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Isochromosome 17q in a case of myelofibrosis with myeloid metaplasia terminating in blastic transformation
Isochromosome 17q in a Case of Myelofibrosis with Myeloid Metaplasia Terminating in Blastic Transformation Hideo Nakamura, Naoki Sadamori, Yasuaki Yamada, Ei-ichi Yao, Masuko Tagawa, Kenji Nishino, Ippei Sasagawa, Shimeru Kamihira, Yukinobu Oyakawa, Masao Tomonaga, and Michito Ichimaru
ABSTRACT: A case of myelofibrosis with myeloid metaplasia in a 61-year-old female patient is reported. Cytogenetic studies were performed using short-term culture without phytohemagglutinin. A chromosomal aberration of an isochromasome 17q, [i(17q)], was revealed in 88% of the metaphases of peripheral blood cells in the blastic phase. However, all metaphases of bone marrow cells in the chronic phase showed a normal karyotype. Furthermore, i(17q) was also observed in 10% of the metaphases of spleen cells examined 8 months before blastic transformation. In this case, therefore, the cells with i(17q) were associated with an abnormal clone of blastic transformation, with the abnormal clone originating in the spleen with myeloid metaplasia.
INTRODUCTION Some cases of myelofibrosis with m y e l o i d metaplasia (MMM) terminate in blastic transformation. However, cytogenetic information in such patients has been scarce. In this report a case of MMM that terminated in blastic transformation with the chromosomal aberration i(17q) is reported. CASE REPORT
Y. H., a 56-year-old female patient was found to have leukocytosis (about 10,000/ ~1) in 1976 with no symptoms. She was a d m i t t e d to Nagasaki University Hospital for thorough examination in February 1979, because the leukocytes gradually increased. The notable physical signs were an enlarged liver 7 cm below the right costal margin and a spleen enlarged to the umbilicus. Hematologic findings were Hb 12.2 g/dl, WBC 13,300/pA (myeloblasts 4%, promyelocytes 7%, myelocytes 12%, metamyelocytes 6%, stabs 34%, segmented 9%, basophils 4%, eosinophils 4%, lyreFrom the Department of Hematology,Atomic DiseaseInstitute, NagasakiUniversity School of Medicine, Nagasaki, Japan. Address requests for reprints to Dr. Hidea Nakamura, Department of Hematology, Atomic Disease Institute, Nagasaki University School of Medicine, 7-1 Sakamoto-machi, Nagasaki 852, Japan. Received January 4, 1986; accepted February 6, 1986.
221 © 1987 Elsevier Science Publishing Co., Inc. 52 Vanderbilt Ave., New York, NY 10017
Cancer Genet Cytogenet 24:221-224(1987) 0165-4608/87/$03.50
222
n. Nakamura et al. phocytes 18%, monocytes 2%), normoblasts 4/100 WBC, and platelets 85.5 x 104/ ixl. Bone marrow biopsy from the iliac bone revealed total replacement of the bone marrow spaces by fibroblastic proliferation. In a ferrokinetic study, iron movement into the spleen at an early time was observed by surface counting. Based on these findings, a diagnosis of MMM was made. She was followed-up, but no therapy was administered. Since May 1980, the spleen markedly enlarged and she was readmitted in September. At that time, the spleen was enlarged to 7 cm below the umbilicus. Splenectomy was performed on September 19. The spleen weighted 3100 g and its histopatholgoic findings showed widespread myeloid metaplasia throughout. After removal of the spleen, the general condition of the patient markedly improved. However, the number of leukocytes increased gradually. She was readmitted April 21, 1981 complaining of anorexia and fever. Physical examination disclosed moderate pallor and marked hepatomegaly (the liver was enlarged to the umbilicus). Hematologic findings were Hb 7.7 g/dl, and WBC 94,250/~xl with 21% blastoid cells containing abundant cytoplasm with no Auer bodies and negative to ~-naphthyl butyrate esterase and peroxidase stains. After admission, she was treated unsuccessfully with methotrexate and dibromomannitol. Finally, the blastoid cells increased rapidly in number and she died of heart failure on May 27, 1981. Autopsy was performed. The liver was enlarged and weighed 3300 g. Lymph nodes, liver, lungs, and kidney revealed diffuse infiltration with blastoid cells; lymph nodes and liver also showed myeloid metaplasia. A sample of vertebral bone marrow showed typical features of myelofibrosis.
CYTOGENETIC STUDIES
Cytogenetic studies were performed using short-term culture without PHA. Chromosomal analyses of bone marrow cells in the chronic phase were performed immediately before and after splenectomy, and all 36 megaphases showed a normal karyotype. As shown in Figure 1, however, those of peripheral blood cells in the blastic phase revealed a chromosomal aberration of i(17q) in 44 of 50 metaphases (88%). Furthermore, i(17q) was also observed in three of 30 metaphases (10%) from spleen cells examined 8 months before blastic transformation. DISCUSSION
Among the chronic myeloproliferative disorders, chronic myeloid leukemia (CML) is a very interesting disease cytogenetically, because of the presence of the Philadelphia (Ph) chromosome and the appearance of new additional chromosomal changes, such as trisomy 8, i(17q), and a double Ph, during the course of the disease in more than 75% of the patients [1]. The majority of additional changes occur shortly before or during the blastic phase [2]. On the other hand, some cases of MMM also terminate in blastic transformation [3, 4]. In MMM, however, specific chromosomal aberrations are absent and reports in the blastic phase have been scarce, consisting of only five [5-9] (Table 1). In these reports a Ph-like chromosome or deletion 22q without a reciprocal translocation was observed in two cases, and a l q + in two others. Isochromosome 17q, which was seen in our case, had not been observed in the reported cases, and it often appears in relation to the blastic phase of CML [2]. In 1982, however, Borgst6m et al. [10] suggested that the appearance of i(17q) may be a crucial event in the development of the terminal stage of myeloproliferative disorders, because the chromosomal aberration was observed not only in the blastic
223
i(17q) in a Case of Myelofibrosis
1
2
3
6
7
8
13
14
15
19
20
4
9
21
5
10
11
12
16
17 I~
18
22
X
X
Figure 1 G-banding of a peripheral blood metaphase from our case in blastic transformation. The major clone 46,XX,i(17q) (44 of 50 metaphases) is shown.
phase of Ph-positive CML but also in the terminal stages of acute n o n l y m p h o c y t i c leukemia (ANLL), preleukemia, and Ph-negative CML. Therefore, i(17q) may possibly appear in the blastic phase of MMM as well, although more cases will need to be studied before drawing any final conclusions. In our case, the i(17q) may have a close relation to the abnormal clone of the blastic phase because the cells with i(17q) dominated the blastic phase, whereas, all of the bone marrow cells in the chronic phase revealed a normal karyotype.
Table 1 Case number
Clinical and cytogenetic data of seven patients with MMM in chronic and blastic phase described in the literature Age/Sex
Source ~
Karyotype in chronic phase (%)
Karyotype in blastic phase (%) ND 46,XX,2fragments (22) 44,XX,-C,-D (80) 49,XX, + 11, + 19, with double Phlike markers Ph-like marker with clonal evolution 46,XY,lq + (56) 45,X,-Y,lq + (44) 46,XX,1q + ,t(3;21)
1
70/M
2 3 4
68/F 79/F 54/F
BM BM BM PB, BM, LN
47,XY, + C (95) 46,XX,2 fragments (10) 44,XX,-C,-D ( 2 5 ) ND
5 6
61/F 55/M
PB, BM PB
ND ND
7
60/F
PB
ND
°BM, bone marrow; PB, peripheral blood; LN, lymph node; ND, not done.
Ref. 5 5 5 6 7 8 9
224
H. Nakamura et al.
Furthermore, i(17q) could also be seen in the spleen cells examined 8 months before blastic transformation. In CML, Hossfeld and Schmidt [11] and Mitelman et al. [12] reported that spleen cells revealed additional chromosomal aberrations far more frequently than the bone marrow cells as blastic transformation was drawing near. Accordingly, they suggested that the cells with additional chromosomal aberrations in the blastic phase may originate i n the spleen. In our case with MMM, cytogenetic examination of spleen and bone marrow cells were performed at almost the same time before blastic transformation, and the same chromosomal aberration, i(17q), as observed in the blastic phase could be seen in the former but not in the latter. The findings suggest that the abnormal clone with i(17q), the appearance of which is characteristic of the terminal stage of myeloproliferative disorders, originated in the spleen with myeloid metaplasia. This p h e n o m e n o n observed in our case with MMM might be similar to that of CML reported by Hossfeld and Schmidt [11] and Mitelman et al. [12].
REFERENCES 1. First International Workshop on Chromosomes in Leukemia (1978): Chromosomes in Ph ~positive chronic granulocytic leukemia. Br J Haematol 39:305-309. 2. Sadamori N, Matsunaga M, Yao E, Ichimaru M, Sandberg 3`3` (1985): Chromosomal characteristics of chronic and blastic phase of phi-positive chronic myeloid leukemia. Cancer Genet Cytogenet 15:a7-24. 3. Silverstein MN, Brown 3,L, Linman JW, Minn (1973): Idiopathic myeloid metaplasia: Its evolution into acute leukemia. Arch Intern Ivied 132:709-712. 4. Bouroucle B3,, Coan CA (1962): Clinical, hematologic and pathologic study of 110 patients. Am J Ivied Sci 243:697-715. 5. Jensen MK, Philip P (1973): Cytogenetic studies in haematological disorders which may terminate in acute leukemia. 3,cta IVied Scand 193:353-357. 6. Cehreli C, Ezdinli EZ, Li CY, Krmpotic E (1976): Blastic phase of agnogenic myeloid metaplasia simulating malignant lymphoma. Cancer 38:1297-1305. 7. Page BM, Watt JL, Reid IN, Davidson RJL, Walker W (1979): Clonal evolution of marker chromosomes in a case of myelofibrosis with myeloid metaplasia and myeloblastic transformation. 3,cta Haemat 61:301-309. 8. Baravika I, Bondare D, Jaworkowski L (1980): Die Trisomie des langen 3,rmes des ersten Chromosomes bei einem Patienten mit prim~rer Myelofibrose w~hrend der Blastenkrise. Folia Hematol, Leipzig 107, 6:885-889 (in German). 9. 3,kahoshi M, Takigawa M, Hagiwara N, Oshimi K, Mizoguchi H (1984): A case of primary myelofibrosis terminating in acute megakaryoblastic leukemia: Identification by the demonstration of platelet peroxidase. Japan J Clin Hematol 25:352-358 (in Japanese). 10. Borgstr~m GH, Vuopio P, de la Chapelle 3. (1982): Abnormalities of chromosome no. 17 in myeloproliferative disorders. Cancer Genet Cytoget 5:123-135. 11. Hossfeld DK, Schmidt CG (1973): Chromosomal data suggesting a primary role of the spleen in the pathogenesis of chronic myelocytic leukemia (CIVIL) and blastic phase of CIVIL. In: Chemotherapy of Cancer Dissemination and Metastasis, S Garottini, G Franchi eds. Raven Press, NY. 12. Mitelman F, Brandt L, Nilsson PG (1974): Cytogenetic evidence for splenic origin of biastic transformation in chronic myeloid leukemia. Scand J Haemat 13:87-92.
ABSTRACT: A case of myelofibrosis with myeloid metaplasia in a 61-year-old female patient is reported. Cytogenetic studies were performed using short-term culture without phytohemagglutinin. A chromosomal aberration of an isochromasome 17q, [i(17q)], was revealed in 88% of the metaphases of peripheral blood cells in the blastic phase. However, all metaphases of bone marrow cells in the chronic phase showed a normal karyotype. Furthermore, i(17q) was also observed in 10% of the metaphases of spleen cells examined 8 months before blastic transformation. In this case, therefore, the cells with i(17q) were associated with an abnormal clone of blastic transformation, with the abnormal clone originating in the spleen with myeloid metaplasia.
INTRODUCTION Some cases of myelofibrosis with m y e l o i d metaplasia (MMM) terminate in blastic transformation. However, cytogenetic information in such patients has been scarce. In this report a case of MMM that terminated in blastic transformation with the chromosomal aberration i(17q) is reported. CASE REPORT
Y. H., a 56-year-old female patient was found to have leukocytosis (about 10,000/ ~1) in 1976 with no symptoms. She was a d m i t t e d to Nagasaki University Hospital for thorough examination in February 1979, because the leukocytes gradually increased. The notable physical signs were an enlarged liver 7 cm below the right costal margin and a spleen enlarged to the umbilicus. Hematologic findings were Hb 12.2 g/dl, WBC 13,300/pA (myeloblasts 4%, promyelocytes 7%, myelocytes 12%, metamyelocytes 6%, stabs 34%, segmented 9%, basophils 4%, eosinophils 4%, lyreFrom the Department of Hematology,Atomic DiseaseInstitute, NagasakiUniversity School of Medicine, Nagasaki, Japan. Address requests for reprints to Dr. Hidea Nakamura, Department of Hematology, Atomic Disease Institute, Nagasaki University School of Medicine, 7-1 Sakamoto-machi, Nagasaki 852, Japan. Received January 4, 1986; accepted February 6, 1986.
221 © 1987 Elsevier Science Publishing Co., Inc. 52 Vanderbilt Ave., New York, NY 10017
Cancer Genet Cytogenet 24:221-224(1987) 0165-4608/87/$03.50
222
n. Nakamura et al. phocytes 18%, monocytes 2%), normoblasts 4/100 WBC, and platelets 85.5 x 104/ ixl. Bone marrow biopsy from the iliac bone revealed total replacement of the bone marrow spaces by fibroblastic proliferation. In a ferrokinetic study, iron movement into the spleen at an early time was observed by surface counting. Based on these findings, a diagnosis of MMM was made. She was followed-up, but no therapy was administered. Since May 1980, the spleen markedly enlarged and she was readmitted in September. At that time, the spleen was enlarged to 7 cm below the umbilicus. Splenectomy was performed on September 19. The spleen weighted 3100 g and its histopatholgoic findings showed widespread myeloid metaplasia throughout. After removal of the spleen, the general condition of the patient markedly improved. However, the number of leukocytes increased gradually. She was readmitted April 21, 1981 complaining of anorexia and fever. Physical examination disclosed moderate pallor and marked hepatomegaly (the liver was enlarged to the umbilicus). Hematologic findings were Hb 7.7 g/dl, and WBC 94,250/~xl with 21% blastoid cells containing abundant cytoplasm with no Auer bodies and negative to ~-naphthyl butyrate esterase and peroxidase stains. After admission, she was treated unsuccessfully with methotrexate and dibromomannitol. Finally, the blastoid cells increased rapidly in number and she died of heart failure on May 27, 1981. Autopsy was performed. The liver was enlarged and weighed 3300 g. Lymph nodes, liver, lungs, and kidney revealed diffuse infiltration with blastoid cells; lymph nodes and liver also showed myeloid metaplasia. A sample of vertebral bone marrow showed typical features of myelofibrosis.
CYTOGENETIC STUDIES
Cytogenetic studies were performed using short-term culture without PHA. Chromosomal analyses of bone marrow cells in the chronic phase were performed immediately before and after splenectomy, and all 36 megaphases showed a normal karyotype. As shown in Figure 1, however, those of peripheral blood cells in the blastic phase revealed a chromosomal aberration of i(17q) in 44 of 50 metaphases (88%). Furthermore, i(17q) was also observed in three of 30 metaphases (10%) from spleen cells examined 8 months before blastic transformation. DISCUSSION
Among the chronic myeloproliferative disorders, chronic myeloid leukemia (CML) is a very interesting disease cytogenetically, because of the presence of the Philadelphia (Ph) chromosome and the appearance of new additional chromosomal changes, such as trisomy 8, i(17q), and a double Ph, during the course of the disease in more than 75% of the patients [1]. The majority of additional changes occur shortly before or during the blastic phase [2]. On the other hand, some cases of MMM also terminate in blastic transformation [3, 4]. In MMM, however, specific chromosomal aberrations are absent and reports in the blastic phase have been scarce, consisting of only five [5-9] (Table 1). In these reports a Ph-like chromosome or deletion 22q without a reciprocal translocation was observed in two cases, and a l q + in two others. Isochromosome 17q, which was seen in our case, had not been observed in the reported cases, and it often appears in relation to the blastic phase of CML [2]. In 1982, however, Borgst6m et al. [10] suggested that the appearance of i(17q) may be a crucial event in the development of the terminal stage of myeloproliferative disorders, because the chromosomal aberration was observed not only in the blastic
223
i(17q) in a Case of Myelofibrosis
1
2
3
6
7
8
13
14
15
19
20
4
9
21
5
10
11
12
16
17 I~
18
22
X
X
Figure 1 G-banding of a peripheral blood metaphase from our case in blastic transformation. The major clone 46,XX,i(17q) (44 of 50 metaphases) is shown.
phase of Ph-positive CML but also in the terminal stages of acute n o n l y m p h o c y t i c leukemia (ANLL), preleukemia, and Ph-negative CML. Therefore, i(17q) may possibly appear in the blastic phase of MMM as well, although more cases will need to be studied before drawing any final conclusions. In our case, the i(17q) may have a close relation to the abnormal clone of the blastic phase because the cells with i(17q) dominated the blastic phase, whereas, all of the bone marrow cells in the chronic phase revealed a normal karyotype.
Table 1 Case number
Clinical and cytogenetic data of seven patients with MMM in chronic and blastic phase described in the literature Age/Sex
Source ~
Karyotype in chronic phase (%)
Karyotype in blastic phase (%) ND 46,XX,2fragments (22) 44,XX,-C,-D (80) 49,XX, + 11, + 19, with double Phlike markers Ph-like marker with clonal evolution 46,XY,lq + (56) 45,X,-Y,lq + (44) 46,XX,1q + ,t(3;21)
1
70/M
2 3 4
68/F 79/F 54/F
BM BM BM PB, BM, LN
47,XY, + C (95) 46,XX,2 fragments (10) 44,XX,-C,-D ( 2 5 ) ND
5 6
61/F 55/M
PB, BM PB
ND ND
7
60/F
PB
ND
°BM, bone marrow; PB, peripheral blood; LN, lymph node; ND, not done.
Ref. 5 5 5 6 7 8 9
224
H. Nakamura et al.
Furthermore, i(17q) could also be seen in the spleen cells examined 8 months before blastic transformation. In CML, Hossfeld and Schmidt [11] and Mitelman et al. [12] reported that spleen cells revealed additional chromosomal aberrations far more frequently than the bone marrow cells as blastic transformation was drawing near. Accordingly, they suggested that the cells with additional chromosomal aberrations in the blastic phase may originate i n the spleen. In our case with MMM, cytogenetic examination of spleen and bone marrow cells were performed at almost the same time before blastic transformation, and the same chromosomal aberration, i(17q), as observed in the blastic phase could be seen in the former but not in the latter. The findings suggest that the abnormal clone with i(17q), the appearance of which is characteristic of the terminal stage of myeloproliferative disorders, originated in the spleen with myeloid metaplasia. This p h e n o m e n o n observed in our case with MMM might be similar to that of CML reported by Hossfeld and Schmidt [11] and Mitelman et al. [12].
REFERENCES 1. First International Workshop on Chromosomes in Leukemia (1978): Chromosomes in Ph ~positive chronic granulocytic leukemia. Br J Haematol 39:305-309. 2. Sadamori N, Matsunaga M, Yao E, Ichimaru M, Sandberg 3`3` (1985): Chromosomal characteristics of chronic and blastic phase of phi-positive chronic myeloid leukemia. Cancer Genet Cytogenet 15:a7-24. 3. Silverstein MN, Brown 3,L, Linman JW, Minn (1973): Idiopathic myeloid metaplasia: Its evolution into acute leukemia. Arch Intern Ivied 132:709-712. 4. Bouroucle B3,, Coan CA (1962): Clinical, hematologic and pathologic study of 110 patients. Am J Ivied Sci 243:697-715. 5. Jensen MK, Philip P (1973): Cytogenetic studies in haematological disorders which may terminate in acute leukemia. 3,cta IVied Scand 193:353-357. 6. Cehreli C, Ezdinli EZ, Li CY, Krmpotic E (1976): Blastic phase of agnogenic myeloid metaplasia simulating malignant lymphoma. Cancer 38:1297-1305. 7. Page BM, Watt JL, Reid IN, Davidson RJL, Walker W (1979): Clonal evolution of marker chromosomes in a case of myelofibrosis with myeloid metaplasia and myeloblastic transformation. 3,cta Haemat 61:301-309. 8. Baravika I, Bondare D, Jaworkowski L (1980): Die Trisomie des langen 3,rmes des ersten Chromosomes bei einem Patienten mit prim~rer Myelofibrose w~hrend der Blastenkrise. Folia Hematol, Leipzig 107, 6:885-889 (in German). 9. 3,kahoshi M, Takigawa M, Hagiwara N, Oshimi K, Mizoguchi H (1984): A case of primary myelofibrosis terminating in acute megakaryoblastic leukemia: Identification by the demonstration of platelet peroxidase. Japan J Clin Hematol 25:352-358 (in Japanese). 10. Borgstr~m GH, Vuopio P, de la Chapelle 3. (1982): Abnormalities of chromosome no. 17 in myeloproliferative disorders. Cancer Genet Cytoget 5:123-135. 11. Hossfeld DK, Schmidt CG (1973): Chromosomal data suggesting a primary role of the spleen in the pathogenesis of chronic myelocytic leukemia (CIVIL) and blastic phase of CIVIL. In: Chemotherapy of Cancer Dissemination and Metastasis, S Garottini, G Franchi eds. Raven Press, NY. 12. Mitelman F, Brandt L, Nilsson PG (1974): Cytogenetic evidence for splenic origin of biastic transformation in chronic myeloid leukemia. Scand J Haemat 13:87-92.