Original Article: Clinical Investigation
Adrenocortical carcinoma: Retrospective study of 14 patients experienced at a single institution over 34 years
Sachiyo Nishida,1 Naoki Itoh,1 Takumi Sasao,1 Naoya Masumori,1 Keisuke Taguchi2 and Taiji Tsukamoto1
“Department of Urology, Sapporo Medical University School of Medicine, and 2Department of Urology, Oji General Hospital, Sapporo, Japan
Objective: To review clinical outcome of patients with adrenocortical carcinoma experienced at a single institute over 34 years. Methods: The study included 14 patients who were diagnosed as having the disease and were treated at the Department of Urology, Sapporo Medical University Hospital between 1973 and 2006. Their clinical features and outcomes were reviewed.
Results: Of the 14 patients, there were nine men and five women. The median follow-up period was 13.0 months (range, 1-213). Two patients were classified as having stage II disease, seven as stage III and five as stage IV. The disease was completely removed in eight patients and incompletely in three. Two other patients received exploratory laparotomy only. The remaining one patient had no indication for surgery. The median survival periods were 2 months in patients with stage IV and 108 months in those with stages II and III (P = 0.136). Mitotane treatment in the adjuvant setting did not clearly affect the clinical courses of patients without metastasis. However, the treatment was effective for metastasis that was repeatedly developed as late recurrence in one patient. Three patients with metastasis at diagnosis received combination chemotherapy with etoposide, doxorubicin and cisplatin (EDP) with or without mitotane treatment, to which lung metastasis completely responded in one patient.
Conclusions: Adrenocortical carcinoma is a rare disease but frequently recurs. The best chance of survival may be achieved by early detection and complete surgical removal. There may be patients who possibly benefit from mitotane treatment with or without EDP, although this remains to be conclusively determined.
Key words: adrenocortical carcinoma, clinical features, treatment outcomes.
Introduction
Adrenocortical carcinoma is a rare malignant disease with poor prog- nosis. The low incidence of the disease makes it difficult to establish a standard treatment of the disease. Indeed, there have only been spo- radic case reports and clinical studies including small numbers of patients, although some multi-institutional studies have recently been reported.1-3 Thus, the accumulation of clinical experience of even a small number of patients with the disease is still needed to provide better care for them. We retrospectively reviewed clinical findings and outcomes of 14 patients with adrenocortical carcinoma treated at Sapporo Medical University Hospital from 1973 to 2006.
Methods
Between 1973 and 2006, 14 patients were diagnosed as having adreno- cortical carcinoma and were managed in the Department of Urology, Sapporo Medical University Hospital. We reviewed their clinical fea- tures and outcomes. Survival rates were determined by the Kaplan- Meier method and the log-rank test was used to analyze the differences between the groups.
The disease was classified into the endocrinologically functioning type when it was associated with clinically manifested endocrine fea- tures and elevated adrenal hormone levels. The stage of the disease was determined according to a previous study4 as: (I) tumor smaller than
Correspondence: Naoki Itoh MD, Department of Urology, Sapporo Medical University School of Medicine, Minami-1, Nishi-16, Chuo-Ku, Sapporo 060- 8543, Japan. Email: nitoh@sapmed.ac.jp
Received 4 February 2007; accepted 19 February 2007.
5 cm in diameter without evidence of regional nodal involvement, and local invasion or metastasis; (II) tumor of 5 cm or larger without the evidence of those as described for stage I; (III) tumor associated with evidence of regional nodal involvement or local invasion but not distant metastasis; and (IV) tumor with distant metastasis.
Results
Age, sex and clinical presentation
Tables 1 and 2 summarize the clinical characteristics of the 14 patients. Patients 11 and 12 have already been reported by us.5,6 Nine of the 14 patients were men and five were women, and the median age at pre- sentation was 46 years. Endocrinologically functioning carcinoma was found in eight patients, five of whom had associated Cushing’s syn- drome. Flank pain or high fever was the chief complaint in patients with non-functioning carcinoma. The median follow-up period was 13.0 months (range, 1-213).
Staging
Most patients had advanced stage carcinoma with seven (50.0%) in stage III and five (35.7%) in stage IV. Tumor sizes ranged 4-18 cm with a mean diameter of 11 cm. Metastasis to the lung alone was found in three patients, lung and liver in one, and liver and retroperitoneal lymph nodes in one at diagnosis.
Surgical treatment
Adrenalectomy was attempted in 13 patients (Table 2). The other patient (patient 10) had no indication for surgery because of poor
| Patient no. | Age (sex) | Chief complaints | Hormonal activity+ | Tumor size (cm) | Stage (metastatic sites) |
|---|---|---|---|---|---|
| 1 | 19 (F) | Hypertension | Yes± | 7 | II |
| 2 | 42 (M) | Gynecomastia | Yes§ | 9 | II |
| 3 | 59 (M) | Moon face and edema | Yes | 8 | III |
| 4 | 55 (F) | Hypertension | Yes#, 1 | 4 | III |
| 5 | 68 (M) | Gynecomastia | Yes§ | 8 | III |
| 6 | 52 (M) | Fever | No | 10 | III |
| 7 | 58 (F) | Fever | No | 16 | III |
| 8 | 46 (M) | Flank pain | No | 8 | III |
| 9 | 58 (F) | Not available | No | 7 | III |
| 10 | 40 (F) | Polymyositis | Yes#,tt | 13 | IV (lung/liver) |
| 11 | 19 (M) | Gynecomastia | Yes+,§ | 18 | IV (lung) |
| 12 | 5 (M) | Abdominal mass | Yestt | 16 | IV (liver/LN##) |
| 13 | 31 (M) | Flank pain | No | 14 | IV (lung) |
| 14 | 62 (M) | Flank pain | No | 12 | IV (lung) |
+Endocrinologically functioning carcinoma; Cushing syndrome; §feminization; [hyperaldosteronism; ttvirilization; lymph nodes.
| Table 2 Treatments and clinical courses of 14 patients with adrenocortical carcinoma | ||||||
|---|---|---|---|---|---|---|
| Patient no. | Resection (adrenalectomy+) | Nxǂ | Adjuvant mitotane | Recurrence or metastasis developed (time)§ | Tx for recurrence or metastasis | Outcomes (months) |
| 1 | Complete | No | No | Lung/liver/LN/local (88) | Mitotane | AWD (205) |
| 2 | Complete | Yes | No | No | – | NED (6) |
| 3 | Incomplete | No | No | Lung/liver/LN (6) | Mitotane | DOD (9) |
| 4 | Incomplete | No | Yes | Lung/liver (7) | Mitotane + EDPtt | DOD (26) |
| 5 | Complete | Yes | Yes | Lung/liver/local (2) | Mitotane + EDP | DOD (3) |
| 6 | Exploratory | No | No | No | – | DOD (1) |
| laparotomy## | ||||||
| 7 | Complete | Yes | No | Contralateral adrenal (80) | Mitotane + surgical resection | Died of other disease (213)§§ |
| 8 | Incomplete | Yes | Yes | No | – | NED (63) |
| 9 | Complete | No | Yes | Thoracic vertebrae, thoracic wall (83) | Mitotane + radiation | DOD (108) |
| 10 | Not done | No | – | – | Mitotane | DOD (1) |
| 11 | Complete | No | – | – | Mitotane | DOD (13) |
| 12 | Complete | No | – | – | Mitotane | DOD (2) |
| 13 | Complete | Yes | – | – | Mitotane + EDP | NED (26) |
| 14 | Exploratory laparotomy | No | – | – | – | DOD (2) |
+Complete resection (adrenalectomy) of carcinoma; simultaneous ipsilateral nephrectomy; §time (months) from surgery to development of recurrence or metastasis; [treatments for recurrence or metastasis at diagnosis or those that developed during follow up; ttcombination chemotherapy consisting of etoposide, doxorubicin and cisplatin; exploratory laparatomy alone; §§died of brain infarction without any evidence of the disease. AWD, alive with the disease; DOD, died of the disease; local, local recurrence; NED, no evidence of the disease.
general condition. Adrenocortical carcinoma was completely resected in eight patients. However, the surgery for three patients (3, 4 and 8) resulted in incomplete resection with a positive surgical margin. In the remaining two patients, extensive invasion of the disease to the sur- rounding tissue (patient 14) and sudden loss of a large amount of blood during operation (patient 6) allowed only exploratory laparotomy. Thrombectomy of the vena cava with extracorporeal circulation was done in two patients (5 and 13). Simultaneous ipsilateral nephrectomy with adrenalectomy was done in five of the 11 patients, depending on
findings in surgery. Nephrectomy identified perinephric fat invasion by carcinoma in three patients (5, 7 and 8).
Treatments post-surgery and those for metastasis and recurrence
Four patients (4, 5, 8 and 9) who had no metastasis at the first presentation received adjuvant therapy with mitotane (1,1-[o,p- dichlorodiphenyl]-2,2-dichlorethane, o,p’-DDD). Patient 7, who
developed recurrence of the disease in the contralateral adrenal 80 months after the initial surgery, received mitotane treatment in the adjuvant setting after resection of the recurrent disease. The dose and treatment schedule for mitotane differed among patients, depending on their characteristics and adverse effects. The median daily dose of mitotane was 3 g with a range of 0.5-12.0 g, which continued for 1-25 months with a median of 11. Although different clinical back- grounds made it difficult to evaluate the efficacy of adjuvant mitotane treatment, three of four patients developed distant metastasis 7, 2 and 83 months after surgery, respectively. The remaining patient with clini- cal stage III (patient 8) showed no evidence of disease for 63 months. Patient 7 was free of the disease for more than 200 months before she died of brain infarction.
Mitotane treatment was tried for eight patients (1, 3, 7, 9, 10, 11, 12 and 13) who had distant metastasis at the first presentation or developed it during the follow-up period. Of these, three patients (7, 9 and 13) received simultaneous treatment with surgical resection, radiation or combination chemotherapy with etoposide, doxorubicin and cisplatin (EDP). Five patients (1, 3, 10, 11 and 12) with metastasis were treated with mitotane alone. Of these, four did not have a favorable response. However, for patient 1, who developed local recurrence and multiple lung metastasis 7 years after surgery, 7.5 g/day mitotane was effective, resulting in a complete response of local recurrent disease and a 95% reduction of lung metastasis on computed tomography. Due to the development of adverse central nerve system events, the patient could not tolerate mitotane treatment for longer than 37 months. Although no progression of the disease was detected subsequently for more than 4 years, she again developed distant metastasis in the liver 14 years after surgery. However, the metastasis partially responded again to mitotane treatment. She continued to have liver metastasis but was free of its progression.
Etoposide, doxorubicin and cisplatin chemotherapy was tried for three patients (4, 5 and 13). The chemotherapy was not effective at all for two patients (4 and 5), who were in stage III at the time of surgery and developed distant metastasis soon after. The other patient (13) with stage IV was treated with the chemotherapy and mitotane, which induced complete remission of multiple lung metastases. He had no evidence of the disease 26 months after operation.
Outcome
The overall 5-year survival rate was 40.2% in all patients (Fig. 1). The mean 50% survival time of all patients was 13 months. Although some patients with stages II and III achieved a long survival period with a mean 50% survival time of 108 months, for those with stage IV it was only 2 months (Fig. 2). Probably because of the small number of patients, there was no significant difference in the overall survival between the two groups (P= 0.163 by the log-rank test).
Discussion
Adrenocortical carcinoma is rare and still has poor prognosis with frequent recurrence. The overall 5-year survival rates have been reported to be 15-47%, depending on clinical backgrounds of patients in the studies.1,7 Stage is a strong influential factor on the survival in most studies. When the disease was locally confined, the rate ranged 30-50%. However, patients with metastasis have a dismal prognosis with almost no survivors at 5 years. In the current study, patients with stage II and III had a 40% 5-year survival rate. For those with metasta- sis at the time of diagnosis, however, even the 2-year-survival was only 20%.
1.0
Overall survival
.8
.6
.4
.2
0
0
50
100
150
200
Months after surgery
1.0
Overall survival
.8
Stage II - III (n = 9)
.6
4
.2
1
Stage IV (n = 5)
0
0
50
100
150
200
Months after surgery
The mainstay of treatment for adrenocortical carcinoma is surgery and complete resection of the disease is prerequisite for a better out- come.3,8 Indeed, the 5-year survival rates ranged from 36-58% when carcinoma was completely resected.8 However, incomplete resection only achieved survival of less than 12 months after surgery in most studies. Thus, resection status may be one of the strong determinants for survival. In this context, simultaneous ipsilateral nephrectomy may provide complete resection of the disease for some patients who have micro-invasion into the kidney that is not preoperatively detected. This was found in our study, in which three of the five patients with nephre- ctomy were long-term survivors.
Although there is no consensus on the role of adjuvant treatment with mitotane for patients with complete resection of the primary lesion, most recent studies did not support the benefit of the treatment.9 Of our four patients with adjuvant mitotane treatment, three did not benefit at all from the treatment. Thus, our experience may not support the use of mitotane treatment in the adjuvant setting.
In the adjuvant setting, the efficacy of treatment with mitotane for metastatic disease has been disputed.8 Alloio and Fassnacht9 reviewed previous studies and concluded that 25% of patients with metastasis responded partially or completely to mitotane treatment, although the rate for complete response was less than 5%. Nevertheless, the French Association of Endocrine Surges Study Group3 showed that stage IV
patients achieved significantly favorable outcome with the use of mito- tane treatment. Although it is likely that mitotane treatment will rarely achieve a complete response in patients with metastatic disease, the treatment may be worth trying for them. This is partly because there are no alternative treatments effective for patients with metastasis of the disease at this time. In addition, there may be some patients who respond favorably to the treatment, and thus have a better clinical course, as it was found in our study that one patient achieved a clearly favorable response to mitotane treatment when she developed recur- rence. The efficacy of treatment should be evaluated by the contempo- rary criteria.8
It is interesting that our study found one long-term survivor (patient 7), even though she had recurrence of the disease in the con- tralateral adrenal gland. Vassilopoulou-Sellin and Schultz2 suggested that there are patients who have a slowly growing carcinoma and thus a comparatively favorable clinical course, although they were not able to identify factors including pathological features of carcinoma respon- sible for this result. She might be one such patient.
Finally, all chemotherapeutic regimens for adrenocortical carcinoma are under investigation. We used EDP chemotherapy for three patients. One patient completely responded to the chemotherapy with mitotane treatment, although the other two did not show any favorable response. Further studies are needed to establish a chemotherapy regimen effec- tive for the disease.
In conclusion, our retrospective study indicates that survival may be best achieved by early detection and complete surgical treatment, as has often been the case with previous studies. Mitotane treatment in the adjuvant setting was not beneficial for patients without distant metasta-
sis. There may be patient who possibly benefit from the treatment with or without EDP chemotherapy, although this remains to be determined.
References
1 Ng L, Libertino JM. Adrenocortical carcinoma: diagnosis, evaluation and treatment. J. Urol. 2003; 169: 5-11.
2 Vassilopoulou-Sellin R, Schultz PN. Adrenocortical carcinoma. Clinical outcome at the end of the 20th century. Cancer 2001; 92: 1113-21.
3 Icard P, Goudet P, Charpenay C et al. Adrenocortical carcinomas: surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons Study Group. World J. Surg. 2001; 25: 891-7.
4 Norton JA. Adrenal tumors. In: Devita J, MD (ed.). Cancer: Principles and Practice of Oncology. Lippincott Williams & Wilkins, Philadelphia, 2005; 1528-35.
5 Kimura M, Itoh N, Tsukamoto T, Kumamoto Y, Takagi Y, Mori Y. Aromatase activity in an estrogen-producing adrenocortical carcinoma in a young man. J. Urol. 1995; 153: 1039-40.
6 Tsukamoto T, Kumamoto Y, Takahashi A et al. Adrenocortical carcinoma in a child with specific pedigree of family associated with cancer aggregation. J. Urol. 1992; 147: 104-6.
7 Wajchenberg BL, Albergaria Pereira MA, Medonca BB et al. Adrenocortical carcinoma: clinical and laboratory observations. Cancer 2000; 88: 711-36.
8 Dackiw APB, Lee JE, Gagel RF, Evans DB. Adrenal cortical carcinoma. World J. Surg. 2001; 25: 914-26.
9 Allolio B, Fassnacht M. Clinical review: adrenocortical carcinoma: clinical update. J. Clin. Endocrinol. Metab. 2006; 91: 2027-37.