Diagnosis and Management of Adrenal Cortical Carcinoma
Brant R. Fulmer, MD
Corresponding author
Brant R. Fulmer, MD Geisinger Health System, Department of Urology, 100 N. Academy Avenue, M.C.13-16, Danville, PA, 17822, USA.
E-mail: brfulmer@geisinger.edu
Current Urology Reports 2007, 8:77-82 Current Medicine Group LLC ISSN 1527-2737 Copyright @ 2007 by Current Medicine Group LLC
Adrenal cortical carcinoma is a relatively uncommon malignancy that represents a significant clinical challenge for the development of optimal treatment strategies. Historically, successful treatment has relied upon rapid identification of the lesion, accurate staging with diagnostic imaging, and complete surgical extirpation. Although the framework of a successful treatment para- digm still relies on these steps, advances in diagnostic imaging have led to increased accuracy in diagnosis, and advances in laparoscopic surgical technique have served to reduce morbidity for patients facing treatment. This review focuses on a discussion of advances in modalities for the diagnosis and treatment of adrenal cortical carci- noma amenable to curative therapy. Patients that present with metastatic or locally advanced disease generally are treated with mitotane-based chemotherapy with or with- out the addition of cytotoxic drugs. Contemporary results of this treatment approach are presented in this review as well as a discussion of further directions for the treatment of patients with advanced disease.
Introduction
Primary adrenocortical carcinoma is a relatively uncommon malignancy having an incidence of about one half to two per 1 million per year and accounting for about 0.2% of all cancer deaths [1,2]. There appears to be a bimodal age distribution with one age peak in the less than 5-year age group and one peak in the 4th or 5th decade of life [3]. The worldwide incidence is considerably lower in children, with some variations in geography. Unfortunately, it is a very deadly disease regardless of age group. Mean survival in reported groups ranges from a low of 2.9 months to a high of 28 months [4]. Published mortality rates are dismal with 50% of affected individuals dead within 2 years and 75%
at 3 years postdiagnosis [5]. Rapid diagnosis and aggressive treatment appear to be the primary variables that have a positive effect on prognosis and survival. This review focuses on current advances in these two areas and also includes a discussion of the contemporary treatment of patients with advanced disease.
Molecular Biology and Genetics
The etiology of adrenal cortical carcinoma is largely unknown. Most authors suggest the oncogenesis of adrenal adenoma into carcinoma as the primary event in the develop- ment of this disease. Sidhu et al. [6] have written an excellent review article on this subject, outlining the genetic and molecular mechanisms implicated in this malignant trans- formation. In brief, the progression from adrenal adenoma to carcinoma appears to be related to the chromosomal duplication at the 11p15.5 locus leading to overexpression of the insulin-like growth factor-2 gene. The authors also suggest that the deletion of the adrenocorticotropic hormone receptor and decreased expression of TP53 may be impor- tant factors in understanding the molecular pathobiology [6]. It is clear that the genetic study of this disease is in its infancy, and it will require considerable, additional study to fully elucidate the molecular mechanisms responsible for either tumorigenesis or disease progression.
Staging and Pathologic Classification
The familiar tumor, nodes, metastasis system is used for the staging of primary adrenal carcinoma and is shown in summary in Table 1. The familiar stage groupings include Stage I-II disease comprising locally confined disease. Stage III disease is locally advanced disease without invasion of adjacent organs, and Stage IV disease represents either adjacent organ invasion or metastatic disease [7.].
Adrenocortical neoplasms appear microscopically as carcinomas with the expected range of degrees of differentiation. The Weis criteria for pathologic classifi- cation was described more than 20 years ago but is still useful for classifying the adrenal lesions as adenoma or carcinoma [8]. The factors contributing to classifica- tion of carcinoma in the Weiss system can be found in Table 2. The Weiss criteria have also been suggested to
| Tumor, nodes, metastasis | |
| T1 | Less than 5 cm, no local division |
| T2 | Greater than 5 cm, no local invasion |
| T3 | Tumor of any size, locally invading but not involving adjacent organs |
| T4 | Tumor of any size, locally invading adjacent organs |
| N0 | No regional lymph nodes |
| N1 | (+) Regional lymph nodes |
| M0 | No distant metastasis |
| M1 | (+) Distant metastasis |
| Stage grouping | |
| Stage I | T1, N0, M0 |
| Stage II | T2, N0, M0 |
| Stage III | T1 or T2, N1, M0 |
| T3, N0, M0 | |
| Stage IV | Any T, any N, M1 |
| T3, N1, M0 | |
| T4, N0, M0 | |
Table 2. Pathologic features of primary adrenal neoplasms
High nuclear grade
Mitoses greater than five per 50 high-powered fields
Atypical mitoses
Greater than 75% eosinophilic cells
Greater than 33% diffuse architecture
Microscopic necrosis
Venous invasion
Sinusoidal invasion
Capsular invasion
(Adapted from Weiss [8].)
predict prognosis. In this case, meeting more criteria for adenocarcinoma portends a more aggressive course for the disease [9].
Clinical Presentation
The most common presenting symptoms of functional adrenal cortical carcinoma are presented in Table 3. In one large series, the incidence of Cushing’s syndrome with virilization was 24%, and 39.5% presented with Cushing’s syndrome alone. Virilization alone is reported in 20% to 30% of patients with adrenal carcinoma [10]. Feminization can also occur due to production of andro- stenedione and peripheral conversion to estrogen. Some
authors believe that presentation with mixed endocrine symptomatology (Cushing’s and virilization) is useful to differentiate adrenal cortical carcinoma from functional adenoma [11], but there is considerable controversy in this area. The overall incidence of feminization with this disorder is about 6% [12]. Functional adrenal carcinoma has also been reported to occasionally produce miner- alocorticoid, and the incidence of hyperaldosteronism at presentation is about 2% to 2.5% [13].
Nonfunctional adrenal carcinomas most commonly present as incidental findings on an unrelated diagnostic imaging study. They may become symptomatic, however, if the lesion is very large in size or locally extends to invade other structures.
Laboratory Evaluation
Hormonal testing is largely driven by the clinical mani- festations at the time of presentation. Symptoms of Cushing’s syndrome (cortisol excess) can be investigated by measurement of 24-hour urinary cortisol, high-dose dexamethasone suppression. In the event of clinical signs of virilization, the measurement of the serum adrenal androgens dihydroepiandrosterone and dihydroepiandros- terone sulfate and/or 24-hour urinary measurement of 17-OH corticosterone and 17-ketosteroids may be helpful in determining the functionality of the lesion. Symptoms of feminization alone are usually investigated by mea- surement of plasma estradiol or estrone. Symptoms of mineralocorticoid excess can be investigated by measure- ment of plasma aldosterone or plasma renin activity. In the event of incidental finding of an adrenal mass suspicious for adrenal cell carcinoma, appropriate laboratory studies include initial measurement of urinary catecholamines and metanephrines to rule out pheochromocytoma, potassium measurement in the presence of hypertension to assess for Conn’s syndrome, and appropriate endocrine studies (as mentioned) if the clinical signs warrant.
Radiologic Imaging
Accurate diagnosis via appropriate radiologic imaging, precise staging, and prompt surgical intervention are key to improving the prognosis or patients diagnosed with adrenal carcinoma.
Findings on plain radiography or intravenous pyelo- graphy may include soft tissue displacement by mass or calcification in the area of the mass. In one study, soft tissue findings were present in 47% and calcification in 18% [14]. Other series suggest calcification in up to 30% [15,16]. Ultrasonography can be useful in children to quickly screen for the presence of adrenal pathology. In skilled hands, studies have shown a detection rate of about 87% with a false-negative rate of 12% [17]. Resolution and staging accuracy change considerably with patient size and operator skill level, making this technology less ideal for adults.
CT with intravenous contrast enhancement has dem- onstrated its prominence as the primary modality for the diagnosis and staging of adrenal carcinoma. The excellent resolution of the adrenal gland on CT scan is due largely to the presence of copious retroperitoneal fat. Modern CT imaging with thin sectioning can identify lesions as small as 0.5 cm and can reliably characterize lesions as small as 1.0 cm [18]. CT scan has reported detection rates as high as 98% with less than 10% false-negative or false-positive rates [17]. Another potential advantage of CT scanning is the ability to examine the contralateral adrenal gland, screen for distant metastasis, and identify primary intravascular extension of tumor into the renal vein or inferior vena cava [16,19,20].
Size, contrast enhancement, and consistency on CT scan have all been suggested as important discriminators of benign from malignant adrenal masses [21]. Most authors agree that an increased size of the lesion increases the sus- picion for cancer, and most malignant adrenal lesions are greater than 5 cm at presentation. In one large series, 92% of adrenal carcinomas were greater than 6 cm when diagnosed [22]. These findings have led to the recommendation that all adrenal incidentalomas greater that 5 cm in size at the time of discovery should be addressed surgically [23].
MRI has also demonstrated considerable utility in characterizing large adrenal masses. This is particularly true in which questions of primary intravascular exten- sion are concerned. In addition, a comparison of T1 to T2 signal intensity can help to differentiate benign adenomas, malignant lesions, and pheochromocytoma. Benign adrenal lesions tend to have low signal inten- sity on T2-weighted images. Malignant adrenal lesions tend to have intermediate-to-high signal intensity, and pheochromocytoma has a very high (light bulb sign) signal intensity on T2 [19,24]. It has also been demon- strated that gadolinium enhancement and chemical shift magnetic resonance evaluation can identify adenoma from carcinoma with high specificity [25].
Selective arteriographic evaluation remains useful in differentiating some functional adrenal disorders but has less utility in the management of adrenal carcinoma. There may be a role for this imaging modality differentiating upper pole renal masses from large adrenal lesions, but even this application has been largely supplanted with multiple reconstructed views available with MRI [24]. Positron emission tomography scanning provides yet another prom- ising potential tool in the diagnostic armamentarium. 18F-fluorodeoxyglucose and 11C-metomidate uptake on positron emission tomography scan have both been used in small series and show some utility in differentiating benign from malignant renal lesions [26].
Surgical Therapy for Primary Adrenal Carcinoma
There is little disagreement in the published literature regarding surgical extirpation as the mainstay of therapy
Table 3. Most common presenting symptoms of functional adrenocortical carcinoma
Centripetal weight gain
Truncal obesity
Muscle wasting Hypertension Acne Hirsutism
Oligomenorrhea
for adrenal carcinoma. Rapid, accurate diagnosis and timely surgical intervention appear to be the keys to curative outcomes. The short, historic survival rates serve to underscore the aggressive and deadly nature of this disease. It is also evident that the widespread penetration of cross-sectional imaging studies for the diagnosis and treatment of adrenal disease has had the added benefit of having patients present at lower stage and thus improved prognosis [27].
Immediate surgical intervention is suggested for all patients presenting with tumor, nodes, metastasis Stage I, II, or III disease. Facilitating a margin negative resection is universally agreed upon as being the most important prognostic variable for survival [23,28].
Recent rapid advances in the development of lapa- roscopic technology has made the minimally invasive treatment of benign adrenal disease, laparoscopic adrenalectomy, the gold standard for treatment. These techniques have only recently been broadly applied to treating patients with adrenal carcinoma. Several groups have reported success with the laparoscopic treatment of adrenal malignancy in both the case of primary adrenal carcinoma and also adrenal metastasis [29 .. ,30,31.,32,33]. In summary, in carefully chosen patients with Stage I and Stage II disease, laparoscopic adrenalectomy can be safely performed while main- taining the oncologic principles of adequate surgical exposure and margin negativity. The transperitoneal approach is favored over the retroperitoneal approach for large lesions and facilitates the laparoscopic man- agement of unexpected local tumor extension [34,35]. Several authors have indicated that the maximum tumor size is 6 cm for laparoscopic intervention, though this is an arbitrary number and is directly influenced by the surgeon’s level of laparoscopic experience [36]. In addition, hand-assisted laparoscopic techniques have also been described as a useful adjunct to conven- tional laparoscopic techniques for removal of adrenal carcinomas or as a primary modality for the treatment of large adrenal lesions [37].
Unfortunately, the somber truth is that even after complete surgical resection, the 5-year, disease-free survival is reported at 30%, underscoring the need for the development of adjuvant therapies [38].
Radiotherapy for the Treatment of Adrenal Carcinoma
Adrenocortical carcinoma is generally considered to be radioresistant, and therefore, there is a paucity of data on the use of radiotherapy for the treatment of this disease. There are no controlled clinical trials exploring the use of radiotherapy as primary treatment. High-dose radiation has been used successfully to address pain in bone metas- tases from adrenal carcinoma but unfortunately conferred no survival advantage in this group [39]. There are some poorly described anecdotal reports of the use of radiation to shrink large adrenal tumors before resection, but none appear to be applicable in the broad sense to this disease. There is additional anecdotal (though concerning) reports of secondary malignancies in patients receiving high-dose radiation therapy for adrenal malignancy [14,17]. Radio- therapy has been successfully used for palliating pain in tumors metastatic to the adrenal gland from sources such as breast, lung, or skin [40].
Chemotherapy for Primary Adrenal Carcinoma The overall dismal prognosis for patients with advanced adrenal carcinoma foreshadows the generally poor response to systemic chemotherapy. The most widely stud- ied drug is mitotane, which is an isomer of the insecticide DDT (chlorophenothane) [2]. This drug was first observed to cause regression of metastatic adrenal carcinoma by Bergenstal and Lipsett [41]. The mechanism of action of mitotane is blockade of 11-ß-hydroxylase, thus disrupting the steroid synthesis cascade.
Response rates to mitotane therapy in the literature range from 10% to 60%, and complete responses are very rare [42]. In a large meta-analysis of trials using mitotane for treatment of nonoperable adrenal carcinoma, Wooten and King [43] examined 551 patients in 52 studies and determined an overall 35% response rate with duration last- ing from 1-205 months. Hutter and Kayhoe [44] showed measurable objective response rates (tumor regression) with mitotane therapy in 34% of 138 patients. Another study showed measurable objective response rates in 61% (or 75 patients), though treatment with mitotane conferred no sur- vival benefit [45]. A possible explanation for the disparate response rates to mitotane may be related to the difficulty in achieving high serum drug levels. Most authors advocate active drug monitoring to maintain mitotane levels between 14 mg/L and 20 mg/L, which is desirable to improve efficacy [1,46]. At these levels, however, mitotane can have serious limiting side effects in up to 88% of patients. These side effects are most commonly gastrointestinal distress, neurotoxicity, and skin rash [44].
The combination of mitotane with other cytotoxic che- motherapy may hold some promise for future treatment of this disease. A well-designed clinical trial examining the use of mitotane combined with cisplatin showed a measurable objective response rate in about one third of patients [47].
Mitotane in combination with cisplatin, etoposide, and doxorubicin has been shown to achieve overall response rate of 53.5%, though duration of response was limited [42]. Mitotane has also been combined with 5-fluorouracil [48] and streptozocin [49] with anecdotal success.
It is clear from the available literature that additional trials are needed to delineate the role of mitotane alone or in combination with cytotoxic therapy, and the results of a large international trial are forthcoming [38]. Moreover, the use of chemotherapy in the adjuvant or neoadjuvant setting is not well-studied and is a fertile area for future investigation. Although beyond the scope of this article, Kirschner et al. [50 .. ] published an excellent review of future directions for chemotherapeutic treatment of adre- nal cortical carcinoma including gene and immunotherapy.
Use of Chemotherapy to Reduce Symptomatology
Although its use in curative treatment of disease is controver- sial, mitotane has been well-established to reduce the morbid symptoms of steroid excess that commonly characterize functional adrenal carcinomas. Mitotane and metyrapone, both 11-ß-hydroxylase inhibitors, have been shown to be active in this setting. Wooten and King [43] report a 75% resolution of these symptoms with mitotane therapy alone. Aminoglutethimide, a desmolase inhibitor, has also been used for the purpose of inhibiting symptoms of functional adrenal cortical carcinoma with mixed success.
Conclusions
Although research has improved our understanding of the pathophysiology and natural history of primary adreno- cortical carcinoma, little has occurred to impact the dismal clinical course in this deadly disease. The keys to favorable diagnosis still appear to be a rapid and accurate diagnosis with cross-sectional imaging followed by aggressive surgi- cal extirpation of the primary lesion. For those individuals with metastatic or locally advanced disease at the time of presentation, combination chemotherapy with mitotane and platinum-based cytotoxic therapy hold the most promise. There has been no evidence to date convincing enough to advocate adjuvant chemotherapy before surgery in localized disease. The utility of combination chemotherapy and the design of controlled clinical trials to evaluate safety and efficacy remain a continued challenge largely due to the rare and deadly nature of this disease. Hopefully, development of more efficacious and less morbid regimens will finally improve survival when used in the adjuvant setting.
In any case, we agree with several other authors [26,38] who have suggested that the key to developing effective treatment strategies will rely in large part on the development of international registries for this relatively uncommon malignancy and well-designed and executed multidisciplinary clinical trials.
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