Fetal Pediatr Pathol Downloaded from informahealthcare.com by McMaster University on 10/28/14 For personal use only.
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NONFUNCTIONING ADRENOCORTICAL CARCINOMA IN A CHILD
Turan Kanmaz, MD, and Savas Demirbilek, MD Surgery, Harran University, Faculty of Medicine, Sanliurfa, Turkey ☐ Department of Pediatric Ilyas Ozardali, MD u ☐ Department of Pathology, Harran University, Faculty of Medicine, Sanliurfa, Turkey Mukerrem Safali, MD u u
☐ Department of Pathology, GATA, Ankara, Turkey Sefik Guran, MD u
☐ Department of Medical Biology, GATA, Ankara, Turkey
Selcuk Yucesan, MD u ☐ Department of Pediatric Surgery, Harran University, Faculty of Medicine, Sanliurfa, Turkey
☐ Pediatric nonfunctioning adrenocortical carcinoma is a very rare tumor. A 4-year-old girl was admitted complaining of abdominal pain. Physical examination revealed an abdominal mass. There were no clinical or laboratory signs of hormonal abnormality. Abdominal ultrasonography revealed a polylobular mass. Intra- venous pyelography showed marked compression of the kidney by a tumor. The tumor was excised together with the right kidney. The histopathological diagnosis was adrenocortical carcinoma. Although there is a greater incidence of germ line p53 mutations with adrenocortical carcinoma, the tumor suppressor gene p53 was not mutated in our case. The girl died 2 months after surgery from complications of chemotherapy. u
Keywords adrenocortical carcinoma, p53 mutation
Adrenocortical carcinoma is a rare malignant tumor with an incidence ranging from 0.5 to 2 cases per million people [1]. The following is a description of the clini- cal, surgical, and histopathological findings of a nonfunctioning adrenocortical car- cinoma case.
CASE REPORT
A 4-year-old girl was admitted to the hospital with abdominal pain of about 3 weeks duration. She also had constitutional symptoms such as fever, malaise, weight loss, weakness, anorexia, and nausea. Physical examination revealed a right-sided large abdominal mass and hepatomegaly. There were also decreased breath sounds and rales over the base of the right lung. Severe anemia, leukocytosis, and hypoproteinemia were present in biochemical studies. Otherwise clinical and laboratory signs were normal. Plain abdominal radio- graphs revealed a large soft tissue mass on the right side. Chest x-ray showed
Address correspondence to Turan Kanmaz, MD, University of Wisconsin Hospital, CSC, Knechtle Lab, HY/733, Madison, WI 53705, USA. E-mail: kanmaz@surgery.wisc.edu
a right pleural effusion. There were no bony metastases on preoperative bone scan. Abdominal ultrasonography revealed hepatomegaly and a polylobular mass (11 ×10 ×5 cm in diameter) adherent to the liver and the right kidney. Intravenous pyelography showed marked compression and deformity of the right kidney by a tumor. Computerized tomography (CT) scans of the abdo- men confirmed these findings. On surgical exploration the tumor invaded to the right kidney, peritoneum, and omentum. This tumor was excised together with the right kidney. The diagnosis of adrenocortical carcinoma was con- firmed both histopathologically and immunohistochemically (Figures 1 and 2). In immunohistochemical studies, our case expressed vimentin-positive, cytoker- atin-negative, S-100 protein-positive (in some cells), neurofilament protein-posi- tive (in some cells), and synaptophysin-negative. The tumor suppressor gene p53 was analyzed using both single-strand conformational polymorphism (SSCP) and immunohistochemical techniques. The gene p53 was not mutated on exons 6 to 9 (Figure 3). This was also confirmed by immunohistochemical investigations. Postoperatively, the child was referred to another medical center for chemotherapy. Combination chemotherapy (including vincristine, cyclophosphamide, doxorubicin, actinomicine, etoposide, and carboplatin) was given to the patient. She died 2 months after surgery from complications of chemotherapy.
DISCUSSION
Pediatric adrenocortical tumors are very rare and comprise only 0.2% of all child- hood malignancies [1]. There is a bimodal occurrence, with one peak occurring at age less than 5 years and other peak in the fourth to fifth decade of life [2]. Liou and Kay found a female predominance [1]. Based on whether adrenocortical carci- nomas are hormonally active and manifest clinically, they can be classified as either functional or nonfunctional. In contrast to tumors in adults, most pediatric adrenocortical carcinomas are functional. Hormonally functional tumors were found in 94.5% of the pediatric series [1]. Ciftci et al. reported no significant differ- ence in survival rate between the functional and nonfunctional adrenocortical car- cinomas in their series [3]. There were no clinical or laboratory signs of hormonal abnormality in our case.
The differential diagnosis of a nonfunctioning adrenal carcinoma presenting as an abdominal mass should include neuroblastoma, Wilms’s tumor, hydronephrotic and cystic diseases of the kidney, and adrenal cyst. Neuroblastomas, ganglioneuro- blastoma, and pheochromocytomas account for the majority of pediatric adrenal gland tumors [4]. It was difficult to diagnose a patient with nonfunctioning adrenal tumor preoperatively. We diagnosed our patient histopathologically in the post- operative period.
Its etiology is unknown; recent evidence demonstrates that adrenocortical carcinomas do indeed arise de novo, and that such tumors do not result from
preexisting adrenal pathology [1]. Multiple studies have confirmed that 100% of adrenal carcinomas are monoclonal, arising from a single progenitor cell. In addition, the proteins (Gas, Gai) regulating cAMP, the second messenger of the ACTH receptor, are found to be predominantly normal in adenomas and carci- nomas [5]. Because aberrations in the ACTH signaling pathway are not the cause of adrenocortical carcinomas, other candidate genes and proteins such as IGFII, transforming growth factor (TGF) alpha, and epidermal growth factor have been studied [1].
Microscopically, adrenocortical carcinoma has typical histological features including architectural disarray, frequent mitoses, broad fibrous bands, marked cel- lular pleomorphism, nuclear atypia, and hyperchromasia [6]. Other distinguishing features include microscopic foci of necrosis, hemorrhage, and calcification, and
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capsular or vascular invasion. Frequent mitoses, marked cellular pleomorphism, nuclear atypia, hyperchromasia, and large foci of necrosis were seen in our case his- topathologically. The immunohistochemical differential diagnosis of adrenocorti- cal carcinoma were shown in Table 1 [7]. Immunohistochemical findings also confirmed the diagnosis of adrenocortical carcinoma in our case.
The tumor suppressor gene p53 is most commonly mutated in human malig- nancy. This mutation occurs within exons 5 to 8 90% of the time. A great incidence of germ line p53 mutations has been found in children with adrenocortical carci- noma [8, 9]. We analyzed the gene p53 both citogenetically and immunohistochemi- cally but we couldn’t find any p53 mutations in our case. Molecular studies have increased understanding of cancer biology and may provide possible novel thera- peutic approaches in the future.
Surgery is the cornerstone of successful treatment of adrenocortical carcinoma. Radical excision with en bloc resection of any local invasion offers the best chance for cure. Mitotane has been used extensively in adults with adrenocortical carci- noma, but its efficacy in children is not as well known owing to the disease paucity in the pediatric population. Other drugs reported in the literature include vincris- tine, vinblastine, carmustine, cyclophosphamide, actinomycin D, 5-fluorouracil, doxorubicin, and methotrexate, all usually with poor results [1]. De Leon et al. reported a successful long-term outcome of a case of metastatic adrenocortical car- cinoma treated with surgical resection and mitotane [10]. In the pediatric literature, two series have reported a 30% and 38% tumor response rate to mitotane [11, 12]. Progress in the chemotherapeutic approach to adrenocortical carcinoma has been slow. The gold standard chemotherapeutic agent is still mitotane, but combination chemotherapy remains promising. The role of radiotherapy in children with adre- nocortical carcinoma has not been well established [1].
Aggressive complete surgical resection continues to be the mainstay of treat- ment and is the best prognostic of overall survival. The role of adjuvant therapy and chemotherapy continues to evolve.
| Tumor Type | Antigens | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| CK | VIM | NF | S100 | EMA | CG | SYN | CEA | BGI | AFP | |
| Cortical carcinoma | -/+ | + | +/- | +/- | - | - | +/- | - | - | - |
| Pheochromocytoma | - | + | + | + | - | + | + | - | - | - |
| Renal-cell carcinoma | + | + | - | +/- | + | - | - | - | + | - |
| Hepatocellular carcinoma | + | +/- | - | +/- | +/- | - | - | + | +/- | + |
| Metastatic adenocarcinoma | + | +/- | - | +/- | + | - | - | + | +/ - | - |
Note. CK, cytokeratin; VIM, vimentin; NF, neurofilament; EMA, epithelial membrane antigen, CG, chromogranin; SYN, synaptophysin; CEA, carcinoembryonic antigen; BGI, blood group isoan- tigen; AFP, alpha-fetoprotein.
REFERENCES
1. Liou LS, Kay R. Adrenocortical carcinoma in children. Review and recent innova- tions. Urol Clin North Am. 2000;27:403-421.
2. Bornstein SR, Stratakis CA, Chrousos GP. Adrenocortical tumors: recent advances in basic concepts and clinical management. Ann Intern Med. 1999;130:759-771.
3. Ciftci AO, Senocak ME, Tanyel FC, Buyukpamukcu N. Adrenocortical tumors in children. J Pediatr Surg. 2001;36:549-554.
4. Young JL Jr, Miller RW. Incidence of malignant tumors in U.S. children. J Pediatr. 1975;86:254-258.
5. Reincke M. Mutations in adrenocortical tumors. Horm Metab Res. 1998;30:447-455.
6. Tang CK, Gray GF. Adrenocortical neoplasms. Prognosis and morphology. Urology. 1975;5:691-695.
7. De Lellis RA. Adrenal glands. In: Sternberg SS, ed. Diagnostic Surgical Pathology. 3rd ed. Vol. 1. Philadelphia: Lippincott Williams & Wilkins; 1999;602.
8. WagnerJ, Portwine C, Rabin K, LeclercJM, Narod SA, Malkin D. High frequency of germline p53 mutations in childhood adrenocortical cancer. JNCI. 1994;86:1707- 1710.
9. Ribeiro RC, Michalkiewicz EL, Figueiredo BC, DeLacerda L, Sandrini F, Pia- novsky MD, et al. Adrenocortical tumors in children. Braz J Med Biol Res. 2000;33:1225-1234.
10. De Leon DD, Lange BJ, Walterhouse D, Moshang T. Long-term (15 years) outcome in an infant with metastatic adrenocortical carcinoma. J Clin Endocrinol Metab. 2002;87:4452-4456.
11. Mayer SK, Oligny LL, Deal C, Yazbeck S, Gagne N, Blanchard H. Childhood adrenocortical tumors: case series and reevaluation of prognosis-A 24-year experience. J Pediatr Surg. 1997;32:911-915.
12. Teinturier C, Pauchard MS, Brugieres L, Landais P, Chaussain JL, Bougneres PF. Clinical and prognostic aspects of adrenocortical neoplasms in childhood. Med Pediatr Oncol. 1999;32:106-111.