Recurrent adrenocortical carcinoma after laparoscopic resection
Angelika Schlamp*, Klaus Hallfeldt, Ullrich Mueller-Lisse, Thomas Pfluger and Martin Reincke
SUMMARY
Background A 53-year-old man presented with left-sided flank pains to the Gastroenterology department of our clinic in September 2004. A left adrenal mass of 6.5 cm by 7.5 cm was detected by a CT scan. The patient showed no evidence of Cushing’s syndrome, and had normal blood pressure and potassium levels. Endocrine tests ruled out excess levels of aldosterone or catecholamines. The patient underwent laparoscopic surgery to remove the tumor mass; histologic work-up revealed an adrenocortical carcinoma. A fluorodeoxyglucose (FDG)-PET scan 1 month, and a CT scan 8 months postoperatively showed no pathologic findings. The patient, however, again presented with left-sided flank pain to our Endocrinology department in August 2005.
Investigations In our department, laboratory work-up for endocrine activity was performed, as well as CT scans of the adrenal region, and FDG-PET scans in order to determine the extension of disease. Histologic work-up of the removed tumor tissue was performed.
Diagnosis Recurrent adrenocortical carcinoma after laparoscopic adrenalectomy.
Management In our department, 10 months after initial laparoscopic surgery, local tumor recurrence was treated by repeated extensive surgery, tumor-bed radiation therapy, and mitotane treatment. A year later, a large lymph-node metastasis was surgically removed from the lower abdomen and mitotane treatment was again started postoperatively. The patient is now scheduled for polychemotherapy because of progressive metastatic disease revealed by follow-up CT and FDG-PET scanning in June 2006.
KEYWORDS adrenocortical carcinoma, FIRM-ACT study, laparoscopic adrenalectomy, mitotane, recurrence
CME
A Schlamp is a Medical Resident in and M Reincke is a Director of Medizinische Klinik Innenstadt, K Hallfeldt is a Professor for Endocrine and Visceral Surgery at Chirurgische Klinik Innenstadt, University Hospital, Munich. U Mueller-Lisse is an Associate Professor of Radiology, an Attending Radiologist, and the Section Chief of Body Imaging in the Department of Clinical Radiology, T Pfluger is an Associate Professor and Consultant in Nuclear Medicine and Radiology in the Department of Nuclear Medicine, University of Munich, Munich, Germany.
Correspondence
*Department of Endocrinology, Medizinische Klinik Innenstadt, University of Munich, Ziemssenstrasse 1, 80336 Munich, Germany
angelika.schlamp@med.uni-muenchen.de
Received 17 July 2006 Accepted 21 September 2006 www.nature.com/clinicalpractice doi:10.1038/ncpendmet0391
This article offers the opportunity to earn one Category 1 credit toward the AMA Physician’s Recognition Award.
THE CASE
A 53-year-old man presented with left-sided flank pains to the Gastroenterology department of our clinic in September 2004. The patient had no relevant medical history and was not taking any medication before admission. During evalua- tion of the abdominal pain, a left adrenal mass that measured 6.5 cm by 7.5 cm was detected by a CT scan. The tumor had regular margins, but showed nonhomogeneous contrast enhancement with a density of 40 HU (Hounsfield Units, a unit of radiodensity) in plain scans. The most likely diagnosis was pheochromocytoma or an adreno- cortical, possibly malignant, tumor (Figure 1A). The patient showed no evidence of Cushing’s syndrome, and had normal blood pressure and potassium levels. Endocrine tests ruled out excess levels of aldosterone or catecholamine.
A laparoscopic approach was chosen to remove the mass because of the presence of an organ- defined lesion without evidence of infiltrative growth; intraoperatively, there were no features suggestive of malignancy, and there were no technical problems in removal of the tumor. Histologic work-up revealed an adrenocortical carcinoma (ACC, classified as T2NxMx, i.e. a tumor >5 cm in size with no confirmed lymph node or distant metastases). Resection was clas- sified as R0 (complete removal of tumor tissue) and no adjuvant therapy was administered to the patient. Both a fluorodeoxyglucose (FDG)- PET scan 1 month, and a CT scan 8 months postoperatively showed no pathologic findings.
In August 2005, the patient presented again with abdominal pain to our Endocrinology clinic. CT and FDG-PET scan (Figure 1B and 1C) showed local recurrence of a tumor that measured 5.5 cm by 3.7 cm in the left adrenal region, which had infiltrated adjacent organs. There was no evidence of metastatic disease. Despite extensive surgery, which included tumor
A
0
0
B
4
C
| Table 1 WHO classification of adrenocortical carcinoma. 19 | |
|---|---|
| WHO stage | Tumor-node-metastasis classification |
| Stage I | T1N0M0 |
| Stage II | T2N0M0 |
| Stage III | T1or T2N1M0 |
| T3N0M0 | |
| Stage IV | T3N1M0 |
| T4N0M0 | |
| T4N1M0 | |
| TxNxM1 | |
Permission obtained from Tumorzentrum München and W Zuckschwerdt Verlag München @ (2006) Manual of the Tumor Center Munich for Endocrine Tumors. Abbreviations: M0, no distant metastases; M1, distant metastases; N0, no lymph node metastases; N1, regional lymph node metastases; T1, tumor <5 cm; T2, tumor >5 cm; T3, tumor outside adrenal fat; T4, tumor that invades adjacent organs.
resection, left nephrectomy, splenectomy, partial resection of colon sigmoideum, diaphragm, and pancreas, the resection was incomplete (R1, i.e. presence of tumor cells in the resection margin), and the tumor was classified as T4N1M0 (i.e. the tumor had invaded adjacent organs, and regional lymph node metastases, but no distant meta- stases were present. The tumor was classified as WHO stage IV, Table 1). The patient received external tumor-bed radiation (single doses of 1.8 Gy five times a week, reaching a total dose of 50.4 Gy after 6 weeks), and adrenolytic treat- ment with high-dose mitotane (1.5 g on day 1; 3.0 g on day 2; 4.5g on day 3; 6.0 g daily from day 4 onwards). The patient developed significant gastrointestinal and neurologic adverse effects, probably related to both radiation treatment and mitotane therapy. Treatment was, therefore, discontinued after 2 weeks and before target serum levels of mitotane could be reached.
In January 2006, follow-up CT and FDG- PET scans (Figure 2A and 2B) showed three suspicious intra-abdominal lymph nodes that had not been detected on previous scans. The largest lymph-node metastasis in the left lower abdomen was surgically removed. Mitotane treatment was restarted at a low initial dose of 0.5 g twice daily that slowly escalated to 4.0 g per day, which was well tolerated by the patient; target serum levels of 15 µg/ml of mitotane were reached within 8 weeks.
A follow-up CT and FDG-PET scan (Figure 2C and 2D) in June 2006 showed further progres- sion of the remaining lymph nodes. The patient is scheduled to receive polychemotherapy.
DISCUSSION OF DIAGNOSIS
ACC are rare, highly malignant tumors with a poor prognosis. With a yearly incidence of two new cases per million individuals worldwide, ACC are responsible for 0.2% of all carcinoma- related deaths.1 The age of ACC presentation has a bimodal distribution, with a peak in children less than 10 years old and a second major peak in the fifth decade. There is no difference in the lateral distribution of ACCs and bilateral ACC are found in 2-10% of all cases.2
About 45-62% of adult patients with ACC show abnormal endocrine activity. Signs of Cushing’s syndrome or a mixture of virilization and Cushing’s syndrome are present in 30-40% of adult ACC patients, 20-30% show signs of virilization alone and few show signs of femini- zation or hyperaldosteronism.2 Nonfunctioning ACC might be diagnosed during evaluation for abdominal pain or by incidental detection of an adrenal mass. Surgical data suggest that about 5.0% of incidentally detected adrenal masses are carcinomas and about 2.5% are meta- stases.3 The probability of malignancy increases with tumor size; surgical studies have shown a probability of malignancy of 2% for tumors <4 cm in size, 6% for tumors 4-6 cm, 13% for tumors 6-8 cm, 21% for tumors 8-10 cm and 55% for tumors >10 cm.4 ACC is staged by the tumor-node-metastasis system (Table 1).
A preoperative endocrinological evalua- tion for possible hormonal excess should be performed even if the patient does not show clinical signs of abnormal endocrine activity (Table 2).5 Not only can elevated hormone levels be used as tumor markers, but the detection of subclinically abnormal endocrine activity is also important.
An early diagnosis clearly improves prognosis. Overall 5-year survival in patients with ACC was 37% in one study, with a median survival of 38 months.6 If a patient is diagnosed with ACC of WHO stage I or II, a study has shown median survival to be 101 months (5-year survival of 60%) and at WHO stage III or IV median survival was 15 months (5-year survival of 10%). Following an R0 resection, median survival was 74 months (5-year survival of 55%), but only 12 months with incomplete resection (5- year survival of 5%).6 Recurrent or metastatic disease is common and affects about two-thirds of patients within 2 years of an R0 resection, and about 85% of patients after 2 years of an R0 resection.3
A
B
C
D
0
| Table 2 Endocrinological laboratory evaluations to rule out hormonal excess caused by an adrenal tumor. | ||
|---|---|---|
| Hormonal excess | Associated disorder | Laboratory evaluations |
| Cortisol | Cushing's syndrome | 24 h urine collection to measure levels of cortisol Measurement of cortisol after application of 2 mg of dexamethasone |
| Aldosterone | Hyperaldosteronism | Aldosterone:renin ratio |
| Sexual hormones | Adrenogenital syndrome, virilization, feminization | Measurement of 17-OH- progesterone and DHEAS levels In women: |
| Measurement of androstendione and free testosterone levels In men: | ||
| Measurement of 17ß-estradiol levels | ||
| Catecholamines | Pheochromocytoma | 24 h urine collection to measure catecholamine metabolites. Plasma metanephrines (if assay available) |
| Permission obtained from Tumorzentrum München and W Zuckschwerdt Verlag München C (2006) Manual of the Tumor Center Munich for Endocrine Tumors. Abbreviation: DHEAS, dehydroepiandrosterone sulfate. | ||
Imaging has a major role in diagnosis and differentiation of benign and malignant adrenal lesions. Criteria for malignancy of the tumor
include irregular shape and margins, hetero- geneity, strong contrast enhancement and necrotic areas. Unenhanced density values of >10 HU are characteristic of adenomas with a high lipid content, and this threshold has a sensitivity of 71% and a specificity of 98% in diagnosing such lesions.7 Adrenal lesions with a density of >10 HU in an unenhanced CT scan or an enhancement washout of <50% and a delayed attenuation of >35 HU are suspicious for malig- nancy,7 as was seen in the patient described. MRI scans can give additional information, as ACC tissue presents as hypointense areas in T1-weighted scans, and hyperintense areas in T2-weighted scans, in comparison with the liver. Chemical-shift technology (comparison of in-phase and opposed-phase T1-weighted images, which shows a lack of fat suppression in the opposed phase) has a sensitivity of 81% and a specificity of 95% for differentiating between benign and malignant adrenal lesions.8
According to early studies, high glucose uptake on FDG-PET scans suggests malignancy; in addition, these scans could be helpful to detect metastases. Primary staging should include a CT scan, a FDG-PET scan and a bone scan.
TREATMENT AND MANAGEMENT Open or laparoscopic surgery?
Surgical resection of tumor tissue is the only curative treatment option. For patients with ACC of WHO stage I-III without metastatic disease, surgery is almost always indicated. Surgery should be carried out en bloc with radical lymphadenectomy and resection of the involved adjacent organs, if required. If the patient has WHO stage IV ACC, tumor debulking might prove beneficial, but a significant influence on survival has not been shown.2
Laparoscopic surgery has become the proce- dure of choice for benign adrenal tumors that require surgery, and the removal of large adrenal tumors (>6 cm) is technically feasible. The contro- versial role of laparoscopic surgery in the manage- ment of malignant adrenal tumors is a matter of debate. Laparoscopic surgery arguably provides similar long-term survival and recurrence rates to open surgery in carefully chosen patients with small, organ-defined primary ACC or solitary adrenal metastases.9,10 Laparoscopic adrenalec- tomy, however, should be converted to open adrenalectomy, or hand-assisted laparoscopic adrenalectomy in cases of difficult dissection, invasion or adhesion.
Several studies have suggested that laparoscopic surgery might increase the risk of local recur- rence of ACC.11,12 On the other hand, long-term remissions after laparascopic surgery have also been reported.10 Patients with recurrent or meta- static disease (as in the case we describe) should undergo repeat surgery, if the tumor is poten- tially resectable, because surgery in this situation significantly prolongs median survival.6,13
External tumor-bed radiation
Tumor-bed radiation after surgery is contro- versial and is not a standard procedure. In patients who have undergone tumor-bed radia- tion after surgery, especially those with metastatic disease or in those who lacked an R0 resection, a benefit in control of local tumor recurrence and an improved prognosis has been reported.5,14 Radiation therapy should be performed in specialized centers, with a total dose of 40-50 Gy over 4-6 weeks. In the patient described, local tumor recurrence was successfully inhibited by tumor-bed radiation.
Drug therapy with mitotane
Mitotane therapy inhibits steroid synthesis by inhibiting the action of ß-hydroxylase and by destroying adrenocortical cells via mito- chondrial toxicity. The dose should be slowly increased from 0.5g three times per day to around 6.0 g per day, with a maximum daily dose of 6.0-12.0 g. Serum levels of mitotane must be monitored and target levels are 14-20 µg/ml. High doses of mitotane might lead to significant adverse reactions such as gastrointestinal problems (>80% of patients), neuropsychiatric reactions (>25% of patients) and exanthema (>10% of patients). High dosages might be tolerated initially but can eventually lead to adverse reactions because mito- tane is a lipophilic molecule with a long half-life. The obligatory adrenal insufficiency caused by surgery must be adequately substituted with hydro- cortisone; additional fludrocortisone might also be necessary with high doses of mitotane. Generally, patients with ACC have to be given higher doses of hydrocortisone than patients with adrenal insufficiency require, because of their increased glucocorticoid metabolism.
Mitotane should be started in patients with metastatic disease or a lack of surgical options, whether the tumor is functioning or not. Adjuvant therapy after tumor surgery is a controversial treatment. Mitotane therapy might be considered in all patients with ACC
because of the high risk of local recurrence or metastatic disease even after an R0 resection, but randomized trials are necessary to address this issue. In patients taking mitotane, a complete, long-lasting remission can be seen in a few cases, and at least temporary tumor regression in 15- 60% of patients. Patients with slow-growing, functional tumors respond best to treatment with mitotane. 15
Systemic polychemotherapy
Several chemotherapy regimens that use different substances and combinations are possible, but only very few studies have investigated chemo- therapy regimens in a high number of patients. A combination of doxorubicin, cisplatin, etoposide, and mitotane induced at least a partial response in 54% of patients with ACC and metastatic disease, but also showed significant toxicity.16 A combination of streptozocin with mitotane was less toxic than a combination of doxorubicin, cisplatin, etoposide, and mitotane, and led to at least a partial response in 36% of patients.17 Patients with metastatic or recurrent ACC who receive polychemotherapy should be treated in specialized centers.
An ongoing, multicenter study-the First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment18 (FIRM-ACT; www. firm-act.org)-will compare etoposide, doxo- rubicin, cisplatin, and mitotane versus strepto- zocin and mitotane in patients with metastatic disease or locally progressive ACC.
CONCLUSIONS
This case illustrates the importance of a correct diagnosis of ACC. Surgery as the only avail- able curative option should comprise complete tumor removal and lymphadenectomy in order to obtain an R0 resection. If there is evidence (or a high probability) of malignancy, surgery should not be carried out laparoscopically. Open surgery is currently the standard treatment and should be performed in cases of suspicious adrenal lesions.
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Competing interests
The authors declared they have no competing interests.