ELSEVIER
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 histo- pathologic 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 per- sons per million inhabitants. Benign adrenocortical tu- mors may be about 10,000 times as frequent, judging from reported series of incidentally detected adenomas at au- topsies or by computerized tomographic (CT) scans of the upper abdomen [1-3]. There are no clear clinical or histo- pathologic features unequivocally distinguishing the be- nign 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 pleo- morphism, 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 con- flicting results. DNA flow cytometry studies have shown that nondiploid cell populations are more frequently de- tected among histologically malignant tumors, but as many
as one-fifth of the adenomas may be aneuploid, too [4-6]. Molecular genetic analysis of allelic imbalances on chro- mosomes 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 hy- bridization (CGH) [8]. In that study, only 2 of 12 benign le- sions 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 hyperdip- loid, 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 pre- mature 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 malig- nant 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
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.), Uni- versity 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.
had elevated plasma levels of DHEA-sulfate. A CT scan re- vealed 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 disap- peared. The hormone levels were all normalized.
Macroscopically, the resected tumor measured 11 × 9 X 6 cm, and the weight of the specimen was 300 g. The outer surface was smooth, and the cut surface showed yellow ar- eas intermingled with darker, hemorrhagic areas. Histolog- ical 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 en- capsulated by fibrotic tissue. A small remnant of normal adrenal tissue was seen outside the tumor capsule. Con- sidering the large size of the tumor and the finding of cel- lular atypia and necrotic areas, the diagnosis was low- grade 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 ana- lyzed. 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 over- represented among several dominantly inherited cancer- associated disorders, such as the Beckwith-Wiedemann syndrome, the Li-Fraumeni syndrome, and multiple endo- crine neoplasia type 1 (MEN1), which may partly explain why children with adrenocortical carcinomas have a sub- stantially increased risk of developing other malignant neoplasms [16, 17]. These clinical observations are in good agreement with recent molecular genetic data show- ing frequent germ-line mutations of TP53, the gene in- volved 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 as- sociated with constitutional mutations at a minimum of three different loci indicates that malignant transforma- tion could be achieved through many genetic pathways. The present finding of a hyperdiploid karyotype with few structural rearrangements further adds to this heteroge- neous picture. Of the four previously reported cytogeneti- cally 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.
| 1 | 2 | 3 | 4 | 5 | ||
|---|---|---|---|---|---|---|
| 6 | 7 | 8 | 9 | 10 | 11 | 12 |
| 13 | 14 | 15 | 16 | 17 | 18 | |
| 21 | Y | X | ||||
| 19 | 20 | 22 |
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 pre- dominate 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 indi- cate that gain of chromosomes 5, 8, and 19 may be charac- teristic of adrenocortical carcinomas.
A substantial subset of many childhood neoplasms (e.g., acute lymphoblastic leukemia, embryonal rhabdomyosar- coma, choroid plexus tumors, Wilms tumor, and ependy- moma) are characterized by hyperdiploid karyotypes with few or no structural rearrangements (Ref. 18, updated). The present findings indicate that adrenocortical carcino- mas may be yet another member of this cytogenetic sub- group 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 an- swers to these questions concerning the biological signifi- cance 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.
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