Adrenocortical Carcinoma in Two Children With Subsequent Primary Tumors
Gail Waldstein Levine, MD
. Two 13-month-old children with adre- nocortical carcinoma were treated surgi- cally; each developed a second primary tumor, four and seven years later, and died shortly thereafter.
Adrenocortical carcinoma is a rare childhood tumor. Second primary tumors in children are also uncommon. The coupling of two unusual events in each child is thought to represent genetic predisposition since potentially carcino- genic therapeutic modalities were not employed in treating their original tumors and neither patient exhibited an immune defense deficit.
(Am J Dis Child 132:238-240, 1978)
A® drenocortical carcinoma is an un- usual tumor of childhood, com- prising only 0.002% of all childhood malignancies.’ From 1931 through 1974, the experience at the Children’s
From the Department of Pathology, Children’s Hospital, Denver.
Reprint requests to Department of Pathology, Children’s Hospital, 1056 E 19th Ave, Denver, CO 80218 (Dr Levine).
Hospital in Denver included six cases of adrenocortical carcinoma among 1,456 malignant neoplasms. Two of these patients also developed second primary tumors. Only six similar cases were found in the literature.
REPORT OF CASES
CASE 1 .- A 13-month-old girl had exces- sive weight gain of two months’ duration. On admission she was obese, plethoric, hirsuit, and hypertensive (220/130 mm Hg); she had moon facies, clitoral enlarge- ment, and acneiform facial rash. She had developed normally, and she had two older normal siblings. The mother had had one miscarriage; a paternal grandfather had stomach carcinoma. Initial laboratory stud- ies disclosed leukocytosis, normal hemo- globin value and urinalysis results, grossly elevated 24-hour urinary steroid excretion (Table 1), and decreased skeletal calcifica- tion. An intravenous pyelogram (IVP) showed a left suprarenal mass. At surgery an adrenal tumor, weighing 188 gm, and 8 em in diameter, was removed. Microscop- ically, there were areas of capsular microinvasion and extreme cellular pleo- morphism. A diagnosis of adrenocortical
carcinoma was made (Fig 1, left). Postoper- atively the patient did well with short-term corticosteroid replacement but no specific antitumor therapy. The blood pressure gradually fell to normal; subsequent urine steroid determinations were also normal (Table 1).
At 5 years of age (four years after the first tumor was diagnosed), the child was admitted to another hospital with ataxia, and was found to have a tumor in the left cerebellar hemisphere. The tumor was biopsied; metastatic adrenocortical carci- noma was initially diagnosed; and a shunt procedure was done. Two months later, the patient died. At autopsy, a 5-cm diameter intracerebellar medulloblastoma was iden- tified. The previous surgical diagnosis of metastatic adrenocortical carcinoma was revised to medulloblastoma (Fig 1, right).
CASE 2 .- The second patient, a boy, was seen at 13 months of age with modest hypertension, acne, enlarged phallus, and obesity. Downward displacement of the left kidney was demonstrated on IVP, and the urinary steroid levels were elevated (Table 1). His history was unremarkable; however, both grandfathers had died of carcinoma of the lung. The child was considered to have the adrenogenital syndrome and was treated with cortisone
| Table 1 .- Urinary Steroid Determinations (mg/24 hr) | ||||||
|---|---|---|---|---|---|---|
| Normal | 2 mo Preoperatively | 1 mo Preoperatively | Immediately Preoperatively | Immediately Postoperatively | 6 wk Postoperatively | |
| Case 1/F 17-ketosteroids | 2 | 38 | 2.2 | 0.4 | ||
| 17-hydroxycorticosteroids | 2-6 | 31 | 8.9 | 2.2 | ||
| Case 2/M 17-ketosteroids | 2.0 | 2.2 | 10 | 64 | 1.0 | |
| 17-hydroxycorticosteroids | 3-10 | 1.9 | 6.7 | |||
| Pregnanetriol | 0.5 | 2.1 | 1.4 | 3.0 | ||
acetate for two months. Persistence of symptoms despite therapy and an increase in urinary steroid excretion (Table 1) resulted in admission to the hospital at 15 months of age. An exploratory laporotomy disclosed a left adrenal tumor weighing 40 gm and measuring 10x8x1.5 cm. In addition to considerable histologie pleo- morphism, there was extension into the adrenal vein. A diagnosis of adrenocortical carcinoma was made (Fig 2, left). The child was given corticosteroid replacement ther- apy, but no antineoplastic drugs were used. He remained well for the next seven years. At 8 years of age, he developed a “flu-like” syndrome with emesis and abdominal pain. Three weeks later he was found to have an abdominal mass. Exploratory laporotomy demonstrated an ileocecal, poorly differen- tiated lymphocytic lymphoma (Fig 2,
right). Despite aggresive chemotherapy and radiation, the patient died within six months of diagnosis.
COMMENT
Recent reports in the literature portend a poor outcome for patients with adrenocortical tumors, either adenomas or carcinomas. Current mortality for childhood adrenal carci- noma is 90%-199 deaths of 222 cases reported.” The established histologic criteria for malignancy include a high mitotic index, vascular or capsular invasion, hemorrhage, marked pleo- morphism, nuclear atypia, and necro- sis.3.+ More recent data suggest that tumor size may be the single most
reliable indicator of biologie behavior, other than the obvious one of metasta- sis. Tumors weighing less than 50 gm are associated with long survival; those weighing more than 95 gm portend a poor prognosis.” Pellerin et ale have suggested that tumors weigh- ing 120 gm or less are benign, while those greater than 200 gm are malig- nant. The cases described here corrob- orate the prognostic implications of this weight-based parameter for be- nignancy. However, the histologic findings in both cases would suggest a poor outcome, since one tumor had invaded the capsule and the other had extended into the adrenal vein.
Multiple etiologic factors relate to
| Table 2 .- Childhood Cases of Adrenocortical Carcinoma and Second Primary Tumor | ||||
|---|---|---|---|---|
| Source | Age at Diagnosis | Sex | Histologic Diagnosis of Adrenal Lesion | Second Primary Tumor |
| Cseh14 | 6 yr | F | Carcinoma | Glioma, eye |
| Dargeon17 | 2 yr | F | Carcinoma | Amelanotic melanoma, cheek |
| Fraumeni & Miller13 | 4 yr | M | Carcinoma | Astrocytoma, left cerebellum |
| 8 yr | M | Carcinoma | Paraventricular astrocytoma | |
| Miller16 | Not stated | NS | Carcinoma | Brain tumor |
| Chebalko et al15 | 12 yr | F | Adenoma | Undifferentiated sarcoma, chest wall |
| Current report | 13 mo | F | Carcinoma | Medulloblastoma, left cerebellum |
| 13 mo | M | Carcinoma | leocecal lymphoma | |
childhood tumor development. Envi- ronmental exposures to recognized carcinogens include irradiation and certain drugs. Some of the latter increase tumor growth7 whether the child is exposed in utero or postna- tally. While environmental agents cannot be unequivocally excluded in the cases described here, neither child had a history suggestive of exposure. Since potentially carcinogenic thera- peutic modalities were not employed in treating either child’s primary tumor, iatrogenic causes can be excluded as a reason for development of the second tumor.
Genetic predisposition is a broad concept, encompassing recognized familial syndromes, multiple endocri- nopathies, congenital immune defi- cits, and the rare “cancer-prone fami- lies.” Specific syndromes with in- creased likelihood of childhood tumor include the phakomatoses, the basal cell nevus syndrome, and glioma-poly- posis syndrome.” Chronic hyperplasia of endocrine organs has been asso- ciated with both familial predilection and increased incidence of malignan- cy.9 No obvious syndrome relationship was recognized in either child, nor was endocrine hyperplasia identified.
1. Young JL, Miller RW: Incidence of malig- nant tumors in U.S. children. J Pediatr 86:254- 258, 1975.
2. Stewart DR, Jones PH, Jolleys A: Carci- noma of the adrenal gland in children. J Pediatr Surg 9:59-67, 1974.
3. Harrison JH, Mahoney EM, Bennett AH: Tumors of the adrenal cortex. Cancer 32:1227- 1235, 1973.
4. Heinbecker P, O’Neil LW, Ackerman LV: Functional and nonfunctional adrenal cortical tumor. Surg Gynecol Obstet 105:21-33, 1957.
5. Tang CK, Gray GF: Adrenocortical neo- plasms: Prognosis and morphology. Urology 5:691-695, 1975.
6. Pellerin D, Harouchi A, Soulier Y: Les tumerus de la cortico-surrenale de l’enfant: A
While immune disturbances, often genetically influenced, are recognized in patients with lymphomas, they were not found in either of the patients described. Immune defense inadequacies have not specifically been noted in other children with either adrenocortical carcinomas or intracranial neoplasms.
Identification of families at high risk for malignant tumor development is of increasing clinical significance. Generally viewed as vertically trans- mitted, the increased tumor suscepti- bility has been established in both maternal and paternal lineage in some kindreds.8.10 Children who develop sar- comas in youth often have siblings with neoplasia11 and parents with malignant neoplasms that have an earlier than anticipated onset.12 Li and co-workers established adreno- cortical carcinomas and rhabdomyo- sarcomas in sibling sets of two sepa- rate families, suggesting a cancer syndrome. In a separate publication, Li and Fraumeni12 proposed a familial cancer syndrome when the propensity for development of brain tumors, adrenocortical carcinomas, and rhab- domyosarcoma was noted in siblings. Interestingly, these particular tumor
types also affect individuals as double primary tumors.
The rarity of second primary tumors in children is demonstrated by the sparse literature on the subject. When the criterion of one primary tumor being adrenocortical in origin was employed, only six similar cases were identified (Table 2). Four of the second primary tumors were central nervous system tumors.13-16 One addi- tional tumor was also of neurecto- dermal derivation, an amelanotic mel- anoma.17
Whether the children described here are members of a “cancer-prone family” is speculative and depends somewhat on one’s definitions. Only three of eight grandparents had carci- noma. Neither patient had sufficient numbers of siblings for valid statis- tical evaluation at the time of report, nor was premature parental malig- nancy evident. However, the associa- tion of two rare events in each child suggests that these specific tumors developed, or that there was decreased resistance to these entities, as a result of locus-adjacent problems in an indi- vidual genome.
David Akers, MD, originally observed the primary tumors in these patients.
References
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