, and lymphadenopathy. Histologically, abnormal lymphoblasts in ALL are characterized by scant, moderately basophilic cytoplasm and nuclei with moderately condensed to dispersed chromatin and occasional nucleoli. Immunohistochemical and flow cytometric results classically are positive for TdT, CD79a, CD19, CD22, CD24, and CD10 in B-type ALL4.  These findings are utilized in conjunction with cytogenetics findings to arrive at a diagnosis of B-ALL.

Translocation between ETV6 and RUNX1 (located on chromosomes 12 and 21 respectively)-t(12;21)(p13;q22) is the most prevalent chromosomal abnormality, seen in about 25% of cases5. This translocation is considered to be predictive of a favorable prognosis6.  In this patient, the second ETV6 signal is lost in about 80% of the cells; this pattern is associated with the ETV6::RUNX1 translocation but confers no additional prognostic value7. Microarray studies in this case are concordant with the abnormalities identified on FISH. The second ETV6 signal loss corresponds directly with the loss of 12p discovered via microarray. A single copy loss of 9p13.2 is present as well. This region is known to contain the PAX5 gene, which encodes a transcription factor that is vital in the differentiation of lymphoid progenitors along a B lymphocyte lineage. Inactivation of PAX5 in early B cells is associated with developmental arrest of the cells and is implicated in a number of acute lymphoblastic leukemias and non-Hodgkin lymphomas8. The 20q gain is likely a secondary abnormality with no known diagnostic or prognostic significance.

Patterns in cytogenetic alterations are well-established in pediatric B-ALL. Hyperdiploidy, resulting in greater than or equal to 50 chromosomes is a recurrent aberration that typically demonstrates a favorable prognosis9. Other translocations beyond ETV6::RUNX1 have been established in B-ALL cases as well. In about 2 to 5% of cases, t(9;22)(q34;q11.2) is observed, resulting in the Philadelphia chromosome (Ph) and BCR::ABL1 fusion10. This translocation, while classically observed in chronic myelocytic leukemia, is seen in B-ALL in association with IKZF1 deletion on the short arm of chromosome 7 in up to 80% of cases11. BCR::ABL1 in B-ALL is associated with higher risk of treatment failure and relapse10. Up to 15% of pediatric patients with B-ALL are negative for BCR::ABL1 fusion but present Ph-like aberrations such as CRLF2, ABL2, JAK2 gene rearrangements. These patients may respond well to tyrosine kinase inhibitors (TKI)12. Another group of acute leukemias involve rearrangements between KMT2A gene and various partner genes. KMT2A::AFF1 rearrangement due to t(4;11)(q21;q23) is seen more commonly in early cases of B-ALL (infants < 12 months of age) and tend to behave aggressively13. Cases with t(1;19)(q23;p13)/TCF3::PBX1, while formerly associated with a poorer prognosis, now fare similarly to B-ALL with known favorable prognoses with current treatments14. In addition to the translocations described above, PAX5, IKZF1, and CDKN2A/B losses are frequently seen in pediatric B-ALL. These losses may have different sizes and breakpoints in different patients and may not be detectable in all cases by FISH probes. Microarray is the reliable method for detection of such losses15. The most recent classification papers by ICC and WHO delineate the significance of various cytogenetic findings in pediatric patients with B-ALL2,3.

Treatment of B-ALL has dramatically improved in the last forty years. Overall survival of lymphoblastic leukemias is greater than 90%. Efforts to personalize treatment based on tumor and patient subtypes mitigate adverse effects of the disease and treatment, including prophylaxis for tumor lysis syndrome and infectious disease, and monitor for recurrence and central nervous system involvement have vastly improved patient outcomes in pediatric B-ALL16.

References

  1. Jia Z, Gu Z. PAX5 alterations in B-cell acute lymphoblastic leukemia. Front Oncol. 2022 Oct 25;12:1023606. doi: 10.3389/fonc.2022.1023606. PMID: 36387144; PMCID: PMC9640836.
  2. Arber DA, Orazi A, Hasserjian R, et al. (eds). International Agency for Research on Cancer. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Geneva, Switzerland: World Health Organization; 2017.
  3. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R (eds). Hematolymphoid Tumours. In: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 5th ed. Geneva, Switzerland: World Health Organization; 2017.
  4. Danielson DT et al. Educational Case: Diagnostic studies for B-cell acute lymphoblastic leukemia. Acad Pathol. 2022 Jul 31;9(1):100045. doi: 10.1016/j.acpath.2022.100045. PMID: 35941876; PMCID: PMC9356032.
  5. Becker M, Liu K, Tirado CA. The t(12;21)(p13;q22) in Pediatric B-Acute Lymphoblastic Leukemia: An Update. J Assoc Genet Technol. 2017;43(3):99-109. PMID: 28809761.
  6. Lee JW, Kim SK, Jang PS, Chung NG, Jeong DC, Kim M, Cho B, Kim HK. Outcome and Prognostic Factors for ETV6/RUNX1 Positive Pediatric Acute Lymphoblastic Leukemia Treated at a Single Institution in Korea. Cancer Res Treat. 2017 Apr;49(2):446-453. doi: 10.4143/crt.2016.211. Epub 2016 Aug 10. PMID: 27506214; PMCID: PMC5398401.
  7. Gmidène A, Elghezal H, Sennana H, Ben Youssef Y, Meddeb B, Elloumi M, Khlif A, Saad A. ETV6-RUNX1 Rearrangement in Tunisian Pediatric B-Lineage Acute Lymphoblastic Leukemia. Adv Hematol. 2009;2009:924301. doi: 10.1155/2009/924301. Epub 2009 Dec 22. PMID: 20049174; PMCID: PMC2799269.
  8. Cobaleda C et al. Pax5: the guardian of B cell identity and function. Nat Immunol. 2007 May;8(5):463-70. doi: 10.1038/ni1454. PMID: 17440452.
  9. Mullighan CG. Molecular genetics of B-precursor acute lymphoblastic leukemia. J Clin Invest. 2012 Oct;122(10):3407-15. doi: 10.1172/JCI61203. Epub 2012 Oct 1. PMID: 23023711; PMCID: PMC3461902.
  10. Meza-Espinoza JP et al. B-cell Acute Lymphoblastic Leukemia With t(9;22)(q34;q11) Translocation and Clonal Divergence Through ider(22) Chromosome and t(13;17)(q14;q25) Translocation. Ann Lab Med. 2016 Mar;36(2):185-7. doi: 10.3343/alm.2016.36.2.185. PMID: 26709271; PMCID: PMC4713857.
  11.  Mullighan CG, Miller CB, Radtke I, Phillips LA, Dalton J, Ma J, White D, Hughes TP, Le Beau MM, Pui CH, Relling MV, Shurtleff SA, Downing JR. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature. 2008 May 1;453(7191):110-4. doi: 10.1038/nature06866. Epub 2008 Apr 13. PMID: 18408710.
  12. Tran TH, Loh ML. Ph-like acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2016 Dec 2;2016(1):561-566. doi: 10.1182/asheducation-2016.1.561. PMID: 27913529; PMCID: PMC6142516.
  13. Sanjuan-Pla A et al. Revisiting the biology of infant t(4;11)/MLL-AF4+ B-cell acute lymphoblastic leukemia. Blood. 2015 Dec 17;126(25):2676-85. doi: 10.1182/blood-2015-09-667378. Epub 2015 Oct 13. PMID: 26463423; PMCID: PMC4683329.
  14. Yen HJ, et al. Pediatric acute lymphoblastic leukemia with t(1;19)/TCF3-PBX1 in Taiwan. Pediatr Blood Cancer. 2017 Oct;64(10). doi: 10.1002/pbc.26557. Epub 2017 Apr 24. PMID: 28436581.
  15. Ou Z, Sherer M, Casey J, Bakos HA, Vitullo K, Hu J, Friehling E, Gollin SM, Surti U, Yatsenko SA. The Genomic Landscape of PAX5, IKZF1, and CDKN2A/B Alterations in B-Cell Precursor Acute Lymphoblastic Leukemia. Cytogenet Genome Res. 2016;150(3-4):242-252. doi: 10.1159/000456572. Epub 2017 Feb 18. PMID: 28214896.
  16. Horton TM, McNeer JL. Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents. UpToDate. 2022 Nov 29. https://www.uptodate.com/contents/treatment-of-acute-lymphoblastic-leukemia-lymphoma-in-children-and-adolescents?search=treatment%20b-all&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1.