Ring chromosome 7 in a child with T-cell acute lymphoblastic leukemia with myeloid markers

Abstract

Ring chromosomes are uncommon in hematological diseases. Here we present the case of a 13-year-old girl with leukocytosis, anemia, and lymphadenopathy. Flow cytometry analysis revealed a predominant precursor T lymphoid population expressing CD7, CD5, CD2, and cytoplasmic CD3 with partial expression of CD33, CD34, CD117, and CD11c; TdT was positive, and myeloperoxidase was negative. The bone marrow aspirate showed markedly increased blasts that were positive for CD3, CD7, CD34, TdT, and myeloperoxidase (rare positivity) by immunohistochemistry stain, consistent with T-cell acute lymphoblastic leukemia (T-ALL) extensively involving a hypercellular marrow for age. The karyotype showed a ring 7 in 12 of the 21 metaphase cells examined and deletions of the subtelomeric regions on chromosome 7. Deletions in the short arm of chromosome 7 and the long arm of chromosome 7 are present in 2% to 4% of pediatric T-ALL cases. Ring chromosome 7 is typically seen in myeloid malignancies, including acute myeloid leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy resulting from the transformation and excessive proliferation of lymphoid T-cell progenitors. T-ALL accounts for 15% of all childhood cases of acute lymphoblastic leukemia (ALL) and 25% of all adult ALL cases, though the majority of T-ALL cases occur before age 40.¹ Historically, T-ALL has been associated with poor clinical outcomes, but advances in intensified chemotherapy have raised pediatric and adult cure rates to over 80% and 50%, respectively.² The presence of ring chromosomes (RCs) in T-ALL is rare, and as such their implications are not well understood within the context of this disease.³ We report a case of a girl diagnosed with T-ALL, in whom cytogenetics revealed the presence of ring 7 and deletions of the subtelomeric regions on chromosome 7.

CLINICAL PRESENTATION

A 13-year-old girl was found to have leukocytosis, anemia, and lymphadenopathy. Flow cytometry analysis revealed a predominant precursor T lymphoid population expressing CD7, CD5, CD2, and cytoplasmic CD3, with partial expression of CD33 (∼40% of the total analyzed events), CD34 (∼40% of the total analyzed events), CD117 (∼18% of the total analyzed events), and CD11c (∼18% of the total analyzed events); TdT was positive (∼50% of the total analyzed events), and myeloperoxidase was negative. The bone marrow aspirate showed markedly increased blasts with variable morphology, including smaller forms with round nuclei and scant cytoplasm as well as larger blasts with ovoid to irregular nuclei and more abundant light blue granular cytoplasm. The bone marrow biopsy showed sheets of blasts replacing hypercellular (>95%) marrow in a background of minimal trilineage hematopoiesis. The blasts were positive for CD3, CD7, CD34, TdT, and myeloperoxidase (rare positivity) by immunohistochemistry stain, consistent with T-ALL, extensively involving a hypercellular marrow for age with an expression of some aberrant myeloid markers.

Chromosome studies were performed using standard cytogenetic methods and the karyotypes were described according to the International System for Human Cytogenomic Nomenclature.⁴ An abnormal composite female karyotype with a ring 7 was observed in 12 of the 21 metaphase cells examined (Figure 1). Ten of these cells showed the double version of this abnormal clone. Additionally, internal DNA fluorescence in situ hybridization studies and RELN(7q22)/TES(7q36) and the subtelomeres for 7p and 7q from Abbott Molecular (Des Plaines, IL) showed deletions of the subtelomeric region on 7p22 and 7q36 (Figure 2a) but confirmed that 7q22/7q26 were present in this RC (Figure 2b). In light of these studies, these findings were described as 46,XX,r(7)(p22q36)[2]/85-91,XXXX,-7,r(7)(p22q36)x1 ∼2,-14[cp10]/46,XX[9].ish r(7)(p22q36)(LPT707 PR/GA-,RELN+,TES+,LPT07QR/GA-). The patient is undergoing treatment.

Figure 1.

Conventional cytogenetic analysis showing karyotype 46XY,r,(7)del(7p22),del(7q36).

Figure 2.

Fluorescence in situ hybridization analysis using (a) DAPI subtelomeric probe showing deletions of 7p22 and 7q36 regions and (b) RELN(7q22)/TES(7q36) probe confirming the presence of 7q22 and 7q26.

DISCUSSION

RCs are uncommon in hematological diseases.^5,6 Because they often develop from double-stranded breaks occurring in each chromosomal arm followed by the subsequent fusion of their proximal ends, ring abnormalities often co-occur with deletions of the associated chromosome, as seen in the present case.⁶ The Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer reported 1864 cases of T-ALL, of which 16 involved RC formation (Table 1).^7–16 Of these 16, five involved r(7) and the majority occurred in the context of a complex karyotype. The significance of RCs in T-ALL is unclear due to their rarity. As such, it is possible that the clinical course may be best inferred from their associated deletions. Deletions of chromosome 7p and 7q are rare in pediatric T-ALL and occur in only ∼4% of all cases.^17,18 Patients with monosomy 7 or del(7p) are expected to have poorer clinical outcomes.¹⁸

Table 1.

Karyotypes of T-cell acute lymphocytic leukemias involving ring chromosome formation, from the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer

References	Karyotype	Case No.
Barber et al7	45,XY,der(1)t(1;9)(p36;q?),del(6)(q2?),r(7),-9	6099
Cauwelier et al8	46,XY,r(7),inc	10
Chang et al9	46,XX,del(5)(q13q33),r(7)(p22q36)	52
Graux et al10	46,XY,r(9)(q34q34),del(12)(p13)	1
Graux et al10	46,XX,r(9)(q34q34)	11
Graux et al10	46,XY,del(9)(p21p21)x2,r(9)(q34q34)	2
Graux et al10	46,XY,del(9)(p21p21),r(9)(q34q34)	4
Graux et al10	47,XY,del(6)(q21),+8,r(9)(q34q34)	5
Graux et al10	46,Y,add(X)(p22),t(8;22)(p22;q12), del(9)(p21p21),r(9)(q34q34), del(13)(q14q22)	6
Grossmann et al11	46,XY,der(1)t(1;9)(p36;?),t(2;7)(p21;p15), der(5)t(5;9)(p13;?),r(9),del(13)(q14q21), der(19)t(9;19)(?;p13)t(5;9)(p13;?)	12
Grossmann et al11	46,XY,t(2;11)(p16;q24)/46,idem,r(5)(p14q12)	48
Jarosova et al12	46,XY,der(2)t(2;7;5)(q37;q36;q34), r(7)(p21q31),del(9)(p21p24)/46,XY, der(2)t(2;7;5),i(7)(q10),del(9)	19
Kaneko et al13	46,XY,t(1;14)(p34;q11),r(21)	13
Le Noir et al14	48,XY,del(6)(q13q22),r(7),+8,+12	233
Schneider et al15	46,XX,t(8;12)(q13;p13),r(16)(p13q24)	7
Stern et al16	49,XX,+10,r(21)c,-r(21),+3r	1

In acute myeloid leukemia (AML), RCs occur in 2% of cases and are generally considered poor prognostic factors, usually occurring in the context of a complex karyotype, which is associated with an adverse prognosis.¹⁹ A study of 96 patients with AML/myelodysplastic syndrome (MDS) showed that overall survival was decreased in complex karyotype MDS patients who were RC positive vs RC negative.²⁰ However, overall survival in the AML subset seemed to be unaffected by this difference. Of note, it was also observed that the majority of these cases involved r(7). Because deletions of chromosome 7 are fairly common in MDS and AML, it is speculated that r(7) may possess functional similarity to del(7p and 7q) in these instances.²¹

The findings of our case pinpoint the presence of an r(7) in a rare case of T-ALL with myeloid markers. The mixed expression of T-cell markers with myeloid markers in the absence of myeloperoxidase within this leukemia appears to coincide with early T-cell precursor lymphoblastic leukemia; however, validation by further gene expression profiling studies is required.²² Deletions of chromosome 7 and r(7) are more common in myeloid leukemias, which may imply a potential relationship between the immunophenotypic results of this case with its mutational profile. Further studies should aim to elucidate the impact of these findings.