ELSEVIER
Case Report Adrenocortical carcinoma with cerebral metastasis in a child: case report and review of the literature
Rita L. Romaguera ª,*, Alireza Minagar b, Jocelyn H. Bruce ª, Jonathan R. Jagid c, Steven Falcone d, Richard G. Curless b, John Ragheb ·, Glenn Morrison c,e,f
a Department of Pathology, University of Miami, Jackson Memorial Hospital, East Tower Room # 2142, 1611 NW 12th Ave., Miami, FL 33136, USA
b Department of Neurology, University of Miami, Jackson Memorial Hospital, 1611 NW 12th Ave., Miami, FL 33136, USA
Department of Pediatric Neurosurgery, University of Miami, Jackson Memorial Hospital, 1611 NW 12th Ave., Miami, FL 33136, USA
d Department of Neuroradiology, University of Miami, Jackson Memorial Hospital, 1611 NW 12th Ave., Miami, FL 33136, USA
e Department of Pediatrics, University of Miami, Jackson Memorial Hospital, 1611 NW 12th Ave., Miami, FL 33136, USA f Miami Children’s Hospital, Miami, FL, USA
Received 9 August 1999; received in revised form 4 January 2001; accepted 8 January 2001
Abstract
Objective and importance: Adrenocortical carcinoma (ACC) is rare in the pediatric population, and brain metastasis seldom occurs. Clinical presentation: The authors report a case of metastatic ACC to the brain in a 9-year-old patient who had an adrenal cortex neoplasm removed at 4 years of age, and was free of symptoms for 5 years. Two weeks before admission she complained of blurred vision in both eyes. Intervention: Examination revealed bilateral papilledema, and a Magnetic Resonance Imaging (MRI) of the brain revealed a mass in the left lateral ventricle with extensive vasogenic edema and hydrocephalus. The tumor was removed, and histopathologic examination demonstrated metastatic ACC. Conclusion: Although ACC is a rare neoplasm it must be considered in the differential diagnosis of cerebral lesions in patients with a history of this tumor. Periodic long-term brain imaging is suggested as part of the follow up in patients with adrenocortical neoplasms. @ 2001 Elsevier Science B.V. All rights reserved.
Keywords: Adrenocortical carcinoma; Adrenocortical neoplasm; Brain metastasis; Brain tumor
1. Introduction
Adrenocortical carcinoma (ACC) comprises only 0.002% of all childhood malignancies and is potentially lethal [1]. These tumors are hormonally functional in children, being diagnosed and treated early when com- pared to the adult population. Multiorgan metastases are common, but central nervous system involvement is exceedingly rare [2-4]. We report a 9-year-old girl with cerebral metastasis 5 years after the successful excision of an adrenocortical neoplasm.
2. Case report
2.1. Clinical summary
The patient was the product of a normal term preg- nancy and delivery. At a few months of age she was noted to have left hemihypertrophy. At age four she developed Cushingoid features, mood swings, and pu- bic hair. Laboratory studies revealed a 24-h urine progesterone level of 2198 ng/dl (normal range 0-30), random urine renin of 10.29 ng/ml per h (normal range 0.15-2.30) and plasma cortisol of 34.4 mcg/ml (normal range 2-18). A 10.5 x 8.5 × 6.0 cm tumor was removed from the left adrenal gland. It weighed 290 g and was described as an ovoid, encapsulated tan-brown tumor
* Corresponding author. Tel .: + 1-305-5853638; fax: + 1-305- 5456735.
E-mail address: rromague@med.miami.edu (R.L. Romaguera).
with focal areas of necrosis. Histologic examination showed that the tumor recapitulated the normal adrenal cortical architecture; it had little cellular pleomorphism and neither vascular nor capsular inva- sions were noted. Only few small areas of necrosis were present. Since the tumor fell in the gray zone between a benign and malignant neoplasm (200-500 g) and there were very occasional mitoses, the diagnosis was that of an adrenocortical neoplasm of unknown biologic be- havior. The tumor was considered to be entirely re- sected, therefore, she did not receive chemotherapy or radiation. Supplemental corticosteroids were given for only 1 year post surgery. She was followed in the endocrinology clinic and remained disease-free for 5 years.
At age nine she presented with a 2-week history of increasing visual difficulty. The patient had no nausea, vomiting, headache, diplopia, retro-orbital pain, fever, rash or constitutional symptoms. There was no an- tecedent viral syndrome, and she did not have any transient visual obscurations or tinnitus. On examina- tion she was alert and cooperative, but had no visual fixation ability. Her acuity was 20/800 bilaterally with 5-mm pupils that responded to light. Fundoscopic exam revealed elevated disks compatible with pa- pilledema and optic atrophy. No nystagmus was present. Her neurologic exam was otherwise intact.
2.2. Radiological findings
MRI of brain with gadolinium (Fig. 1) revealed an 8-cm, lobulated, well circumscribed homogeneously en- hancing mass arising from the atrium of the left lateral ventricle with vasogenic edema and obstructive hydro- cephalus. An angiogram revealed that the vascular sup-
ply was primarily from the left posterior cerebral artery via posterolateral choroidal branches. These feeding vessels were felt to be too small to embolize. The differential diagnosis included choroid plexus papil- loma, ependymoma, metastasis, or less likely a meningioma.
2.3. Operative findings
Following initial treatment with high dose steroids, the patient underwent a left parieto-occipital cran- iotomy with a transcortical approach through a pari- eto-occipital incision. The tumor was firm, reddish gray and covered by ependyma. Efforts at biopsy for resec- tion were met with brisk. Limited visualization of the tumor mass and inability to reach its vascular pedicle via the dominant parietal lobe incision led to the termi- nation of the procedure after biopsy. The plan was to treat the patient with pre-operative chemotherapy for the presumptive frozen section diagnosis of a carcinoma prior to further resection.
Shortly after surgery her mental status deteriorated requiring re-intubation. A CT scan (Fig. 2) showed a partially hemorrhagic tumor with intraventricular hem- orrhage and increased mass effect. She was managed with high dose steroids, mannitol, hyperventilation, and an external ventricular drain. Over the next 2 days she developed multi-compartmental obstructive hydro- cephalus with right hemiparesis and slight anisocoria with the left pupil larger than the right. Multiple exter- nal ventricular drains were placed and, despite maximal medical therapy including hypothermia and barbitu- rates, her intracranial pressure could not be controlled. On post-operative day 3, a second surgical procedure through the previous craniotomy and an occipital corti-
A
B
FP
11
A
B
sectomy was performed providing access to the vascular pedicle. The tumor was removed with 600 cc of blood loss (Fig. 2).
Following the second resection the intracranial pres- sure returned to normal range, the hydrocephalus re- solved, and her mental status improved. Her right hemiparesis resolved completely over several months. A thorough metastatic work-up revealed no other lesions and she did not receive any post-operative chemother- apy or radiation. Her gait is back to normal and her visual acuity is 20/800. Two-year follow up showed no recurrent disease or evidence of other metastasis.
2.4. Pathological findings
The intraventricular tumor excised during the second craniotomy measured 8.0 × 8.0 × 3.0 cm in aggregate. Histologic examination of hematoxylin and eosin (H&E) stained sections displayed cells arranged in cords and nests, occasionally separated by wide fibrous bands. Small foci of necrosis were evident. The cellular cytoplasm was granular and eosinophilic. A few cells were hyperchromatic, pleomorphic or binucleated with a high nucleo/cytoplasmic ratio.
The histologic pattern of the intraventricular tumor was almost identical to the originally classified adreno- cortical neoplasm (Fig. 3). Immunohistochemical stains for cytokeratin, synaptophysin and calretinin were done on paraffin-embedded sections and were positive in both tumors, supporting the impression that the intra-
ventricular tumor was a metastasis from the adrenocor- tical neoplasm excised 6 years prior to the appearance of the brain tumor.
3. Discussion
Adrenal gland neoplasms are infrequent in all age groups and are particularly rare in the pediatric popula- tion. Neuroblastomas represent more than 90% of adrenal tumors in children and 10% of all solid malig- nancies [5]. Carcinoma of the adrenal cortex is rare comprising only 0.002% of all childhood malignancies [1]. There is a female predominance. These hormone-se- creting neoplasms are manifested by virilization, Cush- ing’s Syndrome, aldosteronism, or feminization [6-14]. The single most important procedure for successful treatment of ACC is surgical resection of the adrenal tumor. Radiotherapy has not yielded good results. Ef- fective adjuvant medical therapy for ACC has long been sought. Currently, ortho-para-DDD, also known as mitotane, is the chemotherapeutic agent used to treat ACC [15]. It has been shown lately that surgery and adjuvant chemotherapy with mitotane shortly after surgery increases the survival rate of the patients signifi- cantly [16,17].
In our case the original adrenal tumor was consid- ered to be entirely resected in view of which no adju- vant treatment was given. In view of the histology and clinical presentation of the patient, the initial tumor
was considered to be a neoplasm of the adrenal cortex that did not meet all criteria for malignancy. No symp- toms or signs developed until 5 years later when she had a profound drop in visual acuity caused by in- creased intracranial pressure. Since it is not the usual practice to follow the patients with CNS imaging stud- ies, it is uncertain how long it took for the tumor to become large enough to produce visual symptomatol- ogy. The tumor recurred as a space occupying mass in the left lateral ventricle with obstructive hydrocephalus and occipitoparietal vasogenic edema. After the estab- lished metastasis to the brain, the original tumor is now categorized as an adrenocortical carcinoma.
Because of their rarity the biologic behavior of adrenocortical neoplasms is difficult to predict. Even though histologic criteria to differentiate benign from malignant tumors have been described, they represent a challenge for the pathologist and the clinician since the morphologic criteria may not correlate with the clinical behavior. Several investigators have reviewed the histol- ogy and clinical features of these tumors (mostly in adults) in an attempt to predict their prognosis. The most important biochemical parameters include urinary 17-ketosteroids and 17-hydroxycorticosteroids, dexam- ethasone suppression test, plasma cortisol, estrogen, and testosterone levels. Criteria for malignancy include tumor size, tumor weight, nuclear grade, number of mitoses and atypical mitoses, nucleo-cytoplasmic ratio, architecture, necrosis, hemorrhage, presence of fibrous
bands, calcifications, and vascular, sinusoidal or capsu- lar invasion [2,3,5,11-14,16,18-28]. Weiss et al. studied pathologic features of prognostic significance in ACC. He found that mitotic activity is the most important pathologic determinant of survival in patients with ACC [29]. Markers of cell proliferation have been used in an attempt to predict behavior of adrenocortical tumors [30].
When present, metastasis can be found in lung, liver, lymph nodes, and bone. Metastasis to the brain is extremely uncommon but has been reported [2- 4,21,22,31-33]. In a series of 42 children, reported by Lefevre et al., two developed brain metastases at ages 42 and 17 months [3]. The latter also had metastatic disease in the lungs. In 1988, Saracco et al. described a 1-day-old newborn with histologically documented metastatic adrenocortical carcinoma in the subcutis and enhancing lesions in the frontal and parietal lobe which were noted by computed tomography of the head and presumed to be metastatic [4]. A 35-g adrenal mass was removed at 22 days of age. No antitumor therapy was used but an MRI 4 months later showed resolution of the brain lesions. Lack et al. reviewed 30 cases with an age range of 6 months to 19 years [2]. Seventeen had metastases including a 10-year-old patient with lesions to the brain, liver, lung and kidneys. The patient had been treated with adrenalectomy, thoracotomy for lung metastases, and chemotherapy with mitotane.
A
B
C
D
4. Conclusion
Our case is noteworthy because of the age of the patient combined with the long interval between the original diagnosis of an adrenocortical neoplasm and the occurrence of cerebral metastasis. This patient best fits the cohort of adrenal cortical tumors described by Lack et al. which have an indeterminate malignant potential [2]. By histology and weight it did not meet the criteria suggested for a malignant tumor. Yet it behaved clinically malignant by virtue of the cerebral metastases which occurred after an unusually pro- longed period of time. The absence of endocrinologic manifestations failed to predict a good outcome. We suggest close observation for a prolonged period of time with a periodic metastatic work-up to include brain imaging in patients who develop neurologic symptoms to search for indolent metastatic disease.
References
[1] Young JL, Miller RW. Incidence of malignant tumors in U.S. children. J Pediatr 1975;86:254-8.
[2] Lack EE, Mulvihill JJ, Travis WD, Kozakewich HPW. Adrenal cortical neoplasms in the pediatric and adolescent age group. Clinicopathologic study of 30 cases with emphasis on epidemio- logical and prognostic factors. Pathol Annu 1992;27:1-53.
[3] Lefevre M, Gerard-Merchant R, Gublre JL, Chaussain JL, Lemerle J. Adrenal cortical carcinoma in children: 42 patients treated from 1958 to 1980 at Villejuif. In: Humphrey GB, Grindley GB, Dehner LP, Acton RT, Pysher TJ, editors. Adrenal and endocrine tumors in children. Cancer Treat Res Vol. 17. Boston: Martinus Nijhoff, 1984: pp. 265-276.
[4] Saracco S, Abramowsky C, Taylor S, Silverman RA, Berman BW. Spontaneously regressing adrenocortical carcinoma in a newborn. A case report with DNA ploidy analysis. Cancer 1988;62:507-11.
[5] Miller RW, Young JL, Novakovic B. Childhood cancer. Cancer 1995;75:395-405.
[6] Artigas JL, Niclewicz ED, Silva AD, Ribas DB, Athayde SL. Congenital adrenal cortical carcinoma. J Pediatr Surg 1976;11:247-53.
[7] Cacciari E, Cicognani A, Pirazzoli P, Paolucci G, Mancini A, Tassinari D, Pascucci MG, Tacconi M. Adrenocortical tumours in children: our experience with nine cases. Acta Endocrinol 1986;279:264-74.
[8] Chan HS. Carcinoma of the adrenal gland in children - a study of 12 patients. In: Humphrey GB, Grindley GB, Dehner L, Acton RT, Pysher TJ, editors. Adrenal and endocrine tumors in children. Cancer Treat Res Vol. 17. Boston: Martinus Nijhoff, 1984, pp. 325-330.
[9] Dehner LP, Franciosi RA. Adrenocortical neoplasia in the pedi- atric age group. A clinicopathologic study of seven cases. In: Humphrey GB, Grindley GB, Dehner LP, Acton RT, Pysher TJ, editors. Adrenal and endocrine tumors in children. Cancer Treat Res Vol. 17. Boston: Martinus Nijhoff, 1984, pp. 291-302.
[10] Kay S. Hyperplasia and neoplasia of the adrenal gland. Pathol Annu 1976;11:103-39.
[11] Moore L, Barker AP, Byard RW, Bourne AJ, Andrew-Ford WD. Adrenal cortical tumors in childhood - clinicopathologi- cal features of six cases. Pathology 1991;23:94-7.
[12] Stewart DR, Morris Jones PH, Jolleys A. Carcinoma of the adrenal gland in children. J Pediatr Surg 1974;9:59-67.
[13] Weatherby RP, Carney JA. Pathologic features of childhood adrenocortical tumors. In: Humphrey GB, Grindley GB, Dehner LP, Acton RT, Pysher TJ, editors. Adrenal and endocrine tu- mors in children. Cancer Treat Res Vol. 17. Boston: Martinus Nijhoff, 1984, pp. 217-248.
[14] Weiss LM. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol 1984;8:163-9.
[15] Sandrini R, Ribeiro RC, DeLacerda L. Extensive personal expe- rience childhood adrenocortical tumors. J Clin Endocrinol Metab 1997;82:2027-31.
[16] Dickstein G, Shechner C, Arad E, Best L, Nativ O. Is there a role for low doses of mitotane (o,p’-DDD) as adjuvant therapy in adrenocortical carcinoma? J Clin Endocrinol Metab 1998;83:3100-3.
[17] Schteingart DE, Motazedi A, Noonan RA, Thompson NW. Treatment of adrenal carcinomas. Arch Surg 1982;117:1142-6.
[18] Amberson JB, Vaughan ED, Gray GF, Naus GJ. Flow cytomet- ric analysis of nuclear DNA from adrenocortical neoplasms. A retrospective study using paraffin-embedded tissue. Cancer 1987;59:2091-5.
[19] Cagle PT, Hough AJ, Pysher TJ, Page DL, Johnson EH, Kirkland RT, Holcombe JH, Hawkins EP. Comparison of adrenal cortical tumors in children and adults. Cancer 1986;57:2235-7.
[20] Gandour MJ, Grizzle WE. A small adrenocortical carcinoma with aggressive behavior. Arch Pathol Lab Med 1986;110:1076- 9.
[21] Hajjar RA, Hickey RC, Samaan NA. Adrenocortical carcinoma. A study of 32 patients. Cancer 1975;35:549-54.
[22] Harrison JH, Mahoney EM, Bennett AH. Tumors of the adrenal gland. Cancer 1973;32:1227-35.
[23] Hough AJ, Hollifield JW, Page DL, Hatmann WH. Prognostic factors in adrenal cortical tumors. A mathematical analysis of clinical and morphologic data. Am J Clin Pathol 1979;72:390-9.
[24] Huvos AG, Hajdu SI, Brasfield RD, Foote FW. Adrenal cortical carcinoma. Clinicopathologic study of 34 cases. Cancer 1970;25:354-61.
[25] Moroz K, Robichaux WH, Cheles MK, Dhurandhar N. Adrenal cortical carcinoma with a liver metastasis in a child. Report of a case with fine needle aspiration findings and image analysis of nuclear DNA. Acta Cytol 1997;41:569-76.
[26] Ribeiro RC, Neto RS, Schell MJ, Lacerda L, Dambaio GA, Cat I. Adrenocortical carcinoma in children: a study of 40 cases. J Clin Oncol 1990;8:67-74.
[27] Slooten H, Schaberg A, Smeenk D, Smeeenk D, Moolenaar AJ. Morphologic characteristics of benign and malignant adrenocor- tical tumors. Cancer 1985;55:766-73.
[28] Tang CK, Gray GF. Adrenocortical neoplasms. Prognosis and morphology. Urology 1975;5:691-5.
[29] Weiss LM, Medeiros LJ, Vickery AL. Pathologic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol 1989;13(3):202-6.
[30] Iino K, Sasano H, Yabuki N, Oki Y, Kikuchi A, Yoshimi T, Nagura H. DNA topoisomerase IIx and Ki-67 in human adreno- cortical neoplasms: a possible marker of differentiation between adenomas and carcinomas. Mod Pathol 1997;10(9):901-7.
[31] Evans HL, Vassilopoulou-Sellin R. Adrenal cortical neoplasm. A study of 56 cases. Am J Clin Pathol 1996;105:76-86.
[32] Tartour E, Caillou B, Tenenbaum F, Schröder S, Luciani S, Talbot M, Schulmberger M. Immunohistochemical study of adrenocortical carcinoma. Cancer 1993;72:3296-302.
[33] Seabold JE, Haynie TP, DeAsis DN, Samaan NA, Glenn HJ, Jahns MF. Detection of metastatic adrenal carcinoma using 131I-6-B-iodomethyl-19-norcholesterol total body scans. J Clin Endocrinol Metab 1997;45:788-97.