Adrenocortical carcinoma Sanziana Roman
Purpose of review
Adrenocortical carcinoma is a rare malignancy, accounting for 0.02% of all annual cancers reported. Given the generally advanced stage at diagnosis, the overall 5-year survival remains poor, varying between 20 and 45%. While older studies purported an improved outcome for functional tumors in adult patients, this has not been borne out in more recent studies. In the pediatric population, though, virilizing tumors carry a better survival than non-functional or cortisol- secreting tumors.
Recent findings
Recent studies focusing on the tumorigenesis of adreno- cortical carcinoma have focused on onco-developmental genes present in the fetal adrenal cortex, as well as local adrenal paracrine and autocrine effects of cellular peptides. Summary
Pre-operative diagnostic advances in positron emission scanning are emerging as promising modalities for con- firmation of malignancy of indeterminate adrenal masses. No significant advances in the treatment of adrenocortical carcinoma have been developed. Surgery remains the mainstay for primary and recurrent disease, including select patients with isolated liver metastases. Mitotane has remained the preferred adjuvant treatment agent, showing modest effect in patients with unresectable, residual or metastatic disease. Multi-institutional registries and trials need to be established, with multidisciplinary efforts focused on the development of new therapeutic strategies.
Keywords
activin, adrenocortical carcinoma, 18F-fluorodeoxyglucose positron emission tomography, inhibin, mitotane pediatric adrenocortical carcinoma, vascular endothelial growth factor
Curr Opin Oncol 18:36-42. @ 2006 Lippincott Williams & Wilkins.
Yale University School of Medicine, New Haven, Connecticut, USA
Correspondence to Sanziana Roman, MD FACS, Assistant Professor of Surgery, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA Tel: 203 785 2563; fax: 203 737 4067; e-mail: sanzianaroman@yale.edu
Current Opinion in Oncology 2006, 18:36-42
Abbreviations
| ACC | adrenocortical carcinoma |
| ACTH | adrenocorticotropin hormone |
| FDG | 18F-fluorodeoxyglucose |
| MTO | 11C-metomidate |
| PGE | prostaglandin E |
| SCCRO | squamous cell carcinoma-related oncogene |
| TZD | thiazolidinediones |
| USG | ultrasonography |
| VEGF | vascular endothelial growth factor |
@ 2006 Lippincott Williams & Wilkins 1040-8746
Introduction
Adrenocortical carcinoma (ACC) is a rare malignancy, accounting annually for 0.02% of all cancers reported. It has an incidence of one to two cases per 1.7 million of the population [1]. It has a bimodal age distribution, with an increased incidence in children less than 5 years old, and adults in their fourth and fifth decades of life. It tends to be slightly more common in women than men [2]. Given the generally advanced stage at diagnosis, the overall 5-year survival remains poor, varying between 20 and 45% [3]. This review encompasses the latest advances in the biochemical, molecular and radiographic diagnosis of this disease, as well as developments in surgical and adjuvant treatment options.
Biochemical function
ACCs have been subclassified by their ability to produce hormones. While earlier studies reported up to 50% func- tionality in these tumors, more recent series have noted hormone secretion in up to 79% of cases - an increase most likely due to improvements in assay sensitivity [2,4]. This classification is rather forced, as most ACCs may secrete multiple hormones and may change secretion according to size, growth rate and differentiation. Most commonly, functional tumors produce cortisol, causing Cushing’s syndrome. There tends to be more marked virilization in Cushing’s syndrome caused by ACC than adrenal adenomas, given the higher rate of co-secretion of 17- ketosteroids and di-hydroepiandosterone (DHEA) in malignant tumors. Virilization in women with ACC may be rarely due to free testosterone secretion, while femin- ization of men with ACC, such as gynecomastia, testicular atrophy and low sperm count, has been observed in patients with tumors secreting androstenedione, which is peripherally converted to estrogen [5].
Mineralocorticoid excess is rarely seen. The first descrip- tion of a malignant aldosterone producing tumor was in 1955, by Foye [6]. Lutscher [7] and Seccia et al. [8] reported two cases and performed a world literature search, amas- sing retrospectively 58 cases for review. Most patients presented with hyperaldosteronism and Conn syndrome. They found no significant predictor of outcome based on gender, age, size of tumor or hormone secretion. Necrosis and hemorrhage of the tumors were ominous findings, predicting malignancy. Local invasion and metastatic disease were the only reliable signs of cancer.
An uncommon diagnosis of mineralocorticoid excess has been reported recently by Mussig et al. [9] in a man with
Conn syndrome and isolated plasma 11-deoxycorticoster- one (DOC) excess. Only 11 cases have been reported in the literature, making this isolated malignancy extremely rare. Combined mineralocorticoid and glucocorticoid secretion has also been reported in ACC, emphasizing the need for hormonal screening in patients with adrenal masses [9].
In the 1980s, studies by Karakousis et al. [10] and Hogan postulated that functional tumors had better outcomes than nonfunctional ones. This was believed to be the result of earlier symptoms due to hormonal excess and detection of smaller tumors [11]. Since then, several studies have contradicted this finding. A recent review by Chen et al. [12] analyzed studies from the Mayo Clinic, including 58 patients treated since 1980, finding that non- functional tumors actually had better prognosis than functional ones and a larger study population from Italy, which included 1000 patients with adrenal incidental masses, discovered by radiographic imaging that 4% of these masses were found to be ACC. This is clearly a higher incidence of ACC than reported previously. These studies did not demonstrate that ACC discovered as an incidental mass presents at a lower stage, or has better prognosis overall.
Tumorigenesis
Molecular alterations in ACC have often been related to inherited cancer syndromes, such as Li-Fraumeni syn- drome (p53 gene on 17p13), multiple endocrine neoplasia type 1 (MEN 1, menin gene on 11q13), Carney syndrome (loss of heterozygosity on 2p16) and Beckwith-Wiede- mann syndrome (insulin-like grown factor 2 from 11p15.5) [2]. Additional loss of heterozygosity (LOH) has also been found in loci related to Von Hipple Lindau (3p) and retinoblastoma genes (13q). Insulin-like growth factor (IGF) gene overexpression has been shown to be strongly related to ACC. Both IGF 1 and IGF 2 are involved in differentiation of the adrenal cortex. High levels of these factors may play a role in tumorigenesis and dedifferentiation [12].
Squamous cell carcinoma-related oncogene (SCCRO) is a novel gene involved in the hedgehog signaling pathway of mammalian development, including the adrenal cortex. SCCRO is one of the newly described ‘onco-develop- mental’ genes, important in normal cellular functioning in the regulated state and carcinogenesis in the dysregulated state. In a recent study of murine ACC [13], high levels of SCCRO were observed in 94% of benign adrenal adeno- mas, while loss of SCCRO was related to over 65% of ACC. Loss of expression was related to a worse outcome and may represent a marker for dedifferentiation.
Beuschlein et al. [14°] describe some newly discovered roles of proteins and peptides in the tumorigenesis of
ACC in both the murine and human models. Inhibin and activin are dimeric glycoproteins in the TGFbeta family of ligands. Activin is a ubiquitous protein, while inhibin is expressed mostly in the gonads, adrenal cortex and pituitary gland. They are known to play important roles as paracrine and autocrine factors regulating growth and differentiation. Archival ACC immunostaining has shown strong inhibin and activin receptor presence. Activin has been shown to inhibit proliferation, induce apoptosis and modulate adrenocorticotropin hormone (ACTH)- induced cortisol secretion. In vitro, activin treatment of ACC cultured cells inhibits steroidogenesis in a dose- dependent manner. Luteinizing hormone may also regu- late cortisol secretion by the adrenal cortex, while human chorionic gonadotropin (hCG) and gonadotropin releas- ing hormone (GnRH) have been shown to stimulate DHEAS, and pure androgen-secreting tumors. The exist- ence of luteinizing hormone/hCG receptor found in some ACC tumors has led researchers to postulate that hor- mone stimulated luteinizing hormone receptor expres- sion could act as a tumor promoter when expressed ectopically in the adrenal cortex. Other oncogenetic events, however, may be necessary to induce frank car- cinogenesis [15].
A recent Bulgarian study analyzed serum levels of circu- lating vascular endothelial growth factor (VEGF) and prostaglandin E (PGE) in 75 patients with functional adrenal masses, such as aldosteronoma, pheochromocy- toma, cortisol-secreting adenoma, ACC and normal sub- jects. Researchers found that all patients with adrenal masses had elevated circulating serum levels of VEGF as compared with normal subjects, while patients with ACC had statistically significant higher levels of VEGF than patients with benign tumors. There was no difference in PGE levels across groups. VEGF and PGE are markers for angiogenesis. Overexpression of VEGF has been correlated in the past with functional activity of tumors as well as malignancy [14°,16]. Some studies have corre- lated the serum levels of VEGF with tumor aggressive- ness and patient outcome [17]. In the Bulgarian study, patients with cortisol secreting tumors and ACC had the highest levels of circulating VEGF. All patients with ACC had cortisol hypersecretion; therefore, they postu- lated that while specific angiogenesis in cortisol-produ- cing tumors is higher than other adrenal tumors, this assay alone may not be able to differentiate adenomas from carcinomas.
Diagnosis
Routine abdominal computed tomography scanning has led to the increasing identification of occult adrenal masses. All incidentally discovered adrenal masses should be checked for excess hormonal secretion, including cortisol, aldosterone and catecholamine secretion.
ACTH-independent hypercortisolism is a commonly encountered hormonal activity in ACC. Two or three consecutive 24-hour urine collections for free cortisol should confirm the diagnosis of hypercortisolism. The differentiation between ACTH-dependent and ACTH- independent hypercortisolism can be made by late after- noon or midnight simultaneous measurement of serum cortisol and ACTH levels. If the patient’s cortisol con- centration is above 50 µg/dl, while the ACTH level is below 5 pg/ml, then the cortisol excretion is ACTH- independent. Conversely, if the ACTH level is above 50 pg/ml, then the cortisol excretion is ACTH-depen- dent, such as pituitary or ectopic in origin. In equivocal cases, the high-dose dexamethasone suppression test (2 mg every 6 hours for 2 days) will fail to suppress the serum cortisol and the urinary-free cortisol in patients with adrenal adenomas, ACC or ectopic ACTH, but will show a 50% reduction in patients with pituitary ACTH tumors [1].
The most common first-line imaging modality is a com- puted tomography of the abdomen and pelvis, with thin cuts through the adrenal glands. On non-contrast adrenal computed tomography scanning, ACC can mimic adeno- mas, but usually are larger, have more irregular margins, and may display tumor necrosis and even cystic degener- ation. Some surgeons still believe that all adrenal tumors more than 5 cm in size should be considered for surgical excision. Cystic adrenal masses should still be worked up to rule out malignancy and hyperfunction, as both ACC and pheochromocytoma can present with cystic degener- ation and pseudocyst formation from possible necrosis or hemorrhage. A recent review from the Mayo Clinic analyzed 41 cases of cystic adrenal lesions, which in- cluded pseudocysts, endothelial and epithelial cysts. Up to 2% of ACCs present as cystic neoplasms. The cysts associated with ACC were pseudocysts, and on pathologic analysis, the cyst wall had areas that demonstrated features of malignancy, such as eosinophilic tumor cell cytoplasm, vascular invasion, mitotic figures and necrosis. Rim calci- fications seen on computed tomography scan in these adrenal cysts were only observed in ACC [18,19].
Delayed contrast-enhanced computed tomography scan- ning has been evaluated as a tool to distinguish benign adrenal adenomas from ACC, pheochromocytoma and metastatic disease. Using helical non-enhanced com- puted tomography, followed by contrast-enhanced com- puted tomography 1 and 10 min later, Szolar et al. [20] analyzed 11 patients with ACC, 17 patients with pheo- chromocytomas, 23 patients with benign adrenal adeno- mas and 16 patients with secondary adrenal metastases. The mean attenuation of adenomas (8 HU ± 18 SD) was significantly lower than those in ACC (39 HU ± 14 SD), pheochromocytomas (44 HU ± 11 SD) and metastases (34 HU ± 17 SD) on non-enhanced computed tomo-
graphy. The post-contrast computed tomography enhancement change at 1 and 10 min delay showed an optimal threshold value of 50% for absolute percen- tage of enhancement loss and 40% for relative percen- tage of enhancement loss at 10 min, both with a sensitiv- ity and specificity for the diagnosis of benign adrenal adenoma of 100%. Therefore, the researchers concluded that the percentage change in enhancement loss at 10 min is a useful adjunct in the differentiation of benign tumors compared with malignant ones, or pheochromocytoma [20].
Magnetic resonance imaging (MRI) also can be used to differentiate between benign or malignant adrenal tumors, especially for lesions smaller than 5 cm. In gen- eral, ACC tend to be hypointense relative to the liver or spleen on T1-weighted images and slightly hyperintense relative to the liver or spleen on T2-weighted images. If the mean signal intensity ratio between a lesion and the liver or spleen is greater than 0.8, it is more likely to be malignant. Neuroendocrine tumors, retroperitoneal hemorrhage and lymphadenopathy may also be hyper- intense on T2 imaging [1].
PET has been introduced as a primary diagnostic imaging study in determining malignant compared with benign adrenal masses. A small series from France employed 18F-fluorodeoxyglucose (FDG) to investigate 13 consecu- tive patients with adrenal masses who then underwent surgical resection and pathologic analysis. All patients with ACC (n = 3) had FDG uptake, and one had pre- viously non-diagnosed evidence of liver metastasis (Fig. 1) [21]. Only the malignant tumors had FDG uptake [22].
11C-metomidate (M’TO) is a marker for 11 B-hydroxylase, and has been suggested as a novel PET tracer in adrenal imaging. Sixteen patients with adrenal masses underwent scanning with both MTO and FDG PET, followed by surgical resection and pathologic analysis. While MTO distinguished adrenal cortex tumors from non-cortical tumors very well, it did not effectively distinguish malig- nant lesions from adenomas. FDG uptake was seen only in the malignant tumors (n = 3) [22]. FDG seems to be the tracer of choice in differentiating benign and malig- nant adrenal masses, but as these studies were small, large-scale investigations are needed.
Ultrasonography (USG) generally has limited value in differentiating of adrenal masses, but may be useful to follow adrenal masses over time, and is the screening imaging modality of choice in children and pregnant women. With the development of three-dimensional (3D) and four-dimensional (4D, real-time) USG, visual- ization and identification of feeding and draining vessels of large tumors, with a characteristic adrenal distribution,
Arrows indicate liver metastasis. Reproduced with permission [21].
may permit diagnosis of adrenal tumors that infiltrate or displace adjacent organs with more accuracy than cross- sectional studies. 3D USG may delineate retroperitoneal hemorrhage more precisely than computed tomography, when using multiplanar reformation mode to actively analyze images in three perpendicular planes, and render the object in three dimensions [23].
Radiocholesterol scintigraphy, using 131I-6-beta-iodo- methyl-norcholesterol (NP-59), has been used to identify benign cortical tumors. Tumors with high NP-59 uptake are likely to be benign adenomas, while low or no uptake of NP-59 is more likely to indicate ACC or a space- occupying lesion, such as a metastasis [24]. NP-59’s ability to differentiate benign from malignant tumors has been called into question by Tauchmanova et al. [25]. In a study of 22 patients with ACC, up to 30% of the tumors had uptake of NP-59, thus making its use less reliable. While NP-59 is more often used in Europe, it is not readily available in the United States, except in select institutions.
Treatment: surgical
The treatment of choice and the only chance for cure for ACC is complete surgical extirpation of the tumor and adrenal gland, en-bloc resection of invaded organs and, if necessary, peri-aortic/retroperitoneal lymphadenectomy. Surgical debulking is occasionally the only surgery possible. This may help reduce symptoms by reducing functional tissue, but is not curative. Most surgeons would opt for an open abdominal approach to ACC, in order to avoid tumor spillage, capsule rupture and ade- quate retroperitoneal resection and lymphadenectomy. The anterior abdominal approach also offers easy access to the main vessels, such as renal artery and vein, aorta and inferior vena cava. Laparoscopic adrenalectomy may be performed on tumors which have no evidence of local invasion, extensive lymphadenopathy or distant meta- stasis on pre-operative imaging, thus ensuring clean resection margins, and are not too large to risk tumor spillage from manipulation. Most incidentally identified adrenal tumors have no reliable preoperative signs to determine malignancy definitively; therefore, approach- ing these tumors laparoscopically is becoming common- place. In incidentalomas, the rate of ACC is approxim- ated at 4-5% for tumors less than 4 cm in size, up to 10% for tumors larger than 4 cm, and more than 25% in tumors larger than 6 cm [24,26]. Several studies have shown that imaging studies consistently underestimate the size of tumors when compared with their size at operation [27].
Laparoscopic adrenalectomy should be carried out cau- tiously in patients who may have unclear disease. Onco- logic principles need to be obeyed. If, upon proceeding laparoscopically, metastases, local invasion, vascular inva- sion, lymphadenopathy or obliterated dissection planes are encountered, conversion to an open procedure should not be delayed, as these signs purport a high likelihood of malignancy.
A recent review from Memorial Sloan-Kettering [28] analyzed retrospectively 141 patients who underwent liver resection for isolated non-colorectal, non-neuro- endocrine metastases to the liver. They included 15 patients with ACC who underwent partial hepatectomy for metachronous isolated liver metastases. The median relapse-free survival for these patients was 17 months, while the median cancer-specific survival was 40 months. Factors influencing better outcome included a longer disease-free period from diagnosis of the primary tumor and subsequent development of the distant metastasis, underlining less aggressive tumor biology and achieving a microscopically complete resection of the tumor. Patients with a disease-free interval of less than 24 months achieved an actuarial 3-year survival rate of 36%, but only 5% were free of relapse after 3 years. In contrast, patients with disease-free intervals of more than 24 months had an actuarial 3-year cancer-specific survival
40 Endocrine tumors
rate of 72% and an actuarial 3-year relapse-free survival of 30%. Of the 15 patients with ACC, three were alive at 5 years, with one patient alive at 11.5 years after resection of a liver metastasis. This study underscored that fact that in select patients, resection of liver metastases can be achieved in skilled hands with better-than-expected out- comes, and may be considered a treatment option in ACC.
A recent study from Germany [29] included 20 patients with ACC treated with aggressive surgical therapy. They found that the mean disease-free survival interval ranged from 12 to 22 months. Even in patients who underwent ‘curative’ resection, up to 80% of patients developed locoregional recurrence or distant metastases. In the case of locoregional recurrence, reoperation prolonged the 5-year survival to 27-57%, compared with chemo- therapy, which afforded a 5-year survival of 0-8%. Re-operations provided excellent symptomatic and endocrine relief, supporting the conclusion that repeated, radical resection for recurrent or metastatic disease was the more successful therapy.
Treatment: adjuvant therapy
If surgery is not possible, then tumor extirpation can be achieved by cytoreductive therapy. A short report from Taiwan [30] described a patient with locoregional recur- rence and distant liver and spleen metastasis of ACC who was treated by multiple transarterial embolizations of these tumors. The patient underwent a complete surgical excision 2 years prior to the recurrence. He then under- went three transarterial embolizations over the ensuing 3 years for recurrent and metastatic disease. He died 58 months later.
Other forms of cytoreductive therapy, such as radio- frequency ablation (RFA), have also been reported. Wood et al. [31] reported percutaneous, image-guided RFA in eight patients with fifteen ACC metastases and recurrences. This procedure was efficacious in the short-term control of smaller adrenal tumors.
The chemotherapeutic agent most commonly used in ACC is mitotane, yet its effect has been limited. The overall response rate has been reported to be between 14 and 36%, but most studies have shown no significant survival benefit [32]. The timing of administration of mitotane is still a subject of some debate. Some studies have suggested that patients who had mitotane adminis- tered immediately after curative resection for ACC had a longer disease-free survival than patients who underwent treatment only after developing recurrent or metastatic disease. Ten patients received mitotane or a combination of mitotane and chemotherapy, such as etoposide, adria- mycin, cisplatin or doxorubicin, after presenting with disease relapse. These patients had significant toxicity
and short overall survival. A retrospective Swedish study [33] which looked at 18 consecutive patients treated over 22 years included 14 patients starting in 1991 who received mitotane after surgery, irrespective of disease stage. The dosing of mitotane was titrated by measuring serum concentrations of the drug to 13-20 µg/ml, which most patients tolerated without significant morbidity. They received treatment for 12 months. All patients required cortisone and fluorocortisone replacement. In this small series, no patient had tumor regression on mitotane therapy, but when combined with aggressive surgery and resection of recurrences, the overall survival was observed at 58% at 3 years.
A larger study addressing the timing of adjuvant treat- ment for ACC [3] included 253 patients from the French Association of Endocrine Surgeons group. This study followed patients from 1978 to 1997. They found that over a 19-year period, there was no shift in tumor stage at presentation and there were no significant changes in surgical approaches or improvements in completion of resection. Mitotane use increased significantly and was used with similar frequency in patients of all ages. There was a non-statistically significant trend to use it more commonly in women than in men. It was used more often in patients with hormone-secreting tumors (78 compared with 22%) and more often in patients with advanced stage ACC (stages 3 and 4 compared with stages 1 and 2) (P < 0.05). It was used less often in curative surgical cases (P < 0.05). This study did not show any significant benefit of administering mitotane empirically after cura- tive resection for ACC. There was a survival advantage in patients with advanced disease (stage 4) and patients who underwent palliative surgery who were treated with mitotane, as compared with similar patients treated with surgery alone, doubling the median survival time from 2 to 4 years.
A smaller study [33] of 96 patients with ACC showed that high serum mitotane levels (more than 14 µg/ml) were an independent factor improving survival. The Italian Group for the Study of Adrenal Cancer have reported in a multi-institutional trial over 3 years modest success for a combination mitotane and chemotherapy regimen using etoposide, doxorubicin and cisplatin in 28 patients with measurable inoperable or metastatic disease. This combination chemotherapy was believed to be more efficacious due to the finding that multidrug resistance mediated by MDR-1/P glycoprotein can be reversed by mitotane. The regimen was reasonably tolerated, but only nine patients did well enough to follow the regularly scheduled drug doses. According to the World Health Organization criteria, 53% of the patients achieved at least a partial response, while 30% had stable disease. Time to progression of ACC in patients who responded to the drug therapy was 24.4 months [34,35].
Table 1 (a) Staging system for adults with ACC and (B) modified staging system for children with ACC
(a)
| Stage | Size (cm) | Local extension | Lymph node | Metastasis |
|---|---|---|---|---|
| 1 | < 5 | None | None | None |
| 2 | >5 | None | None | None |
| 3 | Any | þ or | þ | None |
| 4 | Any | Any | Any | þ |
Data from [37 ** ].
(b)
Stage
1
2
Tumor completely excised with negative margins, tumor ≤ 200 g, no metastasis Tumor completely excised with negative margins, tumor > 200 g, no metastasis
3
Residual (microscopic or gross tumor left after surgery) or inoperable tumor
4 Hematogenous metastasis
Data from [38].
A promising new drug class - the thiazolidinediones (TZD) - usually implemented in the treatment of type 2 diabetes is a specific peroxisome proliferators-activated receptor ligand. Recent evidence has suggested that TZD may be used as a tumor differentiation-inducing agent. In-vitro incubation of this drug with ACC cells led to a decrease cell viability, a decrease of cellular prolifer- ation and an increase in apoptosis, as well as steroidogen- esis. Cells also expressed higher ACTH receptor mRNA upon treatment. These data indicate that TZD may have the potential to become an additional treatment option as differentiation-inducing agents [36].
Pediatric adrenocortical carcinoma
ACC occurs in children and young adults. These tumors are rare and not well characterized. The International Pediatric Adrenocortical Tumor Registry was created in 1990. To date, 254 patients under 20 years of age have been registered. The staging system is modified, using completeness of resection and tumor weight of 200 mg as a marker for stage 1 and 2, residual or inoperable tumor as stage 3 and evidence of hematogenous metastasis as stage 4 (Table 1) [37 ** ,38]. The female-to-male ratios varied by age. It was nearly even in patients aged 12 years and younger, while in patients aged 13-20 years, the female- to-male ratio was 6.2 : 1. Ninety percent of children with ACC had evidence of hormonal hyperfunction, with virilizing signs and symptoms seen in 55% of children; mixed hormonal excess was present in 30% of children. The majority of patients presented with stage 1 and 2 disease (75%). The younger the patient at the time of diagnosis, the better the overall 2 and 5-year survival. Patients 13-20 years of age had the lowest overall survi- val, but there was no difference in survival by gender. Other variables conferring survival benefit were early stage at diagnosis, virilizing tumors and complete surgical resection. The overall 5-year survival was 54.2%. All patients with advanced or metastatic tumors were treated
with adjuvant chemotherapy, mitotane and radiation. There was no analysis of the efficacy of adjuvant treat- ment in patients with advanced-stage disease.
ACC in the pediatric population may be related to p-53 mutations. Therefore, children diagnosed with ACC in their first decade of life should undergo genetic testing for Li-Fraumeni syndrome [38].
Conclusion
ACC has remained a tumor that is rare and difficult to treat, in large part due to advanced stage at presentation. There have been no major practical advances in bio- chemical or radiographic diagnostic modalities. FDG PET scanning is a promising pre-operative modality, but larger studies need to be undertaken to evaluate its utility. Complete and aggressive surgical intervention remains the mainstay treatment for both primary and recurrent disease. The use of mitotane seems to confer some benefit in patients with evidence of residual or metastatic disease. Additional chemotherapeutic agents seem to add modest benefit. Given the paucity of patients with ACC at single institutions, multi-institutional regis- tries and trials need to be established, with multidisci- plinary efforts focused on the development of new therapeutic strategies.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
. of special interest
.. of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 84-85).
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