European Journal of Pediatrics c by Springer-Verlag 1978
Wilms’ Tumor and Adrenocortical Carcinoma with Hemihypertrophy and Hamartomas
S. Müller1*, H. Gadner’, B. Weber1, M. Vogel2, and H. Riehm1
1 Department of Pediatrics, Freie Universität Berlin, Heubnerweg 6, D-1000 Berlin 19
2 Department of Pathology, Freie Universität Berlin, D-1000 Berlin 19
Abstract. A girl with hemihypertrophy and hamartomas, now 14 years old, had Wilms’ tumor and subsequently developed adrenocortical carcinoma. The occurrence of the two tumors with the signs of an inborn defect of growth control supports the hypothesis that both tumors can be caused by the same etiologic factors, which are also teratogenic. An alternative explanation of induction of the second tumor by previous radio- and chemotherapy is discussed. Possible relationships between our case and the syndrome of Wiedemann and Beckwith are pointed out.
Key words: Hemihypertrophy - Wilms’ tumor - Adrenocortical neoplasia - Wiedemann-Beckwith syndrome.
Introduction
Reports on congenital anomalies frequently associated with certain tumors in childhood provide an approach to study the pathogenesis of some of these tumors. Furthermore, such anomalies may serve as visible markers for certain tumors, thus contributing to their earlier detection. Wilms’ tumor, adrenocortical neoplasia and liver tumors are frequently associated with hemihypertrophy, hamartomas and other congenital disorders of growth control (Miller et al., 1964; Fraumeni et al., 1967; Fraumeni and Miller, 1967; Miller, 1968; Fraumeni et al., 1968; Pendergrass, 1976). It has therefore been suggested that these three tumors share common etiological factors (Miller, 1968; Fraumeni et al., 1968). This hypothesis is further supported by the following case report of a patient with hemihypertrophy and hamartomas, who successively developed Wilms’ tumor and adrenocortical carcinoma.
Case Report
The girl, S. F., was born in 1963 (birth weight 3900 g, birth length 55 cm) after an uneventful pregnancy. Drugs, viral infections and exposure to irradiation during pregnancy have been
* Corresponding author
cm
180
97
160
3
140
120
100
B
B
11
M
PP
80
HI IV
60
Wilms tumor
Adrenocortical carcinoma
50
YEARS
2
4
6
8
10
12
14
16
explicitly excluded. In 1966, at the age of 21/12 years, she presented with hematuria and a palpable mass in the right upper abdomen.
The intravenous pyelogram strongly suggested the diagnosis of Wilms’ tumor of the right kidney and failed to reveal any other genitourinary anomalies. The right kidney was removed. The tumor proved to be an embryonal adenosarcoma on histological examination. It measured about 5 cm in diameter and was confined to the parenchyma of the kidney. Local or distant metastases were not detected (stage I). The right adrenal gland remained in situ. Chemotherapy was started at surgery and continued for a period of 21/12 years (total dose: 16 mg actinomycin D in 12 treatment courses). Postoperatively the right renal fossa was irradiated with 3000 rads. Radio- and chemotherapy were tolerated without severe side effects. At the age of 7º/12 years- 47/12 years after nephrectomy and radiotherapy and nearly 2 years after discontinuation of chemotherapy-the girl presented with rapid development of pubic hair (stage P IV), marked hypertrophy of the clitoris, acne vulgaris and a sudden growth spurt (Fig. 1). Her growth velocity during the preceding 6 months had increased to more than 13 cm/yr and her skeletal age was advanced by about 2 years (Fig. 1). She had arterial hypertension (145/105 mm Hg), hypernatriaemia (150 mEq/1) and slight hyperchloraemia (108 mEq/1). No estrogen effects were detected (no palpable breast tissue (B I), vaginal smear: Schmitt 1). Plasma testosterone was markedly increased (510 ng/100 ml). The urinary excretion of 17-ketosteroids (5.9 mg/day) and hydroxysteroids were elevated to a lesser extent. The gonadotropin excretion remained below the level of detection.
A tumor of approximately chestnut-size in the area of the right suprarenal gland was detected by arteriography. The tumor was totally removed by surgery, together with a small
residue of the adrenal cortex. Histologically the tumor infiltrated its capsule and the surrounding adrenocortical tissue (Fig. 2, left). It consisted predominantly of polymorphic, adrenal cortex-like epithelial cells with abundant cytoplasm, which was in part densely eosinophilic, and in part vacuolated. Many giant cells were found with one or more nuclei and nucleomegaly (Fig. 2, right). A remarkable finding was of giant cells and nucleomegaly in the residual adrenocortical tissue not involved by the tumor. No local metastases were detected in the abdominal cavity, and distant metastases were excluded by clinical and radiological investigation. Postoperatively, transitory adrenal insufficiency necessitated temporary gluco- corticoid therapy. Chemotherapy with daunorubicin had to be discontinued after a three days’ course because of severe bone marrow depression and toxic effects on the myocardium. Radio- therapy was omitted because of the previous irradiation to the same area and the localized presentation of the tumor. Hormone levels, blood pressure and serum electrolytes returned to normal within a fortnight. In spite of the interruption of the androgenic stimulation, the growth rate remained elevated. Five months after adrenalectomy, at the age of less than 8 years (skeletal age: 10 years) true puberty started with bilateral breast development (B II). At 1010/12 years menarche (M, Fig. 1) occurred. At the present time, 11 years after removal of the Wilms’ tumor and 7 years after removal of the adrenocartical neoplasm, the girl is fully developed, has regular menses and has no signs of recurrence of either tumor.
In addition to these tumors, the girl has marked hemihypertrophy of the right part of the tongue (Fig. 3), and the left leg exceeds the right by 2cm in length and by 1.5cm in circumference throughout. Capillary haemangiomas of the right occipital region and of the left forearm were removed surgically at the end of the first year of life. Several members of the father’s family also have haemangiomas. A bone cyst in the father’s right humerus caused a spontaneous fracture when he was a child. There are no hamartomas known in the mother’s family. The mother herself has a pigmented naevus about 2 cm in diameter on the left upper eyelid.
Discussion
Wilms’ Tumor and Congenital Anomalies
Three major congenital anomalies are associated with Wilms’ tumor (Miller, 1968; Pendergrass, 1976): i.e. non-familial aniridia, genito-urinary anomalies and hemihypertrophy. Incidence rates for non-familial aniridia in Wilms’ tumor have been reported to be 1:73 (Miller, 1964) and 1:91 (Pendergrass, 1976), and genito-urinary anomalies have been found in 1 of 23 (Pendergrass, 1976) and in 1 of 25 cases (excluding hypospadias) (Miller, 1964). The incidence of hemihyper- trophy has been found to be 1 : 147 (Miller, 1964), 1: 32 (Fraumeni et al., 1967) and 1: 37 (Pendergrass, 1976), the increasing incidence in the recent reports being probably due to a greater awareness of this anomaly.
The incidence of hemihypertrophy in the general population is very low. Reviewing the charts of about 860 000 hospital admissions, Parker and Shalko (1969) found 10 cases with hemihypertrophy. An incidence of 1 in 14 000 births followed up to the age of 6 years has been reported by Leck et al. (1968). Many cases of mild hemihypertrophy, however, may have been overlooked.
Hemihypertrophy, Hamartomas and Neoplasia
Hemihypertrophy, in turn, is associated in excess with two other tumors: i.e. prima- ry liver tumors (Fraumeni et al., 1968; Geiser et al. 1970) and adrenocortical neo- plasia (Fraumeni and Miller, 1967; Haicken et al., 1973; Benaily et al., 1975). Two of 62 children with adrenocortical neoplasms reviewed by Fraumeni and Miller (1967) had congenital hemihypertrophy. Hamartomas, especially pigmented or vascular naevi of the skin as present in our patient, have been frequently found in association with hemihypertrophy (Ringrose et al., 1965; Fraumeni et al., 1967; Parker and Shalko, 1969), Wilms’ tumor (Miller et al., 1964; Miller, 1966; Frau- meni et al., 1967; Pendergrass, 1976; Simon et al., 1977), and adrenocortical neo- plasia (Fraumeni and Miller, 1967; Haicken et al., 1973).
Genetic Aspects
The finding of hamartomas in the patient’s parents and in members of the father’s family raises the question of the inheritance of Wilms’ tumor (and adrenocortical neoplasia) associated with congenital anomalies. Some familial cases of Wilms’ tumor (Knudson and Strong, 1972; Pendergrass, 1976) and of adrenocortical neoplasms (Knudson and Strong, 1972), as well as of hemihyper- trophy other than in neurocutaneous disorders, (reviewed by Fraumeni et al., 1967) have been reported. In rare instances, hemihypertrophy has not been evident in the propositus with Wilms’ tumor, but has been found in other members of the family (Fraumeni et al., 1967; Meadows et al., 1974).
By statistical analysis of the pattern of manifestation of Wilms’ tumor, Knud- son and Strong (1972) and Knudson (1975) distinguish “hereditary” and “non- hereditary” types of Wilms’ tumor. However, data of cases of Wilms’ tumor associated with hemihypertrophy were similar to those of the “non-hereditary” type (Knudson and Strong, 1972); i.e., they were unilateral and the patients’ ages at diagnosis were significantly higher than in “hereditary” cases.
Multiple Tumors
The occurrence of hemihypertrophy, a tumor of the adrenal gland and Wilms’ tumor in the same patient has only been reported once by Riedel (1952) in a boy who underwent surgery for adrenocortical adenoma contralateral to the hemi- hypertrophic side when he was 11 months of age. Nearly 5 years later he developed Wilms’ tumor on the side of the prior adrenocortical adenoma. Two of the 400 patients with Wilms’ tumor reviewed by Miller et al., (1964) had nodular hyperplasia of the adrenal cortex.
Several examples of subsequent or preceding malignancies of different origin have been reported in children with Wilms’ tumor: i.e. mixed liver tumor (Fraumeni et al., 1968), fibrosarcoma (Pendergrass, 1976) and bilateral retino- blastoma (Pendergrass, 1976). One child had four different tumors (Valdes- Dapena and Arly, 1971): i.e. Wilms’ tumor, rhabdomyosarcoma, myelomonocytic leukemia and neuroblastoma. None of these children had hemihypertrophy.
EMG-Syndrome
The same organs (kidney, adrenal cortex and liver) which are involved in hemihypertrophy-associated neoplasia, are also affected in hyperplastic viscero- megaly, which is part of the syndrome of Wiedemann (1964) and Beckwith (1963, 1968). Besides the major features of this syndrome, i.e., exomphalos, macro- glossia and gigantism (EMG-syndrome), additional anomalies have been ob- served in many patients (Filippi and McKulick, 1970; Reddy et al., 1972; Wiede- mann, 1973 a; Kosseff et al., 1976; Sotelo-Avila and Gooch, 1976). These include hemihypertrophy, which has been found in 24 of 171 children with EMG syndrome reviewed by Wiedemann (1973b), and intra-abdominal tumors. Wiede- mann (1973 b) compiled 10 such cases from the literature, 4 of which were Wilms’ tumors and 3 adrenocortical carcinomas. Other anomalies which are frequently associated with the EMG syndrome and which were also present in our patient, are cytomegaly of the adrenal cortex, capillary haemangiomas (usually facial) and advanced bone age, commensurate with the gigantism. The girl’s advanced physical maturation is documented by her growth curve, which was above the 97th percentile even before massive androgen secretion started. Her skeletal maturation, which was first determined after the onset of symptoms of the adrenal tumor, was advanced to such an extent that some acceleration prior to the onset of the tumor cannot be excluded. The advanced physical maturation, due to the girl’s constitutional development, may well explain the uninterrupted growth spurt and the early onset of true puberty after surgical removal of the virilizing tumor. These findings may indicate a close relationship between the hemihypertrophy syndrome and the EMG syndrome which has already been stressed by several authors (Fraumeni and Miller, 1967; Fraumeni et al., 1967; Fraumeni et al., 1968; Miller, 1968; Pfister et al., 1975). The hypothetical relation- ships between the two tumors, hemihypertrophy and hamartomas, and the EMG syndrome are outlined in Figure 4.
Radio- and Chemotherapy
Undoubtedly radiotherapy has an oncogenic effect. Together with chemo- therapy it has significantly increased the survival rates of patients with Wilms’ tumor. It may, however, contribute to an increased risk of leukemia in survivors (Schwartz et al., 1975). Since the adrenocortical carcinoma developed in the previously irradiated area, the possibility that the second tumor was induced by irradiation cannot be excluded. However, the interval of 4 years between irradiation and the appearance of the second tumor seems too short, since the
WILMS’ TUMOR
1 EMG-SYNDROME ☒
HEMIHYPERTROPHY, HAMARTOMAS
11 ☒
/Z
ADRENOCORTICAL NEOPLASIA
manifestation of radiation-induced solid tumors less than 10 years after radio- therapy is uncommon (Li et al., 1975). On the other hand, the combination of radiotherapy with chemotherapy may shorten the latent period (Belpomme et al., 1974). Although actinomycin D may be a mutagen due to its mode of action, its oncogenicity has not been proven. Several recent follow-up studies on the prognosis of Wilms’ tumor treated with radio- and chemotherapy do not mention the occurrence of adrenocortical neoplasms among the large number of patients studied (Maier and Harshaw, 1967; Aron, 1974; Wolff, 1975). Thus, since tumor induction by anti-cancer therapy is not likely in our patient, we feel that the occurrence of the two tumors with hemihypertrophy, hamartomas and advanced physical development in the same patient further supports the hypothesis that certain cases of Wilms’ tumor and of adrenocortical carcinoma have common etiological factors, which are both teratogenic and oncogenic. Moreover, our case may provide another link between the hemihypertrophy syndrome and the EMG syndrome.
Note Added in Proof
In October, 1977, a fibroadenoma was detected in the girl’s right breast.
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