A Rare But Challenging Disease

by David E. Schteingart M.D.
Summer, 2004
University of Michigan

Adrenal cancer is a rare adrenal tumor that accounts for only 0.2% of deaths due to cancer. The incidence has been estimated at 2 per million people per year. However, it tends to be highly malignant and difficult to treat. Approximately 50% of these tumors are functioning and produce hormonal and metabolic syndromes leading to their discovery. The other 50% are silent and discovered only when they are so large that they produce localized abdominal symptoms or when they metastasize. Occasional children have been found to have adrenal cancer but most cases occur between ages 30 and 50 (1). An exception to this age distribution occurs in southern Brazil, where the annual incidence of adrenal cancer in children is unusually high, ranging from 3.4-4.2 per million children, compared with a worldwide incidence of 0.3 per million children younger than 15 (2). The cause of adrenal cancer is unknown but studies in the past five years suggest genetic mutations in the adrenal gland leading to the initiation of a malignant tumor (3). Adrenal cancer occasionally develops in families with susceptibility for other types of cancer. Environmental factors have been implicated in southern Brazil because the distribution of the tumors follows a regional rather than familial pattern.

Diagnosis

The early diagnosis of a functioning adrenal cancer is based on the patient’s and physician’s ability to recognize clinical manifestations of excessive cortisol, aldosterone, male or female hormone levels. Computerized tomography or magnetic resonance imaging helps to localize the tumor and determine the presence or absence of local or distant metastases. Cushing’s syndrome is the most common clinical presentation in the adult patient (4). In contrast to benign causes of Cushing’s, patients describe rapid development (3-6 months) of weight gain, muscle weakness, easy bruising, irritability and insomnia. In addition, there commonly are manifestations of male hormone excess, including excessive body hair growth, acne and irregular menstrual periods in women. Patients with metastatic disease may have loss of appetite and weight loss rather than weight gain. Malignant adrenal tumors are usually large, but the clinical manifestations of hormone excess lead to earlier diagnosis and the finding of smaller tumors and earlier treatment. Sex hormone producing cancer leads to virilization in women and feminization in men. Women with virilizing adrenal cancer present with marked body hair growth, male pattern baldness, deepening voice, breast atrophy, clitoral enlargement, decreased libido and irregular periods. Manifestations of male hormone excess are less noticeable in men. Prepubertal boys with male hormone excess present with precocious (early) puberty. Feminizing tumors in women may cause breast tenderness and excessive vaginal bleeding. Female hormone secreting tumors in men are associated with breast enlargement and tenderness and decreased sex drive. In prepubertal girls, feminizing tumors cause early breast and uterine development and onset of menstrual periods. Aldosterone-producing adrenal cancer is rare and presents with high blood pressure and low potassium. Non-functioning tumors are frequently found by chance in the course of investigation of nonspecific abdominal complaints.

A variety of imaging procedures are used to localize and determine the possible benign or malignant character of an adrenal tumor. These include Computerized Tomography (CT) and Magnetic Resonance Imaging (MRI). Malignant adrenal masses are usually larger than 5 cm. The CT procedure helps determine the presence of involved lymph nodes, liver or lung. Knowing the extent of tumor involvement is important in order to determine the stage of the tumor as well as treatment goals for a given patient. Both CT and MRI can help determine if an adrenal mass is benign or malignant by its fat content. Benign masses are likely to be fat-rich. Also nuclear scanning may be helpful, because benign tumors take up radioactive cholesterol while malignant tumors do not.

Cancer staging

Patients with clinical and imaging diagnosis of an adrenal cancer should undergo staging of their disease by appropriate imaging procedures. Staging not only determines prognosis but also the selection of treatment. The MacFarland classification as modified by Sullivan is described (5):

Stage	Size	L Nodes	Local Invasion	Metastases
I	< 5 cm	—	—	—
II	< 5 cm	—	—	—
III	Any Size	+	+	—
IV	Any Size	+	+	+

Patients in stage I have tumors that measure less than 5 cm in size and have no evidence of lymph node involvement or metastases; patients in stage II have tumors larger than 5 cm but are also free of lymph node involvement or metastases. Patients in stage III exhibit tumors of any size with local lymph node invasion or have experienced local recurrence. Patients in stage IV have distant metastases. The most common sites of tumor spread in stage IV are lung, liver, lymph nodes, and bone. The stage at which an adrenal cortical carcinoma is defined determines prognosis for life expectancy (6). While 50% of patients in stages I, II or III are alive 40 months after diagnosis, only 10% of patients in stage IV are alive at that time.

Treatment possibilities of adrenal cancer

Treatments for patients with adrenal cancer include: surgery, radiation therapy, systemic chemotherapy and mitotane (4). Surgical resection, even if the tumor cannot be totally removed, should be considered the initial step in therapy. Since complete removal is the overall objective, the surgery should be performed by a surgeon experienced in the treatment of adrenal cancer. Because most adrenal cancer tumors are large, the surgical approach is an open abdominal resection. Laparoscopic surgery is not indicated in most cases. The surgical goal is the resection of the entire tumor mass when possible. When this is not possible because of local extension into other structures, tumor debulking to the maximum degree possible should be considered. It is often necessary to remove the adjoining kidney together with the tumor because the tumor frequently invades its upper pole. In cases of liver metastases, a resection of the involved portion of the liver has led to long term remission (7). Aggressive effort to excise all visible tumor is justified because it may increase life expectancy. Several of the larger series indicate that surgical resection of the primary tumor and metastases results in extended survival in 56% of patients (8). While adrenal cancer is generally resistant to radiation therapy, three-dimensional conformal radiotherapy may prevent recurrence of tumor if directed to the adrenal bed after local tumor recurrence and repeat surgical excision. Patients have tolerated this form of radiotherapy without complications and without evidence of recurrence after one year of follow up. The number of patients treated is small and the length of follow-up not long enough for a determination of efficacy but more extensive use of this approach will help determine the value of this form of radiotherapy in the treatment of adrenal cancer.

Mitotane (o,p’-DDD), is an adrenalytic (adrenal destroying) drug with selective activity on the adrenal cortex which has been found to be effective in inducing a tumor response in 33% of patients treated (4). The duration of response has varied between 1 and 204 months. Most of the experience with mitotane comes from its use on patients in advanced stages of the disease but its effectiveness under those circumstances has been disputed (9). Decreases in elevated urinary steroid levels, measurable disease response and overall clinical response have been described. Mean survival however is short (8.4 months) when the drug is used after the appearance of metastatic disease. Isolated case reports have described impressive remissions and even cures of adrenocortical carcinoma following mitotane monotherapy. However, the drug has been used more commonly in combination with other systemic chemotherapy. The optimal dose should be determined by measuring blood levels. By following blood levels, it has been possible to decrease the dose and limit drug toxicity (10). The therapeutic threshold is reached after 3-5 months of therapy.

Combination of surgery and mitotane

Early treatment with mitotane following surgical resection is also associated with longer survival. However, the use of mitotane as adjuvant therapy in patients with stages I and II adrenocortical carcinoma is controversial (11, 12) because of lack of convincing data that the drug can prevent tumor recurrence and the significant toxicity associated with its administration. Prospective, large multicenter clinical trials will be necessary to determine the proper role of mitotane as adjuvant therapy.

Systemic chemotherapy has shown response in less than 10% of patients treated for stages III and IV. Several chemotherapeutic protocols have been employed with variable success. They include: 1) combination of 5-fluorouracil, cisplatin and doxorubicin with an overall response rate of 23% but complete remission lasting 42 months achieved in only one patient; 2) combination of cisplatin and etoposide with induction of partial remission only after one cycle of therapy; combination of doxorubicin, cisplatin, etoposide and mitotane given in escalating doses with a 54 % response rate; 3) streptozocin and mitotane with a 36% response rate. It is difficult to assess the effectiveness of published treatment protocols because most series are limited in the number of patients studied and there is great variability in the drugs used, the stage and extent of the tumor, and the malignancy grade. In addition, there is lack of a uniform definition of response, the duration of response is unclear and multiple treatments are given in variable sequence. A response with these protocols does not imply complete or significant reduction in tumor size, just stabilization or some reduction in the size of the lesions. Several treatment strategies have resulted in temporary or partial tumor regression but very few cases have attained long survival (1). Large-scale clinical trials are needed to establish consensus treatment guidelines for patients with state III and IV adrenal cancer. Other anticancer drugs that have been tried, include taxol, gemcitabine, suramin and gossypol but with equivocal results.

Prognosis and response to therapy

The result of therapy for adrenal cancer is generally poor but there are a significant number of patients on whom therapy can extend life expectancy with acceptable side effects. However, recurrence can occur even after long periods of remission. Several series of patients receiving treatment for adrenal cancer have been evaluated for long term response. In a comparison of 18 patients treated with mitotane alone and 15 patients treated with combined surgical resection and mitotane chemotherapy, those who underwent surgical treatment had a more favorable response; 33% of patients lived more than five years from the time of first recurrence (13). In a study of 49 patients with adrenal cancer, surgical excision offered the best opportunity for prolonged survival; 43 % of patients with a completely resectable tumor were alive with no evidence of disease an average of 7.3 years after surgery (14). Comparing various types of therapy in 110 patients with adrenal cancer, it was noted that 56% of patients responded to surgery for localized and regional disease with a disease free survival time of at least two years. In contrast, abdominal radiation therapy was effective in 15%, systemic chemotherapy in 9% and mitotane in 29% (8). In a review of 82 patients, it was noted that survival of patients with metastatic disease was poor and not improved by treatment with mitotane, cytotoxic chemotherapy or radiation therapy (15).

Follow-up of patients with adrenal cancer

A hormonal profile should be determined in every patient with an adrenal mass and especially patients who may have a primary adrenal cancer. Cortisol, male and female steroid hormones are the adrenal cortical steroids most commonly found elevated in these patients. A hormonal profile should also be obtained on patients with apparently non-functioning adrenal tumors. Some apparently nonfunctioning tumors may produce precursors of steroids. It is important to determine the levels of these steroids on patients with adrenal cancer prior to surgery because these hormones can be used as biochemical markers in the postoperative follow-up.

Use of Fine Needle Biopsy in the diagnosis of adrenal cancer

Needle biopsy of adrenal masses may be helpful in diagnosing a metastasis to the adrenal from some other non-adrenal tumor such as lung or breast but it is not recommended when there is a high probability of a primary adrenal cancer because tracking of tumor cells along the path of the needle may result in transplantation of the tumor to the liver and spreading of disease.

Metabolic management of patients with functioning adrenal cancer: If the patient continues to have active residual disease, the metabolic changes associated with excessive hormone production may cause significant disability and shortened life expectancy. A variety of inhibitors of adrenal function have been used to suppress steroid hormone production and improve the clinical manifestations of the disease. The most commonly used inhibitors include ketoconazole and aminoglutethimide. Clinical improvement occurs frequently but regression of metastatic disease is rare. When patients are treated with ketoconazole, adrenal insufficiency is avoided by decreasing the dose sufficiently to maintain normal cortisol levels. The most frequent adverse reactions with ketoconazole are nausea and vomiting, abdominal pain and itching in 1-3% of patients. Aminoglutethimide inhibits the synthesis of cortisol, aldosterone and sex hormones. Cortisol levels fall gradually with regression of the clinical manifestations of Cushing’s syndrome. Aminoglutethimide causes gastrointestinal (anorexia, nausea, vomiting) and neurologic (lethargy, sedation, blurred vision) side effects. Future approaches to the treatment of adrenal cancer are likely to be based on blocking or reversing the biological mechanisms of tumorigenesis. For example, angiogenic and immunological factors may play a role in adrenal tumor growth. Inhibition of these factors may result in inhibition of tumor growth.

Editor’s Note: Dr. David Schteingart is Professor of Internal Medicine in the Division of Metabolism, Endocrinology and Diabetes at the University of Michigan in Ann Arbor, MI. Dr. Schteingart has long standing experience in adrenal cancer and served as Program Chair for the September, 2003 International Consensus Conference on the Treatment of Adrenal Cancer.