Trisomy 14 in hematologic diseases

Trisomy 14 in Hematologic Diseases Another Non-Random Abnormality Within Myeloid Proliferative Disorders Marco Mancini, Michele Cedrone, Mauro Nanni, Maria Beatrice Rondinelli, Maria Concetta Petti, Maria Rosaria De Cuia, and Giuliana Alimena

ABSTRACT: Two cases ofmyelodysplastic syndrome (MDS) and a case of acute nonlymphoblastic leukemia (ANLL) with a trisomy 14 are presented. The series of results derived from our cases, and those previously reported, strongly suggest that this anomaly may be another nonrandom change, confined within myeloid disorders and associated with patients' advanced age, marked tendency to bone marrow dysplastic features, normal platelet values, and not unfavorable prognosis.

INTRODUCTION The cytogenetic studies of blood malignancies have revealed a growing number of non_random structural and numerical chromosome abnormalities [1, 2], some of which have been shown to be specifically associated with well defined subtypes of disease [3]. Trisomy of chromosome 14 as a primary change has to date been reported in 20 cases of hematologic neoplasia [1] (Table 1). In all but one case, this change has been identified in disorders of the myeloid type, i.e., myeloproliferative syndromes (MPS), mostly with atypical features, MDS, or ANLL. In particular, the observation of coexistent myeloproliferative and myelodysplastic features has led in some cases to the suggestion that this change may be a further nonrandom karyotypic abnormality preferentially associated with certain hematologic disorders [4]. We herein refer to three additional cases, two with MDS and one with an ANLL, M2 type, presenting the trisomy 14 as an isolated karyotypic anomaly. The clinical, hematologic, and cytogenetic aspects of these cases are reported. CASE REPORTS Case 1

A 68-year-old housewife was admitted to our hospital in January 1989 with a history of fatigue, anemia, and leukocytopenia in the past few months. At admission, hemoglobin (Hb)

From the Hematology Section, Department of I-Iuman Biopathology, University ~La Sapienza7 Rome, Italy. Address reprint requests to: Dr. Marco Mancini, Hematology Section, Department of Human Biopathology, University "La Sapienza7 Via Benevento, 6, 00161 Roma, Italy. Received August 3, 1992; accepted November 3, 1992.

was 109 g/L, hematocrit 32 %, white blood cell count (WBC) 2.9 × 109/L, platelets (PIts)282 × 109/L. A bone marrow aspirate showed a normal cellularity with erythroblastic hyperplasia and 5% blast cells of myeloid type. Signs of moderate trilineage dysplasia were present. These consisted of erythroblasts with nuclear aberrations, cytoplasmic vacuolization, and Howell-Jolly bodies; granuloblasts with hypogranularity and pseudo-Pelger-Huet anomaly; and megakaryocytes in large mononuclear form, with fragmented nuclei or as micromegakaryocytes. A diagnosis of refractory anemia (RA), FAB classification, was made and treatment started with vitamin B6. At present, 42 months after diagnosis, the patient is still alive in good condition, with stable disease.

Case 2

A 62-year-old man was admired to our hospital in April 1990 with Hb 120 g/L, WBC 3.2 x 109/L and Plts 104 x 109/L. Past history revealed a professional exposure as a welder to toxic agents. A bone marrow aspirate showed dysplastic features, namely 28% of erythroblasts with binuclearity, nuclear-cytoplasmic asynchrony of maturation, cytoplasmic vacuolization, 36% of granuloblasts with hypogranularity, pseudo-Pelger-Huet anomaly, hypersegmentation, 12% of lymphocytes, 12% of monocytes, and 13% of blasts. Megakaryocytes were present in large or small form with dysplastic changes. A diagnosis of refractory anemia with excess blasts (RAEB) was made and therapy with vitamin B6 started. In October 1991, the disease evolved into ANLL, M2 type, with 66% of blast cells in the bone marrow; a blood cell count showed Hb 98 g/L, GB 22.6 x 109/L with 20% neutrophils, 6% lymphocytes, 74% blasts, PIts 102 x 109/L. Therapy with 5-aza-2'-deoxycytidine was started in November 1991. The patient achieved a hematologic remission (HR) in De39

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M. M a n c i n i et al.

Table I

P r e v i o u s l y r e p o r t e d h e m a t o l o g i c m a l i g n a n c i e s w i t h t r i s o m y 14 as p r i m a r y k a r y o t y p i c c h a n g e Hematologic data

Pat

Age/Sex

1) 2) 3) 4) a 5)a 6) 7) 8) 9) 10) a 11) 12) 13) 14) 15) 16) a 17) 18) a 19) 20)

69/M 60/F ? 62/F 81/M 48/F 78/M 58/M 64/M 84/F 81/M 83/F 40/F 61/M. 82/M 74/M 40/F 67/M 67/? 56/M

21) a 22) 23)

69/F 62/M 63/F

Diagnosis ANLL M4 ANLL M1 ANLL M1-M2 ANLL ANLL ANLL CML PhCMPD aCML aCML aCML aCML MDS RAEB . ~RA ~ RA RAEB RA CMMoL T-cell CLL RA RAEB ANLL M2

Hb

WBC

Pits

? ? ? 112 121 100 ? ? 104 92 90 107 ? 100 ? 77 40 96 ? ?

? ? ? 11 42 3.9 ? ? 26 18 23 73 ? 2.6 ? 9.2 4.2 3.3 ? ?

? ? ? ? 551 128 ? ? 114 210 153 5 ? 61 ? 1044 127 130 ? ?

109 120 99

2.9 3.2 3.3

282 104 329

Dysmyelopoeisis 7 ? 7 7 ? 7 ? + + + + + ? 7 + + + ? + + + + + +

? ? ? + + + + + + + + +

Surv

Ref

14,5 + 5+ 1,5 + ? 4+ 5+ ? 40 18 48 12 2 22 24 + 4 ? 12 + 38 + ? ?

14 15 16 17 17 17 18 19 4 4 4 4 8 9 10 11 11 12 13 7

42 + 25 26

PO PO PO

o Trisomy 14 is present as i(14q). Abbreviations: ANLL = acute non-lymphoid leukemia; CML - chronic myeloid leukemia; CMPD ~ chronic myeloproliferative disease; aCML = atypical chronic myeloid leukemia; MDS = myelodysplastic syndrome; RAEB = refractory anemia with excess of blasts; RA = refractory anemia; CMMoL = chronic myelomonocytic leukemia; CLL = chronic lymphocytic leukemia; Hb = hemoglobin (g/L); WBC = leukocyte count (× 1 0 9 / L ) ; Pits = platelets ( × 109/L); + / + + / + + + = single/bi/trilineage dysplasia; Surv = survival (months); Ref = references; PO = present observations.

c e m b e r 1991, after two courses of treatment, and had an early relapse in A p r i l 1992. T h e patient d i e d of progressive disease in May 1992. Case 3 A 63-year-old w o m a n was referred to our h o s p i t a l in February 1990 w i t h a 6 - m o n t h history of m i l d a n e m i a and intermittent fever. O n a d m i s s i o n , Hb was 99 g/L, WBC c o u n t was 3.3 x 109/L, PIts w e r e 329 x 109/L. T h e b o n e m a r r o w was hypercellular, w i t h 13 % erythroblasts showing moderate dysplastic signs s u c h as b i n u c l e a r i t y a n d n u c l e a r - c y t o p l a s m i c a s y n c h r o n y of maturation, 4 % granuloblasts w i t h m i l d dysplasia c o n s i s t i n g of hypogranularity, 2 % e o s i n o p h i l s , 8% l y m p h o c y t e s , a n d 73% blasts. Megakaryocytes w e r e p r e s e n t in large or s m a l l form w i t h dyspoietic changes. Blast cells were p o s i t i v e for p e r o x i d a s e (70%) a n d A S D - c h l o r o acetate esterase (62%). A d i a g n o s i s of ANLL, M2 type, was m a d e , and treatment w i t h Cytarabine and Mitoxantrone was started. C o m p l e t e r e m i s s i o n was o b t a i n e d in June 1990; c o n s o l i d a t i o n t r e a t m e n t w i t h a cycle of c h e m o t h e r a p y i n c l u d i n g Cytarabine, Etoposide, and D a u n o r u b i c i n was p e r f o r m e d in A u g u s t 1990. In S e p t e m b e r 1991, the patient r e l a p s e d w i t h 50% of blast cells in the p e r i p h e r a l b l o o d . A therapy w i t h all-trans-retinoic acid was t h e n carried out until October 1991. After that t i m e the patient was treated w i t h Hydroxyurea, 6-Mercaptopurine, and Prednisone. The patient d i e d in April 1992 of p r o g r e s s i v e disease.

CYTOGENETIC STUDIES Cytogenetic studies w e r e carried out at the t i m e of diagnosis in all three patients and also at the t i m e of acute transform a t i o n in patient 2. B o n e m a r r o w cells w e r e a n a l y z e d by a d i r e c t t e c h n i q u e a n d after a 24-hour culture; GTG b a n d i n g was a p p l i e d . At least 15 cells w e r e a n a l y z e d in e a c h patient. Karyotypes w e r e e x p r e s s e d a c c o r d i n g to standard n o m e n clature (ISCN, 1985). In case 1, the karyotype at d i a g n o s i s was 46,XX,i(14q) (6 cells)/46,XX (9 cells). In case 2, the analysis p e r f o r m e d at d i a g n o s i s s h o w e d the f o l l o w i n g m o s a i c karyotype: 47,XY, + 14 (5 cells)/46,XY (15 cells) (Fig. 1A). A second analysis p e r f o r m e d during the acute phase in December 1991 s h o w e d the a p p e a r a n c e of a n e w c l o n e w i t h a del(20q) (Fig. 1B), in a d d i t i o n to the c l o n e w i t h + 14 and norm a l cells. A third e x a m i n a t i o n carried out in January 1992, w h i l e the patient was in HR, s h o w e d the p r e s e n c e of cells w i t h del(20q) a n d d i s a p p e a r a n c e of the c l o n e w i t h t r i s o m y 14. The karyotypes f o u n d at the two analyses were, respectively, 47,XX, + 14 (3 cells)/46,XY, del(20)(q13) (8 cells)/46,XY (4 cells) ( D e c e m b e r 1991) a n d 46,XY, del(20q)(q13)(16 cells)/46,XY (6 cells) (January 1992). In case 3, the karyotype at d i a g n o s i s was 47,XX, ÷14 (6 cells)/46,XX (9 ceils). DISCUSSION T h e gain of a c h r o m o s o m e as a p r i m a r y clonal c h a n g e is rarely e n c o u n t e r e d in hematologic m a l i g n a n c i e s [2]. T h o u g h

Trisomy 14 in Myeloid Disorders

A

14

B 20 Figure 1 GTG-bandedpartial karyotypes from BM cells of patient I showing i(14q) (A) and frompatient 2 showing del(20}(q13) (B).

it may involve a number of chromosomes, some are more often acquired than others and seem to have a nonrandom association with well defined subsets of disease entities. For example, trisomy 8 and 13 are mostly found in myeloid disorders [3, 5, 6], trisomy 12 in B-cell chronic lymphocytic leukemia, and trisomy 4 and 11 in ANLL of M4 type [3]. Trisomy of chromosome 14 is an unusual finding in hematologic neoplasms [1]. So far, only 20 cases have been reported with this change (Table 1). With the exception of a single instance represented by a T-cell CLL [7], in 19 cases the extra chromosome 14 was found in disorders of myeloid type, which were referred as MDS (7 cases) [8-13], ANLL (6 cases) [14-17], and Ph negative MPS (6 cases} [4, 18, 19]. The median age of 19 patients with available data was 67 years (range 40-84). This series of results thus suggested a nonrandom association of trisomy 14 with the myeloid line proliferation and the patients' advanced age [9, 11, 12]. In particular, a specificity of this anomaly for a hematologic disorder partly myeloproliferative and partly myelodysplastic, compatible with the diagnosis of "atypical" CML, was recently assumed by Mertens et al. [4] on the basis of their observations. Among the other reports with + 14, only a small fraction had a detailed description of the marrow picture; thus the real incidence of these two pathologic aspects of cell proliferation, within the various myeloid disorders in which the anomaly was found, is difficult to assess. Besides the cases of Mertens et al., marrow data are available in only three other cases of MDS (1 RAEB, 2 RA) [9, 11], which presented morphologic changes involving all three myeloid cell lineages. Furthermore, despite no direct evidence for the presence of a dysmyelopoiesis, the two cases of ANLL reported by Meloni-Balliet [17] also showed a clinical history consistent with previously undetected dysplastic phase. Thus, at least 12 of the 19 cases with myeloid disorders would

41 have had some type of morphologic changes. Our three observations are not fully in line with the suggestion by Mertens et al., as their common feature of dysmyelopoiesis involving all three cell lineages was detected in MDS (two cases} and in ANLL (one case); they rather seem to indicate that the more consistent characteristics marking trisomy 14 is represented by the dysplastic changes that can be variously combined with heterogeneous expressions of myeloid cell proliferation. As to the age of our patients, the median was 63 years (range, 62-68), thus confirming the preferential occurrence of the + 14 in elderly patients [9]. Another interesting finding in our patients was represented by a platelet number in the normal range. Normal or increased platelet values were also present in two cases of ANLL [17], in three cases of MPS [4], and in three cases of MDS [11, 12]. This finding, which is rather rare in myeloid malignancies such as ANLL, Ph negative MPS, and MDS, might be related to the acquired trisomy 14. In 26% of the reported cases (in one of our three cases and in five of 19 cases from the literature), the trisomy 14 occurred as an i(14q). Interestingly, this variant form was exhibited by three of the four cases with RA and this finding might represent another nonrandom association. As to the prognostic aspects of +14, no clear indications have so far been provided. Of our three patients, one (RA) is still in stable disease 42 months after diagnosis; the other two patients both achieved HR after induction therapy for acute leukemia. These data, in accordance with previous observations [11, 12], seem to indicate that trisomy 14 per se does not confer a bad prognosis for the disease. Indirect support for this suggestion also comes from our patient 2, who presented in concomitance with the acute phase of his disease the emergence of a new unrelated clone with a del(20} (q13) and a progressive disappearance of the clone with the extra chromosome 14. A possible low level of malignancy connected with + 14 has also been suggested by the case of RAEB described by Pinkerton et al. [11], in which two cell populations were coexisting, the former (myelodysplastic} carrying an isolated + 14, predominant at diagnosis and after treatment of the acute transformation, and the latter, prevalent during the leukemic phase, showing a t{1;13). The real significance of cytogenetic unrelated clones in MDS is unclear; as suggested by Mecucci et al. [20], they might in fact be the consequence of the genetic instability of the affected progenitor cell on which further mutational events might give rise to new unrelated chromosomal abnormalities, with more malignant potentiality. Otherwise, changes occurring in the cell cycle of cytogenetically distinct cell populations derived from a single progenitor might confer a proliferative advantage to a previously silent or undetected cell clone. In conclusion, the available clinical and hematologic data on primary trisomy 14, albeit still limited, seem to clearly indicate that this anomaly is another rare but nonrandom abnormality. It appears mostly confined within myeloid diseases, apparently heterogeneous (MDS, ANLL, MPS) but sharing some common aspects such as patients' old age, tendency to normal or elevated platelet number, favorable prognosis, and, especially, a marked tendency to dysplastic changes. A larger number of similar observations, with careful

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e v a l u a t i o n of h e m a t o l o g i c characteristics w i t h i n the disease entities, is n e c e s s a r y to better define this a p p a r e n t l y n o n r a n d o m c h r o m o s o m e abnormality.

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