CASE REPORT
Gregory Albaugh . Mike Chen Adrenocortical carcinoma in two female children
Accepted: 5 August 1999
Abstract Adrenocortical carcinoma is a rare tumor in children. This tumor is more likely to be hormonally active in children than in adults and tends to cause a variety of symptoms, which may mimic other benign endocrinopathies. These tumors are usually diagnosed at advanced stages and portend a dismal prognosis. We describe two cases of adrenocortical carcinoma. One child presented with Cushingoid symptoms secondary to hypercortisolism, including amenorrhea, hirsutism and weight gain. The other child presented with precocious puberty. Both children underwent resection of the tumors. We describe their presenting symptoms, post- operative course, adjuvant therapy and clinical course. Pertinent literature regarding the anatomy of the adrenal gland, pathology of adrenocortical carcinoma, factors influencing outcome, diagnostic modalities and treat- ment, are discussed.
Keywords Adrenocortical carcinoma · Virilizing tumors . Hypercortisolism . Precocious puberty
Introduction
Adrenocortical carcinoma (ACC) in children is a hormonally active tumor with a dismal prognosis. There is a paucity of clinical data on this tumor due to its rarity. Larger studies have come from Brazil and Europe and took 10 to 20 years to compile. In 1953, early work by MacFarlane demonstrated 2.5-month survival in patients with this diagnosis who went untreated. Im- proved survival depends on early detection and early surgical resection. The two patients described here were treated at our institution between March and May 1998.
Case reports
Case 1
A 13-month-old female had a 2-month history of pubic hair growth and clitoral enlargement. At presentation, the patient was in the 95th percentile for weight and the 70th percentile for height. She was previously healthy prior to onset of symptoms, and on physical examination mass was palpated in her right flank. Work-up included computed tomography (CT) of the abdomen and pelvis and a survey of serum glucocorticoid hormones, estrogen, and andro- gens. CT showed a 6 × 6 × 4-cm mass in the right adrenal gland. Hormonal levels were markedly increased: adrenal androstenedi- one 2,649 ng/dl (8-50 ng/dl), adrenal 17a-OH progestrone 917 ng/ dl (3-90 ng/dl), adrenal progesterone 121 ng/dl (7-52 ng/dl), ad- renal testosterone 153 ng/dl (3-10 ng/dl), adrenal cortisol 22 ng/dl (3-21 ng/dl), serum free testosterone 182 ng/dl, serum free and weakly bound testosterone 361 ng/dl, total testosterone 517 ng/dl, serum 17-OH pregnenolone 7,715 ng/dl (12-221 ng/dl), 17-OH progesterone 676 ng/dl (<200 ng/dl), serum cortisol 0.2 ng/dl, and renin 7.7 ng/dl.
After being placed on replacement glucocorticoid therapy, the patient underwent resection of her adrenal tumor. The right adre- nal gland consisted of a 6 × 6 × 4-cm mass, which was removed in its entirety; the right kidney was spared in the dissection. The tumor weighed 95 g and microrupture of the capsule was noted by the pathology department. Karyotyping was performed to rule out the possibility of a neuroblastoma and the presence of a 1p dele- tion. The specimen showed a 46, XX pattern consistent with a normal female karyotype. The stage II tumor (T2, NO, MO) was resected completely. No chemotherapy was administered and she remained free of disease 10 months post-resection.
Case 2
A 16-year-old female presented to her pediatrician with an 8-month history of amenorrhea after 4 years of normal menstruation. Ad- ditionally, she had a 3-month history of cushingoid symptoms in- cluding a 20- to 30-pound weight gain, facial swelling, acne, hirsutism, and striae over her abdomen and legs. At presentation, she weighed 67 kg and was 164 cm tall. Her vital signs were normal except for a blood pressure of 145/99 mm/Hg. Her past medical history was unremarkable. She had not been on any oral contra- ceptives and denied sexual activity. The physical examination was notable for striae on her abdomen and thighs, central fat deposi- tion, and a large, palpable mass in the midline of the abdomen. An ultrasound examination of her abdomen to assess for polycystic ovarian pathology showed the ovaries within normal limits, but a
G. Albaugh . M. Chen Department of Surgery,
Division of Pediatric Surgery,
Cooper Hospital University Medical Center,
3 Cooper Plaza, Camden, NJ 08103-1439, USA
large adrenal mass was identified. Hormonal assays showed marked increases in serum androgens: androstenedione 623 ng/dl, dehydroepiandrosterone 517 ng/dl, and testosterone 78 ng/dl and hypercortisolism with desoxycortisol 1,000 ng/dl and deoxycorti- costerone 71 ng/dl. CT of the abdomen and pelvis showed a large mass in her right adrenal gland measuring 16 x 16 x 10 cm. She underwent a laparotomy for en bloc resection of the mass.
At laparotomy, the tumor was adherent to the diaphragm with extension to the right retroperitoneum. Additionally, it extended over the inferior vena cava with tumor nodules noted on the left side, which were resected. The right kidney was preserved. She received one unit of packed red blood cells intraoperatively. The surgical specimen weighed 670 g. She was discharged home on postoperative day 5 and started on mitotane postoperatively. She underwent a right middle lobectomy approximately 2 months later for an isolated pulmonary metastasis without incident. Five months after the initial resection she presented with shortness of breath, and a chest radiograph showed a large right pleural effusion that was drained by tube thoracostomy. Cytologic examination of the pleural fluid was negative for malignant cells, however, chest CT showed recurrent tumor. She was started on platinum-based che- motherapy during this hospital stay, but failed to respond. She died on hospital day of 19 of complications of her disease.
Discussion
The adrenal cortex is anatomically and physiologically divided into three populations of hormonally active cells. The outermost layer, or zona granulosa, is responsible for production and secretion of mineralocorticoid hormones, in particular aldosterone. In the zona fasciculata gluco- corticoid hormones are produced and secreted. The deepest layer is the zona radicularis, which produces and secretes estrogens and androgens. Hormonal secretion is under the control of the hypothalamus-pituitary-adrenal (HPA) axis. Corticotropic releasing hormone secreted by the hypothalamus stimulates the anterior pituitary to secrete adrenocorticotropic hormone. Childhood neo- plasms of the adrenal cortex, particularly ACC, function independent of anterior pituitary stimulation with pro- duction of superphysiologic levels of adrenocortical hormones and their precursors. Autonomous adrenal steroid secretion suppresses the HPA axis, resulting in the need for steroid replacement preoperatively.
ACC is a rare tumor, representing 0.05% to 0.2% of all malignancies [14]. There appears to be a bimodal occurrence distribution. In children, the mean age for ACC is 4 years and the vast majority are hormonally active. In adults this tumor affects patients in the 4th or 5th decade of life and conversely, the vast majority are not hormonally active. Adult women outnumber men in cases of ACC [10], and in children females are two to four times as likely as males to have ACC.
ACC maintains complete or partial histologic adrenal architecture and differentiation, and small tumors may resemble adenomas [13]. Differentiation is based on histologic and clinical findings. In tumors greater than 6 cm weighing 100 to 5,000 g with central necrosis and hemorrhage, the diagnosis of ACC is confirmed [14]. Tumors that weigh more than 200 g have proven to have a poor prognosis. Microscopically, cells display large, hyperchromatic nuclei and nucleoli, which are highly
suggestive of ACC. The metastatic potential is increased when vascular or lymphatic invasion, increased mitoses, and/or broad desmoplastic bands are present. Weiss et al. found that median survival can be predicted by counting numbers of mitoses per 50 high powered fields (hpf) [19, 20]. When over 20 mitoses were found per 50 hpf, the mean survival was 14 months. Conversely, when less than 20 were counted, the mean survival was 58 months. As would be expected, aneuploidy correlated with poor outcome [9].
In smaller tumors between 50 and 100 g, it may be difficult to differentiate between a adrenal or renal source. Immunostaining for vimentin, epithelial mem- brane antigen, cytokeratin, and blood-group antigens are useful in distinguishing the two [21], ACC stains positive for vimentin and renal tumors stain positive for the others. Chromosomal studies suggest a recessive oncogene on chromosome 11 [8, 22]. Yano et al. found consistent deletion of alleles on chromosomes 11p,13q, and 17p in nine patients with ACC [22]. The insulin-like growth factor (IGF-II) locus resides on chromosome 11p and is paternally imprinted. Overexpression of IGF- II is associated with sporadic cases of ACC [5]. A mi- nority of patients with ACC show a germline mutation of p53 tumor suppression gene associated with osteo- sarcomas as part of the Li-Fraumeni syndrome [11].
Infants with ACC present with some degree of hor- monal dysfunction. Cushingoid symptoms and viriliza- tion occur in up to 64% of these patients and virilization alone in 32% [17]. Virilization in perpubertal children occurs in 84% to 94% of cases [1], and may be an earlier indicator of pathology than the sometimes subtle pre- sentations of hypercortisolism such as weight gain and acne. An estimated 40% of small tumors secrete no ac- tive hormones, but do secrete precursors such as pregnenolone, 17-OH pregnenolone, and 11-deoxycor- tisol. When this population shows evidence of endocrine dysfunction, the tumors are usually palpable [15].
In children, ACC can be associated with a variety of familial cancer syndromes. Beckwith-Wiedemann syn- drome is associated with an up-regulation of IGF-II and loss of imprinting status. These children present with macroglossia, gigantism, omphalocele, and an increased incidence of ACC [5]. Other syndromes include Lynch familial neoplasia, complex hereditary syndrome with tumors affecting the breast, lung, and connective tissues as sarcomas, and multiple endocrine neoplasia syndrome type I (MEN I) [12]. In infants, it is sometimes necessary to rule out the presence of neuroblastoma in the surgical specimen. Karyotyping of the specimen will show a de- letion of 1p in 90% of cases of neuroblastoma [15].
In prepubertal children, virilization is manifested by genital enlargement, pubic hair, deep voice, weight gain, and breast development. Postpubescent children com- monly present with cushingoid symptoms including centripetal fat deposition, striae, acne, hirsutism, amenorrhea, and thinning hair. In young female patients, ACC is important to consider while ruling out other more common causes of hirsutism, acne, and
balding such as adrenal hyperplasia, functional ovarian hyperandrogenism, and polycystic ovary syndrome [1].
When the child presents with centripetal fat deposi- tion, acne, moon facies, or other cushingoid symptoms, biochemical documentation of hypercortisolism is the first diagnostic step. Dexamethasone suppression testing is the first diagnostic test to identify whether the adrenal gland is the source of endogenous hypercortisolism. When the child presents with virilization, a careful his- tory and physical examination are essential. Serum levels of estrogens, testosterone, and their precursors should be obtained. In both populations of patients CT or magnetic resonance imaging (MR) of the adrenals and pituitary should be done if clinically indicated. When an adrenal mass is identified, MR can help define the biology of the tumor. On MR images, an adrenal mass-to-liver ratio of >0.4, <3.0 on T2-weighted images, correlates with malignancy [4]. Early detection of ACC has been shown to greatly improve survival by Sabbaga et al. In patients with symptoms of less than 6 months’ duration, survival was 70%; it fell to 9% in children with symptoms for longer than 6 months. Children less than 2 years old at diagnosis fared better than older children, with survival of 83% and 36%, respectively [16].
In ACC, total surgical extirpation of gross disease is the treatment of choice as it is the only curative treat- ment. Most of these tumors are already in advanced stages. Resection of ACC manadates an open anterior approach, and if the tumor is large a thoracoabdominal incision may be needed. Depending on the size and stage of the disease, ACC may involve the ipsilateral kidney, overlying bowel, or abdominal wall. The anterior ap- proach is preferred for exposure if perioperative findings necessitate dissection of adjacent viscera to complete an en bloc resection of gross disease. For large tumors adjacent to the inferior vena cava, the latter should be imaged with contrast prior to surgery. Glucocorticoid replacement should be started preoperatively and con- tinued until the recovery of the HPA axis.
Chemotherapy for metastatic or recurrent ACC usually includes o, p, DDD, or mitotane in appropriate doses of 2 to 6 g per day [6, 18]. Mitotane has a small therapeutic window and is associated with numerous adverse side effects involving the gastrointestinal system such as anorexia, nausea, vomiting, and diarrhea. Other side effects include neurologic manifestations and skin rash. Mitotane’s major benefit is in controlling hyper- cortisolism, and it should be started preoperatively in patients presenting with these symptoms [2, 7]. In small studies survival has been improved with mitotane ther- apy, but cure is yet to be demonstrated. Small series have shown a response rate of about 20% to mitotane alone in controlling the tumor [18], but mitotane com- bined with cisplatin improved the response rate to 30% which prompted further trials of combination chemo- therapy [3]. A clinical response occurs in 6 weeks, however, most patients relapse. Combination chemo- therapy with mitotane and streptozotocin preoperatively
have produced long-term survival in two patients. Clinical trials are underway to evaluate other combina- tions including doxyrubicin, alkylating agents, and cis- platin and appear to have promising results.
ACC is a rare tumor in children. Surgery remains the primary treatment modality. Earlier detection of the tumor will improve survival, but this requires a high index of suspicion. Mitotane has been shown to be helpful in controlling the disease, but the response is inconsistent and transient. Optimal chemotherapy for this tumor is yet to be defined; radiotherapy is not helpful. Most patients present late in the course of the disease, and this corresponds with a poorer outcome. Because of the high incidence of hormonally-active tu- mors in children, the presence of this constellation of symptoms requires consideration of this diagnosis by pediatricians and other primary-care providers.
References
1. Degroot IJ, et al (1995) Endocrinology, Saunder, Philadelphia, pp 1813-1852, 2093-2112
2. DeVita VT, Hellman S, Rosenberg SA (1997) Cancer, princi- ples and practice of oncology. Lippencott-Raven, Philadelphia, pp 1659-1669
3. Dogliotti L, Berruti A, Pia A, Paccotti P, Ali A, Angrli A (1995) Cytotoxic chemotherapy for adrenocortical carcinoma. Minerva Endocrinol 20: 105-109
4. Doppman JL, Reinig JW, Dwyer AJ, Frank JP, Norton JA, Loriaux DL, Keiser HR (1987) Differentiation of adrenal masses by magnetic resonance imaging. Surgery 102: 1018
5. Gisquel C, Bertagna X, Schneid H, et al (1994) Rearrange- ments at the 11p 15 locus and overexpression of the insulin like growth factor II gene in sporadic adrenocortical tumors. J Clin Endocrinal Metab 78: 1444
6. Gutierrez ML, Crooke ST (1980) Mitotane (o,p,DDD). Cancer Treat Rev 7: 49
7. Haskell CM, et al (1995) Cancer treatment. Saunders, Phila- delphia, pp 758-762
8. Henry I, Grandjovans S, Couillin P, Barichard F, Iluerre- Jeanpierre C, Glaser T, Philip T, Lenoir G, Chaussain JL, Lunien C (1989) Tumor specific loss of 11p 15.5 alleles in del 11p 13 Wilms tumor and in familial adrenocortical carcinomas. Proc Natl Aca Sci USA 86: 3247
9. Hosaka Y, Rainwater LM, Grant CS, Yong WF Jr, Farrow GM, van Heerden JA, Lieber MM (1987) Adrenocortical carcinoma: nuclear deoxyribonucleic acid ploidy studied by flow cytometry. Surgery 102: 1027
10. Hutter AM Jr, Kayhoe DE (1966) Adrenal cortical carcinoma. Am J Med 41: 572
11. Lanfracone L, Pelicci G, Pellici PG (1994) Cancer genetics. Curr Opin Genet Dev 4: 109
12. Lynch HT, Katz DA, Bogard PJ, Lynch JF (1985) The sar- coma, breast cancer, lung cancer and adrenocortical carcinoma syndrome revisted. Am J Dis Child 139: 134
13. Ohare MJ, Monaghan P, Neville Am (1979) The pathology of adrenocortical neoplasia; a correlated structural and functional approach to diagnosis of malignant disease. Hum Pathol 10: 13
14. Page DL, DeLellis RA, Hough AJ (1986) Tumors of the adrenal. In: Atlas of tumor Pathology. Armed Forces Institute of Pathology, Washington, DC
15. Pizzo PA, Poplack DG (1997) Principles and practices of pediatric oncology, 3rd edn. Lippencott-Raven, Philadelphia, pp 960-962
16. Sabbaga C, Avilla S, Schulz C, Garbers J, Blucher D (1995) Adrenocortical carcinoma in children: clinical aspects and prognosis. J Pediatr Surg 28: 841-843
17. Upadhye PS, Desai MP, Colaco MP, Desai PB, Deshpande RK, Mokal RA (1997) A clinicopathologic profile of adreno- cortical tumors. Indian Pediatr 34 (6): 281-290
18. Van Slooten H, Molenaar AJ, Van Seters AP, Smeek D (1984) The treatment of adrenocortical carcinoma with o,p,DDD: prognostic implications of serum level monitoring. Eur J Clin Oncol 20: 47
19. Weiss LM (1984) Comparative histologic study of 43 metas- tasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol 8: 163
20. Weiss LM, Medeiros LJ, Vickery AL (1989) Pathologic fea- tures of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol 13: 202
21. Wick MR, Cherwitz DL, Meglennen RC, Dehner LP (1986) Adrenocortical carcinoma: an immunohistochemical compari- son with renal cell carcinoma. Am J Pathol 122: 343
22. Yano T, Linehan M, Anglard P, Lerman MI, Kaniel LN, Stein CA, Robertson CN, LaRocca R, Zbar B (1989) Genetic changes in human adrenocortical carcinoma. J Natl Cancer Inst 81: 518