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A case of lipoblastoma with seven copies of chromosome 8
Cancer Genetics and Cytogenetics 190 (2009) 49e51
Letter to the editor
A case of lipoblastoma with seven copies of chromosome 8 Lipoblastoma is a rare benign mesenchymal tumor of embryonal white fat that usually occurs in infancy and early childhood [1]. Histologically, these lesions are composed of variably differentiated lipoblasts, spindled to stellate mesenchymal cells, a plexiform capillary network, myxoid stroma, and mature adipocytes [2]. Infrequently, mainly in older children and young adults, lipoblasts may be limited in number, or the matrix may show a myxoid appearance with a plexiform vascular pattern, making it difficult to distinguish a lipoblastoma from a typical lipoma or a myxoid liposarcoma, respectively [2]. In such cases, cytogenetic analysis may prove helpful in establishing the final diagnosis. Here, we present a case of lipoblastoma in a 4-year-old boy. The tumor was located on the left shoulder and, upon removal, measured 5.0 3.0 0.5 cm. The cut surface of the tumor mass was yellow-brown, glistening with whiteyellow areas possibly consisting of fat necrosis. Microscopically, the sections examined revealed lobules of mature and immature adipose tissue, separated by wellvascularized fibrous septa (Fig. 1). Myxoid stroma was present, and fat cells showed a spectrum of maturation from primitive stellate cells to spindle cells. Mucoid microcysts were also present. A diagnosis of lipoblastoma was made at that time. Metaphase harvest and slide preparation from tumor cell cultures were as described previously, with minor modifications. G banding was performed using trypsineWright staining. [3]. Twenty G-banded metaphases were analyzed, and the chromosome findings were interpreted according to ISCN 2005 [4]. Of the 20 metaphases analyzed, 10 showed the presence of 7 copies of an apparently normal chromosome 8 (Fig. 2). The first cytogenetic cases of lipoblastoma were reported in 1986 by Sandberg et al. [5]. Since then, O40 cases have been reported [6e10]. These studies demonstrate the importance of chromosome 8 in these tumors, and particularly the chromosomal region 8q11wq13 [11,12]. It has been proposed that rearrangements involving the region 8q11wq13 cause upregulation of the PLAG1 gene through promoter swapping [13]. An alternative mechanism for upregulation of PLAG1 is gain of multiple copies of chromosome 8. Previous FISH and chromosome studies have shown the presence of extra copies of chromosome 8 in lipoblastoma [14,15]. The highest number of apparently normal chromosomes 8 previously detected in 0165-4608/09/$ e see front matter Ó 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.cancergencyto.2008.12.007
a lipoblastoma, using conventional cytogenetic analysis was five [14]. Lipoblastomas with gain of chromosome 8 are uniquely characterized by an alternative oncogenic mechanism, in which genetic dosage results in upregulation of PLAG1. Genetic dosage is a frequent alternative mechanism for gene upregulation, and it has been reported in other malignancies, including myeloid disorders (e.g., trisomy 8), acute lymphoblastic leukemia (various trisomies), chronic lymphoblastic leukemia (e.g., trisomy 12), desmoid tumors (e.g., trisomies 8 and 20), and glioblastoma (trisomy 7), to mention a few [6]. Irrespective of the mechanism, it is reasonable to state that structural and numerical abnormalities of chromosome 8 are recurrent in lipoblastoma and as such are helpful in differentiating this neoplasm from lipoma and myxoid liposarcoma. Specifically, lipomas are generally associated with various rearrangements involving chromosome region 12q13wq15, resulting in deregulation of the HMGA2 gene [16,17], and myxoid liposarcomas are characteristically associated with a t(12;16)(q13;p11), resulting in a DDIT3eFUS fusion gene [18]. Analysis of additional cases of lipoblastoma with gain of chromosome 8 may further clarify the existence of two distinct mechanisms resulting in upregulation of the PLAG1 gene in this benign tumor.
Fig. 1. Biopsy specimen of lipoblastoma showing lobules of mature and immature adipose tissue, separated by well-vascularized fibrous septae. Hematoxylineeosin stain; original magnification, 40.
Letter to the editor / Cancer Genetics and Cytogenetics 190 (2009) 49e51
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Fig. 2. G-banded karyogram showing 7 copies of chromosome 8.
Aurelia M. Meloni-Ehrig Laura Riggott Nicole C. Christacos Philip N. Mowrey Department of Cytogenetics, Quest Diagnostics Nichols Institute, 14225 Newbrook Drive, Chantilly, VA 20151 E-mail address: aurelia.m.meloni-ehrig@questdiagnos tics.com (A. Meloni-Ehrig) Jasbir Johal Department of Pathology, Inova Fairfax Hospital Lab, Falls Church, VA 22042
References [1] Sciot R, Mandahl N. Lipoblastoma/lipoblastomatosis. In: Fletcher CDM, Unni KK, Mertens F, editors. Pathology and genetics of tumours of soft tissue and bone. World Health Organization Classification of Tumours. Lyon: IARC Press, 2002. pp. 26e7. [2] Enzinger FM, Weiss SW. Benign lipomatous tumors. In: Soft tissue tumors. 3rd ed.. St. Louis: Mosby, 1995. pp. 401e5. [3] Limon J, Dal Cin P, Sandberg AA. Application of long-term collagenase disaggregation for the cytogenetic analysis of human solid tumors. Cancer Genet Cytogenet 1986;23:305e13. [4] Shaffer LG, Tommerup N, editors. ISCN 2005: an international system for human cytogenetic nomenclature (2005). Basel: S. Karger, 2005. [5] Sandberg AA, Gibas Z, Saren E, Li FP, Limon J, Tebbi CK. Chromosome abnormalities in two benign adipose tumors. Cancer Genet Cytogenet 1986;22:55e61. [6] Morerio C, Panarello C. Soft tissue tumors: lipoblastoma. In: Huret JL, editor. Atlas of genetics and cytogenetics in oncology and haematology. Updated January 2005. Available at: http://Atlas
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
GeneticsOncology.org/Genes/LipoblastomaID5155.html. Accessed August 18, 2008. Batanian JR, Brink DS, Thorpe CM, Haddad BR. Case of lipoblastoma with two derivative chromosomes 8 containing homogeneously staining-like regions and a review of the literature: lipoblastoma and chromosome 8. Cancer Genet Cytogenet 2001;125:10e3. Ohjimi Y, Iwasaki H, Kaneko Y, Ishiguro M, Ohgami A, Kikuchi M. A case of lipoblastoma with t(3;8)(q12;q11.2). Cancer Genet Cytogenet 1992;62:103e5. Fletcher JA, Kozakewich HP, Schoenberg ML, Morton CC. Cytogenetic findings in pediatric adipose tumors (consistent rearrangement of chromosome 8 in lipoblastoma). Genes Chromosomes Cancer 1993;6:24e9. Sawyer JR, Parsons EA, Crowson ML, Smith S, Erickson S, Bell JM. Potential diagnostic implications of breakpoints in the long arm of chromosome 8 in lipoblastoma. Cancer Genet Cytogenet 1994;76: 39e42. Dal Cin P, Sciot R, De Wever I, Van Damme B. Van den Berghe H. New discriminative chromosomal marker in adipose tissue tumors (the chromosome 8q11-q13 region in lipoblastoma). Cancer Genet Cytogenet 1994;78:232e5. Brandal P, Bjerkehagen B, Heim S. Rearrangement of chromosomal region 8q11-13 in lipomatous tumours: correlation with lipoblastoma morphology. J Pathol 2006;208:388e94. Hibbard MK, Kozakewich HP, Dal Cin P, Sciot R, Tan X, Xiao S, Fletcher JA. PLAG1 fusion oncogenes in lipoblastoma. Cancer Res 2000;60:4869e72. Gisselsson D, Hibbard MK, Dal Cin P, Sciot R, Hsi BL, Kozakewich HP, Fletcher JA. PLAG1 alterations in lipoblastoma: involvement in varied mesenchymal cell types and evidence for alternative oncogenic mechanisms. Am J Pathol 2001;159:955e62. de Saint Aubain Somerhausen N, Coindre JM, Debiec-Rychter M, Delplace J, Sciot R. Lipoblastoma in adolescents and young adults: report of six cases with FISH analysis. Histopathology 2008;52: 294e8. Bartuma H, Hallor KH, Panagopoulos I, Collin A, Rydholm A, Gustafson P, Bauer HC, Brosjo¨ O, Domanski HA, Mandahl N,
Letter to the editor / Cancer Genetics and Cytogenetics 190 (2009) 49e51 Mertens F. Assessment of the clinical and molecular impact of different cytogenetic subgroups in a series of 272 lipomas with abnormal karyotype. Genes Chromosomes Cancer 2007;46:594e606. [17] Mandahl N, Heim S, Arheden K, Rydholm A, Wille´n H, Mitelman F. Three major cytogenetic subgroups can be identified among chromosomally abnormal solitary lipomas. Hum Genet 1988;79:203e8.
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[18] Tallini G, Akerman M, Dal Cin P, DeWever I, Fletcher CDM, Mandahl N, Mertens F, Mitelman F, Rosai J, Rydholm A, Sciot R. Van den Berghe H, Van den Ven W, Vanni R, Willen H. Combined morphologic and karyotypic study of 28 myxoid liposarcomas: implications for a revised morphologic typing (a report from the CHAMP group). Am J Surg Pathol 1996;20:1047e55.
Letter to the editor
A case of lipoblastoma with seven copies of chromosome 8 Lipoblastoma is a rare benign mesenchymal tumor of embryonal white fat that usually occurs in infancy and early childhood [1]. Histologically, these lesions are composed of variably differentiated lipoblasts, spindled to stellate mesenchymal cells, a plexiform capillary network, myxoid stroma, and mature adipocytes [2]. Infrequently, mainly in older children and young adults, lipoblasts may be limited in number, or the matrix may show a myxoid appearance with a plexiform vascular pattern, making it difficult to distinguish a lipoblastoma from a typical lipoma or a myxoid liposarcoma, respectively [2]. In such cases, cytogenetic analysis may prove helpful in establishing the final diagnosis. Here, we present a case of lipoblastoma in a 4-year-old boy. The tumor was located on the left shoulder and, upon removal, measured 5.0 3.0 0.5 cm. The cut surface of the tumor mass was yellow-brown, glistening with whiteyellow areas possibly consisting of fat necrosis. Microscopically, the sections examined revealed lobules of mature and immature adipose tissue, separated by wellvascularized fibrous septa (Fig. 1). Myxoid stroma was present, and fat cells showed a spectrum of maturation from primitive stellate cells to spindle cells. Mucoid microcysts were also present. A diagnosis of lipoblastoma was made at that time. Metaphase harvest and slide preparation from tumor cell cultures were as described previously, with minor modifications. G banding was performed using trypsineWright staining. [3]. Twenty G-banded metaphases were analyzed, and the chromosome findings were interpreted according to ISCN 2005 [4]. Of the 20 metaphases analyzed, 10 showed the presence of 7 copies of an apparently normal chromosome 8 (Fig. 2). The first cytogenetic cases of lipoblastoma were reported in 1986 by Sandberg et al. [5]. Since then, O40 cases have been reported [6e10]. These studies demonstrate the importance of chromosome 8 in these tumors, and particularly the chromosomal region 8q11wq13 [11,12]. It has been proposed that rearrangements involving the region 8q11wq13 cause upregulation of the PLAG1 gene through promoter swapping [13]. An alternative mechanism for upregulation of PLAG1 is gain of multiple copies of chromosome 8. Previous FISH and chromosome studies have shown the presence of extra copies of chromosome 8 in lipoblastoma [14,15]. The highest number of apparently normal chromosomes 8 previously detected in 0165-4608/09/$ e see front matter Ó 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.cancergencyto.2008.12.007
a lipoblastoma, using conventional cytogenetic analysis was five [14]. Lipoblastomas with gain of chromosome 8 are uniquely characterized by an alternative oncogenic mechanism, in which genetic dosage results in upregulation of PLAG1. Genetic dosage is a frequent alternative mechanism for gene upregulation, and it has been reported in other malignancies, including myeloid disorders (e.g., trisomy 8), acute lymphoblastic leukemia (various trisomies), chronic lymphoblastic leukemia (e.g., trisomy 12), desmoid tumors (e.g., trisomies 8 and 20), and glioblastoma (trisomy 7), to mention a few [6]. Irrespective of the mechanism, it is reasonable to state that structural and numerical abnormalities of chromosome 8 are recurrent in lipoblastoma and as such are helpful in differentiating this neoplasm from lipoma and myxoid liposarcoma. Specifically, lipomas are generally associated with various rearrangements involving chromosome region 12q13wq15, resulting in deregulation of the HMGA2 gene [16,17], and myxoid liposarcomas are characteristically associated with a t(12;16)(q13;p11), resulting in a DDIT3eFUS fusion gene [18]. Analysis of additional cases of lipoblastoma with gain of chromosome 8 may further clarify the existence of two distinct mechanisms resulting in upregulation of the PLAG1 gene in this benign tumor.
Fig. 1. Biopsy specimen of lipoblastoma showing lobules of mature and immature adipose tissue, separated by well-vascularized fibrous septae. Hematoxylineeosin stain; original magnification, 40.
Letter to the editor / Cancer Genetics and Cytogenetics 190 (2009) 49e51
50
Fig. 2. G-banded karyogram showing 7 copies of chromosome 8.
Aurelia M. Meloni-Ehrig Laura Riggott Nicole C. Christacos Philip N. Mowrey Department of Cytogenetics, Quest Diagnostics Nichols Institute, 14225 Newbrook Drive, Chantilly, VA 20151 E-mail address: aurelia.m.meloni-ehrig@questdiagnos tics.com (A. Meloni-Ehrig) Jasbir Johal Department of Pathology, Inova Fairfax Hospital Lab, Falls Church, VA 22042
References [1] Sciot R, Mandahl N. Lipoblastoma/lipoblastomatosis. In: Fletcher CDM, Unni KK, Mertens F, editors. Pathology and genetics of tumours of soft tissue and bone. World Health Organization Classification of Tumours. Lyon: IARC Press, 2002. pp. 26e7. [2] Enzinger FM, Weiss SW. Benign lipomatous tumors. In: Soft tissue tumors. 3rd ed.. St. Louis: Mosby, 1995. pp. 401e5. [3] Limon J, Dal Cin P, Sandberg AA. Application of long-term collagenase disaggregation for the cytogenetic analysis of human solid tumors. Cancer Genet Cytogenet 1986;23:305e13. [4] Shaffer LG, Tommerup N, editors. ISCN 2005: an international system for human cytogenetic nomenclature (2005). Basel: S. Karger, 2005. [5] Sandberg AA, Gibas Z, Saren E, Li FP, Limon J, Tebbi CK. Chromosome abnormalities in two benign adipose tumors. Cancer Genet Cytogenet 1986;22:55e61. [6] Morerio C, Panarello C. Soft tissue tumors: lipoblastoma. In: Huret JL, editor. Atlas of genetics and cytogenetics in oncology and haematology. Updated January 2005. Available at: http://Atlas
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
GeneticsOncology.org/Genes/LipoblastomaID5155.html. Accessed August 18, 2008. Batanian JR, Brink DS, Thorpe CM, Haddad BR. Case of lipoblastoma with two derivative chromosomes 8 containing homogeneously staining-like regions and a review of the literature: lipoblastoma and chromosome 8. Cancer Genet Cytogenet 2001;125:10e3. Ohjimi Y, Iwasaki H, Kaneko Y, Ishiguro M, Ohgami A, Kikuchi M. A case of lipoblastoma with t(3;8)(q12;q11.2). Cancer Genet Cytogenet 1992;62:103e5. Fletcher JA, Kozakewich HP, Schoenberg ML, Morton CC. Cytogenetic findings in pediatric adipose tumors (consistent rearrangement of chromosome 8 in lipoblastoma). Genes Chromosomes Cancer 1993;6:24e9. Sawyer JR, Parsons EA, Crowson ML, Smith S, Erickson S, Bell JM. Potential diagnostic implications of breakpoints in the long arm of chromosome 8 in lipoblastoma. Cancer Genet Cytogenet 1994;76: 39e42. Dal Cin P, Sciot R, De Wever I, Van Damme B. Van den Berghe H. New discriminative chromosomal marker in adipose tissue tumors (the chromosome 8q11-q13 region in lipoblastoma). Cancer Genet Cytogenet 1994;78:232e5. Brandal P, Bjerkehagen B, Heim S. Rearrangement of chromosomal region 8q11-13 in lipomatous tumours: correlation with lipoblastoma morphology. J Pathol 2006;208:388e94. Hibbard MK, Kozakewich HP, Dal Cin P, Sciot R, Tan X, Xiao S, Fletcher JA. PLAG1 fusion oncogenes in lipoblastoma. Cancer Res 2000;60:4869e72. Gisselsson D, Hibbard MK, Dal Cin P, Sciot R, Hsi BL, Kozakewich HP, Fletcher JA. PLAG1 alterations in lipoblastoma: involvement in varied mesenchymal cell types and evidence for alternative oncogenic mechanisms. Am J Pathol 2001;159:955e62. de Saint Aubain Somerhausen N, Coindre JM, Debiec-Rychter M, Delplace J, Sciot R. Lipoblastoma in adolescents and young adults: report of six cases with FISH analysis. Histopathology 2008;52: 294e8. Bartuma H, Hallor KH, Panagopoulos I, Collin A, Rydholm A, Gustafson P, Bauer HC, Brosjo¨ O, Domanski HA, Mandahl N,
Letter to the editor / Cancer Genetics and Cytogenetics 190 (2009) 49e51 Mertens F. Assessment of the clinical and molecular impact of different cytogenetic subgroups in a series of 272 lipomas with abnormal karyotype. Genes Chromosomes Cancer 2007;46:594e606. [17] Mandahl N, Heim S, Arheden K, Rydholm A, Wille´n H, Mitelman F. Three major cytogenetic subgroups can be identified among chromosomally abnormal solitary lipomas. Hum Genet 1988;79:203e8.
51
[18] Tallini G, Akerman M, Dal Cin P, DeWever I, Fletcher CDM, Mandahl N, Mertens F, Mitelman F, Rosai J, Rydholm A, Sciot R. Van den Berghe H, Van den Ven W, Vanni R, Willen H. Combined morphologic and karyotypic study of 28 myxoid liposarcomas: implications for a revised morphologic typing (a report from the CHAMP group). Am J Surg Pathol 1996;20:1047e55.