10th ANNIVERSARY ARTICLE Cytogenetics and Molecular Biology of Small Round-Cell Tumors and Related Neoplasms Current Status Ludvik R. Donner

ABSTRACT: Recent years have witnessed considerable advances in cytogenetics and molecular biology of small round-cell tumors. These advances are summarized and discussed in this article.

INTRODUCTION Small round-cell tumors traditionally include neuroblastoma, Ewing's sarcoma, peripheral neuroepithelioma, rhabdomyosarcoma, and malignant l y m p h o m a of soft tissue. Although the correct diagnosis is often achieved without major difficulty, and sometimes even with ease, it is a w e l l - k n o w n fact that undifferentiated tumors of each category can present a virtually identical microscopic picture. Ultrastructural, i m m u n o h i s t o c h e m i c a l , cytogenetic, and even molecular biologic studies m a y be necessary to reach a correct diagnosis. This is of p a r a m o u n t importance because of serious therapeutic and prognostic implications. The term "small round-cell tumors of c h i l d h o o d , " w h i c h is c o m m o n l y used, is somewhat misleading. Although the majority of tumors occur during childhood, m a n y occur during adolescence or in early a d u l t h o o d and one can, though very rarely, even encounter some of these tumors among the elderly. Discoveries during the past several years led to a considerable e x p a n s i o n of our u n d e r s t a n d i n g of biology, cytogenetics and molecular biology of these tumors. The pertinent data are s u m m a r i z e d in this article.

NEUROBLASTOMA Neuroblastoma is the most c o m m o n extracranial solid malignant tumor in children, with incidence of 1.4/10,000 in whites and 1/10,000 in blacks. It u s u a l l y arises from the sympathetic ganglia, most frequently in the adrenal gland, but it can also arise from dorsal root ganglia. The tumors are u s u a l l y adrenergic, some are cholinergic and, like normal neurons, they do not express HLA class I and beta 2-microglobulin

Ill. Partial m o n o s o m y for the distal portion of the short arm of c h r o m o s o m e 1 is present in 7 0 - 8 0 % of n e a r - d i p l o i d tumors and cell lines [2-6]. The cause of this abnormality Department of Pathology,Scott and White Clinic, Scott, Sherwood and Brindley Foundation Texas A&M University College of Medicine, Temple, Texas. Address reprint requests to: Dr. Ludvik R. Donner, Department of Pathology, Scott & White Hospital, 2401 South 31st Street, Temple, TX 76508. Received September 4, 1990; accepted October 1, 1990.

© 1991 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010

Cancer Genet Cytogenet 54:1-10 (1991) 0165-4608/91/$03.50

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is most likely a single hemizygous deletion, but a few tumors with t(1;13)(p32;p15), t(1;1)(p32;q21), or t(1;10)(p32;q24) have been reported [7, 8]. An analysis of restriction fragment-length polymorphism using a panel of chromosome 1-specific DNA probes revealed that a putative neuroblastoma suppressor gene, which is probably lost during lp rearrangement, is localized in lp36.1-36.3 [9]. It is now known that hypodiploid, pseudodiploid, and hypotetraploid neuroblastomas display partial monosomy of lp and other structural abnormalities, including occasional double minutes and homogeneously staining regions. This prognostically poor subgroup is usually encountered in stages III and IV but also occasionally in stage I and II tumors. In contrast, hyperdiploid and near triploid neuroblastomas lack partial monosomy of lp, usually have only a few structural chromosomal abnormalities, are mostly encountered in stage I and II, and constitute a prognostically favorable subgroup [9-13]. Chromosomal pattern is a more important prognostic factor than the patient's age, clinical stage, and the presence or absence of N-myc amplification [13]. According to Christiansen et al. [7], the difference in the survival probability is striking: 10% for neuroblastoma patients with partial monosomy of lp vs. 90% survival for patients without this abnormality. An assessment of DNA content of tumor cells by flow cytometry led to similar conclusions [14-17]. Nomyc oncogene can be 3-500 times amplified in neuroblastomas. The amplification of this oncogene is associated with an advanced stage of the disease, rapid progression, and poor prognosis. N-myc is amplified in 31-57% of high-stage tumors but is also amplified in 6-16% of low-stage tumors (5, 6, 18-23). N-myc oncogene amplification occurs most frequently in near-diploid, pseudodiploid, and hypotetrao ploid tumors with partial monosomy of l p and other structural chromosomal abnormalities [6, 9, 12, 13]. N-myc oncogene has been localized to 2p23-24 [24]. It appears that a large region of chromosome 2 containing N-myc oncogene becomes amplified initially as double minutes and, in a small percentage of tumors, as chromosomally integrated homogenously staining regions [25, 26]. It has been suggested that translocation of N-myc oncogene may be the initial event leading to its activation and subsequent amplification [27]. Approximately 30% of neuroblastomas have amplified N-myc oncogene and rapidly progress, but another 30% of tumors in which N-myc oncogene is not amplified also eventually progress. The remaining 40% of tumors present as local, regional, or metastatic disease, do not have amplified N-myc oncogene, and either spontaneously regress or are usually successfully treated [28]. It appears that N-myc oncogene can be overexpressed in some neuroblastomas without being amplified. N-myc protein has been detected in 18 of 97 non-amplified neuroblastomas although, with few exceptions, in lesser quantities than in amplified tumors [28]. Similarly, N-myc RNA has been detected in some non-amplified neuroblastomas [29]. However, other authors were able to detect N-myc RNA only in amplified tumors [30]. These findings suggest that overexpression of N-myc oncogene may be an important cause of biologically aggressive behavior in a subset of non-amplified neuroblastomas. Expression of various other oncogenes in neuroblastomas has been also studied, but the data are insufficient, c-myb and c-ets-1 oncogenes are commonly expressed [31]. Mutations of N-ras oncogene have been detected in a single stage I, one of four stage II, none of six stage III, and none of eight stage IV neuroblastomas [32]. Despite these impressive advances in the field of neuroblastoma research, several important questions remain unanswered. Are there any chromosomal or molecular biological abnormalities specific or characteristic for prognostically favorable, low stage neuroblastomas? Is N-myc amplification merely an important component of tumor progression or are there, in fact, two different groups of neuroblastomas from the beginning--one which is prognostically favorable, with low or no probability of

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N-myc amplification, and another, highly biologically aggressive, in which N-myc amplification readily occurs?

CEREBRAL NEUROBLASTOMA Most of these rare tumors occur in young children and are often classified together with medulloblastomas and even retinoblastomas in current literature as "primitive neuroectodermal tumors." However, unlike a proportion of medulloblastomas, cerebral neuroblastomas show no glial differentiation. They do form Homer Wright rosettes and sometimes display ganglionic differentiation. Cerebral neuroblastomas have the capacity for cerebrospinal dissemination and only 30% of patients will survive 5 years. These tumors have not been cytogenetically studied. A single tumor was tested for N-myc oncogene amplification with a negative result [33].

MEDULLOBLASTOMA Medulloblastoma is the most common pediatric intracranial malignant tumor. It occurs chiefly during the first 2 decades with peak incidence of 3 to 5 years, but can occur at any age. The incidence of the tumor is approximately 1/100,000 per year. The tumor is mostly undifferentiated, but it can differentiate along the neuroblastic, neuronal, glial, rarely myogenous, or melanocytic and, extremely rarely, cartilaginous pathways. This is not surprising if one remembers that the embryonal neural crest is a source of mesenchymal cells in its capacity as mesectoderm. Unlike neuroblastomas, medulloblastomas express HLA-class I I34]. Karyotypic changes in these tumors are often complex, with multiple numerical changes and structural rearrangements. Isochromosome of 17q has been found in the majority of these tumors and a few of them also contained double minutes [35-38]. Aneuploid tumors have been reported to be prognostically favorable and the diploid ones unfavorable [39]. Amplification of N-myc oncogene has been found in two of 19 medulloblastomas [33]. c-myc oncogene was amplified in a medulloblastoma cell line, whereas several other oncogenes IN-myc, L-myc, c-erb B-l, c-erb B-2, c-sis, N-ras) were not rearranged [36].

OLFACTORY NEUROBLASTOMA (ESTHESIONEUROBLASTOMA) Olfactory neuroblastoma is a rare malignant tumor arising in the superior portion of the nasal cavity. It is usually encountered in the second and third decades but may occur at any time from childhood to old age. Our current knowledge of the biology, cytogenetics, and molecular biology of this tumor is based upon a study of three established cell lines [40, 41]. Unlike neuroblastomas, two cell lines studied expressed HLAoclass I [41]. Translocation (11;22) has been found in two cell lines: t(11;22)(q21;q12) in one and t(11;22)(q24;q12) in the other. Moreover, the long arms of chromosomes 11 and 22 have been deleted in the third cell line. The short arm of chromosome 1 has been rearranged in two cell lines [40, 41]. Both cell lines studied were overexpressing c-myc oncogene and did not express N-myc [41]. Based upon these data, the tumor appears to be related to peripheral neuroepithelioma rather than neuroblastoma.

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MELANOTIC NEUROECTODERMAL TUMOR OF INFANCY This is a very rare tumor occurring in infants, mostly in the head and the neck areas, especially in the maxilla, although a few other locations have been observed. Although the majority of these tumors are benign, a few behave in malignant fashion [42, 43]. No cytogenetic or molecular biologic data on this interesting entity are available.

MALIGNANT ECTOMESENCHYMOMA This is an extremely rare pediatric tumor and only a few cases have been described in the literature. This tumor is composed of neuroblastic and, usually, rhabdomyosarcomatous elements. Some tumors additionally show chondroid, liposarcomatous, Schwannian, or melanocytic differentiation [44]. Understandably, no cytogenetic or molecular biologic data are available.

EWING'S SARCOMA--PERIPHERAL NEUROEPITHELIOMA Current terminology used for this closely histogenetically related group of tumors is sometimes confusing. The situation may have been further hindered by the introduction of the term "primitive neuroectodermal tumor," which is often used as a classification "wastebasket." Until relatively recently, the question of the histogenesis of Ewing's sarcoma has been a topic of long- lasting controversy. Cavazzana et al. [45, 46] showed that Ewing's sarcoma cell lines treated with c-AMP or TPA developed neurites, neurotubules, dense core granules, and expressed gamma enolase, cholinesterase, and neurofilaments. These findings demonstrate that Ewing's sarcoma is a neuroectodermal tumor. The characteristic presence of translocation t(11;22)(q24;q12) in Ewing's sarcoma [47, 48], as well as peripheral neuroepithelioma [49], helped to establish the histogenetic relatedness of these two tumors.

Ewing's Sarcoma The age range for Ewing's sarcoma of bone is 1½ to 59 years with a peak in the second decade. Its incidence is 1.7/1,000,000. This tumor occurs mostly in whites and Hispanics; there are no well-documented cases of Ewing's sarcoma among blacks. HLA-class I and beta 2 microglobulin are expressed on the tumor cells [50]. Many primary tumors and cell lines have been cytogenetically analyzed [47, 48, 51-59]. The cytogenetic findings have been reviewed and summarized by Turc-Carel et al. [57] and Mugneret et al. [58]. Translocation (11;22)(q24;q12) has been found in 83% of Ewing's sarcomas. Five percent of tumors contained complex translocations between chromosomes 11, 22, and, additionally, chromosomes 2, 14, 17, or 18. Four percent of tumors showed involvement of 22q12 with chromosomes other than chromosome 11. There were no rearrangements of 22q12 or 11q24 in 8% of the tumars. Ninety-two percent of the tumors contained breakpoint on 22q12 and 88% on 11q24. The majority of tumors contained additional numerical and/or structural changes, most often trisomy 8 and unbalanced t(1;16). Although oncogene c-sis is translocated from chromosome 22 to chromosome 11 in Ewing's sarcomas, the translocated gene is neither altered nor expressed [60, 61]. c-ets-1, which is located in 11q23.3, was expressed at a low level in a few tumor cell lines derived from Ewing's sarcoma and peripheral neuroepithelioma, but was highly expressed in a few tumor samples [62]. A variant of Ewing's sarcoma, which is composed of larger cells with irregularly

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contoured nuclei, is called atypical Ewing's sarcoma. Only three tumors have been cytogenetically studied so far and all contained t(11;22) [63, 64]. Translocation (11;22) has also been found in a case of extraskeletal Ewing's sarcoma [65]. Another extraskeletal tumor, classified as extraskeletal Ewing's sarcoma, contained t(6;12), but not t(11;22). However, ultrastructural examination of the latter case revealed that the tumor cells resembled endothelial cells and formed vascular channels. This suggests that the tumor may have been misclassified [54].

Peripheral Neuroepithelioma This is a rare tumor usually affecting patients older than 20 years, although it may occur at any age. The tumor most commonly involves extremities, trunk (Askin's tumor of the chest walll, and retroperitoneum, but it sometimes presents as a primary bone tumor I66]. Unlike neuroblastoma, the tumor is exclusively cholinergic. Homer Wright rosettes are often present. The most characteristic ultrastructural feature is the presence of neurites with dense core granules and microtubules. A diagnostically useful feature is expression of HLA-class I and beta 2-microglobulin by the tumor cells I50]. Classic peripheral neuroepitheliomas [49, 64, 67] and Askin's tumors I54, 68, 69] contain t/11;22/(q24;q12/, as well as other numerical and structural chromosomal abnormalities. However, this translocation has not been found in five tumor cell lines derived from "primitive neuroectodermal tumors" of soft tissue. Three of the tumors contained additional lq material and trisomy 12 was present in two of the tumors [70]. A single skeletal neuroepithelioma has been cytogenetically examined. The tumor contained multiple chromosomal rearrangements, including questionable der(11), but normal chromosomes 22 [71]. Similar to Ewing's sarcoma, c-sis oncogene is translocated from chromosome 22 to chromosome 11 in peripheral neuroepithelioma, but the translocated oncogene is neither rearranged nor expressed [72]. The pattern of oncogene expression in Ewing's sarcoma and peripheral neuroepithelioma is virtually identical. Both tumors express or overexpress c-myc, express c-myb, and express at low levels N-myc and c-mil/raf1. There was no amplification of N-myc oncogene and c-sis and c-fes oncogenes were not expressed [31, 62, 69, 73]. In summary, close histogenetic relatedness between Ewing's sarcoma, including its extraskeletal and atypical variants, and peripheral neuroepithelioma, including Askin's tumor of the chest wall, have recently been well established. We do not yet know the answer to an obvious question: which genes are activated, and what chain of molecular events is triggered by translocation t(11;22)? Our current knowledge of cytogenetics of skeletal neuroepithelioma (neuroectodermat tumor of bone) remains very rudimentary. Translocation (11;22) has not been present in several neuroectodermal tumors of soft tissue. It is possible that, as in Ewing's sarcoma, a subset of "primitive neuroectodermal tumors" does not contain cytogenetically detectable breakpoints at 22q12 or 11q24. However, the possibility remains that some of those tumors are, in fact, misclassified primitive sarcomas mimicking neuroectodermal tumors. SMALL CELL OSTEOSARCOMA This unusual, high-grade variant occurs at ages ranging from 6 to 28 years. Presence of osteoid, produced by the tumor cells, is an indispensable requirement for the diagnosis. However, detection of tumor osteoid is not always an easy task, particularly when only a small amount of bioptic material is available for examination. There are

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L.R. Donner several morphologic variants of this entity, one of which resembles Ewing's sarcoma [74, 75]. The recent finding of t(11;22)(q24;q12) in a small cell osteosarcoma is, therefore, interesting and suggests a relationship of some of the tumors with Ewing's sarcoma [76].

RHABDOMYOSARCOMA Rhabdomyosarcoma accounts for 3.4% of all childhood malignancies in patients under 15 years of age and its incidence is 4.5/1,000,000 per year for white children and 1.3/1,000,000 for black children. The tumor occurs predominantly in infants and children, less frequently in adolescents and young adults, and rarely beyond age 45. Several alveolar rhabdomyosarcomas have been cytogenetically examined and the majority of them contained translocation (2:13)/q37~q14/. A few tumors without this translocation were near triploid and contained marker chromosomes and double minutes [77-81]. Interestingly, t(2;ll/(q27;q13) has been found in one and t(4;13)(q13;q34) in another, further unclassified rhabdomyosarcoma [54]. Cytogenetic examination of several embryonal rhabdomyosarcomas failed to reveal any characteristic chromosomal abnormality. Rearrangements of 3p and deletions of lp21-qter, were often seen [81-84]. Translocation (2:8)(q37;q131 has been found in a congenital embryonal rhabdomyosarcoma [85]. It is possible that 2q37 contains a gene that plays a role in the development of rhabdomyosarcoma. Loss of heterozygosity for 11p15.5-11pter has been found in several rhabdomyosarcomas studied for restriction fragment length polymorphism. The loss of heterozygosity is likely due to a gene mutation; chromosomes 11 were cytogenetically normal [86]. It is of interest that Beckwith-Wiedemann syndrome, which is associated with cytogenetic aberration of 1 l p 15 is predisposing for the development of rhabdomyosarcoma. A gene at 1 l p 15, when mutated or deleted, probably also plays a role in the development of rhabdomyosarcoma. C-myc or N-myc are only infrequently amplified in rhabdomyosarcomas [23, 73, 87-90], although N-myc amplification in four of six alveolar rhabdomyosarcomas has recently been reported [91]. V-raf oncogene was expressed in cell lines derived from embryonal and alveolar rhabdomyosarcomas [92]. Gli oncogene has been amplified in one of 13 rhabdomyosarcomas. The amplified tumor, which could not be further histologically subclassified, contained t(2;13)lq35:q14/and double minutes [90].

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Cytogenetics and molecular biology of small round-cell tumors and related neoplasms. Current status.

Recent years have witnessed considerable advances in cytogenetics and molecular biology of small round-cell tumors. These advances are summarized and ...
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