Case Report
Successful long-term disease-free survival following multimodal treatments in a patient with a repeatedly recurrent refractory adrenal cortical carcinoma
YASUHISA FUJII,1 YUKIO KAGEYAMA,1 SATORU KAWAKAMI,’ HITOSHI MASUDA,1 CHIZURU ARISAWA,1 HIDEKI AKAMATSU,2 TAKUMI AKASHI3 AND KAZUNORI KIHARA1
Departments of 1 Urology and Reproductive Medicine, 2Cardiothoracic Surgery and 3 Human Pathology, Tokyo Medical and Dental University Graduate School, Tokyo, Japan
Abstract
A 47-year-old male patient underwent surgery for a 10-cm adrenal cortical carcinoma. A large invasive adrenal mass was surgically removed en bloc with the right kidney and the lower lobe of the liver. Two months postoperatively, a 7-cm recurrent mass developed in the right psoas muscle. After a partial response was achieved by irradiation (40 Gy) and high-dose chemotherapy (carbo- platin and etoposide) with peripheral blood stem cell transplantation, the patient underwent surgery with a wide excision of the psoas muscle. Twelve months after the initial surgery, an 8-cm rib metastasis developed and the patient again underwent surgery after a combination of irradiation (50 Gy) and chemotherapy (cisplatin and etoposide). The patient has been doing well without any evidence of recurrence for 5 years. Refractory or metastatic adrenal cortical carcinomas have been thought to be lethal, therefore, the present case provides support for multimodal treatments of refractory adrenocortical cancers.
Key words adrenal cortical carcinoma, multimodal treatments, radiochemotherapy, surgery, survival.
Introduction
Recurring or metastasized adrenal cortical carcinomas are often considered lethal. Previously reported cases indicate that some adrenal tumors are slow-growing, and that aggressive surgical excision of the metastatic lesion may prolong patient survival.1,2 We describe a case of a rapid-growing adrenal cortical carcinoma with repeated recurrence that was successfully treated with multimodal treatments including chemotherapy, radia- tion and surgery, with a longer than 5-year recurrence- free survival period.
Correspondence: Yasuhisa Fujii MD PhD, Department of Urology and Reproductive Medicine, Tokyo Medical and Dental University Graduate School, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Email: y-fujii.uro@tmd.ac.jp
Received 10 September 2002; accepted 20 January 2003.
Case report
In July 1996, a 47-year-old man presented to our insti- tution with right upper abdominal pain. Abdominal ultrasonography and computed tomography (CT) showed a 10 x 10 cm right adrenal mass (Fig. 1a). Find- ings on chest X-ray, CT scan of the chest, and bone scan were normal. Laboratory tests, including a hormonal study, were normal except for an elevated serum lactate dehydrogenases (LDH) level of 1032 IU/L (normal 269-467). The patient underwent surgery, during which a large invasive mass adherent to the surrounding tissue was surgically removed en bloc, along with the right kidney and the right lower lobe of the liver. The para- aortic lymph nodes were not dissected because CT and intraoperative findings were negative. Histologically the tumor was an adrenal cortical carcinoma with liver inva- sion (Fig. 2). After the operation, the serum LDH level normalized (352 IU/L) and the patient was followed up without any adjuvant therapy.
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Two months postoperatively, the patient developed pain in the right leg with an elevation of LDH (832 IU/ L). Abdominal CT scan revealed a 7 x 7 cm mass in the right psoas muscle (Fig. 1b). Even in a retrospective review of the preoperative CT scan, the mass could not be detected. As it was unlikely to be completely resec- table due to the extensive local involvement of surround- ing tissue, irradiation (40 Gy) was administered. Concurrent systemic chemotherapy (cisplatin 20 mg/ body and etoposide (VP-16) 100 mg/body, each for 5 days) was planned, but was discontinued after day 1 because of increased fever in the patient. Although LDH decreased to a normal range (376 IU/L) after radiation, an abdominal CT scan showed only a slight reduction in the volume of the mass. One course of systemic chemotherapy of cisplatin and VP-16 was then admin- istered. A further CT scan showed further reduction in the size of the recurrent lesion (5 x 4 cm), thus achieving a partial response (> 50% reduction in tumor size). Peripheral blood stem cells were harvested after chemo- therapy, followed by the administration of human granulocyte colony-stimulating factor. Two courses of high-dose chemotherapy (carboplatin 300 mg/body and VP-16 300 mg/body, each for 4 days) were administered
with blood stem cell transplantation. The mass reduced to 3×2 cm (Fig. 1c) and LDH decreased further (285 IU/L). Surgery with a wide excision of the right psoas muscle was performed. Pathologically, all tumor cells were necrotic and no viable cancer cells remained.
Twelve months after the initial treatment, a chest wall metastasis appeared together with right chest pain and elevation of LDH (674 IU/L). Chest X-ray showed an 8 × 5 cm mass in the right chest wall (Fig. 1d). Again, the mass seemed to be inoperable due to extensive pleu- ral and pulmonary involvement. Concurrent chemother- apy (two courses of chemotherapy of cisplatin and VP-16) and irradiation (50 Gy) were administered. After these treatments, the metastatic lesion reduced in size (Fig. 1e) and LDH normalized. The patient underwent surgery again, and a wide excision of the chest wall and the right upper lobe of the lung was performed. Patho- logical examination showed that the lesion was a rib metastasis with lung invasion. Although almost all tumor cells were necrotic, some viable cancer cells remained.
Thereafter, the patient was followed up without any additional treatment and has been doing well without any evidence of disease recurrence 5 years after his last operation.
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Discussion
Carcinoma of the adrenal cortex is an extremely rare malignancy. Although complete surgical excision is the only effective form of therapy, many patients develop recurrences despite an apparently curative resection, with between 30 and 50% of patients having metastatic disease at the time of diagnosis.3-5 The prognosis of patients with refractory or metastatic adrenal cortical carcinoma is thought to be very poor, although a few reports have indicated that aggressive treatments could lead to prolonged survival in patients with metastatic adrenal tumors of the slow-growing type.1,2 The present patient repeatedly developed large recurrent masses, only 2 and 12 months after the first operation, showing his tumor to be of a rapid-growing type. Furthermore, mitotic rate has been reported to have a strong statistical association with patient outcome. Weiss et al. have
reported that a mitotic rate greater than 20 per 50 high- power fields has been associated with a shortened median survival period (14 months) compared with tumors having 20 or fewer mitoses (58 months) in adult adrenocortical carcinomas.6 Our case had 36 mitoses per 50 high-power fields, indicating a high-grade tumor.
Recent clinical studies support repeated surgery as the mainstay of treatment for refractory adrenocortical carcinomas.7 Pommier and Brennan reported that the mean survival time for patients with recurrent adreno- cortical carcinoma treated medically was 19 months compared with 56 months for patients who underwent a repeat operation.8 Complete resection is necessary to improve patient prognosis, even with refractory carci- nomas; something that is not easily accomplished. Schulick and Brennan reported that in resections of locally recurrent or distant metastatic disease performed in 47 patients, 32 patients who had a complete second resection had a median survival period of 74 months (5- year survival, 57%), while 15 with incomplete second resections had a median survival period of 16 months (5-year survival, 0%).9 Therefore, effective preoperative adjuvant therapies that can make refractory tumors completely resectable are required.
Some reports have shown the effective activity of a combination of cisplatin and VP-16 in the treatment of metastatic adrenal cortical carcinomas.10,11 However, the objective response rate for this regimen is approxi- mately only 30%, and complete responses are not readily achieved (as shown with mitotane). One poten- tial approach to improve chemotherapy might involve administering agents with disease related activity at much higher than usual doses. Recently, high-dose chemotherapy with blood stem cell transplantation has been applied for several malignancies. Therefore, we employed high-dose carboplatin and VP-16 treatment with peripheral blood stem cell transplantation (PBSCT). To our knowledge, this is the first report of an adrenocortical carcinoma treated with high-dose che- motherapy. However, our patient developed rib metasta- sis even after the high-dose chemotherapy, indicating that any chemotherapy regimen alone is unlikely to cure an advanced or metastatic adrenocortical carcinoma. A recent study demonstrated that the combination of cis- platin and VP-16 had minimal activity in these patients.12
For radiotherapy, only anecdotal data or very small patient series with different tumor stages are available. Radiation may, however, improve local control in high stage tumors, where complete resection is difficult to perform.7 Another study has reported that radiotherapy was moderately effective in 3 (16%) of 19 patients with local abdominal recurrence.13 However, radiotherapy
alone, like chemotherapy, is not likely to cure a refrac- tory adrenal cortical carcinoma.
The combination of chemotherapy and irradiation has been reported to be more effective than each mono- therapy in several cancers.14 In the present case, the effect of the combination of chemotherapy of cisplatin (or carboplatin) and VP-16 and irradiation was remark- able. Both the psoas recurrence and the rib metastasis, which seemed inoperable at first appearance, were com- pletely resected after chemoradiotherapy. Pathological examinations confirmed the effect; no cancer cells could be seen in the psoas recurrence and only a small number of viable cancer cells remained in the rib metastasis. We believe that this concurrent chemoradiotherapy could make most refractory or metastatic adrenocortical car- cinomas completely resectable, and might improve the prognosis for these patients.
In the present case, serum LDH well-reflected the state of the disease, being high at presentation and nor- malized after the primary operation. LDH elevated repeatedly along with tumor recurrences. Johnson and Greco have reported two similar cases.1º In some adrenocortical carcinomas, LDH can be useful as a tumor marker.
In conclusion, the combination of chemotherapy of cisplatin (or carboplatin) and etoposide, and radiation therapy followed by surgical resection, should be con- sidered as a valid treatment option for refractory or metastatic adrenal cortical carcinomas, even with rap- idly repeated recurrences.
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