BRIEF REPORT Adrenocortical Carcinoma Associated With Adrenogenital Syndrome in a Child
Ali Varan, MD,1* Sevim Ünal, MD,2 Şevket Ruacan, MD,3 and Sadi Vidinlisan, MD2
Key words: adrenocortical carcinoma; adrenogenital syndrome; childhood cancer; clinical genetics
Adrenocortical carcinoma (ACC) is very rare in child- hood. Its incidence is reported to be 0.2% among all causes of childhood cancer [1]. The histopathologic dif- ferentiation from benign adenomas is difficult. Some characteristics such as cellular atypia, vessel invasion, capsular invasion, and metastases may indicate a worse prognosis [2,3]. The etiology of this tumor is unclear, but it may be associated with congenital anomalies such as the Beckwith-Wiedemann syndrome, hemihypertrophy, and brain tumors [4,5]. There are only a few reports about the coexistence of adrenogenital syndrome and ACC [6,7], so our experience with such a patient is of interest.
CASE REPORT
He was a 5-year-old, moderately mentally retarded boy, who was admitted to our hospital with complaints of acceleration of growth for the last 2 years, darkening of the skin, and hirsutism. His weight and height were above the 90th percentile. The blood pressure was 130/80 mm Hg. He had hyperpigmentation of the entire body, axillary and pubic hair, and increased muscle mass. His genitalia were ambiguous, with labioscrotal fusion and clitoral hyperplasia (Fig. 1a,b). Testicles were not pal- pated in the scrotum. There was a mass in the right lum- bar region. An X-ray film of the wrist revealed a bone age of 10 years. Serum ACTH and DHEA-SO4 levels were 1,250 pg/ml (normal level 25-100 pg/ml) and 89.2 µg/dl (normal level 13-83 µg/dl), respectively. The al- dosterone level was normal. Serum and urinary 17- ketosteroids were elevated. Abdominal ultrasonography and computed tomography revealed a solid mass of 6 x 5 x 9 cm in the right adrenal gland. Bilateral nodular parenchymal metastases were visible on chest tomogra- phy. Internal genitalia including ovaries and uterus of age-appropriate size were identified on ultrasonography of the pelvis. An encapsulated right adrenal mass that weighed 80 g was totally removed by surgery, and the histopathology was compatible with adrenocortical car-
cinoma with vascular and capsular invasion and nuclear polymorphism. Mitotane therapy was initiated.
DISCUSSION
Endocrinologic tumors are very rare in both adults and children. Some authors report the adrenal carcinoma in- cidence to be 0.2-0.6% [1,3]. Adrenocortical tumors ap- pear to cluster in early childhood; most occur before age 5 years [8,9]. Bilateral carcinomas are present in about 4% cases. Most tumors are unilateral, left and right adre- nal glands being affected equally [9,10]. Our patient was 5 years old with a right adrenal tumor.
There are few reports noting an association between ACC and the adrenogenital syndrome [8]. Some authors stress that hyperstimulation through ACTH secretion may cause hyperplasia, adenoma, and carcinoma of the adrenal gland [6,7]. Beuschlein et al. [11] mentioned controversial findings in their study, in which they ex- amined patients hyperstimulated by ACTH. Three of sev- enteen patients, all adults, had monoclonal pattern ACC and mutations at the DXS255 locus. In childhood, the adrenogenital syndrome may play a role in carcinogen- esis, putatively through hypersecretion of ACTH, leading to malignant cellular changes in the adrenal.
Adrenocortical tumors should be suspected in any child with premature or inappropriate signs of viriliza- tion, feminization, or gynecomastia [10,12-14]. Clini- cally asymptomatic children with only abdominal masses
1Department of Pediatric Oncology, Hacettepe University Faculty of Medicine, Ankara, Turkey
2Department of Pediatric Endocrinology, Ankara SSK Çocuk Hasta- lıkları ve, Eğitim Hastanesi, Dışkapı-Ankara, Turkey
3Department of Pathology, Hacettepe University Faculty of Medicine, Ankara, Turkey
*Correspondence to: Ali Varan, MD, Department of Pediatric Oncol- ogy, Hacettepe University Faculty of Medicine, Ankara, Turkey.
Received 13 April 1999; Accepted 29 February 2000
a
b
have also been reported [8]. Signs of virilization de- scribed with ACC include increased muscle mass, rapid growth, acne, axillary and pubic hair, hirsutism, and cli- toral hyperplasia. Our patient had been reared as a boy because of male phenotype of external genitalia since birth. In virilizing ACC, posterior labial fusion is usually not a feature [10,12]. Additionally, a virilizing tumor, metastatic to the lung and present in the antenatal period, would most probably have been fatal before age 5 years, the age of our patient at diagnosis.
The histopathologic distinction between adenoma and carcinoma can be quite difficult in endocrinologic tu- mors. Thyroid, parathyroid, or adrenal malignant tumors may resemble normal tissue. Specimen weight is an im- portant factor. An adrenal mass of more than 100 g is thought to be malignant [15]. Bugg et al. [16] found that histologic criteria of malignancy were directly associated with greater tumor weight, larger diameter, ploidy, and proliferative index in their patients [16]. Grading, nuclear atypia, vessel invasion and metastases were also impor- tant criteria in other reports [2,3]. Histopathologic ex- amination in our case revealed differentiated tumoral cells with minimal nuclear atypia and capsular and vessel invasion, so that the presence of lung metastases was the determining factor in concluding that the tumor was ma- lignant.
The diagnosis of ACC is difficult and often delayed. Metastases most frequently involve the lungs, liver, re- gional lymph nodes, and less commonly brain and bone. The reported 5-year survival rate has generally been below 20% [13,17,18]. The period of time from the first symptom to diagnosis varies between 1 and 49 months, with a median of 6 months [10,13,17]. Luton et al. [18] found that 50-80% of the patients had metastatic disease at the time of diagnosis. Surgery is the primary mode of therapy [10,12,13]. To date, chemotherapy has not been effective in controlling metastatic disease. Radiotherapy has been used, but its efficacy also has not been estab-
lished [10,12-14]. Treatment should include mitotane, which produces an iatrogenic adrenalectomy. There are, however, no survival data in children so managed.
Our patient is noteworthy because of the association of the adrenogenital syndrome with ACC. We speculate that the uncontrolled adrenogenital syndrome may have led to adrenocortical cellular proliferation and thence to carcinoma. Should this be true, early diagnosis of adre- nogenital syndrome is important both for correcting the endocrinologic abnormalities and for aborting any incipi- ent malignant changes.
REFERENCES
1. Miller RW, Young JL, Novakovic B. Childhood cancer. Cancer 1994;75:395-405.
2. Huvos AG, Hajdu SI, Brasfield RD, Foote FW. Adrenal cortical carcinoma: clinicopathologic study of 34 cases. Cancer 1970;25: 354-361.
3. Didolkar MS, Bescher A, Elias EG, Moore RH. Natural history of adrenal cortical carcinoma: a clinicopathologic study of 42 pa- tients. Cancer 1981;47:2153-2161.
4. Fraumeni JF, Miller RW. Adrenocortical neoplasms with hemi- hypertrophy, brain tumors and other disorders. J Pediatr 1967;70: 129-138.
5. Wiedemann H-R. Tumors and hemihypertrophy associated with Wiedemann-Beckwith syndrome. Eur J Pediatr 1983;141:129.
6. Pang S, Becker D, Cotelingam J, et al. Adrenocortical tumor in a patient with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Pediatrics 1981;68:242-246.
7. van Seters AP, van Aalderen W, Moolenar AJ, et al. Adrenocor- tical tumor in untreated congenital adrenocortical hyperplasia as- sociated with inadequate ACTH suppressibility. Clin Endocrinol 1981;14:325-334.
8. Lee PDK, Winter RJ, Green OC. Virilizing adrenocortical tumors in childhood: eight cases and a review of the literature. Pediatrics 1985;76:437-444.
9. Harrison JH, Jenkins D, Bennett AH. Hyperplasia and tumors of the adrenal cortex. Urol Int 1972;27:81-117.
10. Sandrini R, Ribeiro RC, DeLacerda L. Extensive personal expe- rience: childhood adrenocortical tumors. J Clin Endocrinol Metab 1997;82:2027-2031.
Varan et al.
11. Beuschlein F, Reincke M, Karl M, et al. Clonal composition of human adrenocortical neoplasms. Cancer Res 1994;54:4927- 4932.
12. Morales L, Rovira J, Rottermann M, Julia V. Adrenocortical tu- mors in childhood: a report of four cases. J Pediatr Surg 1989;3: 276-281.
13. Chudler RM, Kay R. Adrenocortical carcinoma in children. Urol Clin North Am 1989;16:469-479.
14. Ribeiro RC, Sandrini Neto R, Schell MJ, et al. Adrenocortical carcinoma in children: a study of 40 cases. J Clin Oncol 1990;8: 67-74.
15. Michalkiewicz EL, Sandrini R, Bugg MF, et al. Clinical charac-
teristics of small functioning adrenocortical tumors in children. Med Pediatr Oncol 1997;28:175-178.
16. Bugg MF, Ribeiro RC, Roberson PK, et al. Correlation of patho- logic features with clinical outcome in pediatric adrenocortical neoplasia: a study of a Brazilian population. Am J Clin Pathol 1994;101:625-629.
17. Gröndal S, Cedermark B, Eriksson B, et al. Adrenocortical carci- noma: a retrospective study of a rare tumor with a poor prognosis. Eur J Surg Oncol 1990;16:500-506.
18. Luton JP, Cerdas S, Billaud L, et al. Clinical features of adreno- cortical carcinoma, prognostic factors, and the effect of mitotane therapy. N Engl J Med 1990;322:1195-1201.