SHORT COMMUNICATIONS Myelodysplastic
Syndrome
and Trisomy 14q
Paul Tumewu and Gordon Royle
ABSTRACT: Trisomy 14 as Q sole karyotypic abnormality in neopJasia is extremely rare. Jn hematoJogic disorders, 18 cases have been reported so far, 17 of which involved disorders of the myeloid lineage. Five were cases of myeJodyspJastic syndrome (MDS), and Q further four involved Philadelphia-negative atypical chronic myeloid leukemia. The case presented here is the second case of trisomy 14q in MDS involving the chronic myelomonocytic leukemia subtype. There were certain features in common with some of the previously reported cases. We raise the possibility that this represents a specific entity.
INTRODUCTION Trisomies as the sole karyotypic change are reported in 6-7s of human malignancies. The most common chromosomes involved are 8,9,12, and 21, which occur in association with specific neoplasms [l]. Myelodysplastic syndrome (MDS) is characterized by a pattern of nonrandom chromosome abnormalities. A finding of trisomy 14 associated with MDS is exceedingly rare [2, 31. To date, only five cases have been reported [4-71. We now report a sixth case of trisomy 14 in MDS. This is the second case occurring in the chronic myelomonocytic leukemia (CMMOL) subtype (MDS-CMMOL).
CASE REPORT A 74-year-old male Caucasian (case TP) was referred for investigation of possible MDS following the finding of monocytosis, thrombocytopenia, and red cell abnormalities. He gave a history of 8 months’ anorexia, tiredness, and dyspnea. There was no past history of significance, and examination revealed no additional findings of note. At the time of presentation, hemoglobin was 116 g/l, white blood cell count 38.0 x log/L, monocytes 16 X log/L, and platelet count 60 x log/L. The bone marrow biopsy taken from the right posterior iliac crest showed increased promyelocytes (27% of the total marrow population) and blasts (14%) with large and giant forms and dysplastic features. Megakaryocytes were markedly increased [up to 10% in some areas) with many small, immature, hypoploid, or mononuclear forms and other dysplastic features noted. There was a mild diffuse increase in reticulin. A diagnosis of MDS-CMML was
From the Cytogenetics Department (P. T.J, Princess Mary Hospital, Auckland Hospital, and Haematology Department [G. R.), Auckland Hospital, Auckland, New Zealand. Address reprint requests to: Dr. Paul Tumewu, Scientific Officer, Cytogenetics Department, Princess Mary Hospital, Private Bag, Auckland, New Zealand. Received October 17, 1991; accepted June 12, 1992.
made. The bone marrow was reviewed by a referral hematopathologist and the diagnosis confirmed. No treatment was undertaken, and the patient returned to his home country. Cytogenetics Cytogenetic analysis of the bone marrow aspirate using GTG banding methods and both direct and synchronized 24-hour cultures revealed one major cell line (18/20 cells observed) with 47,XY, + 14 karyotype and a minor cell line (2/20 cells observed) with a 46,XY karyotype.
DISCUSSION This is the sixth published case of trisomy 14q associated with MDS. The six cases and their karyotypic data are listed in Table 1. Five of the six cases were male, mean age 71. The predominance of male cases is statistically significant when compared to the expected value of three (Z test, p = 0.05). Furthermore, the one female case was an exception in several other ways: She was a triple-cell-line mosaic (see Table l), her age was significantly lower (4.7 SD) than that of the males, and her MDS transformed to acute nonlymphoblastic leukemia (ANLL). Of the five cases for which data is available, three showed increased megakaryocytes, and all five cases showed megakaryocyte dysplasia. This data raises the possibility that trisomy 14q occurring as the sole abnormality may be associated with certain specific features within the MDS group. Nowell and Finan [7] reported a case of pancytopenia and trisomy 14q transforming to ANLL, which the authors termed preJeukemia but that would now likely be classified as MDS (age and gender not specified). There have also been five further reports of trisomy 14q in Philadelphianegative atypical chronic myeloid leukemia (CML), four of which had a monocytosis [8, 91. In all cases trisomy 14q was the sole karyotypic abnormality. Ages were 61, 81, 84, 64, and 78, and three were male. In two of the cases reported by Mertens et al. [8], DNA analysis was performed, and no bcr rearrangement was detected, further reinforcing the atypical nature of these as cases of CML. All these patients 91
0 1992 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010
Cancer Genet Cytogenet 64:91-92 0165-4606/92/$05.00
(1992)
92
P. T u m e w u and G. Royle
Table 1
Reported cases of MDS and their karyotype
Ref.
MDS Subtype
Sex
Age
Present report 4 16 6 6 5
CMMOL
M
74
incr, dysp
46,XY/47,XY, + 14
CMMOL RA RA RAEB RAEB
M M M F M
77 67 74 40 61
incr, dysp Not mentioned incr, dysp incr, dysp dysp
46,XY/46,XY,i(14q) 45,X,i(14q),-Y 46,XY/46,XY,i(14q) 46,XX/46,XX,t(1;13)/47,XX, + 14 46,XY/47,XY, + 14
may in fact represent further cases of MDS, potentially bringing the total to 12. Trisomy 14q occurring as the sole abnormality in hematologic disorders has with one exception been reported only in myeloid malignancies. Until recently the majority of reports involved cases of ANLL. This led to the suggestion that trisomy 14q was specifically associated with ANLL [10]. While our findings provide further support for the association of trisomy 14q with myeloid malignancies, we also note that it has been reported more c o m m o n l y in myelodysplastic/atypical myeloproliferative syndromes. It is possible that in cases where trisomy 14q is reported in ANLL, this may represent blast transformation in preexisting MDS. If this were so, it w o u l d raise the possibility that trisomy 14q may, like other karyotypic abnormalities that occur as specific entities in MDS (eg 5 q - ) , be associated with its own u n i q u e set of clinical and/or pathologic features i n d e p e n d e n t of whether the morphologic diagnosis in MDS or ANLL [11, 12]. Further data will be required to determine whether the prognosis is altered by the presence of trisomy 14q. The association between the presence of an additional 14q and myeloid malignancy raises the possibility that there is some myeloid oncogene or other growth regulator on 14q that is contributing to leukemogenesis. The following are k n o w n to reside on chromosome 14q: c-fos and c-elk2 are both nuclear transcription factors [13]; tcl-1 [14] and akt-1 [15] are less well defined oncogenes; TGF~3 is the only growth factor gene; and TCRc~/8 are the T cell receptor a and 8 genes [14]. A n y direct relationship between these genes and MDS remains speculative. In summary, trisomy 14q as a sole karyotypic abnormality in hematologic disorders is almost exclusively confined to the myeloid lineage and may be a specific entity in MDS.
Megakaryocyte
3. 4.
5.
6.
7.
8.
9.
10.
11.
12. 13. 14. 15.
REFERENCES 1. Heim S, Mittelman F (1986): Numerical chromosome aberra-
tions in human neoplasia. Cancer Genet Cytogenet 22:99-108. 2. Loughran TP, Kadin ME, Starkebaum G, Abkowitz TL, Clark EA, Disteche C, Lum LG, Slichter SJ (1985): Leukemia of large
16.
Karyotype
granular lymphocytes: association with clonal chromosome abnormalities and autoimmune neutropenia, thrombocytopenia and hemolytic anemia. Ann Intern Med 102:169-175. Mittelman F (1988): Catalogue of Chromosome Aberrations in Cancer, 3rd Ed. Alan R Liss, New York. Ribera JM, Aventin A, Milla F, Las Heras G (1991): Isochromosome 14q in chronic myelomonocytic leukaemia. Cancer Genet Cytogenet 52:139-140. Haas OA, Jager u, Ambros, Pabinger I (1987): Trisomy 14 in refractory anemia with excess of blasts in transformation. Cancer Genet Cytogenet 29:315-318. Pinkerton PH, London B, Dube ID, Senn JS (1990): Trisomy 14q in myelodysplastic syndromes. Cancer Genet Cytogenet 49:113-116. Nowell P, Finan J (1978): Chromosome studies in preleukemic states IV. Myeloproliferative versus cytopenic disorders. Cancer 42:2254-2261. Mertens F, Johansson B, Heim S, Kristoffersson U, Turesson I, Maim C, Othzen A, Bartram CR, Catovsky D, Mittelman F (1990): Trisomy 14 in atypical chronic myeloid leukaemia. Leukemia 4:117-120. Shashaty GG, Baumiller RC (1980): Philadelphia chromosomenegative chronic myelogenous leukemia with trisomy D, Arch Pathol Lab Med 104:376-378. Meloni-Balliet A, Morgan R, Poth JI, Kingsley EC, Sandberg AA (1989): Trisomy 14: A new entity within acute nonlymphocytic leukemia. Cancer Genet Cytogenet 44:35-38. Estey EH, Keating MJ, Dixon DO, et al. (1987): Karyotype is prognostically more important than the FAB system's distinction between myelodysplastic syndrome and acute myelogenous leukaemia. Haematol Pathol 1:203. Van den Berghe H, Vermaelen K, Mecucci C, Barbieri D, Tricot G (1985): The 5q-anomaly. Cancer Genet Cytogenet 17: 189-255. Gutman A, Wasylyk B (1991): Nuclear targets for transcription regulation by oncogenes. TIG 7:49-54. Rowley JD (1990): Molecular cytogenetics: Rosetta Stone for understanding cancer--twenty-ninth G.H.A. Clowes Memorial Award Lecture. Cancer Res 50:3816-3825. Park M and Vande Woude GF (1989): Oncogenes: genes associated with neoplastic disease. In: The Metabolic Basis of Inherited Disease, 6th Ed. Scriver CR, Beaudet AL, Sly WS, Valle D, eds. McGraw-Hill, New York, pp. 251-288. Sole F, Caballin MR, Woessner S, Besses C, Palou L, Egozcue J (1991): Isochromosome 14q in myeloid dysplastic disorder. Cancer Genet Cytogenet 54:133-134.
Syndrome
and Trisomy 14q
Paul Tumewu and Gordon Royle
ABSTRACT: Trisomy 14 as Q sole karyotypic abnormality in neopJasia is extremely rare. Jn hematoJogic disorders, 18 cases have been reported so far, 17 of which involved disorders of the myeloid lineage. Five were cases of myeJodyspJastic syndrome (MDS), and Q further four involved Philadelphia-negative atypical chronic myeloid leukemia. The case presented here is the second case of trisomy 14q in MDS involving the chronic myelomonocytic leukemia subtype. There were certain features in common with some of the previously reported cases. We raise the possibility that this represents a specific entity.
INTRODUCTION Trisomies as the sole karyotypic change are reported in 6-7s of human malignancies. The most common chromosomes involved are 8,9,12, and 21, which occur in association with specific neoplasms [l]. Myelodysplastic syndrome (MDS) is characterized by a pattern of nonrandom chromosome abnormalities. A finding of trisomy 14 associated with MDS is exceedingly rare [2, 31. To date, only five cases have been reported [4-71. We now report a sixth case of trisomy 14 in MDS. This is the second case occurring in the chronic myelomonocytic leukemia (CMMOL) subtype (MDS-CMMOL).
CASE REPORT A 74-year-old male Caucasian (case TP) was referred for investigation of possible MDS following the finding of monocytosis, thrombocytopenia, and red cell abnormalities. He gave a history of 8 months’ anorexia, tiredness, and dyspnea. There was no past history of significance, and examination revealed no additional findings of note. At the time of presentation, hemoglobin was 116 g/l, white blood cell count 38.0 x log/L, monocytes 16 X log/L, and platelet count 60 x log/L. The bone marrow biopsy taken from the right posterior iliac crest showed increased promyelocytes (27% of the total marrow population) and blasts (14%) with large and giant forms and dysplastic features. Megakaryocytes were markedly increased [up to 10% in some areas) with many small, immature, hypoploid, or mononuclear forms and other dysplastic features noted. There was a mild diffuse increase in reticulin. A diagnosis of MDS-CMML was
From the Cytogenetics Department (P. T.J, Princess Mary Hospital, Auckland Hospital, and Haematology Department [G. R.), Auckland Hospital, Auckland, New Zealand. Address reprint requests to: Dr. Paul Tumewu, Scientific Officer, Cytogenetics Department, Princess Mary Hospital, Private Bag, Auckland, New Zealand. Received October 17, 1991; accepted June 12, 1992.
made. The bone marrow was reviewed by a referral hematopathologist and the diagnosis confirmed. No treatment was undertaken, and the patient returned to his home country. Cytogenetics Cytogenetic analysis of the bone marrow aspirate using GTG banding methods and both direct and synchronized 24-hour cultures revealed one major cell line (18/20 cells observed) with 47,XY, + 14 karyotype and a minor cell line (2/20 cells observed) with a 46,XY karyotype.
DISCUSSION This is the sixth published case of trisomy 14q associated with MDS. The six cases and their karyotypic data are listed in Table 1. Five of the six cases were male, mean age 71. The predominance of male cases is statistically significant when compared to the expected value of three (Z test, p = 0.05). Furthermore, the one female case was an exception in several other ways: She was a triple-cell-line mosaic (see Table l), her age was significantly lower (4.7 SD) than that of the males, and her MDS transformed to acute nonlymphoblastic leukemia (ANLL). Of the five cases for which data is available, three showed increased megakaryocytes, and all five cases showed megakaryocyte dysplasia. This data raises the possibility that trisomy 14q occurring as the sole abnormality may be associated with certain specific features within the MDS group. Nowell and Finan [7] reported a case of pancytopenia and trisomy 14q transforming to ANLL, which the authors termed preJeukemia but that would now likely be classified as MDS (age and gender not specified). There have also been five further reports of trisomy 14q in Philadelphianegative atypical chronic myeloid leukemia (CML), four of which had a monocytosis [8, 91. In all cases trisomy 14q was the sole karyotypic abnormality. Ages were 61, 81, 84, 64, and 78, and three were male. In two of the cases reported by Mertens et al. [8], DNA analysis was performed, and no bcr rearrangement was detected, further reinforcing the atypical nature of these as cases of CML. All these patients 91
0 1992 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010
Cancer Genet Cytogenet 64:91-92 0165-4606/92/$05.00
(1992)
92
P. T u m e w u and G. Royle
Table 1
Reported cases of MDS and their karyotype
Ref.
MDS Subtype
Sex
Age
Present report 4 16 6 6 5
CMMOL
M
74
incr, dysp
46,XY/47,XY, + 14
CMMOL RA RA RAEB RAEB
M M M F M
77 67 74 40 61
incr, dysp Not mentioned incr, dysp incr, dysp dysp
46,XY/46,XY,i(14q) 45,X,i(14q),-Y 46,XY/46,XY,i(14q) 46,XX/46,XX,t(1;13)/47,XX, + 14 46,XY/47,XY, + 14
may in fact represent further cases of MDS, potentially bringing the total to 12. Trisomy 14q occurring as the sole abnormality in hematologic disorders has with one exception been reported only in myeloid malignancies. Until recently the majority of reports involved cases of ANLL. This led to the suggestion that trisomy 14q was specifically associated with ANLL [10]. While our findings provide further support for the association of trisomy 14q with myeloid malignancies, we also note that it has been reported more c o m m o n l y in myelodysplastic/atypical myeloproliferative syndromes. It is possible that in cases where trisomy 14q is reported in ANLL, this may represent blast transformation in preexisting MDS. If this were so, it w o u l d raise the possibility that trisomy 14q may, like other karyotypic abnormalities that occur as specific entities in MDS (eg 5 q - ) , be associated with its own u n i q u e set of clinical and/or pathologic features i n d e p e n d e n t of whether the morphologic diagnosis in MDS or ANLL [11, 12]. Further data will be required to determine whether the prognosis is altered by the presence of trisomy 14q. The association between the presence of an additional 14q and myeloid malignancy raises the possibility that there is some myeloid oncogene or other growth regulator on 14q that is contributing to leukemogenesis. The following are k n o w n to reside on chromosome 14q: c-fos and c-elk2 are both nuclear transcription factors [13]; tcl-1 [14] and akt-1 [15] are less well defined oncogenes; TGF~3 is the only growth factor gene; and TCRc~/8 are the T cell receptor a and 8 genes [14]. A n y direct relationship between these genes and MDS remains speculative. In summary, trisomy 14q as a sole karyotypic abnormality in hematologic disorders is almost exclusively confined to the myeloid lineage and may be a specific entity in MDS.
Megakaryocyte
3. 4.
5.
6.
7.
8.
9.
10.
11.
12. 13. 14. 15.
REFERENCES 1. Heim S, Mittelman F (1986): Numerical chromosome aberra-
tions in human neoplasia. Cancer Genet Cytogenet 22:99-108. 2. Loughran TP, Kadin ME, Starkebaum G, Abkowitz TL, Clark EA, Disteche C, Lum LG, Slichter SJ (1985): Leukemia of large
16.
Karyotype
granular lymphocytes: association with clonal chromosome abnormalities and autoimmune neutropenia, thrombocytopenia and hemolytic anemia. Ann Intern Med 102:169-175. Mittelman F (1988): Catalogue of Chromosome Aberrations in Cancer, 3rd Ed. Alan R Liss, New York. Ribera JM, Aventin A, Milla F, Las Heras G (1991): Isochromosome 14q in chronic myelomonocytic leukaemia. Cancer Genet Cytogenet 52:139-140. Haas OA, Jager u, Ambros, Pabinger I (1987): Trisomy 14 in refractory anemia with excess of blasts in transformation. Cancer Genet Cytogenet 29:315-318. Pinkerton PH, London B, Dube ID, Senn JS (1990): Trisomy 14q in myelodysplastic syndromes. Cancer Genet Cytogenet 49:113-116. Nowell P, Finan J (1978): Chromosome studies in preleukemic states IV. Myeloproliferative versus cytopenic disorders. Cancer 42:2254-2261. Mertens F, Johansson B, Heim S, Kristoffersson U, Turesson I, Maim C, Othzen A, Bartram CR, Catovsky D, Mittelman F (1990): Trisomy 14 in atypical chronic myeloid leukaemia. Leukemia 4:117-120. Shashaty GG, Baumiller RC (1980): Philadelphia chromosomenegative chronic myelogenous leukemia with trisomy D, Arch Pathol Lab Med 104:376-378. Meloni-Balliet A, Morgan R, Poth JI, Kingsley EC, Sandberg AA (1989): Trisomy 14: A new entity within acute nonlymphocytic leukemia. Cancer Genet Cytogenet 44:35-38. Estey EH, Keating MJ, Dixon DO, et al. (1987): Karyotype is prognostically more important than the FAB system's distinction between myelodysplastic syndrome and acute myelogenous leukaemia. Haematol Pathol 1:203. Van den Berghe H, Vermaelen K, Mecucci C, Barbieri D, Tricot G (1985): The 5q-anomaly. Cancer Genet Cytogenet 17: 189-255. Gutman A, Wasylyk B (1991): Nuclear targets for transcription regulation by oncogenes. TIG 7:49-54. Rowley JD (1990): Molecular cytogenetics: Rosetta Stone for understanding cancer--twenty-ninth G.H.A. Clowes Memorial Award Lecture. Cancer Res 50:3816-3825. Park M and Vande Woude GF (1989): Oncogenes: genes associated with neoplastic disease. In: The Metabolic Basis of Inherited Disease, 6th Ed. Scriver CR, Beaudet AL, Sly WS, Valle D, eds. McGraw-Hill, New York, pp. 251-288. Sole F, Caballin MR, Woessner S, Besses C, Palou L, Egozcue J (1991): Isochromosome 14q in myeloid dysplastic disorder. Cancer Genet Cytogenet 54:133-134.
