Isochromosome 7Q: the Primary Cytogenetic Abnormality In

CORRESPONDENCE

CASE REPORT

Isochromosome 7q: the primary cytogenetic abnormality in hepatosplenic ␥␦ T cell lymphoma ELC Alonsozana1, J Stamberg2, D Kumar1, ES Jaffe3, LJ Medeiros4, C Frantz5, CA Schiffer6,7, BA O’Connell6,7, S Kerman8, SA Stass1,7 and LV Abruzzo1,7

1Department of Pathology, Laboratories of Pathology, 2Division of Human Genetics, 5Department of Pediatrics, 6Department of Medicine, and 7Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, MD; 3Hematopathology Section, Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD; 4Division of Pathology, City of Hope National Medical Center, Duarte, CA; and 8American Medical Laboratories, Chantilly, VA, USA

Malignant lymphomas often have complex, nonrandom Because of its unique clinical and histopathologic features, chromosomal abnormalities. Hepatosplenic ␥␦ T cell lym- ␥␦ ␥␦ hepatosplenic TCL has been proposed as a distinct clinico- phoma ( TCL) is an unusual post-thymic T cell lymphoma that 4 primarily involves liver and spleen, often in young adult males. pathologic entity. Recently isochromosome 7q [i(7q)] was ␥␦ 6,7 Few cases have had cytogenetic analysis. We report a consist- reported in seven cases of hepatosplenic TCL. We have ent isochromosome 7q [i(7q)] abnormality in three cases of previously reported three additional cases of hepatosplenic hepatosplenic ␥␦TCL, one with i(7q) as the sole abnormality ␥␦TCL with cytogenetic analysis in abstract form.8 All three at presentation. Three patients, 15-, 37- and 65-year-old males, cases exhibited a common structural cytogenetic abnormality, presented with hepatosplenomegaly and fevers. Histopatho- i(7q). In one case, i(7q) was the sole abnormality identified on logic, immunophenotypic, and molecular genetic studies sup- ported the diagnosis. Spleen, liver, and bone marrow contained the initial diagnostic study. The second case had three sinusoidal infiltrates of atypical lymphoid cells of T cell immun- additional abnormalities, and the third case had a complex ophenotype. PCR performed on two cases demonstrated clonal karyotype with multiple numerical and structural abnormali- T cell receptor ␥ gene rearrangements. Cytogenetic analysis of ties in addition to the i(7q). These cases represent the ninth to bone marrow showed i(7q) as the sole abnormality at presen- 11th cases of i(7q) reported in hepatosplenic ␥␦TCL, and only tation in one case. The second case showed i(7q) in addition the second case with i(7q) as the sole abnormality. These to two normal chromosomes 7, and other structural and ␥␦ numerical abnormalities. The third case showed i(7q) and a results support the proposal that hepatosplenic TCL is a dis- deletion in the long arm of chromosome 11. These findings tinct clinicopathologic entity. Furthermore, they implicate support the proposal that i(7q) represents the primary nonran- i(7q) as the defining cytogenetic abnormality. dom cytogenetic abnormality in hepatosplenic ␥␦TCL, and plays a role in its pathogenesis. Keywords: T cell lymphoma; hepatosplenic lymphoma; isochromo- Materials and methods some; chromosome 7 All cases were collected from the files of the University of Maryland Medical Center and the Hematopathology Section Introduction in the Laboratory of Pathology of the National Cancer Insti- tute. Two cases (cases 1 and 2) were seen in consultation by ␣␤ The T cell receptor (TcR) normally consists of either an or one of us (ESJ); the clinical and pathologic features of these ␥␦ heterodimer associated with a CD3 complex of proteins cases have been reported recently.5 Two patients (1 and 3) ␣␤ on the cell surface. Most mature T cells express the hetero- were referred to the University of Maryland from outside hos- ␥␦ dimer. A minority of mature T cells express the hetero- pitals for evaluation and treatment. Hematoxylin and eosin dimer. These cells are found primarily in the splenic red pulp (H&E)-stained histologic sections were prepared at the submit- 1 and intestinal epithelium. Like most normal T cells, most lym- ting institutions. Additional sections were prepared from the ␣␤ 2 phomas of T cell lineage express the heterodimer. Hepa- submitted paraffin blocks of formalin-fixed tissue. In all cases, ␥␦ ␥␦ tosplenic T cell lymphoma ( TCL) is an unusual peripheral spleen and bone marrow specimens were studied. Additional ␥␦ 3–5 T cell lymphoma that expresses the TcR. Cytologically, tissue from liver was available in case 1, and transbronchial the neoplastic cells are uniform, medium-sized lymphoid cells biopsy tissue was examined in case 3. with dispersed chromatin, small nucleoli, and a moderate amount of pale cytoplasm. The cells preferentially involve the sinusoids of spleen, liver, and bone marrow. As a result, Immunophenotypic analysis patients often present with hepatosplenomegaly, although peripheral blood involvement is unusual early in the course of Immunophenotypic studies were performed on fixed, paraffin- the disease. This lymphoma has a marked predilection for embedded sections and fresh tissue. Fixed, paraffin-embedded young men. The prognosis is poor, and most patients die sections were analyzed by the avidin-biotin-peroxidase (ABC) within 2 years of diagnosis despite aggressive chemotherapy. technique, as described previously9 using a panel of antibodies to CD3, CD20 (L26), CD43 (Leu22), CD45RO (UCHL- Correspondence: LV Abruzzo, Department of Pathology, University 1, A6) and CD74 (LN-2). Immunophenotypic studies were of Maryland, 22 S Greene St, Baltimore, MD 21201, USA performed on fresh tissue using one of two methods. For cases Received 7 February 1997; accepted 17 April 1997 1 and 3, cell suspensions were analyzed by flow cytometry Correspondence 1368 as described previously.5 In cases 1 and 2, frozen sections were analyzed by the ABC technique.9,10 The panel of antibodies included antibodies to CD1a, CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD11c, CD14, CD16, CD19, CD20, CD21, CD22, CD25, CD56, CD57, TcR␤ and TcR␦. For case 2, flow cytometry was performed at an outside laboratory and results reported.

Cytogenetic analysis

Cytogenetic studies in cases 1 and 3 were performed at the University of Maryland on direct preparations of bone marrow and peripheral blood using standard techniques.11 The divid- ing cells were analyzed by Giemsa–trypsin banding. A series of six bone marrow specimens was examined over a 19 month period in case 1. A single bone marrow and a peripheral blood specimen were examined in case 3. A minimum of 25 (range 25–50) cells were analyzed for each sample, with the exception of the peripheral blood in case 3, in which only 12 cells were available for analysis. In case 2, cytogenetic studies were performed at an outside laboratory, and were available for review. For this case, bone marrow was examined with 20 cells analyzed, using similar techniques.

Molecular diagnostic studies

In all cases, analysis for rearrangement of the TcR␥ chain gene was performed by polymerase chain reaction (PCR) on DNA extracted from formalin-ﬁxed, parafﬁn-embedded tissue as described previously.12,13 Southern blot analysis was also performed in case 3 on DNA isolated from bone marrow. ␤ Hybridizations with probes to the TcR chain gene (J␤/III), the immunoglobulin heavy chain gene (JH), and the immunoglobulin kappa light chain gene (JK) were performed using a com- mercially available kit according to the manufacturer’s instructions (B/T Blue Gene Rearrangement Test System; Oncor, Gaithersburg, MD, USA).

Results

Clinical features Figure 1 Representative photomicrographs illustrate the histologic and immunophenotypic features. (a) Bone marrow and (b) spleen from patient 3 contain inﬁltrates of medium-sized lymphoid cells with The clinical features are summarized in Table 1. All patients irregular nuclear contours and a moderate amount of cytoplasm, were males, aged 15, 65 and 37 years at the time of diagnosis. with a predilection for sinusoidal involvement (H&E). Patient 1 presented with asymptomatic hepatosplenomegaly, (c) Immunoperoxidase stain for CD3 performed on spleen shows a T followed by fevers, nausea and vomiting, and a petechial rash cell immunophenotype (hematoxylin counterstain). on his head and neck. His past medical history was unremarkable. Patient 2 presented with splenomegaly and thrombocy- Histologic and immunophenotypic ﬁndings topenia, and underwent splenectomy 5 months later for pre- sumed idiopathic thrombocytopenic purpura (ITP). After an The histologic and immunophenotypic features in all cases interval of 26 months he was re-evaluated for recurring fevers were similar. Spleen, bone marrow aspirate smears and core and thrombocytopenia. Patient 3 presented with fever and biopsies were available for review in all cases. All patients chills, and was found to have hepatosplenomegaly and lym- underwent splenectomy. The spleens were enlarged (patient phadenopathy. His past medical history was unremarkable. 1, 2264 g; patient 2, 705 g; patient 3, 2050 g) with homo- All patients received aggressive multiagent chemotherapy. geneous, dark red parenchyma. Representative sections of Although patient 1 achieved an initial clinical remission, the bone marrow and spleen from case 3 are presented in disease recurred and he died 25 months after diagnosis. Figure 1. The neoplastic cells were medium-sized lymphoid Patient 2 died 2 months after the diagnosis of ␥␦TCL, and 33 cells with round to irregular nuclear contours, dispersed months after his initial presentation. The lymphoma in patient chromatin, occasional small nucleoli, and a moderate amount 3 was refractory to therapy, and he died 7 months after of pale cytoplasm. The splenic red pulp was expanded and diagnosis. sinusoids were dilated by atypical lymphoid cells in all three Correspondence 1369 Table 1 Summary of clinical features

Case Age/Sex Anemia Dec. Plts H/S LN Skin BM Outcome

1 15/M +++/+− − + DOD, 25 months 2 65/M +++/+− − + DOD, 33 months 3 37/M +++/+− − + DOD, 7 months

Dec. Plts, decreased platelets; H/S, hepatosplenomegaly; LN, lymph node involvement; BM, bone marrow involvement; DOD, died of disease.

Table 2 Summary of immunophenotypic and genotypic data

Case CD2 CD3 CD4 CD5 CD7 CD8 CD43 CD45RO ␤FI ␦ CD16 CD56 CD57 CD19/CD20 ␬,␭ TcR␥

1 ++−−+− + + −+ ± + − − − R 2 ++−−++ ND ND −+−−−−−NA 3 ++−−+− ND + ND ND ++−−−R

ND, not determined; TcR, T cell receptor; R, rearranged; NA, not ampliﬁable.

Table 3 Summary of cytogenetic ﬁndings

Case Analysis Sample Karyotype

1 At presentation BM 46,XY,i(7)(q10)/46,XY +2 months BM 45,X,−Y,i(7)(q10)/46,XY +6 months BM 46,XY +13 months BM 45,X,−Y, i(7)(q10)/46,XY +18 months BM 45,X,−Y, i(7)(q10)/46,XY +19 months BM 45,X,−Y, i(7)(q10)/46,XY 2 At diagnosis BM 48,X,−Y,+3,t(6;10)(p25;p12),+i(7)(q10),+8 der(13),t(13;16)(p11.2;q11.2),−16,+21/46,XY 3 At presentation BM 44,X,−Y,i(7)(q10),del(11)(q14),−21/46,XY +2 months PB 44,X,−Y,i(7)(q10),del(11)(q14),−21/46,XY

BM, bone marrow; PB, peripheral blood.

cases. However, in case 2 these features were subtle in the Cytogenetic findings initial splenectomy specimen, and a diagnosis of involvement by malignant lymphoma was made retrospectively. Mitotic The cytogenetic findings are summarized in Table 3 and are figures were easily found in case 3. Small foci of extramedul- presented in Figure 2. In all three cases, the initial cytogenetic lary hematopoiesis were seen in cases 1 and 2. The bone mar- analyses were performed on bone marrow aspirates that dem- row aspirate smears were characterized by lymphocytosis, onstrated an atypical lymphocytosis. Cytogenetic analysis was and the core biopsies were markedly hypercellular. Immu- also performed on peripheral blood in patient 3 after he nohistochemical stains accentuated the sinusoidal distribution developed peripheral blood involvement following failure of of atypical lymphoid cells of T cell immunophenotype his chemotherapeutic regimen. All patients were mosaic, with (CD20−, CD3+, CD45RO+) that was difficult to discern on H& a cytogenetically normal cell population as well as an abnor- E-stained sections. The liver was examined in case 1, and con- mal population that contained an i(7q). tained a sinusoidal infiltrate of atypical lymphoid cells similar Patient 1 had a series of six specimens analyzed over a 19 to those seen in spleen and bone marrow. A transbronchial month period. The initial diagnostic specimen revealed a biopsy performed in case 3 demonstrated an interstitial infil- clone of cells with an i(7q), in addition to a normal chromo- trate of atypical lymphoid cells that was accentuated by some 7, in seven out of 25 metaphases (28%). Most cells were immunohistochemical stains. karyotypically normal. The i(7q) persisted throughout the The results of immunophenotypic analysis performed by course of the patient’s illness, except on one occasion of clini- flow cytometry of bone marrow aspirates are summarized in cal remission at 6 months, when all karyotyped cells were Table 2. Immunohistochemical stains were also performed on normal. In addition to i(7q), a second abnormality, loss of the frozen sections of liver in case 1. In each case the malignant Y chromosome, appeared in the second specimen, which was lymphoma had a T cell immunophenotype. Cases 1 and 2 obtained 6 weeks after the initial diagnostic specimen. Both expressed the TcR␦ chain. Cases 2 and 3 also expressed abnormalities were found together in all subsequent speci- CD16/CD56, markers associated with natural killer cell lin- mens, with the exception of the clinical remission referred eage. None expressed markers of B cell lineage. to above. Correspondence 1370 Patient 2 had cytogenetic analysis performed on bone marrow approximately 3 years after he had undergone splenectomy. The karyotype of the majority of cells (18/20 or 90%) exhibited multiple structural and numerical abnormalities, including i(7q) and two normal chromosomes 7. In this patient the i(7q) did not replace a normal chromosome 7, but occurred in addition to two apparently normal 7s. The Y chromosome was also missing in these cells. A minor cell population (2/20 or 10%) exhibited a normal male karyotype. Cytogenetic analysis performed on bone marrow of patient 3 at the time of diagnosis also showed two cell populations. A minority of the cells (6/40 or 15%) contained i(7q) in addition to other abnormalities, including loss of the Y chromosome. The remaining cells had a normal male karyotype. The analysis performed on peripheral blood 2 months later was similar.

Molecular diagnostic studies

Analysis of the TcR␥ chain was performed by PCR on DNA extracted from formalin-fixed, paraffin-embedded sections of involved tissue.12 Cases 1 and 3 contained clonal TcR␥ rearrangements (Table 2). Case 1 showed a single band with the V2 primer, and case 3 showed a single band with V11 primer; DNA from case 2 was not amplifiable (data not shown). Southern blot analysis performed on DNA extracted from involved bone marrow in case 3 demonstrated that the IgH gene, the IgK gene, and the TcR␤ gene were in the germline configuration (data not shown).

Discussion

Hepatosplenic ␥␦TCL is a recently described, rare lymphoma of post-thymic T cell origin. Few cases have been reported in the literature,2,3,6,7,14–19 several only in abstract form.20,21 Only 11 cases have had cytogenetic analysis,6,7,14,17–19, including three cases recently reported by Wang and co-workers.6 In their study all three cases had i(7q) and trisomy 8; one case had two copies of the i(7q) as well as additional, unidentiﬁed material on the long arm of chromosome 6. They proposed that i(7q) plays a key role in the pathogenesis of hepatosplenic ␥␦TCL, and that trisomy 8 is a secondary abnormality. Another four cases with i(7q) and trisomy 8 have been reported recently by Jonveaux and coworkers.7 They proposed that i(7q) and trisomy 8 are the primary, nonrandom abnormalities. In this paper, we report three cases of hepatosplenic ␥␦TCL with i(7q). Signiﬁcantly, one patient had i(7q) as the sole chromosomal abnormality at diagnosis. Two patients had i(7q) and other numerical and structural abnormalities, including trisomy 8 in one patient. In all three of our patients the malignant clone also lost the Y chromosome, either at diagnosis or during evolution of the disease. Our data bring the number of patients with hepatosplenic ␥␦TCL and i(7q) to eleven,6,7,14

Figure 2 G-banded karyotypes performed on bone marrow obtained at diagnosis. Arrows indicate missing, extra, or structurally abnormal chromosomes. i(7q) is the only abnormality common to all patients. It replaces a normal 7 in patients 1 and 3, and is an extra chromosome in patient 2. All three patients are mosaic, with a karyotypically normal cell population. (a) Patient 1: 46,XY,i(7)(q10); (b) patient 2: 48,X,−Y,+3,t(6;10)(p25;p12),+i(7)(q10),+8,der(13) t(13; 16)(p11.2;q11.2),−16,+21; (c) patient 3: 44,X,−Y,i(7)(q10),del(11) (q14),−21. Correspondence 1371 two patients with i(7q) as the sole abnormality.8,14 Thus, it 124 cases of predominantly hematopoietic neoplasms, most appears likely that i(7q) is the primary cytogenetic abnormality often associated with other chromosomal abnormalities. It was in hepatosplenic ␥␦TCL. Frequent secondary abnormalities detected as the sole abnormality in four cases of acute acquired during disease evolution are loss of the Y chromo- myeloid leukemia, three cases of myelodysplastic syndrome, some and gain of a chromosome 8. three cases of ALL, and one case of Wilm’s tumor, rep- Cytogenetic analysis failed to demonstrate i(7q) in three pre- resenting a small minority of these tumor types. Cases of ALL viously reported cases of hepatosplenic ␥␦TCL.17–19 In one with i(7q) are usually of B cell lineage, and have other cyto- case, reported by Ross and coworkers,18 the lymphoma arose genetic abnormalities, particularly t(4;11) or der(19), that are in the setting of organ transplantation and had the karyotype believed to represent the primary abnormalities.23,25 Loss of t(7;9)(p15;q13)t(13q;14q). Thus, the malignant cells had a bal- the short arm of chromosome 7, either due to monosomy or anced translocation between chromosomes 7 and 9, as well partial deletion, is a relatively common sole abnormality in as a Robertsonian translocation of chromosomes 13 and 14. ALL.23,26 It has been proposed, therefore, that in ALL with i(7q) Chromosome 7 was broken at band 7p15, with no apparent it is the loss of genetic material from the short arm, rather than gain or loss of genetic material. However, a break within or gain of material from the long arm of the chromosome, that near a coding region can cause dysregulation or loss of gene is important in its pathogenesis. function. In the second case, reported by Wong and cowork- Isochromosome 7q has been reported in several cases of ers,19 cytogenetic studies demonstrated a karyotype of hepatosplenic lymphomas that may represent hepatosplenic 44,X,−Y,−11,−22,+mar. However, the relative size or shape of ␥␦TCL. Colwill and coauthors14 described a 20-year-old man the marker was not described, nor was it characterized by who presented with massive splenomegaly due to involve- additional banding methods, such as fluorescent in situ ment by T cell lymphoma. Although the malignant cells were hybridization with whole-chromosome libraries. In the third not studied for expression of the ␣␤ or the ␥␦ TcR, they had case, reported by Mastovich and coworkers,17 analysis perfor- clonal TcR␦ gene rearrangements, and the i(7q) was the sole med on involved bone marrow demonstrated a normal female chromosomal abnormality. Thus, we believe that this case is karyotype. However, the only cytogenetic study reported was most likely an hepatosplenic ␥␦TCL. A recent report of natural performed at presentation, when the infiltrate was described killer (NK)-like T cell lymphoma of large granular lymphocyte as ‘subtle’. Thus, the karyotype obtained may represent the derivation contained three cases with i(7q) in addition to other normal rather than the neoplastic cell population. This structural and numerical chromosome abnormalities.27 The patient’s lymphoma underwent histologic progression 2 years clinical and immunophenotypic features of these cases are after presentation. Had cytogenetic studies been done at this consistent with the diagnosis of hepatosplenic ␥␦ T cell lym- time, they might have shown a different picture. In fact, the phoma, although the neoplastic cells in one case contained patient reported by Ross and coworkers,18 and one of the prominent azurophilic granules and neither case was studied patients reported by Wang and coworkers,6 had normal chro- for expression of TcR␦. Because of the considerable clinical mosome results at presentation. However, cytogenetic studies and morphologic overlap between hepatosplenic ␥␦TCL, NK performed 9 weeks and 2.5 months later, respectively, leukemia/lymphoma, and NK-like T cell lymphoma, these revealed clonal chromosomal abnormalities. It is conceivable, cases may be difficult to distinguish by routine histopathologic therefore, that for the patients described by Mastovich and and immunophenotypic analysis. Evaluation of cases that fall Wong, further cytogenetic studies might have been informa- within this spectrum for expression of the ␣␤ and ␥␦ TcR, as tive, and might have demonstrated i(7q) or other rearrange- well as cytogenetic analysis, may help to define further ments. these entities. Isochromosomes are found frequently as acquired abnormalities in neoplastic cells, and result in both loss and gain of genetic material. Recent studies indicate that, at least in References constitutionally occurring isochromosomes, there are usually 1 Bucy RP, Chen CL, Cooper MD. 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