BIOL
WORLD Journal of SURGERY @ 2001 by che Société Internacionale de Chirurgie
Adrenal Cortical Carcinoma
Alan P.B. Dackiw, M.D., Ph.D.,1 Jeffrey E. Lee, M.D.,1 Robert F. Gagel, M.D.,2 Douglas B. Evans, M.D.1
1Department of Surgical Oncology, Section of Endocrine Tumor Surgery, Box 444, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77033, USA
2Department of Internal Medicine Specialties, Section of Endocrine Neoplasia and Hormonal Disorders, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
Published Online: June 27, 2001
Abstract. Adrenal cortical carcinoma is a rare endocrine tumor for which complete surgical resection is the only potentially curative treatment. Accu- rate preoperative evaluation (biochemical and radiographic) of the patient who presents with an adrenal mass maximizes the opportunity for the patient to undergo a complete, margin-negative resection of the primary tumor, which is the most powerful prognostic variable for long-term survival. The response to chemotherapy or mitotane is modest in patients with advanced disease. Hopefully, an improved understanding of the molecular pathogen- esis of this challenging tumor will lead to the development of more effective therapies in the future.
Adrenal cortical carcinoma is a rare endocrine neoplasm with a worldwide incidence of approximately two per million population [1]. There is a bimodal age distribution with an increased inci- dence in children less than 5 years of age and in individuals in the fourth and fifth decades of life [2]. Among 1891 cases reported in the English-language literature, adrenal cortical carcinomas were slightly more common in women (58.6%) than in men (41.4%) [3]. Tumors may be functional or nonfunctional, depending on whether they produce cortisol, aldosterone, androgens, or estro- gens. More than 50% of patients with adrenal cortical cancers have clinical evidence of excess hormone production. The etiology of adrenal cortical carcinoma is unknown, although recent studies documenting chromosomal abnormalities and alterations in growth factor production have provided insight into possible mechanisms of molecular pathogenesis. Epidemiologic studies have suggested an increased risk of adrenal cortical cancer in association with cigarette smoking in men and with the use of oral contraceptives in women [4]. Laboratory evidence in support of these data includes reports that adrenal tumors occur in ovariec- tomized mice and in rats given exogenous estrogens [5, 6]. In addition, in a study of cigarette smoke inhalation in rats, research- ers noted a low but statistically significant increase in the expected incidence of adrenal cortical carcinomas and adenomas [7].
Complete surgical resection is currently the only potentially curative therapy for localized adrenal cortical carcinoma. Locally
recurrent or isolated distant metastatic disease may also be ame- nable to surgical resection in carefully selected patients. Response rates to cytotoxic systemic chemotherapy and the adrenolytic agent mitotane have been modest, and the available data are reviewed here in detail. Improved treatment strategies are clearly required for this carcinoma and will likely be developed as our understanding of the molecular pathogenesis of this neoplasm increases.
Molecular Pathogenesis
Studies of the genetic alterations in adrenal cortical tumors have revealed the involvement of multiple chromosomal loci correlate with regions that are abnormal in familial cancer syndromes. Such syndromes include the Li-Fraumeni syndrome (p53 gene on17p13); multiple endocrine neoplasia type I (MEN-I; MEN1 gene on 11q13); Beckwith-Wiedemann syndrome (11p15.5), which correlates with the overproduction of insulin-like growth factor (IGF) II; and the Carney complex (2p16) [8]. Yano et al. [9] also reported a loss of heterozygosity (LOH) on chromosomes 1lp, 13q, and 17p in adrenal cortical carcinomas and their meta- static lesions but not in adenomas or hyperplastic lesions. Subse- quent studies using comparative genomic hybridization analysis showed an aneuploid DNA pattern and loss of genetic material in chromosomes 2, 11q, and 17p as well as gains in chromosomes 4q and 5. In addition, the only benign cortical tumors found to have these genetic changes were 5 cm or more in diameter, suggesting that clonal proliferation and genetic instability lead to malignant transformation in enlarging cortical tumors [10]. A subsequent report from this group and others described LOH at 11q13, the site of the MENI gene, but it was not associated with a MEN1 mutation, suggesting involvement of a second tumor suppressor gene on this chromosome [11-13]. A loss of genetic material at 2p16 (the locus for the Carney complex familial cancer syndrome) was also observed to be strongly associated with the malignant phenotype [11]. A recent report described extensive chromosomal aberrations in cortical tumors, including a consistent gain of ge- netic material in the chromosomal region 9q34, suggesting the
existence of a genetic defect at this site that further contributes to tumorigenesis [14].
Fogt et al. [15] reported finding LOH in 61% of adrenal cortical carcinomas in at least one of five microsatellites, including 17p (p53), 1p, 9p (p16), 3p (VHL), and 13q (retinoblastoma). In contrast, none of the cortical adenomas studied demonstrated LOH at any of these gene markers. These data suggest that genetic analysis could serve as a useful adjunct to the standard histologic evaluation of surgical specimens for distinguishing ma- lignant from nonmalignant adrenal cortical neoplasms [10].
The tumor suppressor gene p53 has also been implicated in the pathogenesis of adrenal cortical cancer. For example, McNicol et al. [16] reported positive immunohistochemical staining for p53 in 22 of 42 adrenal cortical carcinomas. DNA was amplified in 21 of these tumors, and mutations were found in 10 of the 21 specimens by direct sequencing of exons 5 through 8. Although these findings suggested a role for p53 in tumorigenesis, there was no association between positive immunostaining or mutational analysis findings and overall or disease-free survival. A previous report by Reincke et al. [17] described p53 immunoreactivity in 5 of 11 adrenal cortical carcinomas, 3 of which had mutations in exons 5 through 8 shown by direct DNA sequencing. It has also been suggested that the high frequency of germline p53 mutations in children with sporadic adrenal cortical cancer may identify probands of the Li-Fraumeni syndrome in at-risk families [18]. Screening for p53 germline mutations in children who present with adrenal cortical cancer may have important genetic counseling implications, in- cluding the identification of early-onset breast cancer, a Li-Frau- meni syndrome-associated malignancy, in the mothers of affected children [18].
In adrenal cortical neoplasms, malignancy is strongly associated with overexpression of the IGF gene and abnormalities at the 11p15 locus [19]. IGFI and IGFII are involved in growth and differentiation of the adrenal cortex. Specifically, IGFI is the principal mediator of growth hormone action during postnatal life, and IGFI and IGFII and their receptors are produced by most human tissues. High levels of IGFI and IGFII have been shown to be produced in functional adrenal cortical carcinomas; and increased levels of IGF, its binding protein, and its receptor are associated with malignancy, suggesting that these molecules play a role in adrenal cortical tumorigenesis and the autocrine/ paracrine regulation of adrenal cortical tumor growth [20-23]. Another study has documented that LOH of the adrenocortico- tropin receptor may be involved in tumorigenesis and cellular dedifferentiation in adrenal cortical cancer [24]. The K-ras onco- gene does not, however, appear to play a role in adrenal cortical tumorigenesis [25].
Clinical Presentation and Diagnostic Evaluation
Patients with nonfunctioning tumors usually present with abdom- inal pain or pressure secondary to a mass effect. Other less common symptoms of nonfunctioning tumors are weight loss, malaise, hematuria, varicocele, and dyspnea [26]. Functioning adrenal cortical neoplasms most commonly produce cortisol, which is clinically apparent in at least 30% of patients [27, 28]. Less commonly, tumors produce androgens (20%), estrogens (10%), or aldosterone (2%). A mixed pattern of hormone pro- duction is seen in up to 35% of patients. The rapid onset of
Cushing syndrome, often with virilizing features, is characteristic of adrenal cortical carcinoma.
The diagnostic evaluation of a patient with a unilateral adrenal mass includes measurement of serum electrolyte levels to exclude hypokalemia secondary to aldosterone excess, an overnight 1-mg dexamethasone suppression test, a 24-hour urine collection for 17-ketosteroids if a masculinizing or feminizing adrenal tumor is suspected, and a 24-hour urine collection to measure catechol- amine (and metanephrine) concentrations if pheochromocytoma has not been excluded. Our rapid office evaluation begins with obtaining an afternoon blood sample for cortisol and electrolyte measurements and a 24-hour urine collection to measure vanillyl- mandelic acid, metanephrine, and catecholamine concentrations. Dexamethasone (1 mg) is then taken at 10:00 p.m. that evening, and the following morning at 8:00 a.m. blood is obtained for plasma cortisol analysis. During the afternoon of the second day, patients return their timed urine collection specimen. If the pa- tient’s plasma cortisol level is not suppressed below 5.0 µg/dl, the patient undergoes a second timed 24-hour urine collection, this time to measure the cortisol, 17-hydroxysteroid, and 17-ketoste- roid concentrations.
The size of the adrenal mass, as measured on computed tomog- raphy (CT) or magnetic resonance imaging (MRI), remains the single best indicator of malignancy. In a clinical review of six reported series, Copeland [29] in 1983 reported that 92% (105/ 114) of adrenal cortical carcinomas were > 6 cm in diameter. In contrast, large adrenal adenomas (> 6 cm) are probably uncom- mon, although the exact frequency is unknown. Ross and Aron [30] assumed that 0.01% or 1% of adenomas were > 6 cm in diameter and, based on this assumption, calculated that fewer than 1 in 10,000 adrenal neoplasms < 6 cm in diameter would be a cortical carcinoma (in the absence of CT characteristics suggest- ing malignancy, i.e., irregular borders, lack of homogeneity). They further estimated that the likelihood of adrenal cortical carcinoma increases to 35% to 98% in patients with an adrenal mass > 6 cm. In fact, their widely read 1990 article established the routine practice of operating on patients with nonfunctioning unilateral adrenal neoplasms ≥ 6 cm and considering observation in patients with smaller lesions. However, there are reasonable concerns over this recommendation: (1) the calculations made by Ross and Aron were based on an estimate of the frequency of large (> 6 cm) adrenal adenomas, a number that, although probably low, is un- known; (2) adrenal cortical cancer is an aggressive malignancy, and there are no data to support the safety of observing an enlarging adrenal cancer (until it reaches 6 cm); and (3) small (< 5 cm) adrenal cortical cancers have been documented in a number of reported series (Table 1). Therefore clinical reality suggests that few endocrine surgeons would observe a 4 or 5 cm unilateral adrenal mass (regardless of CT characteristics) in an otherwise healthy 40- to 50-year old patient [44].
This point was underscored by the results of a multiinstitutional retrospective study of incidentally found (and nonfunctional) ad- renal neoplasms reported by Terzolo et al. [34]. Of the 210 patients in the study, 115 (54%) underwent adrenalectomy and adrenal cortical carcinoma was found in 15 patients (13% of operated patients and 7% of patients with incidental adrenal neoplasms). Of the 15 cancers, 3 were < 6 cm in diameter (2.6% of operated patients and 1.4% of patients with incidental adrenal neoplasms): In all three of these patients the radiographic char- acteristics suggested malignancy (i.e., inhomogeneous density, ir-
| Study | No. of patients Year Total Tumors < 5 cm | Size of tumors < 5 cm | ||
|---|---|---|---|---|
| Barnet [31] | 2000 | 38 | 5 | 1.7-4.5 |
| Favia [32] | 2000 | 20 | 7 | 3-4 |
| Angeli [33] | 1997 | 39 | 4 | < 4.0 |
| Terzolo [34] | 1997 | 15 | 1 | 3.7 |
| Linos [35] | 1996 | 2 | 2 | 3.0-4.5 |
| Zografos [36] | 1994 | 53 | 6 | < 5.0 |
| Icard [37] | 1992 | 41 | 3 | < 5.0 |
| Pommier [26] | 1992 | 73 | 3 | < 5.0 |
| Yamakita [38] | 1990 | 68 | 5 | < 3.0 |
| Fishman [39] | 1987 | 38 | 2 | 3.0-3.5 |
| Didolkar [40] | 1981 | 42 | 1 | 1.0 |
| Sullivan [41] | 1977 | 28 | 1 | < 5.0 |
| Tang [42] | 1975 | 16 | 3 | 0.7-4.0 |
| Bradley [43] | 1975 | 15 | 1 | 3.0-4.0 |
regular shape and margins). Thus, tumor diameter was highly correlated with the risk of cancer; a diameter of 5 cm had a sensitivity of 93% and a specificity of 64% for identifying adrenal cortical carcinoma. Taking this somewhat further, if the 5 cm size criterion had been used as an indication for adrenalectomy, one would have observed one carcinoma (diameter 3.7 cm) among the 15 patients with cancer. The CT characteristics of this tumor, as noted above, did provide an adequate indication for adrenalec- tomy. During the same 5-year period 16 patients with functional adrenal cortical cancers were treated at the authors’ institutions; none of these tumors were < 6 cm in diameter. On the basis of these findings, the authors recommended surgical excision of adrenal neoplasms > 5 cm in diameter and those of any size with suspicious imaging characteristics.
Similar data were recently published from our institution [31]. Five of 38 adrenal cortical carcinomas were < 5 cm in size; imaging characteristics were suggestive of malignancy (heteroge- neity, irregular shape, irregular margins or hemorrhage on CT, lack of fat suppression on MRI out-of-phase gradient imaging, or heterogeneous signal intensity on T2-weighted MRI) in 4 of 5 patients. The one patient with a < 5-cm adrenal cortical carci- noma and imaging (CT) characteristics which suggested benign disease, had a 4-cm functioning tumor. Therefore, in our experi- ence over the last 30 years, all adrenal cortical carcinomas were either functioning, accompanied by characteristic radiographic findings of malignancy, or were 4 cm in size or larger.
The CT and MRI criteria assume increased importance when evaluating nonfunctioning tumors 3 to 5 cm in diameter. CT characteristics of malignancy include tumor inhomogeneity, irreg- ular shape, and irregular margins [45]. MRI characteristics of malignancy include the signal intensity on T2-weighted images, with adenomas being of low signal intensity comparable to liver (adrenal mass/liver ratio ≤ 1.4), cortical carcinomas and metas- tases are moderately bright (adrenal mass/liver ratio 1.2-2.8), and pheochromocytomas usually are extremely bright (adrenal mass/ liver ratio ≥ 3.0) [46]. Unfortunately. the use of signal intensity ratios to differentiate benign from malignant neoplasms may be unreliable because these ratios overlap in up to 40% of cases [46, 47]. Modifications in the MRI technique that may help improve differentiation of benign and malignant tumors include the intra- venous injection of gadolinium (adenomas show slight enhance- ment and rapid washout; malignant lesions and pheochromocyto-
8.0cm
mas show significant enhancement and slower washout) and T1- weighted chemical shift imaging (depending on the difference in the fat content between benign and malignant neoplasms) [48, 49].
On the basis of a review of the literature and individual expe- rience, the recent recommendations of investigators in endocrine surgery have included resection of nonfunctioning adrenal masses ≥ 3 cm [44], ≥ 4 cm [50, 51], and ≥ 5 cm [34]. At The University of Texas M. D. Anderson Cancer Center, our current practice is to recommend adrenalectomy for all biochemically confirmed functioning cortical neoplasms and those with suspicious radio- graphic findings regardless of tumor size. Nonfunctioning tumors with benign radiographic characteristics 4-cm in size or larger are considered for surgical resection if patient age and general health are acceptable. One obviously cannot be overly dogmatic with regard to the radiographic assessment of tumor size; nonfunction- ing, radiographically benign adrenal cortical neoplasms in the 4-cm range require individualized treatment based on patient age and comorbid conditions. For example, we would recommend adrenalectomy in a healthy 50-year-old woman (adrenal cortical cancers cluster in the 40- to 50-year age range and are more common in women) with a 4-cm unilateral nonfunctioning adre- nal neoplasm. In such a patient, there are no data to suggest that careful follow-up, no matter how frequent, can detect malignancy, if it were to exist, at a curable stage. Therefore. because of her relatively long life expectancy and the high risk of death from disease if the adrenal cortical cancer is not cured at the first surgical procedure, we would proceed with adrenal resection irrespective of radiographic characteristics. In contrast, in a 75- year-old man with a similar 4-cm unilateral nonfunctioning adre-
| Stage | Macfarlane [54] | Sullivan [53] | Icard [27] | Lee [55] |
|---|---|---|---|---|
| I | T1 (≤ 5 cm), NO, MO | T1 (≤5 cm), NO, MO | T1 (≤ 5 cm). NO, MO | T1 (≤ 5 cm), NO, MO |
| II III IV | T2 (>5 cm), NO, MO T3 (local invasion without involvement of adjacent organs) or mobile positive lymph nodes, M0 T4 (invasion of adjacent organs) or fixed positive lymph nodes or M1 (distant metastases) | T2 (>5 cm), NO, MO T3 (local invasion), NO, MO or T1-2, N1 (positive lymph nodes), MO T4 (local invasion), NO, MO or T3, N1, M0 or T1-4, N0-1, M1 (distant metastases) | T2 (> 5 cm), NO, MO T3 (local invasion) and/or N1 (positive regional lymph nodes), M0 T1-4, N0-1, MI (distant metastases) | T2(> 5 cm), NO, MO T3/T4 (local invasion as demonstrated by histologic evidence of adjacent organ invasion, direct tumor extension to IVC, and/or tumor thrombus within IVC or renal vein) and/or NI (positive regional lymph nodes), MO T1-4, N0-1, M1 (distant metastases) |
IVC: inferior vena cava.
| Study | Institution | Year | No. | Margin analysis | Median follow-up (months) | Overall. survival (months) | 5-Year actuarial survival (%) |
|---|---|---|---|---|---|---|---|
| Harrison [56] | MSKCC | 1999 | 46 | No | 20 | 28+ | 36 |
| Khorram-Manesha [57] | Sweden | 1998 | 18 | No | 85 | - | 58 |
| Crucitti [58] | Italy | 1996 | 91 | No | - | 28℃ | 48 |
| Lee“[55] | MDACC | 1995 | 16 | Yes | 43 | 46b | 46 |
| Zografos [36] | Roswell Park | 1994 | 15 | No | - | 136 | 38 |
| Haak [59] | Netherlands | 1994 | 47 | No | - | - | 49 |
| Icarde [27] | France | 1992 | 127 | No | - | - | 42 |
| Icard [37] | France | 1992 | 31 | No | - | 44€ | 45 |
| Pommier“ [26] | MSKCC | 1992 | 53 | No | 28 | 28€ | 47 |
| Gröndal“ [60] | Sweden | 1990 | 22 | No | - | - | - |
| Henley [6]] | Mayo Clinic | 1983 | 31 | No | - | - | 32 |
MDACC: M.D. Anderson Cancer Center; MSKCC: Memorial Sloan-Kettering Cancer Center. “Includes patients who underwent resection of synchronous metastatic disease. Median.
‘Mean.
nal neoplasm, we would likely recommend observation unless radiographic criteria were strongly suggestive of malignancy [31].
Fine-needle aspiration (FNA) biopsy of an isolated adrenal mass should be performed only in patients with a history of cancer or if there is clinical, laboratory, or radiographic evidence of a primary extraadrenal malignancy. There is no indication for ad- renal biopsy in the absence of presumed metastatic cancer to the adrenal. It is critically important to exclude pheochromocytoma before performing a biopsy because of the risk of percutaneous biopsy triggering severe hypertension in a patient with a cate- cholamine-secreting tumor (Fig. 1). Furthermore, occult meta- static cancer presenting as a small, unilateral, asymptomatic ad- renal mass is rare; therefore, perform FNA biopsy in all patients with hormonally inactive adrenal masses to detect occult meta- static cancer would result in a large number of unnecessary biop- sies [52].
Staging
The Sullivan modification [53] of the Mcfarlane system [54] for staging adrenal cortical carcinoma is the most widely used staging system. In contrast to most modern staging systems for solid
tumors, this system groups patients with evidence of adjacent, direct organ invasion and positive lymph nodes with those who have distant metastatic disease. Icard et al. [27] and Lee et al. [55] have suggested modifications to this system that would classify patients with locally advanced tumors in stage III and only pa- tients with distant metastatic disease in stage IV (Table 2). These modifications to the traditional staging systems of Mcfarlane and Sullivan more accurately reflect the natural history of the disease and correlate more closely with cancer staging systems used for other solid tumors.
Treatment
Surgery
Complete surgical resection is the only potentially curative treat- ment for adrenal cortical carcinoma. The strongest predictor of outcome in this disease is the ability to perform a complete resection. A number of series have demonstrated that the 5-year actuarial survival ranges from 32% to 48% for patients who undergo complete resection (Table 3) [26, 27, 36, 37, 55-61]. However, in our experience [55] and in that of others [62-65],
| Study | Institution | Year | No. | Median survival (months) |
|---|---|---|---|---|
| Crucitti [58] | Italy | 1996 | 33 | 16 |
| Lee [55] | MDACC | 1995 | 7 | 8.5 |
| Zografos [36] | Roswell Park | 1994 | 28 | 2 |
| Icard [27] | France | 1992 | 28 | < 12 |
| Icard [37] | France | 1992 | 10 | < 4 |
| Gröndal [60] | Sweden | 1990 | 12 | 10 |
| Henley [61] | Mayo Clinic | 1983 | 14 | <6 |
Patients with incomplete resections included those who underwent incomplete resection of the primary tumor and those who underwent complete resection of the primary tumor in the presence of unresectable distant metastatic disease.
neither extended resection nor the presence of tumor thrombus in the inferior vena cava (IVC) or renal vein predicted a poor prognosis in patients who underwent complete resection. Veno- venous bypass or cardiac bypass techniques may be necessary in patients with tumor extension to the IVC [62, 64, 65]. In contrast, patients who undergo incomplete resection of adrenal cortical carcinomas (less than total resection of the primary tumor or resection of the primary tumor in the setting of unresectable metastatic disease) have a uniformly poor prognosis with a me- dian survival of less than 1 year (Table 4) [27, 36, 37, 55, 58, 60, 61]. Therefore, resection should be performed only if preopera- tive imaging studies indicate that a complete margin-negative resection is possible.
In a report from Memorial Sloan-Kettering Cancer Center, pathologic prognostic factors were analyzed in 46 patients who underwent a complete, potentially curative resection for localized adrenal cortical carcinoma [56]. Predictors of short survival were tumor diameter > 12 cm, six or more mitotic figures per 10 high-power fields, and the presence of histologic evidence of intratumoral hemorrhage. All seven patients whose tumor speci- mens exhibited all three of these risk factors were dead within slightly over 2 years from the time of complete resection of their primary tumor. The six patients whose tumors exhibited no patho- logic risk factors had a 5-year survival of 83%; this survival de- creased to 42% for tumors with one risk factor and to 33% for tumors with two risk factors. Therefore pathologic variables pre- dicted aggressive biologic behavior in a small subset of patients who underwent a complete margin-negative resection. For most patients, however, the technical aspects of tumor resection remain critical for completion of a margin-negative resection, the most important predictor of survival.
We recommend a transabdominal approach through a subcos- tal incision for any suspected or proven adrenal cortical malig- nancy. This facilitates the maximal exposure necessary for com- plete resection, minimizes the chance for tumor spillage, and allows vascular control of the IVC, aorta, and renal vessels when necessary. The surgeon performing operative procedures for ad- renal cortical carcinoma should be prepared for the en bloc resection of contiguous structures including the liver, IVC, kidney, spleen, and pancreas. Areas of technical difficulty during resection of large adrenal tumors are predictable on the basis of fundamen- tal anatomic considerations. For example, a locally invasive right adrenal cortical carcinoma commonly invades the posterior seg-
Portal v.
Common bile duct
Pancreas
Doudenum
Aorta
IVC
Splenic a.
Left gastric a. Common hepatic a.
IVC
SMA
ment of the right hepatic lobe and the IVC (Fig. 2). Positive resection margins can be expected if blunt dissection is used to separate a locally invasive tumor from these structures. Complete mobilization of the liver combined with proximal and distal con- trol of the IVC should therefore be performed routinely at the
time of right adrenalectomy. Large right adrenal tumors may require a thoracoabdominal approach to adequately contend with tumor-induced compression of the liver, which may otherwise prevent the successful hepatic mobilization necessary for vascular control of the suprahepatic IVC. Incomplete resection of a large left adrenal cortical carcinoma is usually due to tumor extension along the mesenteric plexus at the origin of the celiac axis (Fig. 3). Tumor encasement of the celiac axis, aorta, or proximal superior mesenteric artery represents clear evidence of a locally unresect- able tumor. These vital tumor-vessel relations should be apparent before operation on contrast-enhanced CT images. Intraoperative assessment of the relation of a large left adrenal tumor to the celiac axis or proximal superior mesenteric artery is extremely difficult, may be associated with iatrogenic arterial injury, and when incorrect is likely responsible for the high incidence of incomplete tumor resection.
Laparoscopic adrenalectomy should be reserved for resection of presumed benign cortical tumors (< 3 cm in diameter), aldo- steronomas, and pheochromocytomas and for the rare patient who requires adrenalectomy for metastatic disease. Laparoscopic resection of a possible cancer should be done only by surgeons who believe they can technically perform the operation better laparoscopically [66]. In fact, a review of laparoscopic adrenalec- tomy indicated that tumors up to 10 cm in diameter may be approached laparoscopically by experienced surgeons [67]. The authors go on to state that, for any size of tumor, if tissue planes suggest the existence of cancer biopsies should be performed; and if the results are positive, the procedure should be converted to a laparotomy. Such a recommendation is oncologically incorrect, however, because: (1) it may be impossible to determine the malignant potential of an adrenal cortical tumor on the basis of a limited biopsy specimen; and (2) once the tumor capsule has been violated there is a risk of intraabdominal contamination [68]. Therefore if the differential diagnosis of a cortical neoplasm includes adrenal cortical carcinoma, the patient requires the best oncologic operation the surgeon can perform to achieve a wide- margin resection. For most surgeons that would be an open
transabdominal procedure. Preresection biopsies should be avoided. The two patients described below have been seen by the authors within the 6 months preceding the writing of this paper, and their cases illustrate how a laparoscopic and a flank approach to a functioning cortical neoplasm can result in early locoregional tumor recurrence. In such an aggressive malignancy, any potential benefit from a minimally invasive procedure or a smaller incision is insignificant compared with the risk of tumor recurrence result- ing from an incomplete resection.
Case 1. A 46-year-old woman was referred to our institution following a left adrenalectomy performed laparoscopically for a 4 cm functioning adrenal cortical neoplasm. Because of the rela- tively small size of this tumor, it was thought to be a benign cortical adenoma. The adrenal gland was partially fractured dur- ing manipulation prior to extraction, which was performed with an endobag. Pathologic studies revealed that the tumor was an ad- renal cortical carcinoma. Recurrent Cushing syndrome developed 6 months following the primary tumor resection. CT scans sug- gested a tumor nodule underneath the body of the pancreas in the bed of the resected adrenal. The patient was started on oral mitotane therapy. CT scans and chest radiography, repeated 2 months later, demonstrated ascites and marked intraperitoneal carcinomatosis (Fig. 4) with evidence of bilateral pulmonary me- tastases.
Case 2. A 35-year-old man developed hypertension and was found to be hypokalemic. Biochemical and radiographic studies demonstrated production of aldosterone and cortisol from a left adrenal cortical neoplasm measuring just over 4 cm in diameter (Fig. 5). He underwent left adrenalectomy through a flank ap- proach with resection of the eleventh rib; the tumor was fractured during removal. Recurrent hypokalemia was noted approximately 6 months after resection, and multifocal disease was seen in the left pararenal area extending from the retrosplenic region to the inferior pole of the left kidney (Fig. 5). There was no evidence of tumor progression after 4 months of systemic therapy, so he was returned to the operating room for resection of the left upper quadrant disease. No visceral metastases were seen at surgery.
In addition to these cases, local recurrence 19 months after laparoscopic removal of a documented intact adrenal cortical cancer has been reported [69].
Although locoregional recurrence can develop irrespective of the technique used for adrenalectomy, we and others believe that an open transabdominal operation should be performed if one suspects malignancy on the basis of tumor size and if pheochro- mocytoma has been excluded [70]. In contrast, laparoscopic re- section should be considered for palliative removal of metastatic disease to the adrenal gland. Laparoscopic adrenalectomy has been reported in 10 patients with metastases from renal, lung, colonic, adrenal, and melanoma primaries with no local or port- site recurrences at a mean follow-up of 8.3 months [66].
Systemic Therapy
Most investigations of adjuvant treatment for adrenal cortical carcinoma have involved the use of mitotane [o,p-DDD, or 1,1- dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl) ethane], a deriva- tive of DDT originally developed as an insecticide and found to have direct adrenolytic activity [3, 71]. Anecdotal reports and studies in small series of patients have yielded conflicting results concerning the efficacy of mitotane either as adjuvant therapy or
Jul
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B
Fig. 5. CT images. A. Preoperative scan of a functioning left adrenal cortical neoplasm (arrow) measuring 4 to 5 cm in diameter; and (B, C) postoperative scans following resection through a flank (retroperitoneal) approach demonstrating recurrent adrenal cortical carcinoma secondary to tumor seeding at the time of resection. B. Tumor nodule (open arrow) at the posteroinferior aspect of the spleen is easily seen (note the clips in the bed of the resected adrenal gland). C. More inferiorly, a tumor nodule (arrow) is seen extending along the anterior aspect of Gerota’s fascia, posterior to the transverse portion of the duodenum (open ar- row).
C
| Study | Year | Institution | No. | Result/conclusion |
|---|---|---|---|---|
| Kasperlik-Zaluska [72] | 1995 | Poland | 36 | Suggested benefit of adjuvant mitotane |
| Haak [59] | 1994 | Netherlands | 62 | Response rate 21% (6/29) in setting of measurable disease |
| Vassilopoulou-Sellin [73] | 1993 | MDACC | 13 | No effect on survival |
| Pommier [26] | 1992 | MSKCC | 29 | PR 24% |
| Luton [74] | 1990 | France | 37 | PR 22%, no effect on survival |
| Venkatesh [75] | 1989 | MDACC | 72 | Stable disease or PR 29% |
| Karakousis [76] | 1985 | Roswell Park | 10 | Stable disease or response 40% (n = 4) |
| Van Slooten [77] | 1984 | Netherlands | 34 | Serum levels > 14 ng/ml associated with improved survival |
| Henley [61] | 1983 | Mayo Clinic | 24 | PR 4% (n = 1) |
PR: partial response.
for treatment of locally unresectable or metastatic disease (Table 5) [26, 59, 61, 72-77]. For example, in 1993 Vassilopoulou-Sellin et al. [73] reported the University of Texas M. D. Anderson experience with adjuvant mitotane. This retrospective review in- cluded 19 patients: Eight received mitotane as postoperative ad- juvant therapy and continued to receive the drug until the time of
the last contact or recurrence; five began taking mitotane after surgery but discontinued it after 2 to 12 months; and six under- went surgery and had no postoperative therapy. Most patients received 4 to 6 g of mitotane per day, but dose reduction was frequently necessary because of gastrointestinal side effects. Age and tumor size were not different among the three treatment
| Series | Year | Institution | Regimen | No. | Response |
|---|---|---|---|---|---|
| Williamson [83] | 2000 | SWOG | ECM“ | 45 | PR 5 |
| Abraham [84] | 1999 | NCI | MEDV | 28 | CR 1, PR 4 |
| Berruti [85] | 1998 | Italy | MEDP | 28 | CR 2, PR 13 |
| Zidan [86] | 1996 | Israel | EPb | 1 | PR 1 |
| Bukowski [87] | 1993 | SWOG | MP | 37 | PR 11 |
| Berruti [88] | 1992 | Italy | EDP | 2 | PR 2 |
| Schlumberger [89] | 1991 | France | DP5-FU | 13 | CR 1, PR 2 |
| Hesketh [90] | 1987 | Boston University | EPB | 4 | CR 1, PR 1 |
| Johnson [9]] | 1986 | Vanderbilt | EC | 2 | PR 2 |
5-FU: 5-fluorouracil; B: bleomycin; CR: complete response; D: doxorubicin; E: etoposide; M: mitotane; NCI: National Cancer Institute; P: cisplatin; PR: partial response; SWOG: Southwest Oncology Group; V: vincristine. “Mitotane given only after disease progression on EC and only to patients who had not received mitotane previously. “Mitotane failure.
groups. The authors found that there was no difference in survival duration among the treatment groups; in fact, the shortest survival was experienced by patients who received adjuvant mitotane. Only one of the eight patients who received adjuvant mitotane was without evidence of disease 2 years after diagnosis.
In 1990 Luton et al. [74] reported 105 patients with adrenal cortical carcinoma. The response to mitotane was evaluated in a heterogeneous group of 59 of the 105 patients. Luton et al. observed that mitotane therapy had no significant effect on sur- vival (p = 0.24). The effect of mitotane on the subset of patients given postoperative adjuvant therapy was not reported. Mitotane was given to 37 patients with measurable disease for at least 2 months. Eight patients (22%) experienced tumor regression, with the site of response being the lung in six of the eight patients. The duration of response was 5 to 24 months.
A more favorable response to mitotane therapy was reported by Kasperlik-Zaluska et al. [72]. Among their study population of 36 patients given mitotane, 13 received it as adjuvant therapy follow- ing surgery, 13 at the time of local tumor recurrence, and 10 at the time of distant tumor recurrence. Doses of 3 to 5 g/day were used for long-term therapy. Two patients with metastatic disease re- ceived higher doses (up to 10 g/day). The survival of patients treated with adjuvant mitotane appeared encouraging but precise data were not provided, preventing statistically based interpreta- tion. Interestingly, the findings in two cases subsequently de- scribed by the same authors suggested that the dose of mitotane is critical for ensuring a cytostatic effect [78]. The first patient developed local recurrence 16 months after primary surgery while taking mitotane at a dose of 4 g/day. The dose was then increased to 8 g/day for 2 weeks, 6 g/day for 2 months, and 4 g/day for 2 years, after which 3 g/day was continued until approximately 7 years after the time of her primary adrenalectomy. Intraabdomi- nal recurrence was noted 2 months following discontinuation of mitotane. Reoperation was again followed by mitotane therapy. The second case involved a woman who experienced rapid tumor recurrence when the daily mitotane dose was lowered from 4 g/day to 3 g/day during the ninth month of therapy.
The serum levels of mitotane may therefore be related to the clinical response. In support of this hypothesis, van Slooten et al. [77] suggested that serum drug levels > 14 ug/ml resulted in improved tumor response and increased patient survival. Their study population consisted of 34 patients with adrenal cortical carcinoma, 32 of whom underwent resection of the primary tu- mor. Of the 34 patients, 28 were given mitotane for measurable
disease and the remaining 6 as adjuvant therapy. The response, which was not precisely defined, was evaluated in all 34 patients, and 8 (24%) had an objective response lasting 4 to 26 months. In seven of the eight responding patients, serum levels were > 14 µg/ml. Mitotane serum levels > 14 µg/ml were reported in 14 patients, 7 (50%) of whom had a response. In contrast, only 1 of the 20 patients with serum levels < 10 ug/ml had an objective response.
Similar data were reported by Haak et al. [59] from The Neth- erlands. Among their study population of 62 patients, 11 received mitotane as adjuvant therapy following potentially curative sur- gery, 29 as first-line therapy (with or without other systemic chemotherapy), and 26 for tumor recurrence (4 had taken it before), having previously been treated with surgery with or with- out other therapies. The patients who received adjuvant mitotane had a survival duration no different from that of the patients who underwent surgical treatment alone. Of the 29 patients who re- ceived mitotane as first-line therapy for measurable disease, 6 (21%) responded, and the response was complete in 3. In the other group of 26 patients, 9 (35%) responded, and the response was complete in 5. It is of note that all patients who responded to mitotane had serum mitotane levels 14 µg/ml or higher.
The collective findings from these and other retrospective re- views (Table 5) [26, 59, 61, 72-77] and from anecdotal reports [60, 79, 80-82] suggest that mitotane has some activity in adrenal cortical cancer. Translating the information in this body of liter- ature into clinical practice is difficult, however, because: (1) these multiple retrospective reports and case studies lack a uniform definition of response, which prevents comparison of the findings; (2) although higher serum levels of mitotane appear to correlate with treatment response, few studies have monitored serum drug levels; (3) although the therapeutic index of mitotane appears to be quite narrow as a result of significant gastrointestinal (anorex- ia, nausea, vomiting) and neurologic (confusion, somnolence) toxicities, toxicity data are not accurately reported in most retro- spective reports; and (4) because many of the reported patients received non-protocol-based therapy, mitotane was often com- bined with various other cytotoxic agents; however, such drug interactions are not well understood, especially in light of mito- tane’s inhibitory effect on P-glycoprotein. On the basis of the available data, we conclude that mitotane is an unattractive agent for routine use as a postoperative adjuvant treatment because of its low response rate and relatively significant toxicity profile. Nevertheless, the complete responses that have been reported
and the apparently increased rate of response to higher-dose therapy should not be ignored. This drug should therefore be studied further using a contemporary clinical trial design.
Systemic chemotherapy regimens, which have usually included etoposide, cisplatin, and doxorubicin, have been used to treat advanced disease, often in patients who have failed mitotane treatment (Table 6) [83-91]. The most encouraging experience was that of Berruti et al. [84], who treated 28 patients with mitotane combined with etoposide, doxorubicin, and cisplatin (EDP). The EDP schedule (etoposide 100 mg/m2 on days 5, 6, 7; doxorubicin 20 mg/m2 on days 1, 8; cisplatin 40 mg/m2 on days 2, 9) was repeated every 4 weeks and planned for a maximum of six cycles. Mitotane was started at a dose of 1 g/day and escalated to either 4 g/day or the maximum dose tolerated. Response was defined by World Health Organization criteria. Complete re- sponse (CR) was achieved in 2 patients and a partial response (PR) in 13, for an overall response rate of 53.5%. Stable disease was observed in 8 patients and progressive disease in 5. The median time to disease progression in responding patients was 24 months. There were no treatment-related deaths, and most grade 3 toxicities were hematologic. In a second reported study, cyto- toxic chemotherapy (continuous-infusion etoposide, doxorubicin, and vincristine) was also combined with mitotane [84]. The au- thors judged 9 (32%) of 28 patients to be responders [1 CR, 4 PR, 4 minimal response(MR)], with a median duration of response of 9.3 months. Mitotane contributed to an increased incidence of gastrointestinal and neuropsychiatric symptoms, however.
In vitro evidence has shown that paclitaxel may be an effective treatment [92]. Specifically, exposure of an adrenal cortical carci- noma cell line to this drug resulted in dose-dependent inhibition of cell proliferation and an increase in DNA fragmentation, sug- gesting that the induction of apoptosis by the drug is involved in neoplastic cell death. Assessment of its in vivo efficacy awaits clinical study.
Chemotherapy failure may be partially explained by expression of the multidrug resistance 1 gene (MDR-1) and its protein prod- uct P-glycoprotein (Pgp) in adrenal cortical carcinoma cells [93]. However, in vitro, mitotane has been shown to reverse the mul- tidrug resistance mediated by MDR-1 expression and act as a Pgp antagonist [94]. In vitro tumor chemosensitivity testing in which a panel of drugs is tested against a specific tumor may be of benefit in circumventing multidrug resistance. However, a study of in vitro chemosensitivity testing and mitotane modulation of MDR did not predict tumor sensitivity in vivo, suggesting that mecha- nisms other than Pgp-related drug resistance are responsible for treatment failure [95].
Radiation therapy has not been shown to offer any benefit as an adjuvant treatment following complete surgical resection with only anecdotal reports of its efficacy; therefore its use is not generally recommended [96]. In addition, gastrointestinal toxicity resulting from the large treatment volume required makes irradi- ation an unrealistic option as an adjuvant treatment in most patients, although palliative irradiation for painful osseous metas- tases is standard treatment [97].
Follow-up and Reoperation
Postoperative follow-up generally includes physical examination, biochemical assessment if the tumor was originally functional, CT scanning, and chest radiography every 4 months following poten-
L
tially curative resection of the primary tumor. Bone metastases are usually symptomatic and may be suspected on the basis of elevation of the alkaline phosphatase level. In patients with re- currence, systemic therapy for progressive, multisite, recurrent disease may prolong survival, but the potential for long-term survival exists only in patients with isolated recurrence amenable to reoperation (Fig. 6).
Two large series of patients who underwent reoperation for recurrent adrenal cortical carcinoma have recently been reported [98, 99]. The Italian registry report included 140 patients from 21 institutions who underwent potentially curative resection of a primary adrenal cortical carcinoma [98]. Disease recurred in 52 (37%) of the 140 patients: at distant sites (liver, lungs, bone) in 25 patients, locally in 13 patients, and at distant and local sites in 14 patients. The mean disease-free interval was 22 months. Twenty of the 52 (38%) patients, 20 underwent reoperation for recurrent disease. These 20 patients had a 5-year survival of 50% compared with 8% in the 32 patients whose recurrent disease was not amenable to surgical resection. The long survival of these 20 patients was likely due to favorable tumor biology and aggressive therapy. Similar results were recently reported from Memorial Sloan-Kettering Cancer Center [99]. Following resection of local or distant recurrences, complete resection was associated with a median survival of 74 months (5-year survival 57%) and incom- plete resection was associated with a median survival of 16 months (5-year survival 0%). Although the number of patients in these studies is small, these data do support the use of careful clinical and radiographic follow-up in patients after their initial adrenal- ectomy in the hope of discovering recurrent disease that would be amenable to reoperation.
For patients who enjoy a long disease-free interval. the recom-
mended duration of continued radiographic surveillance is un- clear. Because of the unpredictable biologic behavior of adrenal cortical carcinoma, continuing CT scans beyond 5 years after diagnosis is not unreasonable.
Incidental Adrenal Mass: Metastatic Disease versus Primary Carcinoma
True incidentalomas of the adrenal gland are defined as seren- dipitous findings unrelated to the clinical presentation of the patient [100]. Most clinicians would further restrict the definition of incidentalomas to adrenal masses < 4 to 6 cm. Incidentally discovered adrenal masses are relatively common, being found in up to 4% of individuals undergoing abdominal CT and in up to 7% of individuals at autopsy [52, 101]. Most commonly, they are benign nonfunctioning adrenal cortical adenomas; adrenal corti- cal carcinomas are rare whereas metastases to the adrenal glands from malignant solid tumors occur with moderate frequency [50- 52, 100, 102].
As previously discussed, it is generally recognized that large size is the single best clinical indicator of a primary malignancy of the adrenal gland in patients with an incidental adrenal mass. Con- troversy arises regarding the extent of the evaluation necessary to exclude the possibility of metastatic disease in patients with ad- renal incidentalomas. It has recently been recommended that all patients who present with an isolated, incidental adrenal mass undergo FNA biopsy of the mass to exclude the possibility of metastasis from an occult (unknown) primary malignancy [103]. However, in the absence of signs or symptoms of a solid tumor malignancy, unifocal adrenal metastatic disease is uncommon. For example, it was found in only 4 (0.2%) of 1639 patients with a suspected unknown primary cancer [52]. All 4 of these patients had large tumors (6 cm), which strongly supported the diagnosis of malignancy (primary or metastatic). Three of the four patients had bilateral adrenal involvement, and all were symptomatic. Thus no patient with isolated adrenal metastasis from an occult primary tumor fulfilled the criteria for a true adrenal incidenta- loma. Hence there is no compelling evidence to indicate that all patients with nonfunctioning adrenal incidentalomas require bi- opsy to exclude an occult primary malignancy. FNA biopsy of isolated adrenal masses should be performed only in patients with a history of cancer of the lung, breast, stomach, kidney, colon, melanoma, or lymphoma, or in those with symptoms, physical examination findings, or biochemical or radiographic evidence of an underlying malignancy.
The most common site of a primary tumor that metastasizes to the adrenal gland is the lung. Patients, particularly smokers, with an adrenal mass suspicious for metastatic cancer should undergo screening chest radiography to search for occult lung cancer. Patients with an unknown primary cancer and adrenal metastases have a poor overall prognosis, with a median survival duration of only 7 months [52]. The survival is significantly shorter than that in patients with an unknown primary cancer without adrenal involvement. These findings support the previously reported poor prognosis for patients with unknown primary cancer [104]. The short survival of patients with metastatic cancer involving the adrenal glands may be due to occult or overt adrenal insufficiency, particularly in patients with metastatic lung cancer; ACTH stim- ulation testing can identify patients with adrenal insufficiency.
Résumé
Le cancer de la corticosurrénale est une tumeur endocrine rare pour laquelle seule la résection chirurgicale complète offre la possibilité de guérison. C’est par une évaluation préopératoire précise (biochimique et radiographique) d’un patient présentant une masse de la surrénale qu’on s’assure d’une résection complète, avec des marges libres, ce qui est le facteur pronostique le plus puissant pour évaluer la survie à long terme. La réponse à la chimiothérapie ou au mitotane est modeste chez la plupart de patients ayant une maladie avancée. On espère que grâce à une compréhension de la pathogenèse moléculaire de cette tumeur, on pourra développer de nouvelles thérapies plus efficaces dans l’avenir.
Resumen
El carcinoma adrenocortical es un tumor endocrino raro para el cual la resección quirúrgica total es la única modalidad terapéutica potencialmente curativa. La debida evaluación preoperatoria (bioquímica y radiográfica) del paciente que presenta una masa suprarrenal maximiza la posibilidad de lograr la resección completa del tumor primario con márgenes libres, que es la variable pronóstica de mayor importancia en lo relativo a supervivencia a largo plazo. La respuesta a la quimioterapia o al mitotane es modesta en los casos de enfermedad avanzada. Se guarda la esperanza de que una mejor comprensión de la patogénesis molecular de este tumor lleve al desarrollo de nuevas y más eficaces formas de tratamiento.
Acknowledgments
The authors thank Abigail Corona for manuscript preparation and Beth Norton for editorial assistance.
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