Chronic myelogenous leukemia with a hypooctoploid cell population

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SHORT COMMUNICATIONS Chronic Myelogenous Leukemia with a Hypooctoploid Cell Population Tsutomu Shichishima, Yohichi Hamazaki, Rokuo Abe, Yutaka Shiga, Tatsuo Abe, and Yukio Maruyama

ABSTRACT: A patient with chronic myelogenous leukemia who underwent transformation from the accelerated phase to the chronic phase with h~terferon-a treatment is reported. On admission, the numbers of myeloblasts and promyelocytes in the peripheral blood and bone marrow were 7.0% and 12.8%, respectively. The platelet count was 633.6 x 104/txl, and megakaryocytes were frequent in the bone marrow. In the accelerated phase, cytogenetic analyses revealed a hypotetraploid and a hypooctoploid cell population with two and four Philadelphia chromosomes, respectively, in the bone marrow specimen. The hypooctoploid clone disappeared with administration of interferon-a and the hypotetraploid clone also subsequently disappeared. © Elsevier Science Inc., 1997

INTRODUCTION Near-tetraploid cell populations have been reported in many hematologic and some other malignancies [1-6]. We report a case of accelerated phase chronic myelogenous leukemia (CML) with a hypooctoploid cell population and four Philadelphia (Ph) chromosomes. CASE HISTORY AND CYTOGENETIC STUDIES The patient was a 79-year-old Japanese man, who was admitted to the hospital on March 2, 1991, with general fatigue and shortness of breath. Physical examination revealed hepatosplenomegaly, hard subcutaneous tumors of the left arm and the right leg, and subcutaneous hemorrhages. The white blood cell count (WBC) was 15.4 × 104/p~1 with a differential of 5.0% myeloblasts, 2.0% promyelocytes, and 9.0% myelocytes. The hemoglobin concentration was 8.3 g/D1 and the platelet count was 633.6 x 104/txl. A bone marrow aspirate demonstrated hypercellularity with 6.6% myeloblasts, 6.2% promyelocytes, and 31.8% myelocytes. Giant cells including binucleate erythroblasts and eosinophils, and many megakaryocytes were also observed in the

bone marrow specimen (Figure 1). The neutrophil alkaline phosphatase rate and score of the peripheral blood were 46% and 102, respectively. The karyotypes of bone marrow cells were 45,X,-Y,t(9;22)(q34;q11) [42]/90, idem x 2 [7], and 46,XY [1]. The rearrangement of the breakpoint cluster region was shown in the bone marrow specimen by Southern blot analysis. A diagnosis of CML was made, and treatment was initiated with interferon-~ (IFN-c~; 250 × 104 IU/day) at the beginning of March 1991. The dose was increased to 500 x 104 IU/day at the beginning of April, and 1,000 × 1 0 4 IU/day at the beginning of May. Although WBC and platelet counts decreased and the patient's genFigure 1 1991.

Giant cells observed in the bone marrow on April 3,

From Department of Internal Medicine L Fukushima Medical College (T. S., Y. H., R. A., Y. S., Y. M.), Fukushima, Department of Hygiene (T. A), Kyoto Prefectural University of Medicine, Kyoto, Japan. Address reprint requests to: Dr. Yukio Maruyama, Department of Internal Medicine L Fukushima Medical College, 1 Hikarigaoka, Fukushima, Fukushima 960-12, Japan. Received December 29, 1995; accepted May 20, 1996. Cancer Genet Cytogenet94:144-146 (1997) © Elsevier Science Inc., 1997 655 Avenueof the Americas, New York, NY 10010

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H y p o o c t o p l o i d y in CML

Table I

145

S u m m a r y of cytogenetic and hematologic data Peripheral blood

Cytogenetic studies

Bone marrow

Cellularity

Percent myeloblasts (%)

March 5, 1991

154,000

5.0

Hyper

6.6

BM

April 3, 1991

65,700

18.0

Hyper

11.6

BM

April 19, 1991

75,600

32.0

Normo

27.4

BM

August 22, 1991

14,000

0.0

Normo

0.6

BM

September 12, 1991 November 14, 1991

6,500 3,900

0.0 0.0

Normo Hypo

1.0 1.2

BM BM

January 9, 1992

4,700

0.0

Hypo

0.0

BM

September 18, 1992 October 15, 1993 May 26, 1994 May 10, 1995

4,000 8,200 8,900 5,200

0.0 0.0 0.0 O.0

Hypo Normo Normo Hypo

2.8 3.0 4.8 3.0

BM BM BM BM

WBC (/~,1)

Date

Percent myeloblasts (%)

Source

Karyotype 45,X,-Y,t(9;22)(q34;q11) 90, idem x 2 46,XY 45,X,-Y,t(9;22)(q34;q11) 90, idem x 2 180, idem x 4 45,X,-Y,t(9;22)(q34;q11) 90, idem x 2 45,X,-Y,t(9;22)(q34;q11) 46,XY 43,X,-Y,-16,-21 45,X,-Y,t(9;22)(q34;q11) 45,X,-Y,t(9;22)(q34;q11) 46,XY 45,X,-Y,t(9;22)(q34;q11) 46,XY 45,X,-Y,t(9;22)(q34;q11) 45,X,-Y,t(9;22)(q34;q11) 45,X,-Y,t(9;22)(q34;q11) 45,X,-Y,t(9;22)(q34;q11)

Numbers of analyzed cells and incidence 42/50 7/50 1/50 36/50 8/50 6/50 48/50 2/50 31/33 1/33 1/33 40/40 8/9 1/9 2/3 1/3 50/50 50/50 20/20 20/20

Figure 2 A hypooctoploid karyotype of a clone observed in a 24-hour unstimulated bone marrow culture on April 3, 1991, showing four copies of t(9;22).

(84%) (14%) (2%) (72%) (16%) (12%) (96%) (4%) (94%) (3%) (3%) (100%) (89%) (11%) (67%) (33%) (100%} (100%} (100%} (100%}

146 eral condition was stable, the percentage of myeloblasts in the peripheral blood and/or bone marrow remained greater than 5% from a d m i s s i o n to the m i d d l e of May (Table 1). A disturbance of the central nervous system, thought to be a side effect of IFN-cx, occurred toward the end of July. However, the symptoms, i n c o n t i n e n c e of urine and dementia, resolved in a few days after the a d m i n i s t r a t i o n of IFN-c~ was s t o p p e d on August 1. Therefore, IFN-c~ (500 x 104 IU/ day) was restarted on August 23, and it was decreased to twice weekly in the middle of September because of a WBC decrease to about 5,000/p.1. The patient was discharged on September 27, 1991. Thereafter, he received IFN-c~ (500 x 104 IU/day) two to three times a w e e k and has r e m a i n e d clinically stable. Chromosomal analysis using a trypsin-Giemsa b a n d i n g m e t h o d [7] following a short-term culture (24 hour) was carried out 11 times (Table 1). The h y p o o c t o p l o i d karyotype from bone marrow cells was seen on A p r i l 3, 1991 (Figure 2). The h y p o o c t o p l o i d karyotype resolved after app r o x i m a t e l y 2 weeks of IFN-c~. Normal karyotypes were also seen on March 5, August 22, and November 14, 1991, and January 9, 1992. The last chromosomal examination revealed h y p o d i p l o i d y with an absence of the Y chromosome and t(9;22)(q34;q11).

DISCUSSION A h y p o o c t o p l o i d cell p o p u l a t i o n was d e m o n s t r a t e d in 12% (6 of 50 cells) of analyzed metaphases from the bone marrow on April 3, 1991. A hypotetraploid clone with two translocations [t(9;22)] and the absence of the Y chromosome were seen in bone m a r r o w specimens obtained from March 5 to A p r i l 19, 1991 (Table 1). The h y p o o c t o p l o i d cells could represent a d u p l i c a t i o n of the h y p o t e t r a p l o i d cells. The hypotetraploid cell population also disappeared by August 22, 1991. These p o l y p l o i d cells were thought to be more sensitive to IFN-e~ than the other cells with the h y p o d i p l o i d karyotype. To the best of our knowledge, only rare cases of octoploid malignancies have been

T. S h i c h i s h i m a et al. reported. These i n c l u d e d a case of acute myelomegakaryocytic leukemia with sporadic o c t o p l o i d y and other complex chromosomal abnormalities, and a few cases of uterine cervical neoplasia with o c t o p l o i d y detected by DNA measurements on tissue sections [8, 9]. However, no cases of l e u k e m i a w i t h o c t o p l o i d y using chromosomal analysis have been reported to date. Although h u m a n leukemic cell proliferations w i t h karyotypes between the h a p l o i d and tetraploid ranges have been reported, this case demonstrates octoploid CML cells in vivo. REFERENCES 1. Bloomfield CD, Arthur DC, Frizzera G, Levine EG, Peterson BA, Gajl-Peczalska KJ (1983): Nonrandom chromosome abnormalities in lymphoma. Cancer Res 43:2975-2984. 2. Atkin NB, Baker MC (1979): Chromosome 1 in 26 carcinomas of the cervix uteri. Cancer 44:604-613. 3. Ayraud N, Dujardin P, Audoly P (1975): Leucemia aigue lymphoblastique avec chromosome Philadelphie. Role probable d'une translocation 14-22. Nouv Presse Med 4:3013. 4. Abe R, Raza A, Preisler HD, Tebbi CK, Sandberg AA (1985): Chromosomes and causation of human cancer and leukemia. LIV. Near-tetraploidy in acute leukemia. Cancer Genet Cytogenet 14:45-59. 5. Reeves BR (1973): Cytogenetics of malignant lymphomas. Studies utilizing a Giemsa-banding technique. Humangenetik 20:231-250. 6. Whang-Peng J, Bunn Jr. PA, Kao-Shan CS, Lee EC, Gazdar A, Minna JD (1982): A nonrandom chromosomal abnormality, del 3p (14-23), in human small cell lung cancer (SCLC). Cancer Genet Cytogenet 6:119-134. 7. Seabright M (1971): A rapid banding technique for human chromosomes. Lancet 2:971-972. 8. Fujita K, Miyoshi Y, Mori H, Niikura H, Terada H, Takei S, Hirota Y, Yamada K, Ishikawa A, Shinohara T (1992): Complex chromosome aberrations between No. 17 and No. 21 in acute myelomegakaryocytic leukemia: A case report. Jpn J Clin Hematol 33:402-404. 9. Barres DR, Duhr MA, Boivin YA (1985): Discrimination between precancerous and cancerous lesions of the uterine cervix by DNA measurements on tissue sections. Anal Quant Cytol Histol 7:320-326.