From Incidentaloma to Adrenocortical Carcinoma: The Surgical Management of Adrenal Tumors
WEN T. SHEN, MD,1 CORD STURGEON, MD,2 AND QUAN-YANG DUH, MD1*
1 Department of Surgery, University of California, San Francisco, California
2 Department of Gastrointestinal and Endocrine Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
In this article we review the management of benign and malignant adrenal tumors, with an emphasis on oncologic concerns. Concise, logical guidelines for the diagnosis and operative treatment of incidentalomas, aldosteronomas, adrenal Cushing syn- drome, virilizing and feminizing adrenal tumors, isolated adrenal metastases, and adrenocortical carcinoma are provided. We also discuss the choice of optimal surgical approach for performing adrenalectomy (laparoscopic, open, hand-assist). J. Surg. Oncol. 2005;89:186-192. @ 2005 Wiley-Liss, Inc.
KEY WORDS: adrenal tumor; incidentaloma; adrenocortical carcinoma; adrenal metastatis; laparoscopic adrenalectomy
INTRODUCTION
Adrenal tumors represent a spectrum of pathologies ranging from benign non-functioning cortical adenoma to adrenocortical carcinoma. Most adrenal tumors are diagnosed after clinical suspicion (most commonly hypertension or localized abdominal symptoms) leads to biochemical testing and tumor-directed imaging studies. In an increasing percentage of patients, the adrenal tumor is identified serendipitously on an ab- dominal imaging study performed for another clinical indication; these tumors are referred to as incidentalo- mas. A few patients will be diagnosed with adrenal pathology because of known familial or genetic risk factors. The indications for adrenalectomy are hormone secretion or increased risk of malignancy. The risk of malignancy in an adrenal tumor is determined by several factors, including tumor size, radiographic features such as irregular borders or invasion, lymphadenopathy, and distant metastases.
This review addresses several issues concerning the diagnosis and operative treatment of adrenal tumors, with an emphasis on oncologic concerns. First we discuss the choice of optimal surgical approach (laparoscopic, open, hand-assisted) for adrenal tumors. We then provide concise recommendations for the management of inci- dentalomas, aldosteronomas, adrenal Cushing syndrome, virilizing and feminizing adrenal tumors, isolated adrenal metastases, and adrenocortical carcinoma. Pheochromo- cytoma is discussed elsewhere in this volume. Our aim is
to establish a set of logical guidelines for the workup and treatment of benign and malignant adrenal tumors.
LAPAROSCOPIC ADRENALECTOMY
Since its introduction in the early 1990s, laparoscopic adrenalectomy has become the operation of choice for the resection of almost all adrenal lesions, except for known malignant tumors and tumors that are either too large or too difficult to resect laparoscopically [1,2]. Several non- randomized trials over the past decade have demonstrated that patients undergoing laparoscopic adrenalectomy have a shorter hospitalization and return to normal act- ivity, less postoperative pain, and fewer complications such as blood loss and wound infection, when compared to patients undergoing open adrenalectomy [2-6].
As more surgeons have become familiar and facile with the technique of laparoscopic adrenalectomy, the indications and contraindications to operation have evolved. Currently, laparoscopic adrenalectomy is the preferred surgical approach for all benign adrenal tumors, including aldosteronomas, adrenal Cushing, pheochro- mocytomas, virilizing and feminizing tumors, and benign
*Correspondence to: Quan-Yang Duh, MD, Professor of Surgery, Veterans Affairs Medical Center, San Francisco, Surgical Service (112), 4150 Clement Street, San Francisco, CA 94121. Fax: (415) 750-2181.
E-mail: quan-yang.duh@med.va.gov
DOI 10.1002/jso.20180
Published online in Wiley InterScience (www.interscience.wiley.com).
non-functioning tumors; many surgeons also advocate laparoscopic adrenalectomy for isolated adrenal metas- tases [1,2]. The relative contraindications to laparoscopic adrenalectomy include tumors larger than 10-12 cm (although some authors have reported successful laparo- scopic resection of tumors measuring up to 15 cm), significant peritumoral adhesions, invasion of adjacent structures, lymphadenopathy, and evidence of metastatic disease [1,2]. The introduction of the hand-assist device has given surgeons an alternative approach for the resec- tion of selected tumors that might otherwise require open adrenalectomy [7]. The hand-assist device allows the surgeon to palpate the adrenal tumor and resection bed directly, and facilitates removal of large tumors, but does not require as extensive an incision as open adrenalectomy. The safety of hand-assisted laparoscopic adrenalectomy for known adrenal malignancies has not been proven.
Our current practice is to begin nearly all of our adrenal operations laparoscopically; we choose to begin with open adrenalectomy only in patients with preopera- tive imaging studies that definitively demonstrate metas- tases or local invasion. The laparoscopic approach allows us to examine the entire abdomen for evidence of un- expected metastatic disease, and can facilitate difficult dissection, especially in the upper quadrants of the abdo- men. If there is any evidence of tumor adhesion, invasion, lymphadenopathy, or previously unsuspected metastasis, or if the tumor is too large to be safely resected laparo- scopically, we convert to either the hand-assist technique or to open adrenalectomy.
INCIDENTALOMA
Incidentaloma is defined as an asymptomatic adrenal tumor discovered on abdominal imaging performed for another indication [8-11]. Between 1% and 4% of all abdominal imaging studies will reveal an unexpected adrenal tumor [1]; the frequency of incidentalomas is expected to increase with the widespread use of CT scanning and other imaging studies. Ninety percent of incidentalomas are less than 2 cm in size [2]. The majority of incidentalomas are found to be benign, non- functioning cortical adenomas [1,2]. However, appro- ximately 5% of incidentalomas are adrenocortical carcinomas; other possible pathologies include pheochro- mocytoma (5%-10%), cortisol-secreting tumor causing subclinical adrenal Cushing syndrome (5%), adrenal metastasis (2.5%), and aldosteronoma (1%) [2]. Adrenal cysts and myelolipomas are occasionally encountered. Primary tumors of the retroperitoneum, stomach, or tail of the pancreas will sometimes be mistaken for adrenal tumors [11]. While the majority of incidentalomas can be safely observed, operative treatment is required for
patients with functioning tumors and tumors that are more likely to be malignant. The approach to a patient with an incidentaloma should follow logical guidelines in order to establish whether the tumor should be resected or observed.
With rare exceptions, patients with incidentalomas should undergo biochemical testing with overnight dexa- methasone suppression to rule out adrenal Cushing, and plasma metanephrines and normetanephrine (if available) or urinary catecholamines and metanephrines to rule out pheochromocytoma [11]. Patients with hypertension or hypokalemia should also undergo testing for plasma aldosterone and renin activity to rule out hyperaldoster- onism. Androgen and estrogen levels should be evaluated in patients with clinical signs of masculinization and feminization. CT scanning will occasionally identify simple adrenal cysts or myelolipomas that do not require resection unless they are larger than 8-10 cm or are causing localized symptoms [1]. Fine-needle aspiration has no role in the diagnosis and workup of incidentalo- mas except in patients with documented non-functioning tumors and a history of extra-adrenal malignancy, where the cytologic diagnosis of adrenal metastasis would alter the course of treatment [1,2,11].
Although the overall risk of primary malignancy in incidentalomas is estimated to be approximately 5%, the likelihood of malignancy has been shown to increase with increasing tumor size [2]. The risk of adrenocortical carcinoma in an incidentally discovered adrenal tumor is 2% for tumors less than 4 cm, 6% for tumors between 4 and 6 cm, and greater than 25% for tumors larger than 6 cm [11]. The 2002 National Institutes of Health (NIH) consensus statement on incidentaloma recommended adrenalectomy for all non-functioning tumors greater than 6 cm in size [12]. For tumors between 4 and 6 cm, the NIH recommended that the surgeon take into account factors other than tumor size (including tumor features on imaging studies, and age and overall health of the patient) [12]. In the surgical literature, recommendations for operative removal of incidentalomas exist for minimum tumor size thresholds of 3, 4, 5, and 6 cm [2].
Other features besides large tumor size that are indi- cative of malignancy include radiographic findings such as invasion into adjacent structures, lymphadenopathy, or the presence of metastases; some authors have also stated that irregular tumor margins, heterogeneity, and hyper- density are indicative of malignancy, but these findings may be seen in benign tumors as well [1]. Benign adrenal adenomas almost always exhibit CT attenuation values of less than 10 Hounsfield units, but tumors with attenuation values of greater than 10 Hounsfield units are not ex- clusively malignant [13]. Functioning tumors that secrete multiple hormones are at higher risk for malignancy [1,2,11].
Our current practice is to resect all functioning inci- dentalomas as well as incidentalomas larger than 3 cm in young patients with minimal comorbidities, and 5 cm in older patients. We set our resection threshold lower than the NIH recommendations because CT scans tend to underestimate the size of adrenal lesions [14]. Tumors that are too small for resection are observed with follow- up CT scanning in 6 months to 1 year. If no change is observed after two or more follow-up scans, the interval of time between scans can be increased. Up to 25% of incidentalomas will increase in size during follow-up and require resection; up to 10% will develop hormo- nal hypersecretion within 10 years [11]. In addition to
follow-up imaging, annual biochemical screening for Cushing and pheochromocytoma should be performed.
An algorithm for the surgical management of inciden- talomas and other adrenal tumors is provided in Figure 1.
ALDOSTERONOMA
Primary hyperaldosteronism caused by a hyperfunc- tioning tumor of the adrenal cortex is known as Conn syndrome [15]. Seventy-five percent of cases of hyper- aldosteronism are caused by a unilateral adrenal adenoma (aldosteronoma) [15]. Approximately one-fourth of cases are due to bilateral adrenal hyperplasia [15]. It is
Adrenal Neoplasm
Functioning
No
Yes
Adrenal tumor size
< 3 cm
3 -5 cm
> 5 cm
Follow up
Consider Adrenalectomy
No
·Suspicious imaging characteristics
Yes
Adrenalectomy
.Young age and few co- morbidities
.History of cancer
.Growth on follow up
-Patient preference for resection
Laparoscopic
Open
.Localized primary tum ors (no signs of local invasion, nodal or distant metastases)
·Imaging studies suggesting local or vascular invasion, lym phadenopathy or metastases.
.Few or no signs suspicious for malignancy on im aging studies (e.g. irregular tumor margins, heterogeneity, or hyperdensity)
“Imaging studies showing localized disease but signs suspicious for malignancy (irregular tum or margins, heterogeneity, hyper density)
.Small cortical tum ors (<6cm)
.Metachronous metastases
·Large cortical tumors (>8-10cm)
. All aldosteronomas
·Rapid onset of virilization, feminization, or Cushing’s syndrome.
.Most pheochromocytomas
- Multiple elaborated hormones
·Myelolipomas
-Most cortisol, sex-steroid, or mineralocorticoid secreting tum ors
.Family history of malignant pheochromocytoma
important to distinguish between unilateral aldostero- noma and bilateral adrenal hyperplasia, because patients with hyperplasia are not cured by adrenalectomy and should undergo medical therapy for their hyperaldoster- onism. Very rarely (less than 1% of all cases of Conn syndrome) does an adrenocortical carcinoma cause hyperaldosteronism [16].
Patients with Conn syndrome usually present with poorly controlled hypertension [1]. Aldosteronomas are rarely diagnosed incidentally on abdominal imaging. Hypokalemia is common; patients with hyperaldosteron- ism can also have hypernatremia, alkalosis, and hypo- chloremia. The diagnosis of hyperaldosteronism is made by demonstrating elevated plasma aldosterone along with concurrent low plasma renin activity. The aldosterone to renin ratio is usually greater than 25 [1]. CT scan of the abdomen is the initial localizing study of choice for identifying aldosteronomas and ruling out disease in the contralateral adrenal gland. Aldosteronomas typically measure between 0.5 and 2 cm in size and appear well- circumscribed and hypodense on CT scan [15]. Saline loading and postural studies were previously used to differentiate between unilateral and bilateral disease, but have been replaced by thin-cut CT scanning [1].
In equivocal cases or cases where no tumor can be identified, selective venous catheterization to determine the left-right gradient of the aldosterone-cortisol ratio is useful for localizing the hyperfunctioning gland or glands [1]. The sensitivity of selective venous catheterization varies according to institution; the right renal vein can sometimes be difficult to cannulate, and dilution of blood samples by the inferior vena cava or the renal veins can affect results. Iodomethylnorcholesterol (NP-59) scan- ning has been advocated by some institutions for the identification of aldosteronomas; this study utilizes a cholesterol analog that binds to low-density lipoprotein receptors in the adrenal cortex. Dexamethasone suppres- sion of normal adrenal function should be performed prior to NP-59 scanning. Sensitivities of up to 80%-95% have been reported for NP-59 scanning in patients with aldosteronomas; this test is more sensitive for larger aldosteronomas [1].
Laparoscopic adrenalectomy is the operation of choice for resection of aldosteronomas [17]. Blood pressure is normalized or improved in approximately 75% of patients, and hypokalemia resolves in more than 95% of patients [1]. Recurrence is rare in the contralateral adrenal gland after the primary tumor is resected [16].
ADRENAL CUSHING SYNDROME
Glucocorticoid excess causes Cushing syndrome, which is characterized by central obesity, plethora, purple striae, hypertension, glucose intolerance, moon facies,
and other symptoms and signs. The source of excess glucocorticoid secretion in Cushing syndrome can be divided into ACTH-dependent and ACTH-independent causes [1,18]. The ACTH-dependent causes account for 80% of all cases of Cushing syndrome and include pituitary adenomas (70%) and ectopic ACTH-secreting tumors (10%) [1]. The ACTH-independent causes in- clude adrenal cortical adenomas, adrenocortical carcino- mas, and primary adrenal macronodular or micronodular hyperplasia [1]. Exogenous steroid administration for medical therapy or other reasons will also cause Cushing syndrome.
Biochemical testing of either plasma cortisol after low- dose (1 mg) dexamethasone suppression or measurement of 24-hr urinary free cortisol will confirm the diagnosis of Cushing syndrome [1]. ACTH measurement will then distinguish between ACTH-dependent and -independent causes. This article focuses on adrenal Cushing syndrome (ACTH-independent), which is most commonly caused by an adrenal cortical adenoma. These adenomas are usually small and secrete only cortisol [1]. In contrast, adrenocortical carcinomas are usually larger and often secrete more than one hormone [2]. However, tumor size alone is not a reliable criterion for predicting malignancy in cases of adrenal Cushing syndrome. Other features such as irregular tumor borders, heterogeneity, and local invasion are suggestive of malignancy [2].
Laparoscopic adrenalectomy can be performed safely in patients with adrenal cortical tumors lacking features that are worrisome for malignancy [18]. Other tumors with obvious malignant features should be resected by open adrenalectomy. The hand-assist technique may be utilized in selected cases where conversion from laparo- scopic adrenalectomy is required. Patients with Cushing syndrome are at higher risk for wound infections than other patients undergoing adrenalectomy and should therefore receive a single dose of perioperative anti- biotics [1]. Stress dose steroid supplementation (100 mg hydrocortisone intravenously every 8 hr) should be administered in all patients and can be tapered post- operatively; steroid supplementation may be required for weeks to months after adrenalectomy for adrenal cortical adenoma causing Cushing syndrome because of suppres- sion of the contralateral adrenal gland.
Bilateral adrenal hyperplasia is a rare cause of adrenal Cushing syndrome and is almost always benign. In contrast to patients with bilateral adrenal hyperplasia causing Conn syndrome, patients with bilateral adrenal hyperplasia causing Cushing syndrome will benefit from bilateral adrenalectomy, which can be performed lapar- oscopically in most cases [18]. These patients will require lifetime glucocorticoid therapy and are at obvious high risk for Addisonian crisis. In addition, mineralocorticoid supplementation with Florinef (0.1 mg per day) is usually
required [1]. Patients with ACTH-dependent Cushing syndrome may also require laparoscopic bilateral adre- nalectomy if other treatments of their ACTH-secreting tumors have failed [1].
VIRILIZING AND FEMINIZING ADRENAL TUMORS
Adrenal tumors that secrete sex hormones are quite rare, but are nearly always symptomatic [2]. Routine screening for these types of tumors is impractical during the workup of incidentalomas, but should be performed in any patient with evidence of feminization or virilization. Measurements of sex steroids and their precursors con- firm the diagnosis. Approximately one-half of virilizing tumors and nearly all feminizing tumors are malignant [2]; conversely, between 20% and 35% of hormonally active adrenocortical carcinomas cause virilization, and approximately 10% of hormonally active adrenocortical carcinomas cause feminization [2]. The index of suspi- cion for malignancy should be high in cases of adrenal tumors that secrete sex steroids. As with other types of adrenal tumors, the laparoscopic approach may be used in patients with virilizing or feminizing tumors that lack radiographic features suggestive of malignancy, but the surgeon should have a low threshold for conversion to open or hand-assisted adrenalectomy based on intrao- perative findings.
METASTASES TO THE ADRENAL GLAND
The most common malignancies that metastasize to the adrenal gland are lung cancer, breast cancer, colon cancer, renal cell cancer, and melanoma [1,2,19-22]. Adrenal metastasis should be suspected in any patient with a history of cancer who presents with an adrenal tumor, especially if the tumor is larger than 2 cm [1]. Most adrenal metastases are discovered at the same time as multiple synchronous metastases in other organs; isolated adrenal metastases are less commonly encoun- tered [2]. Patients with metachronous solitary adrenal metastases have a better chance of cure than those with synchronous metastases; in addition, a longer time period after initial curative resection for the primary extra- adrenal malignancy is correlated with improved survival [1,2]. Figure 2 shows a CT scan of an adrenal metastasis in a patient with a history of melanoma.
Solitary adrenal metastases are usually confined within the capsule of the adrenal gland, and are therefore amenable to simple adrenalectomy [1,2]. The periadrenal fat should be resected along with the adrenal gland, however, to reduce the risk of local recurrence. The role of laparoscopic adrenalectomy for solitary adrenal metastasis is still being defined [18-21]; we believe that
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laparoscopic adrenalectomy for adrenal metastasis is safe if preoperative imaging studies demonstrate no evidence of tumor invasion, adjacent lymphadenopathy, or extra- adrenal metastases. The surgeon should have adequate experience with laparoscopic adrenalectomy and should not hesitate to convert to the open or hand-assisted ap- proach if he or she encounters difficult dissection or any other factors that might risk tumor spillage or incomplete resection.
Patients who have abdominal pain or other symptoms caused by their adrenal metastasis usually report im- provement of their symptoms after adrenalectomy. Survival ranges from 20 to 30 months after adrenal metastectomy, compared with mean survival of 6- 8 months in patients whose adrenal metastases are not resected [2,19]. Five-year survival is in the range of 25% [2,19].
ADRENOCORTICAL CARCINOMA
The incidence of adrenocortical carcinoma is approxi- mately 1-2 persons per million population per year [23]. The median age at diagnosis is 44 years; the disease has a bimodal distribution, with one peak in the first decade of life and the second peak in the fourth and fifth decades of life [2]. Localized adrenocortical carcinoma can poten- tially be cured by complete surgical resection. Unfortu- nately, the majority of cases of adrenocortical carcinoma
are diagnosed when the tumor has either metastasized or grown outside of the adrenal gland; only 30% of cases are diagnosed when the tumor is limited to the adrenal gland [23]. Sixty to 80% of adrenocortical carcinomas are functioning tumors, with excessive cortisol secretion being most common (30% of functioning tumors), fol- lowed by androgen (20%), estrogen (10%), and aldoster- one (1%-2%) hypersecretion [2]. Thirty-five percent of functioning adrenocortical carcinomas secrete multiple hormones [2]; in general, adrenal cortical tumors that secrete a combination of hormones are more likely to be malignant. Approximately two-thirds of patients with adrenocortical carcinoma have symptoms related to excessive hormone secretion or localized abdominal symptoms due to large tumor size or tumor invasion of adjacent structures [1].
On radiographic imaging such as CT scan or MRI, adrenocortical carcinomas usually appear heterogeneous, with irregular borders and focal areas of hemorrhage and necrosis [1,2]. The majority of adrenocortical carci- nomas are larger than 6 cm [2]. Radiographic imaging can also detect the presence of local invasion, regional lymph nodes, and metastases. The most common sites of metastases are peritoneum, liver, lung, and bone [2,23]. Figure 3 shows a CT scan from a patient with a large right-sided adrenocortical carcinoma.
The only chance for cure in patients with localized adrenocortical carcinoma is complete surgical resection, including regional lymph nodes and involved adjacent organs [23-27]. Open adrenalectomy is the operation of choice; there is minimal role for laparoscopic adrena-
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Large
lectomy for adrenal cortical tumors with invasion of adjacent organs, enlarged regional lymph nodes, or tumors larger than 10-12 cm in size because of the risks of capsular rupture and tumor spillage [1,2]. Hand- assisted laparoscopic adrenalectomy can be utilized in selected cases where intraoperative findings of tumor adhesions, invasion, or other features worrisome for malignancy are seen during laparoscopic adrenalectomy, but in general, open adrenalectomy is the safest operation for cases of known or suspected adrenocortical carci- noma. Patients with extracapsular invasion, lymph node involvement, or distant metastases are at high risk for recurrence [23].
Patients with unresectable or incompletely resected adrenocortical carcinoma can be treated with mitotane at doses of 10-12 g per day [23-30]. Mitotane is a derivative of the insecticide DDT, and causes direct necrosis and atrophy of the adrenal cortex. Unfortunately, the overall long-term efficacy of mitotane in the treatment of adrenocortical carcinoma is suboptimal: only 19%- 34% of patients who undergo mitotane treatment have a measurable partial remission from their disease [23]. However, mitotane has been shown to be highly effective for reducing hypersecretion of functioning tumors; ap- proximately 80% of patients with hormonally active tumors who undergo mitotane treatment will have a clinically significant decrease in hormone production [23]. Mitotane treatment is currently limited to patients with distant metastases and residual tumor after adrena- lectomy [23]. Studies of adjuvant treatment with mitotane after complete surgical resection of adrenocortical carci- noma have not shown any benefit [1]. The use of mitotane in conjunction with other chemotherapeutic agents for advanced adrenocortical carcinoma remains a subject of ongoing investigation, most notably in large European multicenter trials.
Patients taking mitotane for prolonged periods of time often suffer from gastrointestinal and neurologic toxicity, and these side effects are usually the limiting factor in the use of mitotane. In addition, hepatotoxicity, abnormal cholesterol metabolism, platelet dysfunction, and hypo- thyroidism have been reported after mitotane adminis- tration [28-30].
Other chemotherapeutic agents that have been studied include cisplatin, which induces short-term remission in approximately 30% of patients [23,31], and doxorubicin, which when used in combination with mitotane produced a response in fewer than 10% of patients in one study [32]. The role of these and other chemotherapeutic agents in patients with adrenocortical carcinoma remains un- resolved and is the subject of several ongoing multicenter clinical trials. Patients with localized but unresectable adrenocortical carcinomas can be treated with radiation therapy (4,200-5,000 rads for 4 weeks) [23]. Radiation
therapy can also be used for metastases to bone. The overall efficacy of radiation therapy for either primary adrenocortical carcinomas or adrenocortical carcinoma metastases has not yet been established.
The overall prognosis for adrenocortical carcinoma is poor, with a 5-year survival of between 15% and 60% [2,23]. Recurrence is common, even in patients who undergo complete operative resection. Approximately two-thirds of patients develop recurrence within 2 years of treatment; and 85% of patients eventually develop local recurrence or distant metastases [2,23].
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