1995 86: 2365-2370   

 K Offit, DC Louie, NZ Parsa, A Noy and RS Chaganti lymphoma with plasmacytoid featuresDel (7)(q32) is associated with a subset of small lymphocytic

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De1(7)(q32) Is Associated With a Subset of SmaII Lymphocytic Lymphoma With Plasmacytoid Features

By K. Offit, D.C. Louie, N.Z. Parsa, A. Noy, and R.S.K. Chaganti

Deletions of the long arm of chromosome 7, previously docu- mented in myelodysplasias and myeloid leukemias, have also been noted in lymphoid malignancies. Of 558 karyotypi- cally abnormal speeimens of non-Hodgkin’s lymphoma (NHL) serially ascertained over an 8-year period, del(7q) was identified in 24 cases, 10 of which were of the small lympho- cytic Ism lym) subtype. Del(7q) was the third most common karyotypic abnormalii among the cohort of 61 sm lyrn cases in this ascertainment. Mapping of the deletions identified a region of common deletion affecting 7q32, which was the sole karyotypic abnormality in 2 cases. Eight of the ten sm lyrn cases were characterized by plasmacytoid features in

NLIKE THE FOLLICULAR and diffuse large-cell non- Hodgkin’s lymphomas (NHLs), which have been asso-

ciated with recurring translocations, the heterogeneous group of small lymphocytic (sm lym) NHLs have not been specifi- cally associated with a common recurring genetic abnormal- ity.’ Trisomy 12, observed in a subset of sm lym tumors and chronic lymphocytic leukemia (CLL), is nonspecifically observed in other subtypes of NHL.’.’ Deletions of the long arm of chromosome 7 have been described in the myleodys- plastic syndromes and myeloid malignancies but have been infrequently observed in lymphoid neoplasms?-’ However, recent molecular studies have documented loss of heterozy- gosity at 7q loci in a number of human malignancies, includ- ing breast and prostate carcinomas.“8 In this report, we iden- tify chromosome band 7q32 as the commonly deleted segment in a subset of B-cell NHL, including a significant proportion of sm lym neoplasms. De1(7)(q32) sm lym NHLs show most of the features of lymphoplasmacytoid lymphomas with a clinical behavior characteristic of other sm lym neoplasms.

U

MATERIALS AND METHODS Between January 1984 and December 1992, 595 consecutively

ascertained NHL specimens derived from 558 patients at the Memo- rial Sloan-Kettering Cancer Center showed clonal karyotypic abnor- malities. Cases were sequentially submitted for histopathologic, cy- togenetic, immunophenotypic, and immunogenotypic analysis as previously de~cribed.~ Cases were categorized according to the Inter- national Working Formulation’o and, where possible, the revised European-American classification of lymphoid neoplasms.” Sixty- one cases with abnormal karyotypes were classified as sm lym NHL by the Working Formulation. The clinical and histologic features of 4 cases with t(9; 14)(p13;q32) and 14 cases with del(6q) have pre- viously been rep~rted.”.’~ A description of 24 cases in the current series was included in a previous report of the cytogenetic features of 278 karyotypically abnormal NHLs.* Two cases in this ascertainment showed unbalanced rearrangements that presented as add(7q), with breaks in 7q32 (no. 1302) and 7q22 (no. 1474; Fig 1). In both cases, the segment of 7q distal to the breakpoint was deleted, resulting in a functional deletion of 7q. Therefore, these 2 cases were included in this analysis.

Clinical information, including age, stage, and sites of involve- ment at diagnosis, treatment, and survival, was collected and ana- lyzed for all 61 cases. Treatments among the cases were nonuniform, with each patient receiving individualized programs including inter- mittent courses of single agent or combination chemotherapy, ste- roids, or radiotherapy.

Blood, Vol 86, No S (September 15), 1995: pp 2365-2370

histologic sections of iymphoma tumors or circulating cells in the peripheral blood. The de1(7)(q32) was accompanied by 14q32-associated translocations in 11 of the 14 cases with histologies other than sm lyrn, compared with 2 of the srn lyrn cases. Extranodal involvement was more frequent in the de1(7)(q32) sm lyrn NHLs, although median survival was typical of other low-grade lymphomas. These results sug- gest that loss or inactivation of a putative tumor-supressor gene at 7q32 may play a role the progression of lymphomas as well as constitute an early event in the pathogenesis of lymphoplasmacytoid tumors. 0 1995 by The American Society of Hematology.

Comparisons of cases with differing cytogenetic abnormalities were made using the method of inferences from proportions based on x* ana1y~is.l~ Differences in actuarial survival curves were made using the logrank test.

RESULTS

Cytogenetic and histologic associations. Deletions of 7q were found in 24 (4.3%) of the 558 karyotypically abnormal cases in this ascertainment. Mapping of the deletions identi- fied a region of common deletion (RCD) encompassing 7q32. In a single tumor (no. 1394) the deletion spanned the region 7qll-q22. In 8 of the 24 cases, a recurring deletion, de1(7)(q22q32), was noted (Fig 1 and 2).

In this ascertainment, a del(7q) was observed in 10 of 61 sm lym NHLs compared with 14 of 497 NHL with other histologies ( P < .OS). Of the 14 non-sm lym cases, 9 were follicular NHLs and 5 were diffuse large-cell NHLs. In 9 of the 14 cases, the del(7q) was accompanied by a t(14;18)(q32;q21); a t(11;14)(q13;q32) was observed in 1 case and a t(8; 14)(q24;q32) was observed in 1 case. In con- trast, of the 10 sm lym NHLs with de1(7)(q32), none was accompanied by t(14; 18) or t(8; 14), whereas t(l1; 14) was observed in 2 cases (P < .05). The full karyotypes of the 10 sm lym NHLs with del(7q) are shown in Table 1. The

From the Cell Biology and Genetics Program and the Depart- ments of Human Genetics, Medicine, and Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY.

Submitted January 25, 1995; accepted May 16, 1995. Supported by Grants No. CA-34775 and CA-08748 from the Na-

tional Institutes of Health, Bethesda, MD, and the Lymphoma Foun- dation. A.N. is supported by the Mortimer Lacher Lymphoma Foumi- tion and National Institutes of Health Grant No. K12-CA01712-03.

Presented in part at the Thirty-Sixth Annual Meeting of The Amer- ican Society of Hematology on December 5, 1994.

Address reprint requests to Kenneth Ofit, MD, MPH, Memorial Sloan-Kettering Cancer Center, Box 192, 1275 York Ave, New York, NY 10021.

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked “advertisement” in accordance with 18 V.S.C. section 1734 solely to indicate this fact.

0 1995 by The American Society of Hematology. 0006-4971/95/8606-0028$3.00/0

2365

2366 OFFIT ET AL

l I

Small lymphocytic Other NHL N H i

del(7q) was associated with additional numerical or struc- tural chromosomal abnormalities in all 14 non-sm lym NHLs. In contrast, the de1(7)(q32) was the sole karyotypic abnormality in 2 cases of sm lym NHL (Fig 2).

Del(7q) was the third most commonly observed cytoge- netic aberration in sm lym NHLs, behind del(6q) and trisomy 18, which were observed in 23% and 18% of cases, respec- tively.

Morphologic and immunophenotypic features. None of the 10 cases of del(7q) NHLs showed distinct proliferation centers. Lymph node architecture was effaced by infiltrates

l I l

7 del (7)

1321

7 del (7)

I462

Fig 2. De1(7)(q22q32) (left) and de1(7)(q32) (right) in NHL. The de1(7)(q32) was the sole karyotypic abnormality in this tumor (no. 1462).

Fig 1. Mapping of the region of common of 7q in 24 cases of NHL.

deletion

of small lymphocytes with varying degrees of nuclear irregu- larity and amounts of cytoplasm (Figs 3 and 4). Of the 10 sm lym NHLs, 5 showed plasmacytoid differentiation in histologic sections; in 2 of these cases, intranuclear Ig inclu- sions (Dutcher bodies) were identified. Extensive necrosis in 1 case (no. 937) precluded definitive histologic classifica- tion. In 4 cases with circulating tumor cells, plasmacytoid features were observed. These features included irregular shape of the cells, abundant cytoplasm, and occasional nucleoli (Fig 5) . Thus, in 8 of the 10 cases of sm lym NHLs with del(7q), plasmacytoid features were evident in histo- logic section and/or circulating cells.

At least 1 case (no. 1327) of the 10 sm lym NHLs was suggestive of monocytoid B-cell lymphoma, with most of the cells showing ovoid or indented nuclei, moderate amount of clear cytoplasm, and distinct cytoplasmic borders (Fig 4). Another case (no. 1296) showed features of a mantle cell lymphoma with a mantle zone growth pattern and a t(l1; 14)(q13;q32).

Immunohistochemical and flow cytometric analysis of the tissue or bone marrow specimens of the del(7q) sm lym NHLs showed light chain clonal restriction in 9 cases ( 5 ~ and 4X). Ig gene rearrangement studies confirmed B-cell lineage in 4 cases studied; in 1 plasmacytoid NHL (no. 83 l), no tissue was available for lineage assessment. All 7 cases analyzed showed expression of CD20. CD5 was expressed in 3 cases (no. 1327, 1356, and 1462) and absent in 2 cases analyzed (no. 1239 and 1296).

DEL(^^) SMALL LYMPHOCYTIC LYMPHOMA 2367

Table 1. Clinical, Histologic, and Karyotypic Features of l 0 Cases of sm lym Lymphoma With del(7ql

Case No. Agerjex Histology* BMParaprotein LN Cells Disease at DX Survival

Stagetl Circulating Extranodal WBC R 4

173

683

83 1

937

1239

1296

1302

1327

1356

1462

F/66 sm lym (CLUSLL) W / +

F/56 sm lym-p (LP) W/-/ISM

F/66 sm lym-p (LP) W/-

F/17 sm lym-p (LP) l/-

M/61 sm lym-p (LP) W/+

F/65 sm lvm (MCL) IVS/t

M/37 sm lym-p (LP) l/-

F/69 sm lym (MZL) IVS/+

F/46 sm lyrn (CLUSLL) ll/-/lgM

F/59 sm lym (CLUSLL) M / -

+ PF

-

-

-

+ PF

-

-

-

+ PF

+ PF

L 11.0 A, S 84e

B 5.7 A 1 +*

L 6.2 S 66+*

2e Li 15.0 A, S

86e

- 5.7 I

C 4.8 PrM 17e

- 6.0 RT.

BMT 63e

29+* L 8.9 A

P 43.0 1, A

Li 4.6 S 130+$

5e

Abbreviations: p, plasmacytoid; CLUSLL, chronic lymphocytic leukemia/small lymphocytic lymphoma subtype with circulating plasmacytoid forms and absence of proliferation centers (see text); LP, lymphoplasmacytoid lymphoma; MCL. mantle cell lymphoma; MZL, marginal zone lymphoma; BM, bone marrow involvement at diagnosis; IgM, IgM paraprotein detected; LN, lymph node enlargement at diagnosis; PF, plasmacy- toid forms present; L, lung lesions; Li, liver; B, breast; P, pleura; C, colon; WBC at DX, leukocyte count (109/L) at diagnosis; Rx, treatment; A, alkylating agents; S, surgery; PrM, cyclophosphamide, vincristine, procarbazine, prednisone, daunorubicin, prednisone, etoposide, nitrogen mustard; l , interferon; RT. radiation therapy; BMT, allogeneic bone marrow transplantation; e, expired; survival, survival in months from diagnosis.

Diagnosis by International Working Formulation” and revised European-American Classification (in parentheses).” t Stage determined at time of diagnosis. * Alive at last follow-up.

Fig 3. Section of a splenic lymphoma in a case with de1(7)(q32) as the solitary karyotypic abnormal- i t y (case no. 1462). Paraimmunoblasts are scattered among the small lymphocytes.

2368 OFFIT ET AL

Clinical features. The clinical features at the time of diagnosis of the IO cases with sm lym NHLs and del(7q) are shown in Table 1. A circulating IgM paraprotein was observed in 2 cases. In 6 cases, cytogenetic analysis was performed at the time of initial presentation, whereas 4 were studied at relapse. Advanced stage disease was observed at initial presentation in 7 of the I O cases. Bone marrow was involved in 4 cases. Although clinical involvement of spleen and peripheral lymph nodes was common, extranodal sites were also frequently involved (Table 1). In 8 cases there was involvement of extralymphatic sites, compared with 3 1 of 52 cases of sm lym NHL with karyotypic abnormalities other than del(7q) ( P < .05). The mean age (54.2 years), mean leukocyte count at presentation ( I 1 . l X 10y/L), and median survival (84 months) of the del(7q) sm lym NHLs were similar to those of sm lym with other karyotypic abnor-

Fig 4. Section of a lymph node showing features of monocytoid Bcell lymphoma (MZL), including ovoid or indented nuclei, a moderate amount of clear cytoplasm, and distinct cytoplasmic borders (case no. 1327).

malities. There was no prognostic impact of del(7q) in the cohorts of patients with either follicular NHL or diffuse large-cell NHL ( P > .2). None of the 5 cases with del(7q) large-cell lymphoma showed a clinical history of prior low- grade NHL.

DISCUSSION

Although rare in lymphoid malignancies, deletions of the long arm of chromosome 7 are frequently observed in acute myeloid leukemias and preleukemias.2-R Whereas the breakpoints in the myeloid leukemias and preleukemias var- ied, cytogenetic and molecular mapping of regions of dele- tion have localized this region to band 7q22.4 The region of common deletion reported in this series of NHL, 7q32, over- laps with that described for solid tumors, including malig- nancies of the breast, prostate, bladder, testis, and uterine

= . . .,,

Fig 5. Circulating plasmacytoid lymphocyte in a case with de1(7)(q32) as the sole karyotypic abnor- mality (case no. 1462).

P c

DEL(^^) SMALL LYMPHOCYTIC LYMPHOMA 2369

lei~myoma.'~ In these tumors, the del(7q) was observed as one of numerous cytogenetic aberrations or in the setting of clinically aggressive di~ease. '~ In the majority of NHLs in this series, including all of the cases with histologies other than sm lym NHL, there were multiple karyotypic abnormal- ities other than del(7q). This finding suggests a secondary, progression-related role for a tumor-supressor gene at 7q32 in these cases. This observation is also consistent with the statistical correlation in this report of de1(7)(q32) with t( 14; 18) and other translocations in NHLs of follicular and diffuse large-cell histologies and the clinical association of de1(7)(q32) sm lym NHL and extranodal involvement.

The sm lym lymphomas have recently been divided into distinct clinico-pathologic subsets," not all of which are reflected in the International Working Formulation." These subsets include B-cell CLUprolymphocytic leukemidsm lym lymphoma, lymphoplasmacytoid lymphoma (including immunocytomas), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL; including monocytoid B-cell NHL), and hairy cell leukemia (HCL). Whereas the histology and immunophenotype of the del(7q) NHLs did not fulfill all criteria for one of these subsets, half of the cases showed features of the lymphoplasmacytoid variant described in the revised European-American classification." None of the cases showed proliferation centers, a characteristic feature of the CLL subtype of sm lym NHL." Three cases of de1(7)(q32) sm lyrn NHL fulfilled some of the criteria for CLUsm lym by the revised European-American classifica- tion," although the cases did not show proliferation centers and had plasmacytoid circulating cells.

Extranodal involvement, common in the del(7q) cases, is less frequently observed in lymphoplasmacytoid NHL." Whereas the immunophenotype of the del(7q) sm lym cases was consistent with that of lymphoplasmacytoid lymphomas, 2 of the cases with plasmacytoid features also expressed CD5, as did the solitary case with features of a monocytoid B-cell lymphoma (MZL). These are atypical immunopheno- typic findings for these subsets." Similarly, case no. 1296, an MCL with t(l1; 14), lacked expression of CD5. Although none of the cases in this series showed features of HCL or splenic MZL with villous lymphocytes, de1(7)(q32) has previously been documented in 1 case of splenic MZL with villous lymphocytes, 1 case of HCL, as well as 1 case of acute lymphoblastic leukemia!3'6"8 The features of the large lymphoid cells seen in the peripheral blood were not that of HCL or splenic MZL with villous lymphocytes" but resem- bled those of t(9; 14)(p13;q32)-associated plasmacytoid lymphomas'* or variant forms observed in sm lym NHL with de1(6)(q2lq23).l3 Trisomy 3, previously reported in a high proportion of sm lym NHL' and recently associated with a subset of lymphomas of mucosa-associated lymphoid tis- sue," was not observed in any of the de1(7)(q32) sm lym cases.

Although the de1(7)(q32) NHL in this series comprised several categories by the revised European-American classi- fication," the majority of the cases were low-grade lympho- mas with tumor cells or circulating cells showing plasmacy- toid features. In this way, deI(7)(q32) may be similar to the recumng translocations t(8; 14) and t( 14; 18), which are

observed in all grades of NHL but are seen as solitary aberra- tions predominantly in distinct histologic subsets of high- and low-grade NHL, respectively.' The association of de1(7)(q32) with a subset of lymphoplasmacytoid NHL and the observation of de1(7)(q32) as a solitary cytogenetic aber- ration in two of these tumors suggests a pathogenetic role of this aberration in these low-grade lymphocytic neoplasms. The molecular characterization of each of these classes of cytogenetic aberrations will identify novel genes associated with the pathogenesis of these tumors and may serve to provide additional diagnostic criteria for the recently de- scribed clinico-pathologic subsets of peripheral B-cell neo- plasms.''

ACKNOWLEDGMENT

We are grateful to Kin Kong, Stephanie Alton, and Amelia Panic0 for their expert photographic assistance, and to Drs Timothy G e e , Carol Portlock, David Straus, Mark Weiss, and James P. O'Brien for providing clinical information regarding the cases.

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