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Recurrent translocations involving the IRF4 oncogene locus in peripheral T-cell lymphomas.

Feldman AL, Law M, Remstein ED, Macon WR, Erickson LA, Grogg KL, Kurtin PJ, Dogan A - Leukemia (2008)

Bottom Line: Translocations involving IRF4 but not TCRA appear to occur predominantly in cutaneous ALCLs.Detecting these translocations may be useful in lymphoma diagnosis.Further, due to its involvement in translocations, MUM1/IRF4 protein may play an important biologic role in some PTCLs, and might represent a possible therapeutic target.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA. feldman.andrew@mayo.edu

ABSTRACT
Oncogenes involved in recurrent chromosomal translocations serve as diagnostic markers and therapeutic targets in hematopoietic tumors. In contrast to myeloid and B-cell neoplasms, translocations in peripheral T-cell lymphomas (PTCLs) are poorly understood. Here, we identified recurrent translocations involving the multiple myeloma oncogene-1/interferon regulatory factor-4 (IRF4) locus in PTCLs. IRF4 translocations exist in myeloma and some B-cell lymphomas, but have not been reported earlier in PTCLs. We studied 169 PTCLs using fluorescence in situ hybridization and identified 12 cases with IRF4 translocations. Two cases with t(6;14)(p25;q11.2) had translocations between IRF4 and the T-cell receptor-alpha (TCRA) locus. Both were cytotoxic PTCLs, unspecified (PTCL-Us) involving bone marrow and skin. In total, 8 of the remaining 10 cases were cutaneous anaplastic large-cell lymphomas (ALCLs) without TCRA rearrangements (57% of cutaneous ALCLs tested). These findings identified IRF4 translocations as a novel recurrent genetic abnormality in PTCLs. Cytotoxic PTCL-Us involving bone marrow and skin and containing IRF4/TCRA translocations might represent a distinct clinicopathologic entity. Translocations involving IRF4 but not TCRA appear to occur predominantly in cutaneous ALCLs. Detecting these translocations may be useful in lymphoma diagnosis. Further, due to its involvement in translocations, MUM1/IRF4 protein may play an important biologic role in some PTCLs, and might represent a possible therapeutic target.

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Anaplastic large-cell lymphomas (ALCLs) with IRF4 translocations. (a) Primary cutaneous ALCL (C-ALCL), 48 year-old female (case 3). Medium to large tumor cells with admixed histiocytes (H&E, x 40; inset, x 100). (b) Lymph node involvement, same patient, 10 years later. Confluent sheets of large “hallmark” cells (H&E, x 40; inset, x 100). (c) C-ALCL, 67 year-old male (case 4; H&E, x 20; inset, x 100). (d) Lymph node involvement, same patient, 7 mos later (H&E, x 40; inset, x 100). Both biopsies show sheets of “hallmark” cells. (e) C-ALCL, 89 year-old female (case 5), showing positivity for (f) CD30 and (g) MUM1/IRF4 (x 10; insets, x 100). (h) Breakapart fluorescence in situ hybridization (BAP-FISH) shows separation of red and green signals flanking the IRF4 gene locus (arrows). (i) Systemic ALK-negative ALCL, cervical lymph node, 79 year-old male (case 12). Large “hallmark” cells surround a residual reactive follicle (lower left; H&E, x 40; inset, x 100).
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Figure 2: Anaplastic large-cell lymphomas (ALCLs) with IRF4 translocations. (a) Primary cutaneous ALCL (C-ALCL), 48 year-old female (case 3). Medium to large tumor cells with admixed histiocytes (H&E, x 40; inset, x 100). (b) Lymph node involvement, same patient, 10 years later. Confluent sheets of large “hallmark” cells (H&E, x 40; inset, x 100). (c) C-ALCL, 67 year-old male (case 4; H&E, x 20; inset, x 100). (d) Lymph node involvement, same patient, 7 mos later (H&E, x 40; inset, x 100). Both biopsies show sheets of “hallmark” cells. (e) C-ALCL, 89 year-old female (case 5), showing positivity for (f) CD30 and (g) MUM1/IRF4 (x 10; insets, x 100). (h) Breakapart fluorescence in situ hybridization (BAP-FISH) shows separation of red and green signals flanking the IRF4 gene locus (arrows). (i) Systemic ALK-negative ALCL, cervical lymph node, 79 year-old male (case 12). Large “hallmark” cells surround a residual reactive follicle (lower left; H&E, x 40; inset, x 100).

Mentions: IRF4 translocations were detected in 8/14 C-ALCLs tested (57%). All initial diagnostic biopsies were reviewed. Clinical or pathologic features of lymphomatoid papulosis were not observed. None of the patients had a history of mycosis fungoides (MF) or dermatitis suggestive of clinical MF. Four patients developed nodal disease 1 to 126 months after diagnosis (Table 2). The patient with a 1-month interval between cutaneous and nodal disease (Case 7) had multiple skin nodules and local adenopathy. Staging was otherwise negative, suggesting C-ALCL with locoregional spread; however, it is possible the disease originated in the lymph node. Cases 3 and 8 showed different histology in cutaneous and nodal specimens. The skin showed mostly medium-sized tumor cells with admixed histiocytes in the background (Fig. 2 a), and occasional perivascular “hallmark” cells, reminiscent of the small-cell variant of systemic ALCL.21 The subsequent lymph node biopsies showed sheets of large “hallmark” cells (Fig. 2 b). Histologic progression associated with nodal involvement also was seen in a C-ALCL without IRF4 translocation (not shown). The remaining C-ALCLs with IRF4 translocations had typical histologic features (Fig. 2 c-e). CD30 and MUM1/IRF4 were positive (Fig. 2 f,g). FISH showed IRF4 translocations (Fig. 2 h); TCRA, TCRB, and TCRG were negative (not shown). C-ALCLs with and without IRF4 translocations showed similar clinicopathologic features (Table 3). TIA1 positivity was somewhat less common in IRF4-translocated cases than in untranslocated cases and in C-ALCLs in the literature.22-24 Only one untranslocated case developed nodal disease.


Recurrent translocations involving the IRF4 oncogene locus in peripheral T-cell lymphomas.

Feldman AL, Law M, Remstein ED, Macon WR, Erickson LA, Grogg KL, Kurtin PJ, Dogan A - Leukemia (2008)

Anaplastic large-cell lymphomas (ALCLs) with IRF4 translocations. (a) Primary cutaneous ALCL (C-ALCL), 48 year-old female (case 3). Medium to large tumor cells with admixed histiocytes (H&E, x 40; inset, x 100). (b) Lymph node involvement, same patient, 10 years later. Confluent sheets of large “hallmark” cells (H&E, x 40; inset, x 100). (c) C-ALCL, 67 year-old male (case 4; H&E, x 20; inset, x 100). (d) Lymph node involvement, same patient, 7 mos later (H&E, x 40; inset, x 100). Both biopsies show sheets of “hallmark” cells. (e) C-ALCL, 89 year-old female (case 5), showing positivity for (f) CD30 and (g) MUM1/IRF4 (x 10; insets, x 100). (h) Breakapart fluorescence in situ hybridization (BAP-FISH) shows separation of red and green signals flanking the IRF4 gene locus (arrows). (i) Systemic ALK-negative ALCL, cervical lymph node, 79 year-old male (case 12). Large “hallmark” cells surround a residual reactive follicle (lower left; H&E, x 40; inset, x 100).
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Figure 2: Anaplastic large-cell lymphomas (ALCLs) with IRF4 translocations. (a) Primary cutaneous ALCL (C-ALCL), 48 year-old female (case 3). Medium to large tumor cells with admixed histiocytes (H&E, x 40; inset, x 100). (b) Lymph node involvement, same patient, 10 years later. Confluent sheets of large “hallmark” cells (H&E, x 40; inset, x 100). (c) C-ALCL, 67 year-old male (case 4; H&E, x 20; inset, x 100). (d) Lymph node involvement, same patient, 7 mos later (H&E, x 40; inset, x 100). Both biopsies show sheets of “hallmark” cells. (e) C-ALCL, 89 year-old female (case 5), showing positivity for (f) CD30 and (g) MUM1/IRF4 (x 10; insets, x 100). (h) Breakapart fluorescence in situ hybridization (BAP-FISH) shows separation of red and green signals flanking the IRF4 gene locus (arrows). (i) Systemic ALK-negative ALCL, cervical lymph node, 79 year-old male (case 12). Large “hallmark” cells surround a residual reactive follicle (lower left; H&E, x 40; inset, x 100).
Mentions: IRF4 translocations were detected in 8/14 C-ALCLs tested (57%). All initial diagnostic biopsies were reviewed. Clinical or pathologic features of lymphomatoid papulosis were not observed. None of the patients had a history of mycosis fungoides (MF) or dermatitis suggestive of clinical MF. Four patients developed nodal disease 1 to 126 months after diagnosis (Table 2). The patient with a 1-month interval between cutaneous and nodal disease (Case 7) had multiple skin nodules and local adenopathy. Staging was otherwise negative, suggesting C-ALCL with locoregional spread; however, it is possible the disease originated in the lymph node. Cases 3 and 8 showed different histology in cutaneous and nodal specimens. The skin showed mostly medium-sized tumor cells with admixed histiocytes in the background (Fig. 2 a), and occasional perivascular “hallmark” cells, reminiscent of the small-cell variant of systemic ALCL.21 The subsequent lymph node biopsies showed sheets of large “hallmark” cells (Fig. 2 b). Histologic progression associated with nodal involvement also was seen in a C-ALCL without IRF4 translocation (not shown). The remaining C-ALCLs with IRF4 translocations had typical histologic features (Fig. 2 c-e). CD30 and MUM1/IRF4 were positive (Fig. 2 f,g). FISH showed IRF4 translocations (Fig. 2 h); TCRA, TCRB, and TCRG were negative (not shown). C-ALCLs with and without IRF4 translocations showed similar clinicopathologic features (Table 3). TIA1 positivity was somewhat less common in IRF4-translocated cases than in untranslocated cases and in C-ALCLs in the literature.22-24 Only one untranslocated case developed nodal disease.

Bottom Line: Translocations involving IRF4 but not TCRA appear to occur predominantly in cutaneous ALCLs.Detecting these translocations may be useful in lymphoma diagnosis.Further, due to its involvement in translocations, MUM1/IRF4 protein may play an important biologic role in some PTCLs, and might represent a possible therapeutic target.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA. feldman.andrew@mayo.edu

ABSTRACT
Oncogenes involved in recurrent chromosomal translocations serve as diagnostic markers and therapeutic targets in hematopoietic tumors. In contrast to myeloid and B-cell neoplasms, translocations in peripheral T-cell lymphomas (PTCLs) are poorly understood. Here, we identified recurrent translocations involving the multiple myeloma oncogene-1/interferon regulatory factor-4 (IRF4) locus in PTCLs. IRF4 translocations exist in myeloma and some B-cell lymphomas, but have not been reported earlier in PTCLs. We studied 169 PTCLs using fluorescence in situ hybridization and identified 12 cases with IRF4 translocations. Two cases with t(6;14)(p25;q11.2) had translocations between IRF4 and the T-cell receptor-alpha (TCRA) locus. Both were cytotoxic PTCLs, unspecified (PTCL-Us) involving bone marrow and skin. In total, 8 of the remaining 10 cases were cutaneous anaplastic large-cell lymphomas (ALCLs) without TCRA rearrangements (57% of cutaneous ALCLs tested). These findings identified IRF4 translocations as a novel recurrent genetic abnormality in PTCLs. Cytotoxic PTCL-Us involving bone marrow and skin and containing IRF4/TCRA translocations might represent a distinct clinicopathologic entity. Translocations involving IRF4 but not TCRA appear to occur predominantly in cutaneous ALCLs. Detecting these translocations may be useful in lymphoma diagnosis. Further, due to its involvement in translocations, MUM1/IRF4 protein may play an important biologic role in some PTCLs, and might represent a possible therapeutic target.

Show MeSH
Related in: MedlinePlus