Cytogenetic Follow-up in a Case of S6zary Syndrome

Elvira D'Alessandro, Patrizia Paterlini, Maria Luisa Lo Re, Mario Di Cola, Claudio Ligas, Dennis Quaglino, and Giuseppe Del Porto

ABSTRACT: A cytogenetic follow-up study was performed for a 3-year period on a 70-year-old patient with S~zary syndrome (SS). The results showed formation of hypotetraploid cell clones with 60 to 89 chromosomes and 19 markers, same of which appeared during the period of study and stabilized thereafter. The incidence of these clonal cells increased from 29% to 85% during the follow-up study. The results confirm the presence of hypotetraploid cell clones, especially in the more advanced stages of SS. Moreover, some marker chromosomes in our patient (M2 and M3), derived from chromosome 2, were similar to those observed in SS by other investigators. According to our data and to those in the literature, SS appears to involve preferentially chromosomal regions 2p12-13, 2p21-22, 2q37, 17p13, 13ql, 9q11, 10p13, 14q11, 14q32, 7pl and, to a lesser extent, 5q and 6q.

INTRODUCTION

Although cytogenetic studies indicate a monoclonal origin for S~zary syndrome (SS) and other cutaneous T-cell lymphomas (CTCL) and although existence of possible relationships between chromosome abnormalities, clinical stage, and prognosis has been postulated [1-3, 5, 6], at present there is no evidence of specific chromosomal rearrangements in SS and in general in CTCL. However, heteroploidy [1-4], particu- larly hypotetraploidy [5], and occurrence of some similar chromosomal markers have been frequently reported, especially in advanced clinical stages [eg, a large submeta- centric marker, partially derived from chromosome 2 ( p l l - p l 3 ) , has been described repeatedly (3, 5-12)]. Furthermore, chromosomes 1, 17, 10, 6, 7, 15, 13, 11, and 12 are usually involved in numerical and/or structural changes. Recently some investigators [12-14] indicated 14q l l as a preferential breakpoint in T-cell leukemias and lymph- omas. We report the results of a cytogenetic study with a follow-up of 3 years in a case of SS.

From the Cattedra di Genetica Medica (E. D'A., M. L. L R, M. D. C., C. L.), Cattedra di Clinica Medica (P. P., D. Q.), Universit~ degli StudL L'Aquila, Italy, and Cattedra di Genetica Medica (G. D. P ), Universit~ "La Sapienza," Rome, Italy.

Address reprint requests to: Professor Elvira D'Alessandro, Dipartimento di Medicina Interna e Sanitd Pubblica, Cattedra di Genetica Medica, Via San Sisto, 67100 L'Aquila, Italy.

Received May 26, 1988; accepted August 10, 1989.

231

© 1990 Elsevier Science Publishing Co., Inc. Cancer Genet Cytogenet 45:231-236 (1990) 655 Avenue of the Americas, New York, NY 10010 0165-4608/90/$03.50

232 E. D'Alessandro et al.

CASE REPORT AND CYTOGENETIC STUDIES

R. A., a 70-year-old man, was admitted to our unit in 1982 with a typical chnical picture of SS. Physical examination showed generalized erythroderma and plantar hyperkeratosis associated with diffuse superficial lymphadenopathy. His spleen and liver were not enlarged. Results of a computed tomography scan of the abdomen, a liver and spleen isotopic scan, and chest roentgenograms were normal. The hemoglo- bin level and the red blood cell count were within the normal range; the white blood cell count was 11.1 x 109/L with 54% lymphocytes, including 32% typical large S6zary cells. Serum concentrations of IgG and IgM were normal, but IgA was persis- tently high. The diagnosis of SS was confirmed by the results of a skin biopsy, which showed a conspicuous lymphoid infiltrate and Darrier-Pautrier abscesses in the epidermis, and of a lymph node biopsy which showed massive lymphoid infiltration with partial loss of nodal architecture and predominance of abnormal cells in the paracortical area. The bone marrow was moderately infiltrated (7%) by neoplastic cells. Results of cytochemical and cytoimmunological studies performed on circulat- ing S6zary cells were in keeping with those reported in the literature [15].

The patient initially received combination chemotherapy according to a protocol of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), which proved poorly effective on both cutaneous itching and lymphadenopathy and therefore re- mained untreated for the next 3 years, with little change of the clinical picture apart from a progressive extension of hyperkeratosis.

Cytogenetic studies were performed at diagnosis and repeated yearly during the follow-up period. Analysis was performed with standard techniques and GTG banding on phytohemagglutinin-stimulated circulating lymphoid cells cultured for 72 hours.

RESULTS

The cytogenetic findings (Table 1) showed formation of abnormal cell clones, mostly hypotetraploid, with a chromosomal number ranging from 60 to 89 (modal number 82). The chromosome losses observed in hypotetraploid metaphases (as compared with a 4n ploidy) and the rearranged chromosome gain are shown in Fig. 1. Nineteen marker chromosomes could be recognized in the abnormal cell clone. Of these, 18 have been identified; 15 were already present in the first culture at diagnosis, one appeared during the second year of follow-up, and three appeared during the last year. Figure 2 shows the markers, their chromosomal rearrangements, and the respective frequencies observed at sequential controls. Pseudodiploid cells, as well as aneuploid cells with 47 to 50 chromosomes, also showed some of the identified markers.

DISCUSSION

The above-reported results confirm a high incidence of hypotetraploid cells in this variant of lymphoma. Although the percentage and absolute number of circulating S6zary cells remained almost unchanged in our patient during the course of the disease, a remarkable increase in the percentage of hypotetraploid cells emerged from our cytogenetic data. This finding suggests a probable proliferative advantage or an acquired higher responsiveness to mitogens, and was apparently paralleled by an increase of some markers, mostly involving chromosomes 7, 10, and 11, and by formation of a new marker from chromosome 5 and of a second from chromosome 4. Our results appear to be at variance with those of other investigators, who report the frequent involvement of chromosomes 1, 3, and 14. One copy of chromosome 14 was missing in 100% of the metaphases and two were lacking in 75%, but this chromosome was not implicated in the formation of clearly identifiable markers. Obviously the

Tab

le

1 N

um

eric

al

cyto

gen

etic

fi

nd

ing

s

No.

of

chro

mo

som

es

No.

of

-<45

46

dip

loid

46

pse

ud

od

iplo

id

47

-50

6

0-8

9

Mo

dal

Id

enti

fied

C

ultu

re

met

aph

ases

n

(%)

n (%

) n

(%)

n (%

) n

(%)

Ran

ge

nu

mb

er

mar

ker

s

I 15

0 82

(54

.6)

20 (

13.3

) 1

(0.6

) 3

(2.0

) 44

(29

.3)

66

-89

84

15

II

95

22

(23

.1)

4 (4

.2}

--

2 (2

.1)

67 (

70.5

) 6

0-8

4

80

16

III

250

11 (

4.4)

24

(9.

6)

1 (0

.4)

1 (0

.4)

213

(85.

2)

78

-89

82

19

T

otal

49

5 11

5 (2

3.2)

48

(9.

69)

2 (0

.4)

6 (1

.2)

324

(65.

4)

60

-89

82

19

C,O

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Cytogenetic Follow-up in SS 235

I I001 II 1 0 0 ~ Ill IOOZ

t (2;13;13) (p22q37;ql l ;ql l )

M7

I 25% II 40% III 50%

del (7) (p l4)

MI3

I 100% II fOOl III fOOl

t

17p+

M2

I 1001 II IOOZ III 100~

t(2;12)(p12;q13)

M8

I 45% II 40% III 85g

t (?;?)(p22;?)

MI4

I 50% II 70% II1 351 ~'~

M15

i loo1 II 100% III 100%

mlnutes

H3

1001 ~ ~ II 100% III 1001

t (2 ;?) (pI3;7)

H9

I 25% ~ I I 90% I l l 89% ~

t (7 ;9) (p l l -12 ;q l l -13)

N16

II 50% I I l 85%

del(4)(pl4)

M4

I 1001 ~,~ II 100% III IOOZ ~

t (4 ;? ) (p lS .2 ;? )

H l O

I 75% II 70% IIl 92%

t ( l O ; l l ) ( q l l ; p l l )

MI7

I - - II --

III 88.5Z

del(5)(q33)

N5

I 55% II 43% I I I 61%

de l (6 ) (q l l )

KII

I 50~ II 50% >~ I I I 58~

d e l ( l l ) ( q l l )

M6

I 501 II 80%

III 96~

del(7)(q21)

M12

I 50% II 201 III 5~

del(15)(q26.1)

H18 M19

I ~ I - - - II ~ II

III 27Z In 27~

t (10;?) (p l3-14;?) lip+

Figure 2 Our 19 markers, their chromosomal rearrangements, and frequencies during the follow-up.

presence of fragments of chromosome 14 in unidentified markers cannot be ruled out. On the contrary, there is a good agreement with respect to other chromosomes as well as for the preferential breakpoints. In view of the numerous reports in the literature and of the three markers observed in our case in 100% of "heteroploid" cells, we emphasize the nonrandom involvement of chromosome 2 in CTCL. Chromosome 2 might potentially be considered a marker for these forms of lymphoma, with break- points clustered around bands p12-13, p21-22, and q37. Indeed various investigators [4-12] have observed a large submetacentric marker, mainly derived from this chro- mosome, very similar to our M2 and/or M3.

According to the literature [1-14, 16-18] other regions appear to be nonrandomly involved (13ql, 17p13, 9q11, 10p13, 10q11, 6q, and 5q) but the latter two have scattered breakpoints, except 6q21. Chromosomes 4, 7, 11, and 12, less frequently mentioned by other investigators in T-cell lymphomas, appear to assume particular relevance in our case. Because many of the genes apparently involved may be con- cerned with the growth, functional activation, or proliferation of T-cells or all three, and possibly in their neoplastic transformation as well, the breakpoints on rearranged chromosomes are probably nonrandom. Moreover, the acrokeratoelastoidosis gene, mapped in 2p, may have some relevance in relation to the erythroderma and hyperker- atosis commonly found in SS and particularly remarkable in our patient as well as in two other cases which share a marker derived from chromosome 2 [3, 9].

In conclusion, the relative infrequency of the cases and the technical difficulties

236 E. D'Alessandro et al

involved have precluded identification of specific chromosome rearrangements m CTCL. The finding of a high number of markers should be considered as possible expression of mult iple pathogenetic steps involved in the origin, selection, and evolu- tion of the aberrant cell clone rather than as an indication of randomness [8, 12].

We hope that further cytogenetic follow-up studies may contribute to clarification of the breakpoints and gene involvements and their pathogenetic role in onset and progression of CTCL.

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