American Journal of Medical Genetics 53:24-28 (1994)

Microscopic Neuroblastoma in a Fetus With a De Novo Unbalanced Translocation 3 ; l O

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Faisal Qureshi, Suzanne M. Jacques, Mark P. Johnson, Avihai Reichler, and Mark I. Evans Departments of Pathology (F.Q., S.M.J.) and Obstetrics and Gynecology (M.P. J., A.R., M.I.E.), Hutzel Hospital and Wayne State University, Detroit, Michigan

We report on a fetus with a de novo unbal- anced translocation 3;lO and a microscopic neuroblastoma. The fetus had the kary- otypic and phenotypic manifestations of partial dup (3q). The finding of a constitu- tional chromosomal abnormality and a mi- croscopic neuroblastoma, although possibly coincidental, supports Knudson’s two hit hypothesis for development of neuroblas- tomas and other embryonal tumors. In this case the first mutation is represented by the constitutional abnormality, possibly result- ing in the microscopic neuroblastoma. A second mutation affecting the abnormal cells, which may be more prone to mutagen- esis, may trigger a neuroblastoma. 0 1994 Wiley-Liss, Inc.

KEY WORDS: microscopic neuroblastoma, chromosomal abnormality, partial duplication 3q

INTRODUCTION Constitutional chromosome abnormalities have been

described in infants with tumors, including retinoblas- toma [Johnson et al., 19821, Wilms tumor [Riccardi et al., 19781, and familial renal cell carcinoma [Cohen et al., 19791. Chromosomal breakage syndromes, includ- ing Fanconi anemia, Bloom syndrome, and ataxia telangiectasia, also are associated with an increased in- cidence of malignancies [Brock, 19931. In neuroblas- tomas (NB) chromosome abnormalities of the distal portion of l p have been noted consistently in tumor cells and tumor cell lines [Brodeur, 19901; however, only occasional cases associated with a constitutional ab-

Received for publication November 19, 1993; revision received May 5, 1994.

Address correspondence to F. Qureshi, M.D., Department of Pathology, Hutzel Hospital, 4707 St. Antoine Blvd., Detroit, MI 48201.

0 1994 Wiley-Liss, Inc.

normality have been reported [Feingold et al., 1971; Moorhead and Evans, 1980; Niven et al., 1971; Pegelow et al., 1975; Sanger et al., 19841. We report a case with a de novo unbalanced t(3;lO) and a microscopic NB.

CLINICAL HISTORY This 18-week gestational age fetus was delivered to a

35-year-old g2pO mother. An amniocentesis performed for advanced maternal age showed an unbalanced translocation (3;lO) with a karyotype of 46,XX- 10, der(lO),t(3;10)(q21;q26) (Fig. 1). Cytogenetic analysis of the parents was normal, indicating the fetus to have a de novo rearrangement. Ultrasound examination findings included oligohydramnios, moderate bilateral pyelectasia, a cystic structure in the nuchal region sug- gestive of a cystic hygroma, and a single umbilical artery. After genetic counseling, the mother decided to terminate her pregnancy. A repeat karyotypic analysis of the fetus confirmed the findings of the initial study.

PATHOLOGY At fetopsy, the fetus weighed 210 g, had a crown-

rump length of 14.5 cm, a head circumference of 14.1 cm, and a foot length of 2.2 cm. Minor anomalies included hypertelorism, microphthalmia, small ears, a broad-based nasal bridge, anteverted, hypoplastic nares with a relatively long philtrum, thin lips, and mi- crognathia (Fig. 2). There was redundant skin at the back of the neck; however, a cystic hygroma was not present. Examination of the genitourinary system showed bilateral hydroureters, hydropelvis, and hy- dronephrosis. Cardiac anomalies consisted of a subpul- monic ventricular septa1 defect associated with hy- poplastic lungs (lung to body weight ratio of 0.015). The left adrenal was larger than the right, and had a gray- white cut surface (Fig. 3).

On histopathologic examination, the left adrenal showed clusters of neuroblasts which were aggregated around the central vein (Figs. 4, 5) . Nests of neuro- blasts with rare rosettes and cystic changes were also

NB and Unbalanced Translocation 3;lO 25

21.2

14.3 14.1

:::# 21 R

:! 2a ! 3 3

12.3 12.1

I a . 2 u u I 24.2 u u

U

der( lo), t( 3; 10) (92 1 ;q26)

Fig. 1. Idiogram and composites of chromosomes 3 and 10 showing the translocation.

seen to infiltrate the fetal cortex. Some of the nests were adjacent to the capsule and appeared to broach the capsule; however, evaluation of this feature was hampered by autolytic changes. The right adrenal also showed clusters of neuroblasts around the central vein, but these were not prominent. Although hydropelvis was seen on microscopic examination, no cystic or dys- plastic changes were seen in the kidneys.

DISCUSSION NB and its related neoplasms (ganglioneuroblas-

tomas and ganglioneuromas) are thought to arise from primitive neural crest cells. While small nodules of primitive neuroblasts are routinely found in the devel- oping adrenal gland, Beckwith and Perrin [19631 de- scribed NB in situ as microscopic nodules that were cy- tologically similar to clinical NB. Guin et al. [19691 termed similar nodules incidental or microscopic NB. These lesions are associated with a high incidence of se- vere congenital malformations, including cardiac anomalies [Beckwith and Perrin, 1963; Guin et al., 1969; Shanklin and Sotelo-Avila, 19691.

The incidence of microscopic NB in various studies has varied from 1:39 to 1:1,000 infants, with an average

of about 1:200, while the incidence of clinical NB is much lower and is about 1:10,000 infants [Shanklin and Sotelo-Avila, 19691. This has led some investiga- tors to propose that these lesions may undergo involu- tion or degeneration, mature to normal or hyperplastic medulla, or transform into clinical NB [Beckwith and Perrin, 19631. However, other investigators [Shanklin and Sotelo-Avila, 19691, noting the relationship to con- genital malformations and to cardiac anomalies in par- ticular, have suggested that these are hyperplastic le- sions resulting from secondary hypoxia.

Partial duplication (3q) is uncommon. Francke [19781 reported 3 cases of partial dup(3q) and pointed out that this is generally found in the unbalanced off- spring of parents, most of whom are heterozygotes for a pericentric inversion of chromosome 3. The most com- mon segment involves the area 3q 21 -+ qter. Van Essen et al. [1991] reported a single case and reviewed 5 ad- ditional cases of partial dup(3q). Clinically, the patients show microcephaly, brachycephaly, synophrys, short nose with anteverted nares, long philtrum, and geni- tourinary and cardiovascular system anomalies. This fetus fit the phenotypic profile of the partial dup(3q) syndrome. In rare cases hemangiomas may be seen with this syndrome [Sciorra et al., 19791; however, NB

26 Qureshi et al.

and other neural crest tumors have not been identified in the reported cases.

Although there are a number of reported cases of fa- milial NB [Kushner et al., 19861, no constitutional cy- togenetie abnormalities or heritable syndromes are consistently associated with NB. However, the cytoge- netic and molecular aspects of NB cells have been well studied [Brodeur, 19901. Deletion of the short arm of chromosome 1 has emerged as the most characteristic cytogenetic abnormality in primary human NB and tu- mor-derived cell lines. The most commonly deleted re- gion is between lp32 + lpter, suggesting the loss of a putative NB suppressor gene at this site. Rudolph et al. [ 19881 have also described fragile sites in up to 15% of examined metaphases in NB patients and relatives, with the most frequent break sites being found on the short arm of chromosome 1.

The association of microscopic NB and partial dup(3q), although possibly coincidental, is of interest. Only a few cases of NB have been reported in constitu- tional abnormalities. These include “trisomy D” [Niven et al., 19711, trisomy 13 [Feingold et al., 1971]), bal- anced translocations of (4p;7p) and (llq;16q) [Moor- head and Evans, 19801, a patient with possible sepa-

Fig. 3. Urinary tract and adrenals showing the larger left adrenal. Both renal pelves are dilated.

rate structural abnormalities involving chromosomes 21 and 11 [Pegelow et al., 19751, and an unbalanced translocation of chromosome 15 (46,XY,- 13,+der (13)t(13;15)(q34;23) [Sanger et al., 19841. According to these last investigators, most of the previously reported cases as well as their own were unbalanced transloca- tions, except for the cases of Moorhead and Evans [1980], which were balanced translocations. Wakonig- Vaartaja et al. [1971] described aneuploidy in 12 of 14 cases of untreated NB patients, but found no consistent abnormalities.

Although the association of microscopic NB and par- tial dup(3q) in this case may be purely coincidental, it supports the plausability of Knudson’s two-hit model for the development of embryonal tumors such as NB [Knudson and Meadows, 19761. This hypothesis states that all NB derive from a single cell that is transformed from a normal embryonal cell by 2 mutations. These mutations may be prezygotic which might be the basis of familial NB, or postzygotic, when they may give rise to non-familial NB. Since in the postzygotic state both mutations occur after conception, the tumors occur

quired cases. The association in the present case sug- Fig. 2, Fetus with hypedelorism, microphthalmia, anteverted later in life when ‘Ompared to the prezygotically ac-

nares, broad-based nasal bridge, and long philtrum.

NB and Unbalanced Translocation 3;lO 27

Fig. 4. Low power photomicrograph of the adrenal shows clusters of neuroblasts involving the medulla and extensively infiltrating the fetal cortex (Hematoxylin and eosin; X40).

Fig, 5. Left: Clusters ofneuroblasts are present in the adrenal gland (Hematoxylin and eosin; X100). Right: On higher power, the cells ap- pear hyperchromatic with some pleomorphism, resembling those of a neuroblastoma. A rosette is also present (Hematoxylin and eosin; X250).

28 Qureshi et al.

gests that the first mutation was a chromosomal re- arrangement resulting in the partial dup(3q) and po- tential disruption of the gene sequences at the translo- cation points. This rearrangement might have resulted in growth regulatory changes leading to the formation of a microscopic NB. The cells of the microscopic NB may become more susceptible to second mutational events at the critical region of chromosome 1 [Brodeur, 19901. If a second mutation occurs a t chro- mosome 1, a clinical NB could possibly result. Knudson and Meadows [19801 have similarly suggested that mi- croscopic NB and stage IV-S NB are single mutation le- sions. Why all microscopic NB do not transform into clinical NB is not known; however, it is possible that deletions of l q are limited only to a subset of patients.

REFERENCES Beckwith JB, Perrin EVD (1963): In situ neuroblastomas: A contribu-

tion to the natural history of neural crest tumors. Am J Path01

Brock DJH (1993): “Molecular Genetics for the Clinician.” Cambridge: Cambridge University Press, pp 136-167.

Brodeur GM (1990): Neuroblastoma: Clinical significance of genetic abnormalities. Cancer Surv 4:673-688.

Cohen AJ, Li FP, Berg S, Marchetto DJ, Tsai S, Jacobs SC, Brown RS (1979): Hereditary renal-cell carcinoma associated with a chromo- somal translocation. N Engl J Med 301592-595.

Feingold M, Gherardi GJ, Simons C (1971): Familial neuroblastoma and trisomy 13. Am J Dis Child 121:451.

Francke U (1978): Clinical syndromes associated with partial duplica- tions of chromosomes 2 and 3: dup(Zp), dup(Zq), dup(3p), dup(3q). New York Alan R. Liss, Inc., for the National Foundation-March of Dimes. OAS X I V (6C):191-217.

43:1089-1104.

Guin GH, Gilbert EF, Jones B (1969): Incidental neuroblastoma in in- fants. Am J Clin Pathol51:126-136.

Johnson MP, Ramsey N, Cervenka J , Wang N (1982): Retinoblastoma and its association with a deletion in chromosome #13: A survey using high resolution chromosome techniques. Cancer Genet Cy- togenet 6:29-37.

Knudson AG, Meadows AT (1976): Developmental genetics of neurob- lastoma. J Natl Cancer Inst 57:675-682.

Knudson AG, Meadows AT (1980): Regression of neuroblastoma IV-S: A genetic hypothesis. N Engl J Med 302:1254-1256.

Kushner BH, Gilbert F, Helson L (1986): Familial neuroblastoma. Cancer 57:1887-1893.

Moorhead PS, Evans AE (1980): Chromosomal findings in patients with neuroblastoma. In Evans AE (ed): “Advances in Neuroblas- toma Research.” New York Raven Press, pp 109-118.

Niven NC, Dodge JA, Allen IV (1971): Two cases of trisomy D associ- ated with adrenal tumors. J Med Genet 9:119-122.

Pegelow CH, Ebbin AJ, Powars D, Towner JW (1975): Familial neu- roblastoma. J Pediatr 87:763-765.

Riccardi VM, Sujansky E, Smither AC, Francke U (1978): Chromoso- mal imbalance in the aniridia-Wilms’ tumor association: l l p in- terstitial deletion. Pediatrics 61:604-610.

Rudolph B, Harbott J , Lampert F (1988): Fragile sites and neuroblas- toma: Fragile site at lp13.1 and other points on lymphocyte chro- mosomes from patients and family members. Cancer Genet Cyto- genet 31:83-94.

Sanger WG, Howe J , Fordyce R, Purtilo DT (1984): Inherited partial trisomy #15 complicated by neuroblastoma. Canc Genet Cytogenet 11: 153-159.

Sciorra LJ, Bahng K, Lee ML (1979): Trisomy in the distal end of the long arm of chromosome 3: A condition similar to the Cornelia de Lange syndrome. Am J Dis Child 133:727-730.

Shanklin DR, Sotelo-Avila C (1969): In situ tumors in fetuses, new- borns and young infants. Biol Neonate 14286-316.

van Essen AJ, Kok K, van den Berg A, de Jong B, Stellink F, Bos AF, Scheffer H, Buys CHCM (1991): Partial 3q duplication syndrome and assignment of D3S5 to 3q25-3q28. Hum Genet 87:151-154.

Wakonig-Vaartaja T, Helson L, Boren A, Koss LG, Murphy ML (1971): Cytogenetic observations in children with neuroblastoma. Pedi- atrics 47:839-843.