ELSEVIER SAUNDERS
Laparoscopic adrenalectomy for malignancy
Cord Sturgeon, MDb, Electron Kebebew, MDa,b,*
a Department of Surgery, University of California, San Francisco, 513 Parnassus Avenue, S-320, San Francisco, CA 94143-0104, USA
Department of Surgery, University of California, San Francisco Comprehensive Cancer Center at Mount Zion Medical Center, 1600 Divisadero Street, Hellman Building, Room C3-47, San Francisco, California 94143-1674, USA
Laparoscopic adrenalectomy has become the preferred surgical approach for the treatment of benign functioning and nonfunctioning adrenal disorders [1]. When compared with open adrenalectomy in nonrandomized studies, laparoscopic adrenalectomy has been shown to be associated with less pain, shorter hospitalization and convalescence, less operative blood loss and need for transfusion, and fewer early and late incision complications [2- 6]. Because of these benefits and increasing expertise with laparoscopic adrenalectomy, some surgeons have expanded the indications for this procedure. Although controversial, resection of progressively larger adrenal neoplasms has been reported in the literature [7-9]. Potentially malignant primary tumors and adrenal metastases, once considered contraindications to a laparoscopic approach, are now being removed laparoscopically in some centers [10,11].
Unfortunately, in the majority of patients who present with a localized adrenal mass, there are no reliable preoperative biochemical, imaging, or cytologic criteria that help predict which tumors may be malignant and warrant an open approach. In this article, we review the clinical features and risk factors for primary and metastatic malignant adrenal tumors, and the results of laparoscopic adrenalectomy for these lesions. The optimal surgical approach may differ, depending on characteristics of the patient and tumor. Surgeons may choose diagnostic laparoscopy, laparoscopic adrenalectomy, hand-assisted adrenalectomy, or open adrenalectomy. The reader is
* Corresponding author. Department of Surgery, Mount Zion Medical Center, 1600 Divisadero Street, Hellman Building, Room C3-47, San Francisco, California 94143-1674. E-mail address: kebebewe@surgery.ucsf.edu (E. Kebebew).
provided with a rational management approach for adrenal neoplasms that may represent a primary or metastatic malignant tumor.
Primary adrenal neoplasms
Incidentalomas
Clinically inapparent, asymptomatic adrenal tumors identified by an imaging study performed for another indication are referred to as incidentalomas. The frequency of adrenal incidentalomas found on abdominal imaging studies is 1% to 4% [1]. The majority (36%-94%) are small, nonfunctioning, benign cortical adenomas [12]; however, some are found to be functioning or malignant. The prevalence of adrenocortical carcinoma among incidentalomas is approximately 5% [13-15]. The need for surgical resection of an incidentaloma is determined by hormonal hyperse- cretion or imaging features that are concerning for malignancy. Patients who have adrenal tumors with imaging findings of local invasion, regional lymphadenopathy, or metastases should have an open adrenalectomy.
Although the overall risk of an incidentaloma being a primary adrenal malignancy is estimated to be about 4% to 5% [13-15], this risk has been reported to increase to 10% for tumors larger than 4 cm [16], and to 25% to 98% for adrenal neoplasms larger than 6 cm in diameter [17-19]. Different size criteria for the removal of nonfunctioning adrenal tumors have been espoused, including equal to or larger than 3 cm [20,21], 4 cm [15,22-27], 5 cm [13,20,28,29], or 6 cm [19,30]. Our current approach is to resect adrenal incidentalomas larger than 3 cm in young patients with low operative risk, and 5 cm or larger in older patients with significant comorbidities [10,20]. Lesions initially too small to merit resection are removed if growth is observed during the follow-up period [10] (Fig. 1).
Malignancy should be suspected in association with the following findings: (1) large size [13,16,28,31]; (2) multiple elaborated hormones, or imaging studies demonstrating local or vascular invasion (Fig. 2); (3) adjacent lymphadenopathy; or (4) the presence of metastases [28]. Imaging studies demonstrating irregular tumor margins, heterogeneity, and hyper- density have also been reported to be predictors of malignancy [13], but may also be seen in benign tumors [16]. At the recent National Institutes of Health (NIH) conference on adrenal incidentaloma, it was concluded that a homogeneous mass with low attenuation (less than 10 Hounsfield units [HU]) on CT scan usually represents a benign adenoma [19].
Conn’s syndrome
Primary hyperaldosteronism (Conn’s syndrome) due to a cortical adenoma is almost never malignant. A laparoscopic approach has been shown to be a safe and effective method for the removal of these lesions [32].
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 tumors (no signs of local invasion, nodal or distant metastases)
· Imaging studies suggesting local or vascular invasion, lymphadenopathy or metastases.
· Few or no signs suspicious for malignancy on imaging studies (e.g. irregular tumor margins, heterogeneity, or hyperdensity)
· Imaging studies showing localized disease but signs suspicious for malignancy (irregular tumor margins, heterogeneity, hyperdensity)
· Small cortical tumors (<6cm)
· Metachronous metastases
· Large cortical tumors (>10cm)
· All aldosteronomas
· Rapid onset of virilization, feminization, or Cushing’s syndrome.
· Most pheochromocytomas
· Most cortisol, sex-steroid, or mineralocorticoid secreting tumors
· Multiple elaborated hormones
· Family history of malignant pheochromocytoma
Cushing’s syndrome
Primary diseases of the adrenal gland are responsible for up to 20% of cases of Cushing’s syndrome. Cortical adrenal adenomas are the most common, and account for 15% of cases. These benign tumors are usually unilateral, smaller than 4 cm, and secrete cortisol. Adrenocortical carcinomas (ACCs) may also be responsible for adrenocorticotropic hormone (ACTH)-independent Cushing’s syndrome. They are also usually
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unilateral, but in contrast to adenomas, they are usually larger than 6 cm, and may hypersecrete more than one hormone [28,33].
Virilizing or feminizing tumors
Adrenal tumors associated with sex-hormone hypersecretion are rare, but nearly always symptomatic. One third of these tumors are carcinomas. Routine screening for excess sex hormones is not necessary when evaluating incidentalomas; however, when a patient presents with an adrenal tumor and feminization, virilization, or isosexual precocious pseudopuberty, the measurement of sex steroids and their precursors confirms the diagnosis.
Approximately 20% to 34% of hormonally active ACCs cause virili- zation [22,23,28]. Conversely, one third of virilizing tumors are malignant [23]. Ninety-five percent of patients younger than 5 with ACCs present with virilization. The rapid onset of virilization in any age group is suggestive of ACC [28]. Feminizing tumors in adult males are almost always malignant [23], and approximately 10% of hormonally active ACC cause feminization [22].
Although adrenal neoplasms associated with excess sex steroid secretion are not necessarily malignant, there should be a high index of suspicion for ACC when this syndrome is encountered. A laparoscopic approach may be appropriate in syndromes of sex-steroid excess for lesions lacking imaging features suggestive of ACC.
Adrenocortical carcinoma
ACC is associated with a dismal prognosis. Fortunately, it is rare, accounting for only up to 0.2% of all cancers [34]. It has a bimodal incidence, with the first peak in the first decade (usually before age 5), and the second in
the fourth and fifth decades of life. Functioning ACC may secrete excess cortisol (~30%), androgens (~20%), estrogens (~10%), aldosterone (1%- 2%), or a combination thereof (~35%) [22]. Approximately 50% are hormonally functioning [15]. Both CT and MRI are useful in the evaluation of the primary tumor and for detecting regional disease, vascular and lymph node involvement, and liver and lung metastases. Adequate imaging is critical for the accurate staging of disease and operative planning. ACCs are usually larger than 6 cm, are heterogenous, have irregular margins, are locally invasive, and are associated with nodal or liver metastases (see Fig. 2) [28]. Patients who have a rapid onset of Cushing’s syndrome or virilization, feminization (in adult men), or the secretion of multiple hormones have a higher risk of ACC. Complete surgical resection is the only potentially curative treatment. Local disease at diagnosis and complete tumor resection are the two most important prognostic factors associated with an improved survival [35]. Five-year actuarial survival for patients with ACCs ranges from 16% to 60% [15,36]. Recurrent and metastatic disease is common, even in patients who undergo complete resection. Approximately two thirds of patients develop recurrence within 2 years, and approximately 85% eventually develop local recurrence or distant metastases [36,37].
Pheochromocytoma
A diagnosis of malignant pheochromocytoma can only be made reliably by the findings of local invasion, or nodal or distant metastasis. There are no accurate histologic criteria by which to make the diagnosis, and 2.5% to 26% of pheochromocytomas are malignant [38-42]. Some malignant pheochromocytomas are not recognized initially, and are only identified during follow up (Fig. 3) [43]. Malignant pheochromocytoma is more likely in extra-adrenal pheochromocytomas (30%-40%), tumors 6 cm or larger, dopamine-only secreting tumors, and in patients with postoperative persistent hypertension [29,43,44].
In the absence of local invasion or nodal or distant metastases on preoperative imaging, a laparoscopic approach should be considered. The choice of surgical approach is dictated by tumor size, signs of local invasion, and surgeon experience. Historically, an open anterior approach was used, because it allowed en-bloc tumor resection with exploration of the contralateral adrenal and possible metastatic sites. Due to the improved accuracy of localization studies, contralateral adrenal exploration is unnecessary. Furthermore, an evaluation of the liver and peritoneum for metastases is also possible with a laparoscopic transperitoneal approach.
Metastatic adrenal neoplasms
Although the adrenal gland is a common site for metastases from many cancers, the finding of an isolated metastasis is rare (Fig. 4). Fortunately,
5
cm
F
3
adrenal metastases are often confined within the adrenal capsule, which suggests that simple adrenalectomy may be sufficient to achieve negative margins [11,45,46]. There is growing evidence that suggests resection of isolated, metachronous adrenal metastases from various primary cancers (eg, lung, renal cell, colorectal, melanoma, and breast cancer) may improve survival [46-60]. Most studies demonstrate median survival of between 20 and 30 months following adrenal metastasectomy, as compared with 6 to 8 months in historical controls with unresected adrenal metastasis [55]. Nevertheless, resection of isolated adrenal metastases remains controversial, as is the role of laparoscopy for these lesions.
Risk assessment for malignant adrenal tumors
Tumor size
For nonfunctioning adrenal tumors, size has been used to stratify patients based on the likelihood of cancer into low- and high-risk categories. In many centers, a size threshold of ≥6 cm is used as an indication for adrenalectomy [18,30]. Unfortunately, many of the data supporting this position are from small surgical series. Numerous arguments to support tumor size thresholds between 3 cm and 6 cm can be found in the surgical literature [13,15,18-30]. At the recent NIH conference on adrenal incidentaloma [19], no consensus was reached regarding the optimal management of incidentalomas 4 cm to 6 cm in size, because of the lack of level-one clinical evidence.
Copeland [30] examined the data from six published series of patients with adrenal tumors, and reported that 92% of 114 ACCs in these series were > 6 cm. Ross and Aron [18], in a complimentary study, calculated that in the absence of imaging findings consistent with malignancy, less than 1 in
A
B
10,000 adrenal neoplasms smaller than 6 cm would be a carcinoma. They concluded that the likelihood of ACC is 35% to 98% in masses > 6 cm. Those clinicians who recommend observation for adrenal neoplasms smaller than 6 cm frequently cite these two studies.
In a multi-institutional retrospective study of 210 incidentalomas, Terzolo et al [13] reported that tumor size was the only independent factor associated with cancer. Their recommendation was to remove all lesions larger than 5 cm or with imaging characteristics suspicious for cancer. In this study, a threshold
for removal at a size > 5 cm had a sensitivity of 93%, a specificity of 64%, and positive and negative predictive values of 28% and 98%, respectively.
Based on their series of 38 ACCs, Barnett et al [61] concluded that all tumors that are functioning, suspicious for malignancy on radiographic studies (heterogeneity or hemorrhage), or 4 cm or larger should be resected.
We recently compared ACC cases from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database with cases of benign functioning or nonfunctioning adrenal cortical adenomas (exclud- ing aldosteronomas) that underwent adrenalectomy at our institution (Sturgeon C et al, submitted for publication, 2004). Four hundred and fifty- seven ACCs and 48 adrenal adenomas were identified. For localized ACCs, tumor size was the only significant predictor of malignancy. The sensitivity, specificity and likelihood ratios (LR) of tumor size to predict malignancy were 96%, 51%, and 2.0, respectively, for tumors ≥4 cm; 90%, 78%, and 4.1 for tumors ≥6 cm; and 77%, 93%, and 11.5 for tumors ≥8 cm. These data suggest that adrenalectomy for tumors ≥4 cm would yield a sensitivity of 96% for cancer, with a modest decrease in specificity compared with using 6 cm. Furthermore, for tumors > 8 cm, the specificity for cancer was 93%.
We also recently compared patients with malignant pheochromocytomas in the SEER database to patients treated for benign pheochromocytomas at our institution [62]. Ninety malignant and 56 benign pheochromocytomas were identified. Tumor size was significantly larger in the malignant group (7.6 ± 4.2 cm versus 5.3 ± 2.3 cm, P < 0.05). The sensitivity, specificity, and LR of tumor size to predict malignancy were 81%, 20%, and 1.0, respectively, for tumors ≥4 cm; 62%, 65%, and 1.8 for tumors ≥6 cm; and 44%, 89%, and 4.0 for tumors ≥8 cm.
The current literature suggests that 4 cm is a reasonable size threshold for the resection of most nonfunctioning cortical tumors. Although all pheochromocytomas should be resected, the exact tumor size threshold that is associated with a high risk of a malignant tumor is less clear.
Several reports have shown that imaging studies consistently underesti- mate the true size of adrenal neoplasms when compared with direct measurement at operation [61,63-66]. CT underestimates tumor size by 16% to 47%, and appears to be less accurate in smaller tumors. MRI may also underestimate tumor size by up to 20% [64]. This should be kept in mind when considering those tumors on the border of size thresholds for resection.
In light of the low morbidity and mortality of laparoscopic adrenalec- tomy, we use an aggressive size threshold for adrenalectomy of incidenta- lomas. It is our practice to observe nonfunctioning adrenal tumors <3 cm. We resect those tumors ≥3 cm in young, healthy patients, or those with suspicious imaging features, and recommend resection of all incidentalomas ≥5 cm (see Fig. 1). Regardless of the nature and size of the tumor, surgeons should not hesitate to convert to an open approach when they encounter signs of local invasion or any difficulty in dissection that may risk incomplete resection or tumor fracture.
Imaging features
Large tumor size (>6 cm), irregular tumor margin, heterogeneity, hemorrhage, necrosis, rapid tumor growth rate, adjacent lymphadenopathy, and density >10 HU on noncontrast CT have all been reported to be indicators of malignant potential on CT or MRI [22,67-69]. Metastases and local invasion into adjacent organs or the vena cava are common radiographic features of ACC (see Fig. 2). Central necrosis and calcifications are also common in ACC, the latter occurring in approximately 20% to 30% of cases [69]. Benign adrenal tumors such as cysts, hematomas, and myelolipomas can be usually identified based on characteristic CT scan findings.
In the study by Terzolo et al [13], most carcinomas were hyperdense or inhomogeneous, with irregular shape and margins. Larger adrenal tumor size was also associated with malignancy. Most adenomas in their series were hypodense, round or oval, and had smooth margins. Similar radiographic features of malignancy were noted by Barnett et al [61].
Most adenomas, because of their high lipid content, are hypodense on noncontrast CT scans [68]. Likewise, MRI T2-weighted signal intensity is low in adenomas. Unfortunately, the range of signal intensity has a 20% to 30% overlap with that of adrenal metastases [68,70]. Adrenal-to-liver signal intensity ratios, measured by T2-weighted MRI, have been investigated but found to be unreliable, because of the overlap between ACC and adenomas and the fact that in 20% of the cases, metastases could not be distinguished from nonfunctioning adenomas [70].
There is currently tremendous enthusiasm for the use of positron emission tomography (PET) scanning to detect metastatic disease in patients with a variety of cancers. Several reports suggest that malignant and metastatic lesions of the adrenal can be identified by PET scanning [68,71- 73], but these studies require further validation.
Radiocholesterol scintigraphy, using 131I-6-beta-iodomethyl-norcholes- terol (NP-59), has been used to determine if an adrenal cortical tumor is benign [74]. Nonfunctioning tumors with high NP-59 uptake are likely to be benign adenomas [75,76]. Decreased or no uptake of NP-59 is more likely with a cancer or space-occupying lesion [77,78]. Most ACCs have no uptake of NP-59 [24].
History of malignancy
In a patient with a history of an extra-adrenal primary malignancy, an adrenal incidentaloma represents metastatic disease in 32% to 73% of cases [10,79]. Many primary malignancies have the propensity to spread to the adrenal glands, including cancers of the colon, lung, stomach, breast, kidney, melanoma, and lymphoma. In fact, the most common malignant tumor found postmortem in the adrenal gland is a metastasis [48].
Several studies suggest that resection of metachronous isolated adrenal metastases may improve survival [45-50,52-56,59,79,80]. Suspicion of an
adrenal metastasis is an indication for FNA biopsy only when the information gained would change the clinical management. For example, in some cases, a patient might undergo systemic therapy instead of resection if an adrenal lesion is found to be a synchronous adrenal metastasis.
Functioning tumors
Approximately 50% of ACC are functioning at diagnosis. The risk of malignancy in functioning adrenal cortical neoplasms is variable. As previously mentioned, aldosteronomas are almost always benign. Catechol- amine levels do not distinguish benign from malignant pheochromocyto- mas. Cortisol, sex-steroid, or mineralocorticoid secreting tumors are more likely than aldosteronomas to be malignant, and the risk appears to be higher in larger tumors and tumors secreting multiple hormones [18,22,28,30]. The rapid onset of hormonal hypersecretion in cortical lesions is more common in ACC.
Syndrome association
Malignant pheochromocytomas and ACCs may occur sporadically, or as a component of several endocrine syndromes. ACC has been associated with multiple endocrine neoplasia type 1 (MEN 1), Beckwith-Widemann syndrome, and Li-Fraumeni syndrome. Pheochromocytomas in patients with familial syndromes are more likely to be benign and bilateral or multifocal, unless there is a family history of malignant pheochromocytoma [43,81,82]. Familial syndromes associated with the development of pheo- chromocytomas include MEN 2A and 2B and some neuroectodermal syndromes: von Recklinghausen’s neurofibromatosis (NF1), von Hippel- Lindau syndrome (VHL), Sturge-Weber syndrome, and tuberous sclerosis. Carney’s triad is associated with multifocal extra-adrenal pheochromocytomas.
Is fine-needle aspiration useful?
Ultrasound or CT-guided fine-needle aspiration (FNA) biopsy is advocated by some experts to distinguish malignant from benign adrenal tumors [83,84]. Disadvantages of this procedure are a high false-negative rate and the potential for complications, including seeding of the needle tract, hemorrhage, or fatal hemodynamic instability if the tumor is a pheochromo- cytoma [85]. For these reasons we do not use FNA. Furthermore, the FNA result rarely alters clinical decision-making regarding the need for adrenalectomy. FNA may be useful in patients with a history of prior malignancy who are found to have a very small adrenal lesion that would otherwise be observed. FNA may also be indicated when tumors of adjacent tissues (eg, retroperitoneal lymphoma or sarcoma) are possible diagnoses.
Results of laparoscopic adrenalectomy for cancer
Malignant pheochromocytoma
Despite more than 225 laparoscopically resected pheochromocytomas reported in the current literature [86], there is a lack of data on the long-term follow up of patients who have undergone laparoscopic adrenalectomy for malignant pheochromocytoma. The natural history of laparoscopic surgery for malignant pheochromocytoma is essentially unknown. In the pre- laparoscopic era, recurrence was observed in 6% to 8% of patients [87,88]. This is probably the benchmark to which recurrence after laparoscopic adrenalectomy will be compared. Li and colleagues [89] have reported three cases of pheochromocytomatosis following laparoscopic adrenalectomy; however, it is unclear if these cases represent dissemination of benign tumor following incomplete tumor resection and spillage, or malignant tumors. Malignant pheochromocytoma may recur early or late (see Fig. 3). Following open resection, patients with malignant pheochromocytoma have a variable disease-free survival [90-95]. Recurrence has been reported as late as 24 years following apparent curative resection [96]. For this reason, it may be impossible to detect a difference in recurrence with laparoscopic adrenalectomy. In addition, a randomized prospective trial comparing the two methods is not feasible considering the rarity of malignant pheochro- mocytoma, the difficulty in accurately diagnosing malignancy preopera- tively, and the distinct advantages of the laparoscopic technique.
Malignant primary cortical tumors (adrenocortical carcinomas)
Laparoscopic adrenalectomy is controversial for potentially malignant adrenal cortical tumors. The risk of locoregional recurrence, tumor dissemination, and port-site metastasis resulting from laparoscopic adre- nalectomy is unclear, because of the limited data in the literature and the variable frequencies of these events. Henry et al [97] reported a series of laparoscopic adrenalectomies for tumors larger than 6 cm that included six cases of ACC (Table 1). Half were nonfunctioning. At a mean follow up of 34 months (range 8-83 months) there was one patient who recurred with liver metastases and died. The other five patients were disease-free at follow up. In contrast, Porpiglia and colleagues [98] observed no locoregional recurrences or port-site metastases in four patients with ACCs who had laparoscopic adrenalectomy.
In our experience with laparoscopic adrenalectomies for suspected and unsuspected malignant adrenal neoplasms, six patients had ACCs [31]. In four patients these tumors presented as incidentalomas, and in two patients as Cushing’s syndrome. One lesion was suspected to be malignant preopera- tively, and the patient underwent open resection following diagnostic laparoscopy. The mean tumor size in these six patients was 6.6 cm. In the five patients who underwent laparoscopic adrenalectomy, three patients had
| Adrenal tumor | Author | Year | Total number of patients | Median/ Mean follow up | Local recurrence | Port site mets | Distant mets | Positive tumor margin |
|---|---|---|---|---|---|---|---|---|
| Primary | Henry [97] | 2002 | 6 | 33.8 mos | 0 | 0 | 1 | None |
| Porpiglia [98] | 2002 | 4 | 19 mos | 0 | 0 | 0 | NR | |
| Kebebew [31] | 2002 | 6 | 3.3 yrs | 3 | 0 | 0 | None | |
| Heniford [11] | 1999 | 1 | 8.3 mos | 0 | 0 | 0 | None | |
| Total | 17 | 25 mos | 3 | 0 | 1 | None | ||
| Metastasis | Sarela [46] | 2003 | 11 | 21 mos | NR | 0 | NR | None |
| Heniford [11] | 1999 | 11 | 8.3 mos | 0 | 0 | 3 | None | |
| Porpiglia [98] | 2002 | 4 | 19 mos | 1 | 0 | 0 | NR | |
| Rassweiler [99] | 2003 | 11 | 58 mos | 1 | 1 | 1 | None | |
| Feliciotti [100] | 2003 | 6 | 7 mos | 0 | 0 | 2 | None | |
| Kebebew [31] | 2002 | 13 | 3.3 yrs | 0 | 0 | 4 | None | |
| Chen [110] | 2002 | 1 | 5 mos | NR | 1 | 1 | NR | |
| Valeri [111] | 2001 | 6 | 19 mos | 0 | 0 | 3 | None | |
| Total | 63 | 22 mos | 2 | 2 | 14 | None |
Abbreviation: NR, not reported.
locoregional recurrences and none had port-site metastases, with a mean follow up time of 3.3 years. Although laparoscopic adrenalectomy in our series was associated with a high recurrence rate, the reported recurrence rate for ACC following open resection is approximately 67% [36]. Most series of open adrenalectomy for ACC published before 2000 report a 5-year actuarial survival of about 45% (range 32%-58%) for patients who undergo complete resection and a median survival of less than 1 year (range 2-16 months) for patients who undergo incomplete resection [22].
Although it appears that the survival rate, locoregional recurrence, and distant metastasis may be similar to open adrenalectomy, there are insufficient data to conclude that the results of laparoscopic adrenalectomy for ACC are equivalent to those of open adrenalectomy. Furthermore, in most reports of laparoscopic adrenalectomy for ACC, a cancer diagnosis was not established or suspected preoperatively. Because the ACCs in these reports were localized tumors, possibly representing less aggressive disease, results may not reflect the true survival and risk of locoregional recurrence or port-site metastasis.
Metastatic tumors
Adrenalectomy for isolated, metachronous adrenal metastasis appears to result in improved survival. This was originally demonstrated in studies on open adrenalectomy. Most studies demonstrate a median survival of
between 20 and 30 months following adrenal metastasectomy, as compared with an expected 6 to 8 months without adrenalectomy [55]. Nevertheless, resection of isolated adrenal metastases remains controversial, as is the role of laparoscopic adrenalectomy.
Haigh et al [59] showed that potentially curative open adrenalectomy for melanoma metastatic to the adrenal gland (see Fig. 4) is associated with improved survival as compared with palliative or no surgery (median survival 25.7, 9.2, and 7.7 months, respectively). Luketich and Burt [47] showed that open adrenalectomy for non-small cell lung cancer metastases improved median survival compared with chemotherapy alone (31 versus 8.5 months), and resulted in a 3-year actuarial survival of 38%.
In a series of 37 open adrenalectomies for adrenal metastasis from various primary tumors, Kim et al [55] observed that complete tumor resection conferred a survival advantage in patients diagnosed after a disease-free interval (DFI) of greater than 6 months. The median survival was 21 months, and the 5-year survival was 24%. Sarela et al [46] updated this series with an additional 41 patients and compared open with laparoscopic adrenalectomy (30 open and 11 laparoscopic). In this study, lung cancer was the most common primary, followed by renal cell cancer. The overall median survival was 28 months, and the 5-year actuarial survival was 29%. They found no difference in positive resection margin or survival between open and laparoscopic adrenalectomy. There were no incisional or port-site recur- rences. They also found that DFI greater than 6 months was the only significant predictor of improved survival.
Heniford et al [11] reported 12 laparoscopic adrenalectomies for cancer (1 primary and 11 adrenal metastases). The most frequent metastasis was from renal cell carcinoma (40%). All specimens had negative histologic margins. At a follow-up of 8.3 months there were no local or trocar site recurrences, but there was one death from melanoma metastasis to the brain.
In four patients with adrenal metastasis who had laparoscopic adrenal- ectomy, Porpiglia et al [98] observed one locoregional recurrence in a patient with breast cancer but no port-site metastases or carcinomatosis during a median follow-up period of 19 months. Rassweiler et al [99] reported one local recurrence and one port-site metastasis after laparoscopic adrenalec- tomy for adrenal metastases from renal cell carcinoma (8), lung cancer (2) and melanoma (1). In contrast, Feliciotti et al [100] observed no local recurrence or port-site metastasis in six patients who underwent laparoscopic adrenalectomy for adrenal metastasis from renal cell carcinoma (2), lung cancer (1), gastric cancer (1), melanoma (1), and breast cancer (1). After a mean follow-up time of 7 months, four patients were disease-free and two patients died from metastatic disease (at 15 and 24 months, respectively).
We recently reviewed our experience in 17 patients with adrenal metastasis who underwent laparoscopic adrenalectomy [31]. The most frequent primaries were non-small cell lung cancer (41%), and renal cell cancer (18%). All surgical margins were negative. At a mean follow-up of 3.3 years,
there were no locoregional and trocar site recurrences, but there were four distant recurrences.
These data show that the laparoscopic approach for suspected adrenal metastasis may be both diagnostic and therapeutic, and can be used to achieve complete tumor resection. For adrenal metastasis, the indications for laparoscopic adrenalectomy may be: (1) curative intent for solitary adrenal metastasis, (2) palliative intent for large symptomatic lesions, and (3) diagnostic. Most studies show no difference in survival or resection margin status between laparoscopic and open adrenalectomy.
Caveats to selecting the approach to adrenalectomy
All adrenal masses should be regarded as potentially malignant, regardless of tumor size, imaging characteristics, and clinical manifestations. Laparoscopic adrenalectomy should be cautiously performed, with the goals of achieving complete tumor resection without disruption of the adrenal capsule. This is especially important because an initial complete resection represents the best opportunity to cure patients, and even small primary adrenal tumors may be malignant. The principles of oncologic surgery should not be compromised to provide the patient with a laparoscopic operation. Regardless of the risk factors for cancer, if a complete resection cannot be performed safely, the operation should not be continued laparoscopically.
Laparoscopy should be the initial step in the surgical approach to localized primary adrenal tumors. Laparoscopic techniques can be used to establish if the tumor has features suggestive of malignancy, such as intra- abdominal metastases, local invasion, obliterated peri-adrenal tissue planes, or regional lymphadenopathy. Such an approach offers laparoscopic adrenalectomy to the majority of patients who have a benign primary adrenal tumor, while allowing selective conversion to an open approach for those with a high likelihood of malignancy.
Surgeon experience is important to consider. Laparoscopic adrenalec- tomy is more difficult and requires a more experienced surgeon when there is a history of prior upper abdominal surgery or when tumors are larger than 8 or 10 cm. In addition, tumors that are large are not only more difficult to resect laparoscopically, but they are more likely to be malignant.
Summary
Most studies show that the results of laparoscopic adrenalectomy for cancer are similar to those of open adrenalectomy, without the morbidity of an open approach. It is important to note, however, that: (1) the diagnosis of ACC was often made retrospectively without clinical recognition of a malignant tumor preoperatively; (2) most of the tumors removed laparoscopically showed no suspicious features of ACC preoperatively, and
thus may represent earlier stage or less biologically aggressive tumors; and (3) small, retrospective cohort series do not establish equivalency between techniques.
Although concerns have been raised regarding the risks of peritoneal carcinomatosis, local recurrence, and port-site metastases following laparo- scopic adrenalectomy [101-103], most larger cohort series have not observed an increased frequency of these events [11,31,46,98,99,100]. Furthermore, in larger cohort studies or prospective nonrandomized studies, laparoscopic resection of other more common primary intra-abdominal malignancies (colon and renal cell) have not demonstrated an increased risk of local recurrence, peritoneal dissemination, or port site recurrence [99,104-109].
In our view, a laparoscopic approach is contraindicated for known malignant primary adrenal tumors, or those tumors with local or vascular invasion (see Fig. 1). A laparoscopic approach can be used for most incidentalomas, because the risk of a primary malignant adrenal tumor is low [14,15]. A primary malignant adrenal tumor is more likely if the following findings are present: (1) large size; (2) hypersecretion of multiple hormones, and imaging studies demonstrating local or vascular invasion; (3) adjacent lymphadenopathy; or (4) the presence of metastases [13,16,28,31]. Imaging features such as irregular margins, heterogeneity, and attenuation coefficients > 10 HU on noncontrast CT have also been cited to be more common in malignancy [13], but may also be seen in benign lesions [16]. Laparoscopic resection is appropriate in selected patients with solitary metastases to the adrenal gland from cancers of the lung, kidney, colon, breast, and melanoma, and the indications for laparoscopic metastasectomy should be the same as for an open approach.
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