Intensive Chemotherapy With Autologous PBSCT for Advanced Adrenocortical Carcinoma in a Child
Jeong Ok Hah, MD
Summary: Adrenocortical carcinoma (ACC) is a rare tumor in children. Surgical excision is the most effective therapy for ACC. However, the prognosis of ACC with metastases or unresect- ability is poor and the therapies for these are not well established. We report successful treatment of a 3-year-old girl with ACC and lung metastases. She had adrenalectomy followed by chemotherapy with cisplatinum, etoposide, and bleomycin. Thoracotomy for lung metastases was done after partial response to chemotherapy. Autologous peripheral blood stem- cell transplantation was performed after preconditioning with carboplatinum, etoposide, and melphalan. She has been well for 2 years since the time of diagnosis. Surgical resection of the primary and metastatic lesions with chemotherapy followed by autologous peripheral blood stem-cell transplantation could be an effective treatment for advanced ACC. However, prospec- tive-controlled studies are necessary for firm conclusion as this is a single case report and the follow-up is not long enough.
Key Words: adrenocortical carcinoma, chemotherapy, autolo- gous peripheral blood stem-cell transplantation, metastasis, child
(J Pediatr Hematol Oncol 2008;30:332-334)
A drenocortical carcinoma (ACC) is a rare tumor in children presenting with hormonal activities and composing approximately 0.2% of all childhood cancers.1 Surgical excision is the most effective therapy for ACC when complete resection is possible. However, a signifi- cant proportion (30% to 85%) of patients have distant metastases at the time of initial presentation and the prognosis is dismal unless excision of both primary and metastatic lesions is possible.2,3 Systemic chemotherapy regimens usually including cisplatin, etoposide, doxoru- bicin, and mitotane have been tried for residual disease after surgery or metastatic disease with variable responses.4-8 We report successful treatment of a child with ACC and lung metastases with surgical resection of the primary and the metastatic lesions after chemo-
therapy followed by autologous peripheral blood stem- cell transplantation (auto-PBSCT).
CASE REPORT
A 3-year-old girl presented with precocious puberty, which started several months before admission. Body weight was 18.2 kg (90th percentile) and height was 102 cm (75th to 90th percentile). Vital signs were all within normal limits (pulse rate, 100/min; respiratory rate, 24/min; blood pressure, 110/60; temperature, 37℃). Physical examination revealed breast engorgement (Tanner stage II) with nipple color change, enlarged clitoris with pubic hair, and hyperpigmentation of the whole body.
Hormonal study results were as follows: serum estradiol, 32 pg/mL (normal at <9.2y, 0.5 to 2.0pg/mL); serum dehydroepiandrosterone (DHEA), >1000 ng/dL (normal at <9.2y, 31 to 345 ng/dL); 24 hours urine 17-KS, 207.8 mg/g creatinine/24 h (normal 0 to 8y, 0 to 3 mg/g creatinine/24 h). Plasma rennin (4.89 ng/mL/h) and angiotensin II (9 pg/mL) levels were normal.
Radiologic findings were as follows: bone age of the left hand, compatible with a 5 to 6 years old; chest x-ray revealed slightly increased pulmonary vasculature and prominent pul- monary conus shadow with clear lungs; adrenal gland ultra- sonogram revealed a 6.4cm sized homogeneous, hypoechoic, and slightly hypervascular suprarenal mass on the right adrenal gland; magnetic resonance imaging (MRI) of adrenal gland showed about 6.5 cm sized mass in the right suprarenal area, which showed intermediate SI on T2WI and mild enhancement on contrast study but no significant lymph node enlargement.
Exploratory laparotomy disclosed an enlarged right adrenal gland, which was attached to the kidney with adhesion to the right inferior hepatic vein. Right adrenalectomy was performed under the impression of a right adrenal cortical tumor.
Pathologic findings revealed a grossly well encapsulated mass measuring 165.5 g in weight and 7.3 x 6.7 x 6.5 cm in size. On section, the cut surface showed a yellowish brown solid homogenous appearance with vague nodularity. Microscopic findings revealed diffuse growth pattern with necrosis, marked nuclear atypia, atypical mitoses, mitotic activity > 5/50 high- power field, oncocytic feature, capsular invasion, and vascular invasion. Regional lymph node revealed no tumor metastasis. Immunohistochemical staining revealed inhibin (+), melan A (+), S-100 protein (-), synaptophysin (-), chromogranin A (-), Cam 5.2 (+), vimentin (+), Ki-67 (high), and p53 (-). Pathologic diagnosis of ACC was made.
After the diagnosis of ACC, whole body fusion positron emission tomographic-computed tomography (CT) was per- formed showing 2 nodular lesions on the right lung with mild fluorodeoxyglucose uptake. Chest CT also showed 2 nodules in the right lung, 1 each in the right upper and lower lobes.
Received for publication October 5, 2007; accepted November 29, 2007. From the Departments of Pediatrics, College of Medicine, Yeungnam University, Daegu, Korea.
Reprints: Jeong Ok Hah, MD, Departments of Pediatrics, College of Medicine, Yeungnam University, 317-1 Daemyung-dong, Nam-gu, Daegu, 705-717, Korea (e-mail: johah@med.yu.ac.kr).
Copyright @ 2008 by Lippincott Williams & Wilkins
Chemotherapy with cisplatinum 100 mg/m2 intravenous (IV) by continuous infusion on day 0, etoposide 100 mg/m2 IV over 1 hour on days 0, 1, 2, and bleomycin 15 IU/m2 on day 1 was administered every 3 to 4 weeks. With thoracotomy, 2 metastatic lung nodules were removed after partial response to 3 cycles of chemotherapy. After 6 more cycles of chemotherapy, auto-PBSCT was performed after preconditioning with cispla- tinum 400 mg/m2/d by continuous infusion on days -7, - 6, -5, - 4, etoposide 200 mg/m2/d by continuous infusion on days -7, -6, -5, -4, and melphalan 120 mg/m2/d IV on days -3, - 2. Her post-auto-PBSCT course was uneventful and she has been well for 2 years with normalized physical findings, serum DHEA, and 24 hours urine 17-KS. Radiologic findings with MRI of adrenal gland, chest CT, and whole body fusion positron emission tomographic CT on follow-up exam- ination have been normal.
DISCUSSION
Childhood ACC usually present during the first 5 years of life (median age 3 to 4y) with a second, smaller peak during adolescence. Constitutional mutations of the p53 gene are frequently reported in young children with a diagnosis of ACC.9 ACC is associated with excessive androgen production and virilization in 80% to 90% of cases.10,11 In the largest series in children, signs of virilization were pubic and/or body hair in 95%, clitoris or penile enlargement in 70%, and voice changes in 50% of cases.10 Cushing syndrome was present in 74% and 3.6% were asymptomatic.10 These signs and symptoms are often unrecognized for several months because of its gradual onset.11 As many benign lesions such as adrenal adenomas are hormonally active, it is often difficult to determine a malignant lesion preoperatively. Ciftci et al11 reported that 80% of carcinoma and 90% of adenomas were functional. The present case showed elevated levels of androgen and glucocorticoids such as serum estradiol, DHEA, 24 hours urine 17-KS, and signs of premature thelarche and virilization.
Unfortunately, malignancy was not determined until the biopsy result was available, although ultrasono- gram and MRI of adrenal gland showed a mass lesion in right suprarenal area without significant lymph node enlargement. Thus, CT of the lung was obtained only after diagnosis of ACC.
Surgical excision is the most effective therapy for ACC. When complete excision is possible, no further therapy is indicated. However, recurrence even after an apparently complete surgical removal occurs in 22% to 40% cases.4,12 The place of chemotherapy in the manage- ment of childhood ACC has not been well established. Systemic chemotherapy should be considered if patients have unresectable or residual diseases although responses are variable.4 8 Mitotane, an insecticide derivative produ- cing adrenocortical necrosis, is commonly used in adults, especially in cases of nonresectable, recurrent, or meta- static ACC. With mitotane, the endocrinologic symptoms could be alleviated with a response rate of 10% to 60%. However, mitotane is not curative, and does not influence the mortality rate.4,5,13 Mitotane has occasionally been used in children with considerable toxicity, mainly
gastrointestinal and neurologic.14 A response rate of 30% (6/20) in children has been demonstrated.4 There seems to be no role for adjuvant mitotane after complete resection.5
Bleomycin is an anticancer antibiotic, which binds to and damages DNA. The drug is active against Hodgkin disease, lymphomas, testicular cancers, and other germ cell tumors but lung and skin are the tissues with the greatest susceptibility to bleomycin cytotoxi- city.15,16 The dose-limiting toxicity of bleomycin is interstitial pneumonitis that can lead to pulmonary fibrosis. Below a total cumulative dose of 450 U, sporadic cases of pulmonary toxicity are reported, with an incidence of 3% to 5%.17 For the present case, a total cumulative dose of 135 U was administered without any evidence of pulmonary toxicity by chest CT or pulmonary function test.
Chemotherapy with cisplatin or carboplatin and etoposide, some in combination with mitotane, was shown to be effective in 30% to 60% of children with ACC.4-8 In some cases, response rates are relatively low (30%) and response durations are short (7.9mo) with median survival of 11.8 months.5 Factors such as large tumor size (measuring ≥ 5 cm, weighing ≥ 100 g), older age of the patient (≥2y old), advanced histologic grade, long interval between initial symptoms and diagnosis, and a high urinary steroid hormone output have been associated with poor prognosis. However, the exact roles of these features have not been well elucidated yet.4,12,18 We performed auto-PBSCT with intensive precondition- ing chemotherapy as our patient had many poor prognostic factors.
Surgical resection of the primary and the metastatic lesions with chemotherapy followed by auto-PBSCT could be an effective treatment for advanced metastatic ACC. However, prospective-controlled studies are neces- sary for firm conclusion as this is a single case report and the follow-up is not long enough.
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