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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
• Pt:
41-year-old Asian female
• CC:
Worsening fatigue
Easy bruising
Progressive abdominal pain
• PMH:
Iron Deficiency Anemia
Laboratory Studies
CBC
• WBC: 24.4 K/cumm
• Hb:
8.9 g/dL
• HCT:
23.9%
• PLT:
36 K/cumm
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
Molecular Analysis: PCR
• Negative for FLT3 ITD and FLT3 D835 mutations
• Negative for NPM1 mutation
• Negative for CEBPA mutation
• Negative for KIT D816V mutation
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]
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
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
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)
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)
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)
t(12;17)(p13;q11)
This translocation
rearranges:
• CIZ / ZNF384 (12p13)
– Transcription factor
• TAF15 (17q11)
– Encodes TFII subunit
http://atlasgeneticsoncology.org/Anomalies/t1217p13q11ID1369.html
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.
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
• CIZ rearrangements in 8/9 pts by 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
Diagnosis at 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 Second Relapse (3 months later):
• AML (FAB M5b acute monocytic leukemia)
• Positive for t(12;17)(p13;q11) by cytogenetics
• 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.
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).
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, BilhouNabera 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)/TAF15ZNF384 rearrangement. Leuk Lymphoma. 2013 Aug;54(8):1802-5.Blood. 2013 Feb
28;121(9):1495-500.
Any Questions?
Thank You