15 Metastatic Adrenocortical Carcinoma D. E. Tsakayannis, Dimitrios A. Linos

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contents

15.1 Epidemiology . . . 151 15.2 Clinical Presentation . . . 151 15.3 Diagnosis . . . 152

15.3.1 Imaging Techniques . . . 152 15.3.2 Fine-Needle Aspiration . . . 153 15.4 Treatment . . . 154

15.4.1 The Role of Laparoscopic Adrenalectomy . . . 155 References . . . 156

15.1 Epidemiology

Metastatic tumor is the most common lesion in the ad- renal gland at postmortem [1]. The common occur- rence of this adrenal lesion is related to its rich sinu- soidal blood supply. With continuing progress in im- aging techniques, particularly computed tomography (CT), an increasing number of adrenal metastases can be detected incidentally during follow-up or at the time of presentation of extra-adrenal malignancy. The most frequent types of malignancy that manifest ad- renal metastases in Western countries are primary ma- lignancies of the lung, kidney, breast, melanoma and gastrointestinal tract [2, 3]. Metastases to the adrenals have also been reported for hepatocellular carcinoma [4,5],carcinoma of the bladder [6],lymphoma [7],tes- ticular seminoma [8], osteogenic sarcoma [9], ovarian cancer [10] and thyroid cancer [11]. About one-third of patients dying from lung cancer have adrenal metastases at autopsy [12]. Preoperative staging with a CT scan will reveal adrenal lesions in 7.5% of patients with non-small cell lung carcinoma [13]. Among pa- tients with lung cancer, 4.1% of those who have oper- able disease will be found to have a coexistent unilat- eral adrenal lesion [14].

In a large series from Hong Kong, 464 patients with metastatic disease to the adrenal glands,over a 30-year

period, were reviewed. A high prevalence of gastric, esophageal and liver/bile duct metastases was noted, which was explained by the high prevalence of these tumors in Hong Kong as compared to Western coun- tries. Most adrenal metastases were discovered within a short period after the detection of the primary tumor (median latent period of 7 months) and less than 2%

were detected more than 5 years after diagnosis of the primary tumors [15]. In the literature, late presenta- tion of adrenal metastases, occurring after a latent pe- riod of 15 years,has been reported for renal cancer [16, 17], colorectal cancer and lymphoma [15]. Thus the presence of an adrenal mass in a patient with a histo- ry of previous malignancy should be regarded as po- tentially metastatic, even though the primary tumor may have been adequately treated many years previ- ously.

15.2 Clinical Presentation

The clinical presentation of adrenal metastasis is often

quite indolent. The majority of lesions are asympto-

matic and are discovered on initial staging or routine

follow-up. When symptomatic, pain seems to be the

most common presenting symptom in up to 25% of

patients and can alert the physician to investigate for

possible metastatic disease [16]. Addison’s disease is

not a frequent clinical manifestation. Fewer than 100

cases have been reported in the literature and the

prevalence of adrenal metastases in patients with

Addison’s disease ranges from 2% to 6% [19, 20], with

the exception of one series,where it was reported to be

42% [15]. This low incidence may be attributed to the

fact that more than 90% of the adrenal gland must be

destroyed before there is clinical adrenal insufficiency,

which usually requires bilateral adrenal involvement,

by the tumor. In some cases adrenal insufficiency is

caused by unilateral adrenal destruction by the cancer

and concurrent pituitary metastasis [21]. Clinically

D. E. Tsakayannis, Dimitrios A. Linos

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significant hemorrhage secondary to metastasis is ex- ceedingly rare and only 11 such cases have been re- ported; with the exception of 2 patients all had a pri- mary lung cancer. Acute severe pain was the present- ing symptom and must be recognized promptly, because decisive surgical intervention might be neces- sary. Many of these patients can be stabilized hemo- dynamically and there have been reports where there was response to radiation therapy [22, 23] following hemorrhage.

15.3 Diagnosis

The characterization of an adrenal lesion as benign or malignant (primary or metastatic) preoperatively can be very difficult. Imaging techniques and fine-needle aspiration (FNA) are the usual diagnostic tools. The size of the adrenal lesion has been used by many cen- ters as a predictor of malignant potential and a size of greater than 5 cm correlates with a 35–98% risk of ma- lignancy [24]. But size represents by no means defini- tive diagnosis.In addition,in an analysis of 76 patients with incidentalomas, Linos et al. found that CT scan- ning underestimated the true size of adrenal tumors by an average of 25% [25].

15.3.1 Imaging Techniques

The most widely used and accepted imaging tech- niques for the detection of metastatic adrenal tumors are computed tomography (CT) and magnetic reso-

nance imaging (MRI). However, they are not accurate

enough to diagnose or to exclude primary or metasta- tic adrenal tumors preoperatively.Allard et al reviewed 91 patients with lung cancer who were examined by CT scan to assess for adrenal metastases. In all these pa- tients at postmortem, all adrenal glands underwent histopathological examination for metastatic lesions.

The calculated sensitivity and specificity of the CT scan for the detection of adrenal metastases was 41%

and 99% respectively [12]. Porte et al. studied the use of combined CT scan and MRI in 443 patients with re- sectable non-small cell lung cancer,of whom 32 had an adrenal lesion. Sensitivity and specificity of the com- bination of both tests in detecting the adrenal lesions was 80% and 100% respectively. Despite the fact that adrenal metastases tended to be larger and less well defined on CT scan,their imaging characteristics were non-specific. Furthermore the authors showed that size alone was not sufficient to discriminate between

metastatic adrenal lesion and non-functioning adeno- mas [26]. Burt et al. prospectively evaluated the accu- racy of MRI in distinguishing a benign from a malig- nant adrenal mass in patients with otherwise operable non-small cell lung cancer. They found that MRI had a high false-positive rate of 67% and could not replace CT-guided percutaneous needle biopsy of the adrenal mass [27].

Iodocholesterol adrenal scan has been used for the

detection of adrenal metastases. The reasoning is based on the fact that any metastatic tissue replacing normal adrenal tissue will not accumulate iodocho- lesterol, which will be shown as a lack of uptake dur- ing scanning.This technique has not been widely used, has shown some promising results, but more studies are necessary to evaluate its true sensitivity, specifici- ty and accuracy [28].

Positron emission tomography (PET) scanning is a

promising novel diagnostic modality that can be very helpful in characterizing adrenal masses. The major utility of PET in the evaluation of patients with lung cancer is staging of the entire body. PET is more accu- rate than the conventional imaging modalities of CT and bone scans in the detection of metastatic disease.

PET is accurate in the staging of the mediastinum, ad-

renal glands and skeletal system [29]. In particular

PET scan can either identify lesions in the adrenals

that could not be detected on CT or MRI, or can help

differentiate an adrenal mass as being metastatic or

benign (Fig. 1).Yun et al. studied 50 adrenal lesions in

patients with proven or suspected primary cancers

with FDG-PET scan and found that increased FDG up-

take by the adrenal gland,which signified high glucose

tumor metabolism, was characteristic of adrenal

metastatic involvement. FDG-PET scan showed a sen-

sitivity of 100%, a specificity of 94% and an accuracy

of 96% [30]. Therefore PET scan will soon become a

very useful tool in confirming isolated metastatic dis-

ease and selecting patients for adrenalectomy. Howev-

er, even though the preliminary results are promising,

more studies evaluating its accuracy will be necessary

[31–33]. PET scan could also be cost effective because

it has the additional advantage of evaluating not only

the adrenal mass, but at the same time can be used to

stage the whole body by identifying extra-adrenal tu-

mor sites in cancer patients.

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15.3.2 Fine-Needle Aspiration

Fine-needle aspiration (FNA) biopsy of a non-func- tioning adrenal tumor is inaccurate in differentiating between a primary adrenal carcinoma and a benign le- sion, has a risk of disruption of the tumor capsule and potential dissemination of cancer cells and is therefore not recommended [24].Nevertheless it may be of great value in the diagnosis of adrenal metastases since many studies have shown that the accuracy of FNA in this situation is excellent. The combination of CT and aspiration cytology can provide a conclusive diagno- sis of metastatic adrenal tumors and it seems reason- able that all patients with known malignant disease

and an adrenal mass should undergo FNA cytology to determine if the lesion is a metastasis or a non-func- tioning adenoma [34, 35] (Fig. 2). In patients with re- sectable non-small cell lung cancer who present with synchronous or metachronous isolated adrenal mass- es, CT-guided biopsy has shown to have an up to 100%

accuracy, sensitivity and specificity and is required to select patients for adrenalectomy with a potentially curative intent [14, 26, 36].

Aspiration cytology under CT or ultrasound guid- ance should be regarded as the procedure with the highest diagnostic yield in evaluating a possible metastasis to the adrenal gland from another primary malignancy.

Fig. 1. A PET scan detected a small isolated adrenal metastasis (with a concurrent negative CT scan) in this 69-year-old male patient treated for mesothelioma. Laparoscopic adrenalectomy of this single metastasis was performed

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15.4 Treatment

In most cases an adrenal metastasis occurs in the face of multiple synchronous metastases in other sites. The prognosis for these patients is dismal,with few reports of survivors past 5 years.A broad range of treatments, including chemotherapy, hormonal therapy and radi- ation therapy, have failed to impact significantly on their survival.A few studies using immunotherapy for melanoma and renal cell carcinoma are encouraging, but, once again, 5-year survival with metastatic dis- ease remains an unusual event [37].

Isolated adrenal metastasis is rare and presents a therapeutic dilemma. The discovery of an isolated ad- renal metastasis is considered synonymous with sys- temic carcinomatosis and therefore many clinicians do not consider these patients as candidates for adre- nal resection [14, 38]. The stated reasons are that adrenalectomy has appreciable risks and, if the resec- tion is bilateral, commits a patient to lifelong therapy.

It remains unclear whether the survival benefits for these patients outweigh the risks of adrenalectomy.

Evidence is, however, accumulating that adrenalec- tomy for patients with isolated adrenal metastases may be curative [39–43]. Individual case reports and small series are available but few large series have been pub- lished [42]. Lo et al. reported the Mayo Clinic experi- ence over a 10-year period in 52 patients undergoing adrenalectomy for metastatic disease. In this study, open surgical resection was associated with rare mor- tality and low morbidity rates and overall survival

rates were 73% at 1 year and 40% at 2 years [39]. Kim et al. from the Memorial Sloan Kettering Cancer Cen- ter conducted a retrospective review of 37 patients who had undergone open adrenalectomy for isolated metastatic disease over a 10-year period. Five-year survival for the entire group was 24% (median, 21 months) with acceptably low mortality and mor- bidity. In their study, the only predictors of improved survival were complete resection and a disease free in- terval of greater than 6 months [41]. Given that the highest reported median overall survival in patients treated non-surgically for solitary adrenal metastasis was only 8.5 months [44] and that no long-term sur- vivors appeared in any other series [45,46],the authors argued that resection could alter the natural history of this disease. Long-term survival could be achieved in selected patients where complete resection was achieved and with a disease-free interval of more than 6 months. Heniford et al. reviewed 40 cases of unilat- eral or bilateral adrenal resections for isolated metas- tases from non-small cell lung carcinoma; the esti- mated 5-year survival for these patients was approxi- mately 45% [37]. Porte et al. retrospectively studied 43 patients with solitary adrenal metastasis from non- small cell lung cancer treated in eight centers with cur- ative intent. The metastases were discovered synchro- nously in 32 patients and metachronously in 11. Medi- an survival was 11 months and three patients survived more than 5 years. There was no difference in survival and recurrence between the synchronous and meta- chronous groups [43]. Paul et al. did a meta-analysis of published series and case reports reported in the liter- ature and identified 77 patients with isolated metasta- tic adrenal cancer in whom complete resection with negative margins was achieved. The median survival time after open adrenalectomy was 23 months,with an operative mortality of 3.9% [42].A longer disease-free interval from the time of primary cancer therapy to adrenal metastasis was associated with a longer post- operative survival after adrenalectomy. A longer dis- ease-free interval presumably reflects less aggressive tumor biology.

The primary tumor site appears to significantly af- fect survival as well.A significantly longer survival has been observed for patients with primary kidney,colon, lung carcinoma and melanoma. Poorer results were found for patients with unknown primary cancer, sar- coma, esophageal and hepatocellular carcinoma [42].

The size of the metastases has not been shown to af- fect survival, and patients with tumors greater than 7 cm fared just as well as patients with smaller metas- tases [41,42].Therefore metastasis size should not pre-

Fig. 2. CT-guided fine-needle aspiration disclosed a meta-

static right adrenal carcinoma

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clude an aggressive surgical approach, assuming com- plete resection is possible.

Most published data support that resection of iso- lated adrenal metastases clearly benefits carefully se- lected patients. One should consider overall patient health, tumor aggressiveness and complete resectabil- ity in selecting those patients in whom adrenalectomy should be attempted. Medically fit patients, particu- larly those with a long disease-free interval (greater than 6 months) and resectable tumors, should be of- fered resection with low operative mortality.It must be kept in mind though that these patients are not cured by this approach and therefore careful extent-of-dis- ease (staging) workup is clearly indicated prior to adrenalectomy.

15.4.1 The Role of Laparoscopic Adrenalectomy

Laparoscopic adrenalectomy has proven to be effective and safe for the treatment of benign functioning and non-functioning adrenal tumors [47–52]. Skepticism exists, however, currently for laparoscopic removal of primary adrenocortical carcinoma [53, 54]. In the pa- tient with isolated adrenal metastases there are, how- ever, several factors that support the minimally inva- sive approach. The laparoscopic approach offers ex- cellent visualization, early control of the organ’s vasculature and the ability to effectively screen for signs of unresectability. Another factor that may support the use of laparoscopy is the fact that most often simple adrenalectomy is sufficient to remove metastatic lesions, because these lesions seldom pene- trate the capsule of the gland [37, 55] (Fig. 3). When extraglandular extension is found, extended resection including the involved organs should be performed (Fig. 4). Initiating a laparoscopic exploration does not preclude subsequent conversion to an open, more ex- tensive resection.There are few absolute contraindica- tions for laparoscopic adrenalectomy: (1) the presence of a locally invasive adrenal or metastatic carcinoma, because of the possible extent and complexity of the operation required; (2) the identification of wide- spread systemic disease. Other relative contraindica- tions include previous trauma or surgery in the area that may create dense adhesions, and an adrenal size of 10 cm or larger, which would require extensive laparoscopic and probable open adrenal surgical expertise.

The role of laparoscopy for metastatic adrenal tu- mors remains unclear, since rare and limited outcome

data exist in the literature. These reports have been limited to case reports and small cohort studies with short follow-up. In a search of the English literature 11 authors have reported 46 cases of synchronous or metachronous adrenal metastases treated laparoscop- ically [10, 37, 50, 56–64]. Heniford et al. in a two-insti- tution review of ten patients with metastatic adrenal tumors and one patient with primary adrenal cancer, which were all removed laparoscopically, reported no port-site or local recurrence at a mean follow-up time of 8.3 months [37]. Kebebew et al. retrospectively studied 23 patients who underwent laparoscopic adrenalectomy for metastatic adrenal cancer (13 pa- tients) and adrenocortical carcinoma (10 patients).

There were no locoregional or port-site recurrences

Fig. 4. Large (13¥9.5¥4 cm) metastatic lung carcinoma that was removed en bloc with the spleen, kidney and tail of the pancreas

Fig. 3. Metastatic carcinoma laparoscopically removed in a patient treated for cervical cancer several years previously.

The capsule of the adrenal remained intact

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in any of the 13 patients who underwent laparoscop- ic adrenal metastasectomy at a mean follow-up time of 3.3 years. Their overall disease-free survival was 65%. Four of the 13 patients who were thought to have solitary adrenal metastasis at the time of their laparoscopic adrenalectomy later had distant re- currences [61]. Feliciotti et al. reported their ex- perience of six patients with isolated adrenal meta- stasis managed laparoscopically. No postoperative complications occurred, tumor free margins were achieved in every case and no port-site metastasis or local recurrence was observed at follow-up to 24 months [63].

The current available literature is too sparse to al- low any treatment management recommendations for metastatic adrenal neoplasms.Unlike for colon cancer, a prospective randomized study comparing open with laparoscopic adrenalectomy is impractical because of the rarity of isolated metastatic adrenal tumors. How- ever, this limited experience has shown that resection of metastatic adrenal lesions is laparoscopically fea- sible. Because of the many known advantages of the laparoscopic as compared to the open approach, we believe that laparoscopic adrenalectomy for solitary adrenal metastasis should be preferred when techni- cally and oncologically feasible in a highly selective group of patients.

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