Urologia Internationalis
Urol Int 2009;82:222-226 DOI: 10.1159/000200804
Received: April 24, 2007 Accepted after revision: January 28, 2008
A Twelve-Year Experience with Adrenal Cortical Carcinoma in a Single Institution: Long-Term Survival after Surgical Treatment and Transcatheter Arterial Embolization
Hideo Soga Atsushi Takenaka Takeshi Ooba Yuzo Nakano Hideaki Miyake
Masashi Takeda Kazushi Tanaka Isao Hara Masato Fujisawa
Division of Urology, Department of Organ Therapeutics, Kobe University Graduate School of Medicine, Kobe, Japan
Key Words
Adrenal cortical carcinoma . Transcatheter arterial embolization · Long-term survival
Abstract
Introduction: We retrospectively analyzed 6 cases of adre- nal cortical carcinoma (ACC) treated during a 12-year period at a single institution. Patients and Methods: We reviewed the clinical and pathological records and updated the fol- low-up of the patients treated and observed in our institu- tion between 1995 and 2006. Results: All 6 patients under- went surgery for ACC. The mean age at diagnosis was 53.3 years (range 36-72). The median follow-up was 50.7 months (range 13-132). Three patients were clinically classified as stage II, 2 as stage III and 1 as stage IV with bone metastasis. The 5-year overall survival was 62.5%. Recurrences or metas- tases occurred in 4 patients. Two patients without reopera- tion for metastases died, and others with radical treatments such as surgery, chemotherapy, transcatheter arterial embo- lization and/or radiation remain alive. Conclusions: In our experience, transcatheter arterial embolization was effec- tive against liver metastasis.
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Introduction
Adrenal cortical carcinoma (ACC) is a rare malignan- cy with an annual incidence of 1-2 persons per million population per year, with poor prognosis [1]. Although ACC may occur at any age, the disease shows a bimodal distribution with the first peak in children less than 10 years of age and the second peak in the fourth and fifth decade of life [2-5]. Compared with pediatric patients, adult patients tend to present with clinical manifestation related to tumor growth or with incidental findings of an adrenal mass on imaging performed for unrelated rea- sons [3, 6]. Thus, the diagnosis is often delayed in adults, especially with nonfunctioning tumors. Therefore, most adult patients present at advanced stages of disease or with symptoms of metastatic diseases before a primary diagnosis is established [7, 8]. Recently, increasingly sen- sitive imaging techniques have led to more frequent de- tection of this tumor [9].
The mainstay of therapy is the radical resection of the tumor and adjacent organs. It has also been widely report- ed as the only effective treatment for ACC, particularly, at clinical stage I or II [10-16]. Mitotane and other chemo- therapeutic agents are also widely used as adjuvant thera- py for patients with metastatic diseases or incomplete re-
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| Patient No. | Site | Age/ gender | Symptoms | Manifestation of tumor growth | Hyper- tension | Hormonal activity | Size of tumor, | cm | Tumor weight, g | PT | Postopera- tive stage | Adjuvant therapy |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | right | 43/F | back pain, fever | + | – | – | 7 | 650 | 2 | II | – | |
| 2 | right | 72/F | vomiting | + | + | – | 10 | 180 | 3 | III | – | |
| 3 | left | 58/F | back pain | + | + | – | 9.6 | unknown | 3 | IV | mitotane | |
| 4 | right | 57/F | – | – | + | Cushing's syndrome | 7 | 32 | 2 | II | – | |
| 5 | right | 54/M | back pain | + | – | – | 20 | 3,080 | 3 | III | – | |
| 6 | left | 36/M | fever | – | – | – | 8 | 150 | 2 | II | – | |
| F = Female; M = male; - = absence; + = presence. | ||||||||||||
section. Furthermore, there are some reports that chemo- therapy contributes to a better prognosis [14].
We experienced 6 cases during a 12-year period at our institution. In this series, transcatheter arterial emboli- zation (TAE) performed against liver metastasis in 2 cas- es presented good responses. Here, we report the series of 6 cases of ACC treated at our institution where the pa- tients were diagnosed and treated.
Patients and Methods
We reviewed the clinical and pathological records and updat- ed the follow-up of 6 patients with ACC treated and observed at Kobe University Hospital, Japan, between 1995 and 2006. None of the patients had received a previous diagnosis of ACC.
The preoperative evaluation of malignancy and detection of the extension of the tumor were carried out with ultrasonography, radiological methods including intravenous pyelography, com- puted tomography (CT), magnetic resonance imaging and bone scintigraphy in all patients. Patients were considered to have a functional tumor if there was a manifestation of a clinical syn- drome of excess steroid production, such as Cushing’s syndrome, virilization, feminization, hyperaldosteronism or a combination of these conditions. Patients who exhibited neither biochemical nor clinical evidence of excess steroid secretion were considered to have nonfunctional tumors.
The diagnosis of ACC was based on the histologic criteria pro- posed by Weiss [17], and staging of the diseases was performed retrospectively according to the new Union Internationale Contre le Cancer staging system [18]. Post-treatment clinical data were obtained by a review of all medical records.
Results
Patient Characteristics
Six patients (4 females, 2 males; 36-72 years of age at diagnosis, mean age 53.3) were operated on for ACC be-
tween 1995 and 2006. The median follow-up was 50.7 months (range 13-132). The most common clinical fea- tures were moderate hypertension and back pain (in 3 patients each). The tumor with Cushing’s syndrome was found during routine investigation with ultrasonogra- phy. Abdominal CT scans showed that the size of the tu- mors ranged from 7 to 20 cm (median 10.3) (table 1).
As primary treatment, 5 patients underwent surgical treatment considered to be complete resection. One pa- tient (case No. 5) underwent adrenalectomy plus nephrec- tomy, and others underwent thoracoabdominal (2 pa- tients) or abdominal (2 patients) adrenalectomy. There was no apparent tumor thrombus in the renal vein or in- ferior vena cava. The patient (case No. 3) who did not un- dergo surgery as primary treatment was not initially re- garded as having malignant disease since both the tumor was 2.7 cm in diameter on CT and did not demonstrate endocrinal function at the initial presentation. A further CT scan revealed that the tumor was 9.6 cm in diameter 3 months after first presentation. The tumor was diag- nosed as ACC by a biopsy, and bone scintigraphy also revealed metastasis. This patient received medical thera- py including mitotane and cisplatin. Although the lesion of the adrenal gland demonstrated partial response for a few months, it gradually increased in size, and symptoms related to tumor growth appeared, such as abdominal pain and nausea. Therefore, this patient underwent adre- nalectomy as palliative surgery 6 months after the start of primary treatment and continued to receive mitotane as adjuvant therapy.
Outcome
The 5-year overall survival rate was 62.5%. Recurrenc- es or metastases occurred in 4 patients, 3-33 months after the initial surgery. Metastatic regions and time after ini- tial surgical treatment of the primary tumor are shown
a
b
c
| Patient No. | Interval until re- currence or me- tastasis, months | Location of recurrence or metastasis | Treatment for recurrence or metastasis | Effect | Survival period, months | Prognosis |
|---|---|---|---|---|---|---|
| 1 | – | – | – | CR | 132 | NED |
| 2 | 11 | liver (multiple) lung (multiple) retroperitoneal LN | mitotane only | PD | 17 | DOD |
| 3 | 3 | right adrenal lung (multiple) bone (multiple) | mitotane only | PD | 13 | DOD |
| 4 | 33 | liver (solitary) retroperitoneal LN | mitotane + cytotoxic chemotherapy - TAE retroperitoneal lymphadenectomy | CR PR | 77 | AWM |
| 5 | 6 | bone (left 6th rib) | radiation (50 Gy) -> complete resection | CR | 51 | NED |
| liver (solitary) | mitotane + cytotoxic chemotherapy + TAE | CR | ||||
| left adrenal gland | mitotane + cytotoxic chemotherapy | CR | ||||
| left lung | lobectomy | CR | ||||
| 18 | right lung | proton beam therapy (56 Gy) -> lobectomy | CR | |||
| 6 | – | – | – | CR | 14 | NED |
CR = Complete response; NED = no evidence of disease; PD = progressive disease; DOD = death of disease; LN = lymph node; AWM = alive with metastasis; PR = partial response.
in table 2. Two patients (cases No. 2 and 3) who did not receive surgical treatment for recurrences or metastases died of progressive tumor disease during the follow-up period. Four patients are still alive (14, 77 and 132 months, stage II at diagnosis; 51 months, stage III at diagnosis).
TAE for liver metastasis was performed in 2 patients (cas- es No. 4 and 5) after mitotane administration with cyto- toxic chemotherapy including etoposide, doxorubicin and cisplatin and produced complete response (fig. 1). Although the effect of proton beam therapy was not ap-
parent in case No. 5, that of radiation therapy for bone metastasis was obvious [19].
Discussion
Adrenal tumors are revealed unexpectedly in 1-4% of all abdominal imaging studies, and approximately 5% of those incidentalomas are ACCs [20, 21]. Unenhanced CT is a useful technique for characterization of incidentally detected adrenal masses. Adrenal lesions with a density of >10 Hounsfield units in an unenhanced CT scan [22] or an enhancement washout of <50% and a delayed attenu- ation of >35 Hounsfield units are suspicious for malig- nancy [23]. Further, ACCs are inhomogeneous with ir- regular margins and irregular enhancement of solid com- ponents in enhanced CT. ACCs also typically present isointense to the liver on T1-weighted images and show intermediate to increased intensity at T2-weighted images in magnetic resonance imaging [24]. Recent studies dem- onstrated that fluorodeoxyglucose positron emission to- mography was useful to differentiate between benign and malignant adrenal masses [25, 26]. However, the size of the adrenal mass is one of the best indicators of malig- nancy. Tumors >6 cm are highly suspicious for malignan- cy [24]. Some authors recommended that all adrenal cor- tical tumors ≥4 cm be removed [27]. In our experience, the size of the tumor ranged from 7 to 20 cm in diameter at diagnosis. We encountered a small adrenal tumor, mea- suring 2.7 cm in diameter at the initial presentation, which we did not recognize as malignant disease. Rapid growth of this tumor within a few months promoted recognition of the mass as a malignant tumor.
The mean survival rate of treated tumors was approx- imately 20 months, and the overall 5-year survival rate after diagnosis ranged from 10 to 60% [3, 28-30]. In our limited series, the 5-year overall survival is 62.5%, and 2 of 3 patients with stage II diseases at diagnosis have remained alive without evidence of disease since the ini- tial treatment. The important factors affecting progno- sis are early stage and curative resection [10-15]. Con- ventional open adrenalectomy is considered the ap- proach of choice for ACC, since it provides a large, complete and oncologically correct en bloc resection. Thus, most ACCs were extracted by open adrenalecto- my. Some authors described the feasibility of laparo- scopic adrenalectomy for small-sized ACCs without lo- cal infiltration [31, 32]. However, laparoscopic adrenal- ectomy for adrenal malignancies at the early stage is still controversial [33].
Another important factor affecting prognosis is treat- ment for recurrent or metastatic diseases, which are ex- tremely common even for patients who undergo com- plete resection. Of patients undergoing complete resec- tion, 37-85% develop recurrences or metastases. Further, patients who were surgically treated for recurrence after the first curative surgery developed further relapse. This means that patients with a single recurrence are very likely to develop further relapses of ACC [34]. Some au- thors described the benefit of adjuvant radiotherapy of the tumor bed to reduce the rate of local recurrence. However, no significant reduction in disease-free and overall survival was found [35]. Therefore, complete re- section for recurrent or metastatic disease is still the best individual factor for a good prognosis and prolonged survival whenever complete resection is possible [10, 30, 34, 36].
It has been reported that cisplatin alone or in combi- nation with etoposide shows some activity in advanced ACC [37]. In our experience, 2 patients undergoing cy- totoxic chemotherapy with mitotane and TAE for liver metastasis showed a good response. Reviewing the previ- ous literature, there is no report concerning TAE as the treatment for metastatic disease of ACC with good prog- nosis except for a few case reports such as that of Li et al. [38]. These 2 patients treated with TAE may belong to a good response group [39]. Although we also recognized the effect of surgical resection of metastasis, TAE treat- ments for metastases contributed to the good prognosis. Sasano et al. [40] showed that the vascular density of ACC was 573.2 + 185.2/mm2. ACC is considered to be comparable in intratumoral vascularity with hepatocel- lular carcinoma, since the intratumoral microvessel den- sity of hepatocellular carcinoma was 297 ± 185.2/0.74 mm2 [41]. We assumed that TAE might be one of the treatments worth performing, especially to liver metas- tasis, when cytotoxic chemotherapy with mitotane has a poor effect.
Conclusion
In conclusion, the 5-year overall survival was 62.5% in our series. Although this may be the result of the small numbers of patients in our series, TAE was effective against liver metastasis. We assume that patients with long-term survival particularly benefited from not only complete resection but also from radical treatments in- cluding TAE and systematic chemotherapy.
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