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The Journal of Clinical Endocrinology & Metabolism 87(10):4452– 4456 Copyright © 2002 by The Endocrine Society doi: 10.1210/jc.2002-011978

CLINICAL CASE SEMINAR Long-Term (15 Years) Outcome in an Infant with Metastatic Adrenocortical Carcinoma ´ N, BEVERLY J. LANGE, DAVID WALTERHOUSE, DIVA D. DE LEO

AND

THOMAS MOSHANG

Divisions of Endocrinology (D.D.D.L., T.M.) and Oncology (B.J.L.), Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104; and Division of Oncology, Department of Pediatrics, Children’s Memorial Hospital (D.W.), Chicago, Illinois 60614 Adrenocortical carcinoma is a rare malignancy in children, with a high mortality. Little is known about long-term outcome, especially in infants treated with mitotane. We report the successful long-term outcome of a case of metastatic adrenocortical carcinoma presenting in infancy treated with surgical resection and mitotane. The patient presented at 2 months of age with Cushing’s syndrome, a large adrenal mass, and elevated adrenal steroid levels. The tumor was removed surgically. Intraoperative findings included an adrenal tumor (confirmed malignant pathologically) invading the adrenal vein and vena cava. After surgery he was treated with mitotane at a dose of 2 g/d. Six months after surgery 11-deoxycor-

A

DRENOCORTICAL CARCINOMA (ACC) is a rare malignancy, accounting for only 0.05– 0.2% of all cancers. The overall incidence is approximately 2 cases/million per year worldwide (1). In children the overall incidence of adrenocortical tumors is approximately 0.3 cases/million per year, with only 25 new cases of ACC reported each year in the United States (2, 3). The recurrence and mortality rates associated with ACC are very high (4). In a series of 54 patients the mortality rate was 44% (2). Pediatric ACC typically occurs before 5 yr of age, affects girls more commonly than boys, and may be associated with hemihypertrophy and Beckwith-Wiedemann and Li-Fraumeni syndromes (5). In contrast to adults in whom nonfunctional tumors are more common, hormone-secreting tumors and the associated classic endocrine syndromes (virilizing, feminizing, Cushing’s, and Conn’s syndromes) are more common in children. Urinary 17-ketosteroid levels are elevated in the majority of the patients tested [48 of 49 patients in a review (2)] regardless of whether the tumors cause Cushing’s syndrome or simple virilization. Plasma dehydroepiandrosterone sulfate (DHEA-S) is elevated in approximately 90% of the cases and represents the second most sensitive tumor marker (3). Pathological classification of pediatric adrenocortical tumor is difficult because there is considerable overlap in the histological criteria for malignancy (6) compared with the criteria for benign adrenocortical adenoma. Attempts to distinguish adrenocortical adenomas from carci-

Abbreviations: ACC, Adrenocortical carcinoma; DHEA-S, dehydroepiandrosterone sulfate.

tisol levels increased, and a computed tomography scan showed a pulmonary metastasis. Mitotane was increased to 2.5 g/d, and the metastasis was removed surgically. Plasma mitotane levels ranged 10 –15 ␮g/ml. Tumor markers remained normal, and mitotane was discontinued at 18 months. During therapy the patient’s somatic growth was poor. His motor and speech development was delayed. After mitotane was discontinued he demonstrated catch-up growth. This case shows successful long-term outcome and recovery from the toxic effects of mitotane. (J Clin Endocrinol Metab 87: 4452– 4456, 2002)

nomas have been made based on tumor weight, clinical findings, and histological features (6 –10). Complete surgical resection is the single most important component of therapy for ACC. The role of adjuvant chemotherapy with mitotane remains controversial, with improved survival reported in only a few series (11, 12). Its efficacy in children is not known. Mitotane [1,1-dichloro2-(o-chlorophenyl)-2-(p-chlorophenyl)-ethane] is an insecticide derivative that inhibits the intramitochondrial conversion of cholesterol to pregnenolone and the conversion of 11-deoxycortisol to cortisol. It produces selective adrenocortical necrosis in both the adrenal tumor and metastases (13, 14). In a multiinstitutional study to determine the efficacy and toxicity of mitotane as an adjuvant therapy for newly diagnosed children at high risk of relapse, mitotane did not modify the rate of relapse (3). Studies in adults have suggested that achieving active plasma levels is important to achieve a therapeutic response (15). Values ranging from 15–25 ␮g/ml have been considered active mitotane levels (16). The experience with other cytotoxic agents is more limited. The most important toxicities are gastrointestinal and neurological. The side effects are dose related and include anorexia, nausea, vomiting, diarrhea, abdominal pain, rashes, gynecomastia, leukopenia, somnolence, lethargy, and ataxia. There is limited experience with this drug in infants and children, and pediatric dosing has not been established. Its use in children, especially in young infants, raises special concern about its potential toxicity to the developing central nervous system as well as failure to thrive. We report a case of metastatic ACC presenting in in-

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fancy with a long-term survival of 15 yr and minimal sequelae after surgical resection and early therapy with high doses of mitotane. The emphasis of this report is that the toxic effects of mitotane are reversible, and its use in very young infants with minimal metastases may be beneficial and justified. Case Report

The parents of this child provided informed consent, including the use of the unblinded photograph, and the report followed the guidelines of the institutional review board of Children’s Hospital of Philadelphia. The patient was born full term after an uncomplicated pregnancy and delivery. The birth weight was 3.0 kg. Rapid and excessive weight gain prompted an evaluation by endocrinology at 2.5 months of age. At that time his weight was 6.1 kg, and he was found to have Cushingoid facies, facial acne, and poor muscle tone (Fig. 1). The family history was unremarkable. A large mass was palpable in the right upper quadrant of the abdomen. There were no signs of virilization. An abdominal ultrasound showed a 6.4 ⫻ 6.1-cm mass in the right adrenal gland with areas of cystic necrosis (Fig. 2). Laboratory evaluation revealed abnormally elevated adrenal steroid levels: 11-deoxycortisol, 54,797.7 pmol/liter [normal, 758 – 4,479.8 pmol/liter (1,896 ng/dl; normal, 20 –155 ng/ dl)]; 17␣-hydroxyprogesterone, 26,253.8 pmol/liter [normal, 3,625.4 – 6,042.3 pmol/liter (869 ng/dl; normal, 120 –200 ng/ dl)]; 17-hydroxypregnenolone, 16,216.2 pmol/liter [normal, 300.3–5,675.7 pmol/liter (540 ng/dl; normal, 10 –189 ng/dl)]; DHEA-S, 16,195.6 nmol/liter [normal, 543.5–2581.5 nmol/ liter (596 ␮g/dl; normal, 20 –95 ␮g/dl)]; cortisol, 6,336.1 nmol/liter [normal, 77.1– 633.6 nmol/liter (230 ␮g/dl; normal, 2.8 –23 ␮g/dl)]; and testosterone, 17,500 pmol/liter [normal, 2,083.3–13,888.9 pmol/liter (504 ng/dl; normal, 60 – 400

FIG. 1. Patient at presentation. Note the Cushingoid appearance and facial acne.

FIG. 2. Abdominal ultrasound showing a 6.4 ⫻ 6.1-cm mass in right adrenal gland with areas of cystic necrosis.

ng/dl)]. A chest x-ray was normal, showing no pulmonary metastasis. The patient underwent surgical resection, and intraoperative findings revealed a large (7.5 ⫻ 5.5 ⫻ 2.0-cm) right upper quadrant tumor with extensive neovascularity displacing the kidney and the hepatic flexure of the colon. The mass was adherent to the right lobe of the liver and kidney. There was invasion into the right adrenal and renal veins as well as a large tumor thrombus in the inferior vena cava. The tumor was resected, and a histological diagnosis of ACC was made (Fig. 3). The cells were well differentiated, with mild nuclear variability and rare mitotic figures. The diagnosis of malignancy was based primarily on the intravascular extension of the tumor. Postoperatively all tumor markers returned to the normal range with a 11-deoxycortisol level of 2948 pmol/liter (102 ng/dl), testosterone of 208.3 pmol/liter (6 ng/dl), and 17␣-hydroxyprogesterone of 51.4 pmol/liter (1.7 ng/dl). The patient was treated with pharmacological doses of hydrocortisone during and after surgery. Due to the poor prognosis associated with this diagnosis, with clear invasion of the vena cava, the patient was immediately started on mitotane. The starting dose was 250 mg/d. The dose was gradually increased to 2 g/d while following the mitotane levels. On these doses of mitotane plasma levels were below the presently suggested active levels. The patient was treated with replacement doses of hydrocortisone and fludrocortisone. Adrenal markers were determined at monthly intervals. Six months after surgery his 11-deoxycortisol level increased to 8179.2 pmol/liter (283 ng/dl), and a right lower lobe pulmonary metastasis was found on chest x-ray. A computed tomography scan confirmed this finding. Bone scan was negative. The dose of mitotane was increased to 2.5 g/d, and the patient underwent a right lower pulmonary lobectomy. Histology confirmed metastatic nodule of ACC. Postsurgically his 11-deoxycortisol level was 2948 pmol/liter (102 ng/dl). He was maintained on 2.5 g/d mitotane, with plasma levels above 10 ␮g/ml (Fig. 4). The patient developed gynecomastia and anorexia during the mitotane therapy. Tumor markers remained in the normal range, and mitotane

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De Leo´ n et al. • Clinical Case Seminar

FIG. 4. Tumor marker (11-deoxycortisol) and mitotane plasma levels during therapy. The arrows show the dose increases (B) and the time of tumor recurrence (A). FIG. 3. Histological appearance of adrenal tumor (A) and tumor thrombus resected from inferior vena cava (B).

was discontinued at 18 months of age (15 months after tumor resection). During therapy with mitotane the patient’s somatic growth was poor, declining to below the fifth percentile, with weight and head circumference being the most affected parameters (Fig. 5). After mitotane was discontinued, he demonstrated catch-up growth, and by 3 yr of age he reached the 10th percentile for height and head circumference and the 25th percentile for weight. His development was particularly delayed in motor and speech areas. He sat at 9 months of age, stood at 19 months, and walked at 24 months. Formal developmental assessment at 37 months of age showed a developmental age of 26 months, with speech and fine motor skills the most affected. He received speech therapy and showed considerable improvement in speech skills at 4.5 yr of age. He continued to receive hormonal replacement with hydrocortisone and fludrocortisone, and his adrenal markers remained in the normal range. By age 12.5 yr he showed signs

of puberty, with testicular enlargement and elevation of LH and testosterone levels. The patient is now 15 yr old and growing at the 25th percentile for height (midparental height, 50th percentile) and the 50th percentile for weight. He has average intellectual potential, but developmental weaknesses in areas of perceptual organization and attention. Discussion

ACC is a rare malignancy in children. In many cases the diagnosis is delayed because of the generally healthy appearance of the child and the lack of a palpable abdominal mass. In young children the presence of acne, Cushing’s syndrome, and pubarche should trigger an evaluation for adrenocortical tumors. Routine evaluation for patients with suspected adrenocortical tumors includes measurement of urinary 17-ketosteroids, 17-hydroxysteroids, and free cortisol, as well as plasma cortisol, DHEA-S, testosterone, androstenedione, 17␣-hydroxyprogesterone, aldosterone, renin activity, and 11-deoxycortisol. This comprehensive panel provides useful markers for diagnosis and for the detection

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De Leo´ n et al. • Clinical Case Seminar

J Clin Endocrinol Metab, October 2002, 87(10):4452– 4456 4455

FIG. 5. Patient’s growth chart during the first 3 yr of life. Note the weight arrest during therapy with mitotane (6 –18 months).

of tumor recurrence, as it did in our case. Because of the heterogeneity and rarity of adrenocortical tumors, prognostic factors and therapeutic guidelines have been difficult to establish, especially in infants. In our patient the tumor behavior, with local invasion and distant metastases, made the prognosis poor. The staging system proposed by MacFarlane (17) and modified by Sullivan et al. (18) is the system most commonly in use today (19, 20). Based on this system, our patient’s tumor is classified as stage IV, which has been associated with a very poor prognosis and long-term survival of 10% in a series with a median follow-up of 6.2 yr compared with 90% in patients with stage I disease (3).

The most important intervention in patients with ACC is complete surgical excision of the primary tumor and any local or distant metastases. Even after complete resection, the patients are at risk for recurrence as late as 10 –12 yr (21), and continued surveillance is required. The role of chemotherapy in the management of ACC in children is not clear. Although mitotane has been used extensively in adults, there is little knowledge of its efficacy and long-term effects in children. Perhaps the lack of response reported in many series is due to the use of low doses of mitotane resulting in subtherapeutic plasma levels. It is important when using mitotane to keep in mind that it significantly alters steroid hormone

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metabolism, and therefore the utility of measuring steroid levels as markers of tumor relapse may be lost. In our patient plasma levels were below the considered active levels during the first 6 months of treatment with mitotane, and the dose was not adjusted given the severe toxic effects the patient was experiencing. After tumor recurrence, higher doses were used to achieve active plasma levels during the rest of the therapy. The patient had significant toxic effects during mitotane treatment, including severe growth arrest and developmental delays that recovered once mitotane was discontinued. The toxic effects of mitotane experienced by our patient were previously reported (22), but this patient demonstrates that long-term recovery from those toxic effects is possible. The long-term effect on growth has been insignificant, as our patient is growing according to expected heights for his family. Developmentally it is difficult to assess whether his outcome resulted from the effects of mitotane or other factors. This patient has also been diagnosed with attention deficit hyperactivity disorder that perhaps has contributed to his learning disability. Elevated levels of steroids during early infancy may have also played a role in this patient’s developmental delay and learning disability. Studies in animals have shown that chronic exposure to high levels of glucocorticoids during early development results in morphological, physiological, and behavioral modifications in later life (23). Although there are relatively few data on the long-term effects of corticosteroids in developing humans, the existing data on the effects of prenatal exposure to corticosteroids suggest that humans may show effects similar to those seen in animals (24, 25). Even if mitotane caused the mild developmental delay, 15 yr of disease-free survival appears to justify its use. In conclusion, the combination of surgical resection and mitotane therapy resulted in long-term survival in this patient, who had an extremely poor prognosis. Although acute toxicity with mitotane was severe, effects were at least in part reversible, as long-term height outcome was not severely affected. The learning disability in this patient may be a sequelae of mitotane therapy. It is important to emphasize that the cure achieved for this particular patient may be related to a relatively nonaggressive tumor and the total resection of the metastasis. Patients with complete resection of the tumor have the best chance of survival, especially if the tumor is small. In patients with signs of local tumor invasion or patients with evidence of metastases (by elevation of hormonal markers) that cannot be resected, mitotane should be considered even in very young infants, because the apparent severe toxic effects even in the central nervous system appear to be reversible. Acknowledgments Received December 12, 2001. Accepted June 23, 2002. Address all correspondence and requests for reprints to: Thomas Moshang, M.D., Division of Endocrinology, Room 8416 Main Building, Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, Pennsylvania 19104-4399. E-mail: [email protected].

De Leo´ n et al. • Clinical Case Seminar

This work was supported in part by NIH Grant 5T32-DK-07314 and an Elli Lilly-Lawson Wilkins Pediatric Endocrinology Society Training Grant (to D.D.D.L.). Data were presented in part at the 83nd Annual Meeting of The Endocrine Society, June 20 –23, 2001, Denver, Colorado, and at the LWPES/ESPE 6th Joint Meeting, July 6 –9, 2002, Montreal, Canada.

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