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Complex Karyotype in a Childhood Adrenocortical Carcinoma
Complex Karyotype in a Childhood Adrenocortical Carcinoma Fredrik Mertens, Carl-Magnus Kullendorff, Christian Moëll, Jan Alumets, and Nils Mandahl
ABSTRACT: Cytogenetic analysis of short-term cultured cells from an 11-cm adrenocortical carcinoma in a 3.5-year-old girl revealed the karyotype 46,XX,inv(9)(p11q12)c[2]/56–57,XX,⫹2,⫹4,⫹5,⫹7,⫹8, inv(9)c,⫹10,⫹add(13)(p11),⫹14,⫹15,⫹19,⫹20,⫹20,⫹mar[cp19]. To our knowledge, this is the first description of an abnormal karyotype in a pediatric adrenocortical tumor. Inasmuch as the distinction between benign and malignant adrenocortical tumors is often difficult to make from clinical and histopathologic data alone, the present findings suggest that cytogenetic analysis may be a valuable adjunct in the differential diagnosis. © Elsevier Science Inc., 1998
INTRODUCTION Primary carcinomas of the adrenal cortex are exceedingly rare tumors, with an annual incidence of about two persons per million inhabitants. Benign adrenocortical tumors may be about 10,000 times as frequent, judging from reported series of incidentally detected adenomas at autopsies or by computerized tomographic (CT) scans of the upper abdomen [1–3]. There are no clear clinical or histopathologic features unequivocally distinguishing the benign from the malignant adrenocortical tumor. In general, however, adenomas are relatively small (size ⬍5 cm, weight ⬍100 g), rarely cause adrenogenital syndromes, and display few or no mitoses, tumor necrosis, or cellular pleomorphism at microscopy. Carcinomas, on the other hand, are often larger (size ⬎5 cm, weight 100–5,000 g), sometimes cause weight loss and feminization or virilism, and may display classical histopathological malignancy features such as increased mitotic activity, cellular pleomorphism, tumor necrosis, and vascular invasion [3]. In recent years, several attempts to utilize the genetic characteristics of the tumor cells for diagnostic as well as prognostic purposes have been made, sometimes with conflicting results. DNA flow cytometry studies have shown that nondiploid cell populations are more frequently detected among histologically malignant tumors, but as many
From the Department of Clinical Genetics (F. M., N. M.), the Department of Pediatric Surgery (C.-M. K.), the Department of Pediatrics (C. M.), and the Department of Pathology (J. A.), University Hospital, Lund, Sweden. Address reprint requests to: Fredrik Mertens, Department of Clinical Genetics, University Hospital, S-221 85 Lund, Sweden. Received June 28, 1997; accepted January 13, 1998. Cancer Genet Cytogenet 105:190–192 (1998) Elsevier Science Inc., 1998 655 Avenue of the Americas, New York, NY 10010
as one-fifth of the adenomas may be aneuploid, too [4–6]. Molecular genetic analysis of allelic imbalances on chromosomes 11, 13, and 17 has revealed frequent losses on 11p, 13q, and 17p in carcinomas but not in adenomas or hyperplastic lesions [7]. The same three chromosome arms were found to be deleted relatively often in a series of eight carcinomas analyzed by comparative genomic hybridization (CGH) [8]. In that study, only 2 of 12 benign lesions were shown to have abnormal CGH profiles, and the results indicated a good correspondence between tumor size and total number of gains and losses and between presence of imbalances and malignant clinical features [8]. Very few cytogenetic investigations of adrenocortical tumors have been reported. The only recurrent change among 15 analyzed aldosterone-producing adenomas was loss of the Y chromosome, detected in five cases [9, 10]. Of the four carcinomas with clonal aberrations that have been described, two were pseudodiploid, one was hyperdiploid, and one was hypodiploid, and no recurrent changes were found among them [10–13]. We herein present the first description of clonal chromosome aberrations in a childhood adrenocortical tumor. MATERIALS AND METHODS A girl aged 3 years 7 months was referred from a county hospital, where she had been investigated because of premature adrenarche and erythema of the thighs. She had acne on her nose, sparse but obvious dark pubic hair, and a deepening of the voice. The only family history of malignant disease was that her maternal grandmother had died from cancer at the age of about 55 years. The urinary levels of dihydroepiandrostendione (DHEA), pregnantriol, and pregnandiol were increased. She also
0165-4608/98/$19.00 PII S0165-4608(98)00018-1
191
Complex Karyotype in Adrenocortical Carcinoma had elevated plasma levels of DHEA-sulfate. A CT scan revealed a mass in the right adrenal gland. The tumor, which at surgery was found to be strictly localized to the adrenal gland, was extirpated and the postoperative course was uneventful. Six months after surgery, the girl was healthy and all clinical signs of the disease had disappeared. The hormone levels were all normalized. Macroscopically, the resected tumor measured 11 ⫻ 9 ⫻ 6 cm, and the weight of the specimen was 300 g. The outer surface was smooth, and the cut surface showed yellow areas intermingled with darker, hemorrhagic areas. Histological examination showed densely packed, rather small cells without intracytoplasmic fat. Nuclear atypia was mostly moderate but occasionally pronounced. The tumor had small necrotic and large hemorrhagic areas. Only a few mitoses were found. The tumor was completely encapsulated by fibrotic tissue. A small remnant of normal adrenal tissue was seen outside the tumor capsule. Considering the large size of the tumor and the finding of cellular atypia and necrotic areas, the diagnosis was lowgrade malignant adrenocortical carcinoma. The cytogenetic methods have been described in detail elsewhere [14]. Chromosome aberrations were classified according to ISCN [15]. RESULTS After short-term culture, 21 metaphase cells could be analyzed. Two cells had an apparently constitutional inv(9) (p11q12) as the sole change. The remaining 19 cells were hyperdiploid, with mostly numerical changes: 56–57,XX,
⫹2,⫹4,⫹5,⫹7,⫹8,inv(9)c,⫹10,⫹add(13)(p11),⫹14,⫹15, ⫹19,⫹20,⫹20,⫹mar[cp19] (Fig. 1). DISCUSSION Adrenocortical tumors have been reported to be overrepresented among several dominantly inherited cancerassociated disorders, such as the Beckwith-Wiedemann syndrome, the Li-Fraumeni syndrome, and multiple endocrine neoplasia type 1 (MEN1), which may partly explain why children with adrenocortical carcinomas have a substantially increased risk of developing other malignant neoplasms [16, 17]. These clinical observations are in good agreement with recent molecular genetic data showing frequent germ-line mutations of TP53, the gene involved in the Li-Fraumeni syndrome, in children with adrenocortical carcinomas [16] and, albeit only indirectly, with the demonstration of somatically occurring allelic imbalances at the Beckwith-Wiedemann (11p15) and MEN1 (11q13) loci [7]. The fact that adrenocortical carcinogenesis may be associated with constitutional mutations at a minimum of three different loci indicates that malignant transformation could be achieved through many genetic pathways. The present finding of a hyperdiploid karyotype with few structural rearrangements further adds to this heterogeneous picture. Of the four previously reported cytogenetically abnormal adrenocortical carcinomas, only one was hyperdiploid [11], and that case had multiple structural rearrangements and had few aberrations (⫹5,⫹8, and ⫹19) in common with the present carcinoma. The finding of a
Figure 1 Hyperdiploid karyotype with trisomies for chromsomes 2, 4, 5, 7, 8, 10, 13, 14, and 20, constitutional inv(9), and addition of unknown material to 13p. Structurally rearranged chromosomes are indicated by arrows. The absence of trisomies 15 and 19, tetrasomy 20, and the marker chromosome was nonclonal.
192 hyperdiploid karyotype is also at odds with the results from a CGH analysis by Kjellman et al. [8]. Loss of genetic material was detected in seven of the eight carcinomas studied by them, and in only three cases did gains predominate over losses. Interestingly, however, the CGH profiles indicated that most imbalances involved entire chromosomes or chromosome arms, and nine polysomies were recurrent: gain of chromosome 5 (three cases) and chromosomes X, 7, 8, 12, 15, 16, 19, and 20 (two cases each). Thus, the combined cytogenetic and CGH data indicate that gain of chromosomes 5, 8, and 19 may be characteristic of adrenocortical carcinomas. A substantial subset of many childhood neoplasms (e.g., acute lymphoblastic leukemia, embryonal rhabdomyosarcoma, choroid plexus tumors, Wilms tumor, and ependymoma) are characterized by hyperdiploid karyotypes with few or no structural rearrangements (Ref. 18, updated). The present findings indicate that adrenocortical carcinomas may be yet another member of this cytogenetic subgroup of pediatric tumors. Why this karyotypic pattern is particularly frequent among certain childhood tumors, what the mechanisms behind the origin of hyperdiploidy are, and how the supernumerary chromosomes influence the tumor remain unknown. How-ever, even without answers to these questions concerning the biological significance of the chromosomal changes, genetic analyses by chromosome banding techniques or by CGH, could serve as valuable clinical adjuncts in the management of children and adults with adrenocortical tumors. This study was supported by grants from the Children Cancer Fund of Sweden and the Swedish Association for Cancer and Traffic Victims.
REFERENCES 1. Russell R, Masi A, Richter E (1972): Adrenal cortical adenomas and hypertension. A clinical pathologic analysis of 690 cases with matched controls and a review of the literature. Medicine 51:211–225. 2. Abecassis M, McLoughlin M, Langer B, Kudlow J (1985): Serendipitous adrenal masses: prevalence, significance and management. Am J Surg 149:783–788. 3. Norton JA, Levin B, Jensen RT (1993): Cancer of the endocrine system. In: Cancer: Principles and Practice of Oncology, ed 4, VT De Vita, S Hellman, SA Rosenberg, eds. Lippincott, Philadelphia. 4. Hosaka Y, Rainwater LM, Grant CS, Young WF, Jr, Farrow JF,
F. Mertens et al. Van Heerden JA, Lieber MM (1987): Adrenocortical carcinoma: nuclear deoxyribonucleic acid ploidy studied by flow cytometry. Surgery 102:1027–1034. 5. Cibas ES, Medeiros LJ, Weinberg DS, Gelb AB, Weiss LM (1990): Cellular DNA profiles of benign and malignant adrenocortical tumors. Am J Surg Pathol 14:948–955. 6. Suzuki T, Sasano H, Nisikawa T, Rhame J, Wilkinson DS, Nagura H (1992): Discerning malignancy in human adrenocortical neoplasms: utility of DNA flow cytometry and immunohistochemistry. Mod Pathol 5:224–231. 7. Yano T, Linehan M, Anglard P, Lerman MI, Daniel LN, Stein CA, Robertson CN, LaRocca R, Zbar B (1989): Genetic changes in human adrenocortical carcinomas. J Natl Cancer Inst 81:518–523. 8. Kjellman M, Kallioniemi O-P, Karhu R, Höög A, Farnebo L-O, Auer G, Larsson C, Bäckdahl M (1996): Genetic aberrations in adrenocortical tumors detected using comparative genomic hybridization correlate with tumor size and malignancy. Cancer Res 56:4219–4223. 9. Gordon RD, Stowasser M, Martin N, Epping A, Conic S, Klemm SA, Tunny TJ, Rutherford JC (1993): Karyotypic abnormalities in benign adrenocortical tumors producing aldosterone. Cancer Genet Cytogenet 68:78–81. 10. Herrmann ME, Rydstedt LL, Talpos GB, Ratner S, Wolman SR, Lalley PA (1994): Chromosomal aberrations in two adrenocortical tumors, one with a rearrangement at 11p15. Cancer Genet Cytogenet 75:111–116. 11. Limon J, Dal Cin P, Kakati S, Huben RP, Rao U, Sandberg AA (1987): Cytogenetic findings in a primary adrenocortical carcinoma. Cancer Genet Cytogenet 26:271–277. 12. Limon J, Dal Cin P, Gaeta J, Sandberg AA (1987): Translocation t(4;11)(q35;p13) in an adrenocortical carcinoma. Cancer Genet Cytogenet 28:343–348. 13. Marks JL, Wyandt HE, Beazley RM, Milunsky JM, Sheahan K, Milunsky A (1992): Cytogenetic studies of an adrenocortical carcinoma. Cancer Genet Cytogenet 61:96–98. 14. Mandahl N, Heim S, Arheden K, Rydholm A, Willén H, Mitelman F (1988): Three major cytogenetic subgroups can be identified among chromosomally abnormal solitary lipomas. Hum Genet 79:203–208. 15. ISCN (1995): An International System for Human Cytogenetic Nomenclature. F Mitelman, ed. S. Karger, Basel. 16. Wagner J, Portwine C, Rabin K, Leclerc JM, Narod SA, Malkin D (1994): High frequency of germline mutations in childhood adrenocortical cancer. J Natl Cancer Inst 86:1707– 1710. 17. Iida A, Blake K, Tunny T, Klemm S, Stowasser M, Hayward N, Gordon R, Nakamura Y, Imai T (1995): Allelic losses on chromosome band 11q13 in aldosterone-producing adrenal tumors. Genes Chromosom Cancer 12:73–75. 18. Mitelman F (1994): Catalog of Chromosome Aberrations in Cancer. ed. 5, Wiley-Liss, New York.
ABSTRACT: Cytogenetic analysis of short-term cultured cells from an 11-cm adrenocortical carcinoma in a 3.5-year-old girl revealed the karyotype 46,XX,inv(9)(p11q12)c[2]/56–57,XX,⫹2,⫹4,⫹5,⫹7,⫹8, inv(9)c,⫹10,⫹add(13)(p11),⫹14,⫹15,⫹19,⫹20,⫹20,⫹mar[cp19]. To our knowledge, this is the first description of an abnormal karyotype in a pediatric adrenocortical tumor. Inasmuch as the distinction between benign and malignant adrenocortical tumors is often difficult to make from clinical and histopathologic data alone, the present findings suggest that cytogenetic analysis may be a valuable adjunct in the differential diagnosis. © Elsevier Science Inc., 1998
INTRODUCTION Primary carcinomas of the adrenal cortex are exceedingly rare tumors, with an annual incidence of about two persons per million inhabitants. Benign adrenocortical tumors may be about 10,000 times as frequent, judging from reported series of incidentally detected adenomas at autopsies or by computerized tomographic (CT) scans of the upper abdomen [1–3]. There are no clear clinical or histopathologic features unequivocally distinguishing the benign from the malignant adrenocortical tumor. In general, however, adenomas are relatively small (size ⬍5 cm, weight ⬍100 g), rarely cause adrenogenital syndromes, and display few or no mitoses, tumor necrosis, or cellular pleomorphism at microscopy. Carcinomas, on the other hand, are often larger (size ⬎5 cm, weight 100–5,000 g), sometimes cause weight loss and feminization or virilism, and may display classical histopathological malignancy features such as increased mitotic activity, cellular pleomorphism, tumor necrosis, and vascular invasion [3]. In recent years, several attempts to utilize the genetic characteristics of the tumor cells for diagnostic as well as prognostic purposes have been made, sometimes with conflicting results. DNA flow cytometry studies have shown that nondiploid cell populations are more frequently detected among histologically malignant tumors, but as many
From the Department of Clinical Genetics (F. M., N. M.), the Department of Pediatric Surgery (C.-M. K.), the Department of Pediatrics (C. M.), and the Department of Pathology (J. A.), University Hospital, Lund, Sweden. Address reprint requests to: Fredrik Mertens, Department of Clinical Genetics, University Hospital, S-221 85 Lund, Sweden. Received June 28, 1997; accepted January 13, 1998. Cancer Genet Cytogenet 105:190–192 (1998) Elsevier Science Inc., 1998 655 Avenue of the Americas, New York, NY 10010
as one-fifth of the adenomas may be aneuploid, too [4–6]. Molecular genetic analysis of allelic imbalances on chromosomes 11, 13, and 17 has revealed frequent losses on 11p, 13q, and 17p in carcinomas but not in adenomas or hyperplastic lesions [7]. The same three chromosome arms were found to be deleted relatively often in a series of eight carcinomas analyzed by comparative genomic hybridization (CGH) [8]. In that study, only 2 of 12 benign lesions were shown to have abnormal CGH profiles, and the results indicated a good correspondence between tumor size and total number of gains and losses and between presence of imbalances and malignant clinical features [8]. Very few cytogenetic investigations of adrenocortical tumors have been reported. The only recurrent change among 15 analyzed aldosterone-producing adenomas was loss of the Y chromosome, detected in five cases [9, 10]. Of the four carcinomas with clonal aberrations that have been described, two were pseudodiploid, one was hyperdiploid, and one was hypodiploid, and no recurrent changes were found among them [10–13]. We herein present the first description of clonal chromosome aberrations in a childhood adrenocortical tumor. MATERIALS AND METHODS A girl aged 3 years 7 months was referred from a county hospital, where she had been investigated because of premature adrenarche and erythema of the thighs. She had acne on her nose, sparse but obvious dark pubic hair, and a deepening of the voice. The only family history of malignant disease was that her maternal grandmother had died from cancer at the age of about 55 years. The urinary levels of dihydroepiandrostendione (DHEA), pregnantriol, and pregnandiol were increased. She also
0165-4608/98/$19.00 PII S0165-4608(98)00018-1
191
Complex Karyotype in Adrenocortical Carcinoma had elevated plasma levels of DHEA-sulfate. A CT scan revealed a mass in the right adrenal gland. The tumor, which at surgery was found to be strictly localized to the adrenal gland, was extirpated and the postoperative course was uneventful. Six months after surgery, the girl was healthy and all clinical signs of the disease had disappeared. The hormone levels were all normalized. Macroscopically, the resected tumor measured 11 ⫻ 9 ⫻ 6 cm, and the weight of the specimen was 300 g. The outer surface was smooth, and the cut surface showed yellow areas intermingled with darker, hemorrhagic areas. Histological examination showed densely packed, rather small cells without intracytoplasmic fat. Nuclear atypia was mostly moderate but occasionally pronounced. The tumor had small necrotic and large hemorrhagic areas. Only a few mitoses were found. The tumor was completely encapsulated by fibrotic tissue. A small remnant of normal adrenal tissue was seen outside the tumor capsule. Considering the large size of the tumor and the finding of cellular atypia and necrotic areas, the diagnosis was lowgrade malignant adrenocortical carcinoma. The cytogenetic methods have been described in detail elsewhere [14]. Chromosome aberrations were classified according to ISCN [15]. RESULTS After short-term culture, 21 metaphase cells could be analyzed. Two cells had an apparently constitutional inv(9) (p11q12) as the sole change. The remaining 19 cells were hyperdiploid, with mostly numerical changes: 56–57,XX,
⫹2,⫹4,⫹5,⫹7,⫹8,inv(9)c,⫹10,⫹add(13)(p11),⫹14,⫹15, ⫹19,⫹20,⫹20,⫹mar[cp19] (Fig. 1). DISCUSSION Adrenocortical tumors have been reported to be overrepresented among several dominantly inherited cancerassociated disorders, such as the Beckwith-Wiedemann syndrome, the Li-Fraumeni syndrome, and multiple endocrine neoplasia type 1 (MEN1), which may partly explain why children with adrenocortical carcinomas have a substantially increased risk of developing other malignant neoplasms [16, 17]. These clinical observations are in good agreement with recent molecular genetic data showing frequent germ-line mutations of TP53, the gene involved in the Li-Fraumeni syndrome, in children with adrenocortical carcinomas [16] and, albeit only indirectly, with the demonstration of somatically occurring allelic imbalances at the Beckwith-Wiedemann (11p15) and MEN1 (11q13) loci [7]. The fact that adrenocortical carcinogenesis may be associated with constitutional mutations at a minimum of three different loci indicates that malignant transformation could be achieved through many genetic pathways. The present finding of a hyperdiploid karyotype with few structural rearrangements further adds to this heterogeneous picture. Of the four previously reported cytogenetically abnormal adrenocortical carcinomas, only one was hyperdiploid [11], and that case had multiple structural rearrangements and had few aberrations (⫹5,⫹8, and ⫹19) in common with the present carcinoma. The finding of a
Figure 1 Hyperdiploid karyotype with trisomies for chromsomes 2, 4, 5, 7, 8, 10, 13, 14, and 20, constitutional inv(9), and addition of unknown material to 13p. Structurally rearranged chromosomes are indicated by arrows. The absence of trisomies 15 and 19, tetrasomy 20, and the marker chromosome was nonclonal.
192 hyperdiploid karyotype is also at odds with the results from a CGH analysis by Kjellman et al. [8]. Loss of genetic material was detected in seven of the eight carcinomas studied by them, and in only three cases did gains predominate over losses. Interestingly, however, the CGH profiles indicated that most imbalances involved entire chromosomes or chromosome arms, and nine polysomies were recurrent: gain of chromosome 5 (three cases) and chromosomes X, 7, 8, 12, 15, 16, 19, and 20 (two cases each). Thus, the combined cytogenetic and CGH data indicate that gain of chromosomes 5, 8, and 19 may be characteristic of adrenocortical carcinomas. A substantial subset of many childhood neoplasms (e.g., acute lymphoblastic leukemia, embryonal rhabdomyosarcoma, choroid plexus tumors, Wilms tumor, and ependymoma) are characterized by hyperdiploid karyotypes with few or no structural rearrangements (Ref. 18, updated). The present findings indicate that adrenocortical carcinomas may be yet another member of this cytogenetic subgroup of pediatric tumors. Why this karyotypic pattern is particularly frequent among certain childhood tumors, what the mechanisms behind the origin of hyperdiploidy are, and how the supernumerary chromosomes influence the tumor remain unknown. How-ever, even without answers to these questions concerning the biological significance of the chromosomal changes, genetic analyses by chromosome banding techniques or by CGH, could serve as valuable clinical adjuncts in the management of children and adults with adrenocortical tumors. This study was supported by grants from the Children Cancer Fund of Sweden and the Swedish Association for Cancer and Traffic Victims.
REFERENCES 1. Russell R, Masi A, Richter E (1972): Adrenal cortical adenomas and hypertension. A clinical pathologic analysis of 690 cases with matched controls and a review of the literature. Medicine 51:211–225. 2. Abecassis M, McLoughlin M, Langer B, Kudlow J (1985): Serendipitous adrenal masses: prevalence, significance and management. Am J Surg 149:783–788. 3. Norton JA, Levin B, Jensen RT (1993): Cancer of the endocrine system. In: Cancer: Principles and Practice of Oncology, ed 4, VT De Vita, S Hellman, SA Rosenberg, eds. Lippincott, Philadelphia. 4. Hosaka Y, Rainwater LM, Grant CS, Young WF, Jr, Farrow JF,
F. Mertens et al. Van Heerden JA, Lieber MM (1987): Adrenocortical carcinoma: nuclear deoxyribonucleic acid ploidy studied by flow cytometry. Surgery 102:1027–1034. 5. Cibas ES, Medeiros LJ, Weinberg DS, Gelb AB, Weiss LM (1990): Cellular DNA profiles of benign and malignant adrenocortical tumors. Am J Surg Pathol 14:948–955. 6. Suzuki T, Sasano H, Nisikawa T, Rhame J, Wilkinson DS, Nagura H (1992): Discerning malignancy in human adrenocortical neoplasms: utility of DNA flow cytometry and immunohistochemistry. Mod Pathol 5:224–231. 7. Yano T, Linehan M, Anglard P, Lerman MI, Daniel LN, Stein CA, Robertson CN, LaRocca R, Zbar B (1989): Genetic changes in human adrenocortical carcinomas. J Natl Cancer Inst 81:518–523. 8. Kjellman M, Kallioniemi O-P, Karhu R, Höög A, Farnebo L-O, Auer G, Larsson C, Bäckdahl M (1996): Genetic aberrations in adrenocortical tumors detected using comparative genomic hybridization correlate with tumor size and malignancy. Cancer Res 56:4219–4223. 9. Gordon RD, Stowasser M, Martin N, Epping A, Conic S, Klemm SA, Tunny TJ, Rutherford JC (1993): Karyotypic abnormalities in benign adrenocortical tumors producing aldosterone. Cancer Genet Cytogenet 68:78–81. 10. Herrmann ME, Rydstedt LL, Talpos GB, Ratner S, Wolman SR, Lalley PA (1994): Chromosomal aberrations in two adrenocortical tumors, one with a rearrangement at 11p15. Cancer Genet Cytogenet 75:111–116. 11. Limon J, Dal Cin P, Kakati S, Huben RP, Rao U, Sandberg AA (1987): Cytogenetic findings in a primary adrenocortical carcinoma. Cancer Genet Cytogenet 26:271–277. 12. Limon J, Dal Cin P, Gaeta J, Sandberg AA (1987): Translocation t(4;11)(q35;p13) in an adrenocortical carcinoma. Cancer Genet Cytogenet 28:343–348. 13. Marks JL, Wyandt HE, Beazley RM, Milunsky JM, Sheahan K, Milunsky A (1992): Cytogenetic studies of an adrenocortical carcinoma. Cancer Genet Cytogenet 61:96–98. 14. Mandahl N, Heim S, Arheden K, Rydholm A, Willén H, Mitelman F (1988): Three major cytogenetic subgroups can be identified among chromosomally abnormal solitary lipomas. Hum Genet 79:203–208. 15. ISCN (1995): An International System for Human Cytogenetic Nomenclature. F Mitelman, ed. S. Karger, Basel. 16. Wagner J, Portwine C, Rabin K, Leclerc JM, Narod SA, Malkin D (1994): High frequency of germline mutations in childhood adrenocortical cancer. J Natl Cancer Inst 86:1707– 1710. 17. Iida A, Blake K, Tunny T, Klemm S, Stowasser M, Hayward N, Gordon R, Nakamura Y, Imai T (1995): Allelic losses on chromosome band 11q13 in aldosterone-producing adrenal tumors. Genes Chromosom Cancer 12:73–75. 18. Mitelman F (1994): Catalog of Chromosome Aberrations in Cancer. ed. 5, Wiley-Liss, New York.