SURGERY TODAY
@ Springer 2008
Successful Treatment of Adrenocortical Carcinoma with Pulmonary Metastasis in a Child: Report of a Case
HIROMASA ARAI1, YASUSHI RINO1, SUMITAKA YAMANAKA1, NORIO YUKAWA1, NOBUYUKI WADA1, HIROMI KATO2, MASAKATSU YANAGIMACHI2, HIROAKI GOTO2, HISASHI OSHIRO3, SHOJI YAMANAKA3, YOSHIAKI INAYAMA3, JIN LEE4, and MUNETAKA MASUDA1
Departments of 1 General Surgery, 2Pediatrics, 3Pathology, and 4Radiology, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
Abstract
Adrenocortical carcinoma (ACC) in childhood is rare: in 2002, only three new cases were reported in Japan. Although there is no established therapeutic manage- ment system, margin-free complete surgical excision of the tumor is very important to a satisfactory outcome. We report a case of ACC with bilateral pulmonary metastasis in a 10-year-old boy. Preoperative chest com- puted tomography (CT) showed pulmonary metastasis with near-water density. The patient was treated suc- cessfully with complete surgical resection of the primary tumor and adjuvant chemotherapy, including mitotane. After bilateral lung surgery for the metastatic lesions, the plasma dehydroepiandrosterone sulfate level be- came negative.
Key words Adrenocortical carcinoma · Lung metastasis . Child . Computed tomography · Operation
Introduction
Adrenocortical carcinoma (ACC) is rare, particularly in childhood. Unlike adult ACCs, most pediatric ACCs are functional, so they have peculiar clinical and bio- logical features that contrast with those of other pedi- atric carcinomas.1,2 Many treatment strategies for ACC in childhood have been tried, but the rarity of the disease and difficulty of its diagnosis have prevented the establishment of a standard therapeutic system, includ- ing adjuvant chemotherapy. Surgery, including en bloc resection of adjacent organs such as the liver, inferior vena cava, kidney, spleen, and pancreas, is still manda- tory for successful treatment.16 We report how we
treated ACC with pulmonary metastases in a child, by aggressive resection of the primary tumor and pulmo- nary metastatic lesions, with combined chemotherapy, including mitotane (1,1-dichloro-2-(o-chlorophenyl)-2- (p-chlorophenyl)ethane). We also describe the unusual computed tomography (CT) findings of pulmonary metastasis from ACC, which have not been described previously, and discuss the lung surgery.
Case Report
A 10-year-old boy was admitted to our Emergency Department after suffering blunt abdominal trauma while playing baseball. He had severe abdominal pain and marked abdominal distention. A full blood count showed slight leukocytosis of 10590 /mm3 and hemoglo- bin of 9.2 g/dl. Abdominal bleeding was strongly sus- pected. Emergency chest-abdominal CT showed a large lobulated, hypodense mass with heterogeneous enhance- ment in the right suprarenal region, suggestive of a right adrenal tumor (Fig. 1). The mass was about 110mm in diameter with a hematoma caused by rupture of the tumor in the retroperitoneal cavity. A small nodular lesion was already present in the upper lobe of the left lung (S1+2).
The patient had facial and pubic hair and hypertri- chosis since the age of 9 years. A hormonal examination showed elevation of plasma dehydroepiandrosterone sulfate (DHEA-S) to 7130ng/ml (normal range, 248- 2260 ng/ml at age 12); serum cortisol to 21.0 µg/dl (normal 4.0-18.3 µg/dl); urinary 17-ketosteroid (17-KS) to 98.9mg/day (normal 1-6mg/day at age 12); and urinary 17-hydroxycorticosteroid (17-OHCS) to 9.3 mg/ day (normal 1.0-5.6mg/day in childhood). After the tests, the anemia did not progress and we thought that active bleeding in the retroperitoneal cavity had stopped. Histological findings of a tumor biopsy taken via the retroperitoneal space were strongly suggestive of ACC.
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Ultrasonography and abdominal magnetic resonance imaging were not performed.
The patient underwent complete resection of the primary tumor, which was adhered to the liver and right kidney. Thus, we performed right adrenal tumorectomy, with right nephrectomy, and segmentectomy of the pos- terior segment of the liver. No tumor was identified in the parenchyma of the liver or kidney, but tumor emboli were found in the hepatic vein. Grossly, the tumor was located between the liver and the right kidney. It mea- sured 130 × 110 × 85mm, and contained necrosis and hemorrhage. Almost all of the right adrenal gland had been replaced by the neoplasm (Fig. 2).
Histologically, viable neoplastic cells with round nuclei and hyperchromasia were scattered in the tumor. The cell size varied and the cytoplasm was abundant, eosinophilic, and clear. The architectural pattern was like a large nest or a cord (Fig. 3a). Immunohistochemi- cally, the neoplastic cells were positive for melan A, a- inhibin (Fig. 3b,c) and synaptophysin, but negative for cytokeratin (AE1/AE3) and chromogranin A. Our find- ings resulted in a score of 8 out of 9 based on the criteria proposed by Weiss et al.7 with the modification of Aubert et al.8 These pathological results and the other findings were consistent with the features of ACC. Pul- monary metastasis was recognized at the initial diagno- sis, so the tumor was classified as Stage IV.2
After the operation, the plasma DHEA-S level decreased immediately to 44ng/ml. The patient was
5
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9
20
.
-
30
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4
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treated with adjuvant chemotherapy9 including mito- tane (carboplatin 200mg/m2 for days 1-9+etoposide 100 mg/m2 for days 5-7+doxorubicin 20mg/m2 for days 1-8+mitotane at an initial dose of 1 g/day and a mainte- nance dose of 3 g/day, orally). Cisplatin 40 mg/m2 was changed to carboplatin 200 mg/m2 to prevent renal dys- function since the patient had undergone right nephrec- tomy. After seven courses of adjuvant chemotherapy, no local recurrence or other metastatic lesions were detected on follow-up head and chest-abdominal CT scans.
The metastatic lesion in the left lung gradually increased in size and another metastatic lesion appeared in the right upper lobe (S2). A few months later, the bilateral pulmonary metastatic lesions had not changed in size or number. Chest CT showed small lung nodules of about 10mm or less in diameter with near-water density in the right S2 segment and the left S1+2 segment. The CT attenuation of the tumor was 0.74HU (Houn- sfield Units) on lung window CT images, but a tumor was not detected on mediastinal window images (Fig. 4a,b). Video-assisted thoracoscopic surgery (VATS) for the left metastatic lesion identified the mass as a raised lesion in a deflated lung, and wedge resection was per- formed. After two courses of the same chemotherapy, wedge resection for the right metastatic lesion was also performed. The tumor was located deep in the lung behind the right main bronchus, so the operation was performed via thoracotomy. The plasma DHEA-S level was negative (<20ng/ml) on postoperative day 4 (Fig. 5). All specimens obtained from the lung surgery were consistent with the features of pulmonary metastasis from ACC. No serious adverse side effects were observed throughout the course of treatment. The patient is currently well and continues on the same adjuvant chemotherapy.
a
b
c
Discussion
Adrenocortical carcinoma is a rare and highly malig- nant tumor. It accounts for only 0.05%-0.2% of all cancers, and has an overall incidence of approximately 1-2 cases/million per year worldwide.43 The age distri- bution is bimodal with a first peak in childhood and a higher peak in the 4th to 5th decade of life; the mean age at diagnosis is around 45 years old and it is more common in women than in men.5 The prognosis is extremely poor and the overall survival rate is 38%.5 According to one report of 35 patients with untreated ACC, the mean survival period was only 2.9 months.10
Adrenocortical carcinoma is especially rare in chil- dren, with an overall incidence of approximately 0.3
cases/million per year in the United States.4 In 2002, only three new cases of malignant adrenal tumor (involv- ing one boy and two girls) were reported in Japan.11 Given its rarity, the true prognosis of ACC in childhood is unclear. Diagnosis is often delayed because of the generally healthy appearance of the child and the lack of a palpable abdominal mass; however, most adreno- cortical tumors in children are hormonally active, and the frequently dramatic clinical presentation caused by steroid overproduction makes adrenocortical carcinoma a unique diagnostic entity.1 Symptoms include viriliza- tion, axillary and pubic hair, deepening of the voice, acne, enlargement of the penis or clitoris, and Cushing’s syndrome. These symptoms, especially in younger chil- dren, should prompt the examining doctor to test for
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a
DHEA-S (ng/ml)
7,000
7,130
1,000
1,350
109
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chemotherapy x 7 courses
2 courses
<20
1
Event
Admission
Resection of left lung metastasis
+
Resection of right lung metastasis
1
Resection of the primary tumor
adrenocortical tumors,4 with the possibility of ACC in mind.
The diagnosis of ACC is based on the gross and his- tological appearance of tissue obtained at surgery. The Weiss histopathology system,7 revised by Aubert et al. in 2002,8 is most commonly used to diagnose ACC. The presence of three or more of the nine criteria in this system is strongly correlated with subsequent malignant behavior. Biochemically, elevated levels of glucocorti- coids and androgen are a strong indication of an adrenal tumor, and measurements of 17-KS, plasma DHEA-S,
b
of 0.74 HU on a chest computed tomography scan in the lung field window. b The tumor could not be detected in the medi- astinal window
and urinary 17-OHCS can provide the pivotal clue in diagnosis of ACC.2 Margin-free resection and complete surgical excision of the primary tumor improve the outcome of ACC therapy,1-6 so early diagnosis is impor- tant. No standard regimen of adjuvant therapy has been established and the role of chemotherapy for ACC in children is unclear.2 Mitotane, an isomer of the insecti- cide p,p’-DDD and a chemical congener of DDT, blocks 11-ß-hydroxylation and decreases cortisol production. It is also capable of producing selective adrenocortical necrosis both in the ACC primary tumor and in metas- tases.12 However, the role of adjuvant chemotherapy with mitotane remains controversial and pediatric dosages have not been established.4
The staging system of ACC13 (I to IV) reflects its natural history. Ribeiro et al.2 proposed a set of staging criteria for the classification of childhood ACC. Distant metastasis is classified as Stage IV, but two separate studies reported finding metastasis at the initial diagno- sis in 5%-64% (average 21.4%) of children with ACC.1 The 5-year survival rate for each stage of childhood ACC is unclear. Allolio et al.5 emphasized the impor- tance of margin-free resection of the tumor and aggres- sive combination chemotherapy, including mitotane. They also proposed that aggressive surgical resection of the metastatic site should be considered even for selected patients with Stage IV disease.
A metastatic pulmonary tumor from a malignant neoplasm such as colon carcinoma or osteosarcoma is
generally recognized as a solid mass on mediastinal window CT. In our patient, a metastatic pulmonary tumor with a low CT value (0.74 HU) was detected on lung window CT images, but not on mediastinal window images. However, histological evaluation revealed more prominent cytoplasmic, vacuolated degeneration in the pulmonary metastatic tumor than in the primary lesion (Fig. 6). This specific prominent vacuolated degenera- tion of the tumor may have caused the low CT value and detection only on lung window images, since the lung metastatic tumors were confirmed to be solid masses by palpation during lung surgery.
Moreover, this 10-year-old boy had facial and pubic hair and hypertrichosis, but no other symptoms, abdom- inal mass, or physical findings. Precocious puberty was the only presentation, suggesting an adrenal tumor, and he already had pulmonary metastasis at the time of his initial diagnosis of Stage IV ACC. Nevertheless, we treated him successfully with surgery and aggressive chemotherapy. Although he is currently well with no evidence of recurrence or metastasis to other sites after
the lung surgery, he is being followed up carefully. Adrenocortical carcinoma is extremely rare in children, its etiology is not well understood, and a treatment pro- tocol has yet to be established. Our case suggests that in addition to early diagnosis, systemic progress in the management of ACC is required.
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11. Committee of Pediatric Malignant Neoplasm in Japan, Report of Pediatric malignant neoplasms in 2002. Shonigan 2005;42:281- 306.
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13. Lee JE, Berger DH, EL-Nagger AK, Hickey RC, Vassilopoulou- Sellin R, Gagel RF, et al. Surgical management, DNA content, and patient survival in adrenal cortical carcinoma. Surgery 1995; 118:1090-8.