Surgical Outcome of Stage III and IV Adrenocortical Carcinoma

Surgical Outcome of Stage III and IV Adrenocortical Carcinoma Susumu Ohwada 1, Masaru Izumi 2, Susumu Kawate 1, Kunihiro Hamada 1, Hiroyuki Toya 1, Nozomi Togo 1, Jun Horiguchi 1, Yukioi Koibuchi 1, Toru Takahashi 1 and Masanobu Yamada 3 1 Department of Surgery, Gunma University Graduate School of Medicine, Maebashi, 2 Department of Surgery, Sudo Hospital, Annaka, Gunma and 3 Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan Received July 21, 2006; accepted September 23, 2006; published online February 2, 2007 Jpn J Clin Oncol 2007;37(2)108 113 doi:10.1093/jjco/hyl127 Background: Adrenocortical carcinoma (ACC) is a rare tumor usually diagnosed at an advanced stage on invasion of or adherence to adjacent organs. We report surgical outcome of stage III and IV ACCs. Methods: ACCs from seven patients at clinical stage II (n ¼ 1), III (n ¼ 4), or IV (n ¼ 2) were resected. Combined resection of the liver and inferior vena cava was performed in six patients. Morbidity, mortality, recurrence and survival were analyzed. Results: The pathological stage was stage III in five patients and stage IV in two patients. The mortality was zero and the morbidity was two of seven (29%) patients. The estimated 3- year disease-free and overall survivals for stage III were 20% and 40%, respectively, with a median follow-up of 32 months (range, 11 58). The mean disease-free survival was 21.0 + 9.0 months (95% CI: 3.3 38.7). The 3-year disease-free and overall survivals for stage III and IV were 14.3% and 28.6%, respectively. The mean disease-free survival time was 18.6 + 6.7 months (95% CI: 5.4 31.8). The most frequent site of metastasis was the lungs, seen in four patients, and liver in three patients. Loco-regional, intra-abdominal lymph node, peritoneum, bone, brain recurrences were also seen in one patient each. The mean survival after recurrence was 19.0 + 3.3 months (95% CI: 12.6 25.5), and the 50% survival was 18.4 months with mitotan and cytotoxic drug therapy. Conclusions: Resection for stage III, IV ACCs affords the possibility of negative margins, acceptable peri-operative morbidity and mortality, and prolongs survival in selected patients. Key words: adrenocortical carcinoma inferior vena cava (IVC) replacement liver resection IVC resection stage III stage IV INTRODUCTION Adrenocortical carcinoma (ACC) is a rare tumor of which complete surgical resection is the treatment of choice (1). A margin-free resection (R0 resection) is a strong predictor of long-term survival (2 4). ACC is usually diagnosed at an advanced stage with invasion of or adherence to the adjacent organs like liver, kidney, and inferior vena cava (IVC) (5), i.e. stage III or IV tumor, which often requires en bloc resection of the liver, IVC, kidney, spleen and pancreas to achieve R0 resection and also to avoid tumor spillage (4). In this paper we report surgical outcome of stage III and IV ACCs including combined liver and IVC resection. For reprints and all correspondence: Susumu Ohwada, Department of Surgery, Gunma University School of Medicine, 3-39-15 Showa-Machi, Maebashi, Gunma 371, Japan. E-mail: sohwada@med.gunma-u.ac.jp PATIENTS AND METHODS CLINICAL EVALUATION AND STAGING ACCs from seven patients were resected between 1993 and 2005 in Gunma University Hospital. There were four women and three men, with a median age of 52.9 years (range, 32 68 years). Cushing s syndrome and hypertension were present in one woman each (14.3%). Edema of the lower extremities was seen in two patients. In four patients, the tumors were non-functioning and had been detected on screening CT images for other diseases. The right adrenal gland was involved in six patients, the left, in one. The mean tumor diameter was 13 cm [range, 7 20 cm;,10 cm in three patients (42.9%) and.15 cm in four patients (57.1%)]. Loco-regional invasion was present in six patients (85.7%), and synchronous distant metastases at the time of initial presentation were present in two patients (13.6%). # 2007 Foundation for Promotion of Cancer Research

Jpn J Clin Oncol 2007;37(2) 109 Clinically, one case (14.3%) was stage II, four (57.1%) were stage III, and two (28.6%) were stage IV (Table 1) (6). SURGERY The tumor was resected en bloc with the adjacent tissues or organs not to expose or spill out tumor cells. The surgical procedure for liver and IVC resection has been described elsewhere (7). Briefly, first the inflow arteries of the tumor, including the adrenal, phrenic, lumbar and renal arteries when nephrectomy was required, were ligated. Liver resection was performed anatomically according to Couinaud s liver segments after ligating the inflow arteries and portal branches to be resected. To expose the supra- to retrohepatic IVC, an anterior transhepatic approach (dividing the liver parenchyma first) was used. The supra- or retrohepatic IVC just below the hepatic venous confluence was clamped and resected the IVC en bloc with the tumor and liver. When IVC replacement was required, 18- to 22-mm expanded polytetrafluoroethylene (eptfe) was used. STATISTICAL ANALYSIS Statistical analyses were carried out using the SPSS program (SPSS, version 11.0J, Tokyo, Japan). Disease-free, overall survival and recurrence hazards curve were generated using the Kaplan Meier method. RESULTS SURGICAL AND PATHOLOGICAL RESULTS Typical CT and MRI findings, en bloc resected specimen and a photomicroscopic picture of patient No. 7 are shown in Fig. 1. Combined IVC and liver resection was performed in six patients. Two patients underwent extended right hepatectomy, while four patients underwent segmentectomy (posterior segment in three patients, transverse segmentectomy in one patient). Two patients had their right kidney resected. One patient required portal vein resection and reconstruction, extrahepatic bile duct resection and hepaticojejunostomy. The IVC was resected segmentally in four patients and partially in two. Of the four patients with segmental IVC resection, the IVC was replaced using eptfe in three patients and was not reconstructed in the remaining patients. In the two patients with partial IVC resection, the IVC was closed directly. All patients underwent clinical R0 resection. Two patients who underwent combined resection of the IVC and extended right hepatectomy had post-operative complications: hyperbilirubinemia, hepatic failure, acute renal failure and lower extremities edema. The morbidity rate was two out of seven patients (29%). There was no operative or hospital death. One patient clinically diagnosed as T2 ACC was T3 pathologically. The mitotic index ranged from 2 to 30/10 high power field (HPF). The resection margins were Table 1. Patients characteristics Patient Age (yr) Sex Symptom Previous history Tumor location Elevated hormones Cushing s syndrome Clinical Tumor size (cm) T N M Staging* 1 32 F Sarcoidosis Left 17-OHCS Preclinical 9 T2 0 0 II 17-KS 2 61 M Right No 8 T4 0 0 III 3 47 F Myoma uteri Right No 18 T4 0 0 III 4 68 M Right No 16 T4 0 0 III 5 62 M Weight loss Right No 20 T4 0 0 III Lower extremities edema 6 57 F Hypertension Cortical Right 17-OHCS Preclinical 7 T4 0 Liver IV adenoma 17-KS 7 43 F Moon face Right 17-OHCS Clinical 15 T4 0 Lung IV Lower extremities edema 17-KS Liver DHEA 17-OHCS, hydroxycorticosterone; 17-KS, ketosteroid; DHEA, dehydroepiandrosterone. *We applied the staging of Lee et al. (6).

110 Surgical outcome of stage III and IV adrenocortical carcinoma Table 2. Surgery and pathology Patient Combined resection Liver resection } IVC resection/repair Morbidity Mitotic Index 10HPF Microscopic R Pathology T N Staging* 1 None None No resection None 2 0 T3 0 III 2 IVC S6, S7 Direct closure None 2 0 T4 III 3 IVC S6, S7 Direct closure None 3 0 T4 0 III 4 IVC, Kidney S6, S7 eptfe None 3 0 T3 0 III 5 IVC, Kidney Portal vein Bile duct S4a, S5, S6, S7, S8 No reconstruction Hyperbilirubinemia, Lower extremities edema, Ascites Hepaticojejunostomy leakage, Acute renal failure 8 0 T4 0 III 6 IVC S4a, S5, S6 eptfe None 2 0 T4 0 IV 7 IVC S4a, S5, S6, S7, S8 eptfe Hyperbilirubinemia, 30 0 T4 0 IV Ascites IVC, inferior vena cava; HPF, high power field; Microscopic R, Microscopic residual tumor; eptfe, expanded polytetrafluoroethylene. } Couinaud s segment; *Lee et al. microscopically clear of tumor in all patients. The pathological stage was stage III in five cases and stage IV in two (Table 2). SURVIVAL AND RECURRENCE No patients received adjuvant mitotane (o,p DDD) or radiation therapy. The median follow-up was 32 months and ranged from 11 to 58 months. The most frequent site of metastasis was the lungs, seen in four patients and liver in three patients. Loco-regional, intra-abdominal lymph node and peritoneum recurrences were also seen in one patient each. They were not resectable because of bulky local recurrence or disseminated distant metastasis. Later, brain and bone metastasis occurred. In the cumulative hazard of recurrence, four of seven patients (57.1%) recurred within 8 months (Table 3). The estimated 3-year disease-free and overall survivals for stage III was 20% and the mean disease-free survival was 21.0 + 9.0 months (95% CI: 3.3 38.7) (Fig. 2). The estimated 3-year recurrent-free survival was 14.3% and the mean disease-free survival was 18.6 + 6.7 months (95% CI: 5.4 31.8) in stage III and IV (Fig. 3). A total of five patients were treated with mitotane with or without chemotherapy after tumor recurrence. The basic chemotherapy regimen was etoposide of 140 mg/body, days 1 3 and cisplatin 140 mg/body day 1 for a 4-week interval. The dosage was reduced and the interval was prolonged depending on the toxicities and tolerability. The responses were either static disease or progressive disease. Any metastatic lesions were not resected. The estimated 3-year overall survivals for stage III was 40% and the mean overall survival for stage III was 40.4 + 5.2 months (95% CI: 30.2 50.6) (Fig. 3). The 3-year estimated overall survival for all patients was 28.6% and the mean overall survival for all patients was 32.2 + 6.9 months (95% CI: 18.6 45.9). The mean survival after recurrence was 19.0 + 3.3 months (95% CI: 12.6 25.5) and the 50% survival was 18.4 months. Table 3. Recurrence and outcome Patient Recurrence site Treatment after recurrence Time to recurrence (months) Outcome (months) 1 Lymph nodes, Liver, Peritoneum Mitoane/Taxol 8.5 Died (24.5) 2 Lung CDDP/VP16 5.6 Died (34.2) 3 No recurrence Alive (48.9) 4 Lung Mitotane 36.5 Alive (50.5) 5 Local Mitotane 6.1 Aline (9.5) 6 Lung, Liver Mitotane/CDDP/VP16 3 Died (15.9) 7 Lung, Liver, Brain, Bone Mitotane/CDDP/VP16, RT 21.7 Died (23.7)

Jpn J Clin Oncol 2007;37(2) 111 Figure 1. Abdominal CT scan and MR imaging in patient No. 7 showing a huge mass invading the liver and the inferior vena cava (A, B). A resected specimen showing an yellowish white, multinodular tumor invading the liver (C). A photomicrogram showing adrenocortical carcinoma invading the liver (D). DISCUSSION Complete tumor removal (R0 resection) offers by far the best chance for long-term survival, and thus surgery is the treatment of choice in stages I III ACC (8). The reported 5-year actuarial survival rates are 38% overall; 50% in the curative group; and 66, 58, 24 and 0% for stages I IV, respectively (4). Although ours was a small series, the study show that combined resection of the liver, kidney and IVC is feasible and achieves a 40% 3-year overall survival, and a 20% 3-year disease-free survival in stage III patients. Four of seven patients (57.1%), however, who were thought to be resected recurred within 8 months. Four of seven patients (57.1%) who were thought to be completely resected recurred within 8 months. ACCs may have two different types of tumor biology, early or late recurrence after resection. It may be determined by the biological aggressiveness of the tumor, but any specific pathologic or biologic factors have not been defined yet. Generally, Stage III tumors, tumor size, abnormal mitotic figures or mitotic index and intratumor hemorrhage are significant progonostic factors (9 11). Patients with primary tumors of at least 12 cm had a worse outcome compared with those with smaller tumors (5-year survival of 22% versus 53%) (10). As for mitosis, patients with abnormal mitotic figures of more than six per HPF had poor prognostics compared with zero to six (5-year survival of 13% versus 51%) (10), and finally, patients with more than 20 per 50 HPF had negative survival compared with 20 of fewer mitoses (median survival time 14 versus 58 months) (9). Hemorrhage into the tumor was also a negative prognostic factor when compared with lesions without intratumoral hemorrhage (5-year survival of 22% versus 53%) (10). Furthermore, Stojadinovic et al. demonstrated that significant histologic predictors for recurrences were venous, capsular and adjacent organ invasion; tumor necrosis, mitotic rate, atypical mitosis and mdm-2 overexpression, and with more than four of these adverse histologic parameters the survival was the poorest (11). It is also reported that molecular phenotypic expression of Ki-67(2)p53(2)mdm-2(þ) cyclind1(2)bcl-2(2)p21(2)p27(þ) was more heterogeneous in malignant ACC. These histopathologic factors and molecular markers should predict high-risk for

112 Surgical outcome of stage III and IV adrenocortical carcinoma Figure 2. The estimated disease-free and overall survival for stage III ACC patients. recurrence or prognosis. In our series, however, any of these factors, namely tumor size, the mitotic index and hemorrhage into the tumor, were not conclusively discriminant. We need to consider adjuvant therapy after surgical resection for cure, as the majority of ACC patients develop local recurrence or metastatic disease. The most frequent sites of metastasis were the lungs and liver, as reported (4,8). The effects of adjuvant therapy with mitotane alone have not been determined (4). In contrast, the survival of stage III ACC patients who underwent postoperative radiotherapy in a small series was higher than expected from historic series (12). Adjuvant treatment options, such as mitotane with or without chemotherapy or adjuvant radiotherapy of the tumor bed, need to be evaluated in such high-risk patients. One of the key issues to prolong in survival of patients with recurrence or metastasis is the efficacy of repeat resection of local recurrence and distant metastasis (13 15). Patients who had a complete second resection had far better survival (median survival;74 months, 5-year survival, 57%) compared with the patients who had incomplete second resection (a median survival; 16 months, 5-year survival; 0%). In this series, the mean survival of patients having Figure 3. The estimated recurrence-free and overall survival for stage III and IV ACC patients. recurrence with unresectable primary lesions was 19.0 months, similar to those patients who underwent incomplete resections. A total of 83 repeated resections from second to seventh was performed for pulmonary lesions (55%), liver lesions (28%), or bone lesions (11%) with the 30-day mortality rate of 3.6%. Sixty-two of these repeat resections were complete and patients who undergo complete repeat resection of local recurrence or distant metastasis also have improved survival. It is clear that patients with recurrent or metastatic disease should undergo re-operation if they have potentially resectable disease and can withstand an operation. Fujii et al. reported a 5 year recurrence-free survival case of repeatedly recurrent refractory ACC by combined chemotherapy with cisplatin (carboplatin) and etoposide, and radiation therapy followed by surgical resection (16). Furthermore, Berruti et al. recently reported that surgical resection of residual disease subsequent to etoposide, doxorubicin and cisplatin (EDP) plus mitotane chemotherapy for patients who were not amenable to radical surgery lead to a more favorable outcome. EDP plus mitotane will be an active and manageable combination scheme for ACC patients with metastasis and recurrence after radical resection (17). Thus, multimodal treatments with chemotherapy and radiation therapy for recurrent ACC followed surgery is a promising option. The role of tumor debulking in metastatic ACCs is controversial. Allolio et al. reported that stage IV ACC is not amenable to surgery and that mitotane remains the first-line therapy (8). Conversely, Icard et al. reported that mitotane should be administered to stage IV patients after debulking surgery because its use significantly prolongs survival (4). The reported median survival of stage IV ACC is less than 12 months (6,15). Our two patients who underwent resection of the primary tumor and liver metastases survived 16 and 25 months and mitotane was administered after recurrence. We believe that local R0 resection and resection of metastases could prolong survival. Furthermore, tumor debulking may help to control hormone excess and facilitate other therapeutic options in individual cases. However, Berruti et al. reported that a prospective, multicenter phase II study of EDP plus mitotane for 72 ACC patients who were not amenable to radical surgery showed an overall response rate of 48.6% with five complete responses and 30 partial responses (17). In addition, radical surgical resection of residual disease after chemotherapy was performed in 10 patientsandleadtoamorefavorableoutcome(17).edp plus mitotane is an active and manageable combination scheme for ACC patients with metastasis and recurrence after radical resection and may be a standard regimen for metastatic and advanced ACC. Further, surgical resection of residual disease subsequent to chemotherapy leads to a more favorable outcome and will be an option for stage IV ACC. Despite the current grim outlook, active and manageable combination schemes for ACC patients have been developed. The recent applications of emerging technology to the study of ACC and the development of newer, targeted therapies

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