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SH/EAHP 2013 Workshop Case 285

SH/EAHP 2013 Workshop Case 285. Sara-Eloína Cuadra-Acree , MD,* Kiran Qidwai , MD,* Brit Shackley , MD,** & Imran N. Siddiqi, MD, PhD*. * University of Southern California/LAC+USC Medical Center **Huntington Memorial Hospital, Pasadena, California. Clinical History.

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SH/EAHP 2013 Workshop Case 285

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  1. SH/EAHP 2013 Workshop Case 285 Sara-Eloína Cuadra-Acree, MD,* KiranQidwai, MD,* Brit Shackley, MD,** & Imran N. Siddiqi, MD, PhD* * University of Southern California/LAC+USC Medical Center **Huntington Memorial Hospital, Pasadena, California

  2. Clinical History • Pt: 41-year-old Asian female • CC: Worsening fatigue Easy bruising Progressive abdominal pain • PMH: Iron Deficiency Anemia

  3. Laboratory Studies CBC • WBC: 24.4 K/cumm • Hb: 8.9 g/dL • HCT: 23.9% • PLT: 36 K/cumm

  4. Molecular Analysis: FISH • Negative for t(9;22) BCR/ABL fusion • Negative for t(8;21) AML1/ETO [RUNX1/RUNX1T1] fusion • Negative for t(15;17) PML/RARA fusion • Negative for RARA break apart rearrangement

  5. Molecular Analysis: PCR • Negative for FLT3 ITD and FLT3 D835 mutations • Negative for NPM1 mutation • Negative for CEBPA mutation • Negative for KIT D816V mutation

  6. Cytogenetics • 82-84, XXXX,-1,-2,-3,-4,-7,+8,-9,-10, t(12;17)(p13;q11.2)x2, der(12)t(12;17)(p13;q11.2),+13,-15, -16, -17,-20,-21,+22[cp7]/46,XX[13]

  7. Final Diagnosis? WHO (2008) CLASSIFICATION • B-LINEAGE CRITERIA: • Strong CD19 with at least 1 of the following strongly expressed: CD79a, cytoCD22, CD10 or • Weak CD19 with at least 2 of the following strongly expressed: CD79a, cytoCD22, CD10

  8. Final Diagnosis? WHO (2008) CLASSIFICATION • B-LINEAGE CRITERIA: • Strong CD19 with at least 1 of the following strongly expressed: CD79a, cytoCD22, CD10 or • Weak CD19 with at least 2 of the following strongly expressed: CD79a, cytoCD22, CD10

  9. Final Diagnosis? WHO (2008) CLASSIFICATION • MYELOID LINEAGE CRITERIA: • Myeloperoxidase (FCM, IHC, or cytochemistry) or • Monocytic differentiation (at least 2 of the following: NSE, CD11c, CD14, CD64, lysozyme)

  10. Final Diagnosis? WHO (2008) CLASSIFICATION • MYELOID LINEAGE CRITERIA: • Myeloperoxidase (FCM, IHC, or cytochemistry) or • Monocytic differentiation (at least 2 of the following: NSE, CD11c, CD14, CD64, lysozyme)

  11. Final Diagnosis PROPOSED DIAGNOSIS • Acute leukemia with mixed phenotype (B/myeloid) associated with t(12;17)(p13;q11.2) CONSENSUS DIAGNOSIS • Mixed phenotype acute leukemia (B/myeloid), associated with t(12;17)(p13;q11.2)

  12. t(12;17)(p13;q11) This translocation rearranges: • CIZ / ZNF384 (12p13) • Transcription factor • TAF15 (17q11) • Encodes TFII subunit http://atlasgeneticsoncology.org/Anomalies/t1217p13q11ID1369.html

  13. Leukemia. 1992 Apr;6(4):251-5. t(12;17)(p13;q21) in early pre-B acute lymphoid leukemia. Krance RA, Raimondi SC, Dubowy R, Estrada J, Borowitz M, Behm F, Land VJ, Pullen J, Carroll AJ. Department of Hematology-Oncology, St Jude Children's Research Hospital, Memphis, TN 38101. Abstract: Structural rearrangements involving the short arm of chromosome 12 occur in 10% of cases of childhood acute lymphoid leukemia. The translocation t(12;17)(p13;q21), an uncommon 12p abnormality, was identified in five of 2620 cases (0.2%) successfully karyotyped by the Pediatric Oncology Group or St Jude Children's Research Hospital. All five cases were classified as early pre-B; however, CD10 (common acute lymphoblastic leukemia antigen) was expressed at lower levels than other markers of B-cell lineage. Two cases also expressed the myeloid-associated antigen CD33. Leukemic cells were pseudodiploid in four cases, with an extra chromosome 21 in the fifth case. All of these patients achieved complete remission. Two relapsed during subsequent therapy, and three remain in continuous remission for greater than or equal to 20 months.

  14. Discussion • 9 patients total: 8 ALL + 1 AML • 8 ALL (early pre-B ALL phenotype) • Coexpression of myeloid antigens (MPO, CD13, CD33) • 1 AML (FAB M1) • Auer rods, Positive for MPO, CD13, CD33 • Coexpression of strong CD19

  15. CIZ rearrangements in 8/9 ptsby FISH or PCR • t(12;17)(p13;q11) in 6 cases • t(12;22)(p13;q12) in 2 cases • t(12;19)(p13;p13) in 1 case • Clinical: • Young adults and children • No gender predilection • No bulky disease • Leukocytosis absent or moderate • Relatively good prognosis http://atlasgeneticsoncology.org/Genes/ZNF384ID42881ch12p13.html

  16. Diagnosisat Initial Presentation: • pro-B ALL • Normal cytogenetics and FISH (retrospective analysis) Diagnosis at First Relapse (26 months later): • pro-B ALL • Positive for t(12;17)(p13;q11) by cytogenetics and FISH Diagnosis at SecondRelapse (3 months later): • AML (FAB M5b acute monocytic leukemia) • Positive for t(12;17)(p13;q11) by cytogenetics

  17. Clinical: • Meningeal involvement with paralysis • Died from disease progression, 3 months later • Conclusion: • Hypothesize that the t(12;17)/TAF15-ZNF384 rearrangement may have been present in an early common progenitor that is capable of differentiating along both the lymphoid and myeloid lineages.

  18. Unique Features • The t(12;17)(p13;q11) translocation has not previously been reported in cases meeting WHO criteria for mixed phenotype acute leukemia. • Ambiguous B/myeloid phenotypes have rarely been attributed to t(12;17)(p13;q11).

  19. References • WHO. World Health Organization classification of tumours. Pathology and genetics: tumours of haematopoietic and lymphoid tissues. Lyon: IARC Press 2008. • Krance RA, Raimondi SC, Dubowy R, Estrada J, Borowitz M, Behm F, Land VJ, Pullen J, Carroll AJ. t(12;17)(p13;q21) in early pre-B acute lymphoid leukemia. Leukemia. 1992 Apr;6(4):251-5. • Starza R, Aventin A, Crescenzi A, Gorello P, Specchia G, Cuneo A, Angioni A, Bilhou-Nabera C, Boqué C, Foà R, Uyttebroeck A, Talmant P, Cimino G, Martelli M, Marynen P, Mecucci C, and Hagemeijer A. CIZ gene rearrangements in acute leukemia: report of a diagnostic FISH assay and clinical features of nine patients. Leukemia (2005) 19, 1696–1699. • Grammatico S, Vitale A, La Starza R, Gorello P, Angelosanto N, Negulici AD, De Propris MS, Nanni M, Meloni G, Mecucci C, Foà R. Lineage switch from pro-B acute lymphoid leukemia to acute myeloid leukemia in a case with t(12;17)(p13;q11)/TAF15-ZNF384 rearrangement. Leuk Lymphoma. 2013 Aug;54(8):1802-5.Blood. 2013 Feb 28;121(9):1495-500.

  20. Any Questions? Thank You

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