FUNCTIONING AND NONFUNCTIONING ADRENOCORTICAL CARCINOMA Clinical Presentation and Therapeutic Strategies
Michael J. Demeure, MD, and Lewis B. Somberg, MD
Carcinoma of the adrenal cortex accounts for between 0.02% and 0.2% of all cancer deaths.25,32,67 It is one of the least commonly occurring en- docrine malignancies. Adrenal cortical cancers are aggressive neoplasms having already undergone metastatic spread in approximately 40% to 70% of patients at the time of diagnosis. Over 50% of these tumors are func- tional in that there is clinical evidence of excess hormone production. The remaining nonfunctional adrenal cortical cancers are generally diagnosed after they become large enough to cause symptoms by compression or by mass alone. The relatively late diagnosis leads to a relatively poor overall 5-year survival rate of 20% to 35%. Although not well accepted, there is some suggestion that adrenal cortical cancers in children may portend a somewhat better prognosis than do those that occur in adults.7
INCIDENCE
The incidence of functioning adrenocortical neoplasms is approxi- mately 4 per million with about one half of these tumors being benign. The incidence of nonfunctional malignant tumors can only be estimated. It has been suggested that nonfunctional malignant tumors occur at an annual rate of 0.6 to 1.7 cases per million persons.59 With the frequent application of abdominal computerized tomography (CT), the inciden-
From the Departments of Surgery (MJD, LBS), and Cell Biology, Neurobiology, and Anatomy (MJD), Medical College of Wisconsin, Milwaukee, Wisconsin
tally discovered mass of the adrenal gland has become a well-described and common entity. Experience suggests that these tumors, if malignant, are more likely to be a metastasis from another primary cancer or a med- ullary neoplasm (pheochromocytoma) than a primary adrenocortical can- cer. The chance that an adrenal incidentaloma, 1.5 to 6 cm in diameter, is malignant is slim (<0.03%); however, the rate of malignancy increases up to 15% if the adrenal neoplasm is greater than 6 cm.33,46 The smallest re- ported adrenocortical neoplasm that has metastasized was 3 cm in di- ameter.29
CLINICAL PRESENTATIONS
The clinical presentation of carcinoma of the adrenal cortex is well- described.41,54 It can occur at any age from infancy to the eighth decade of life but most commonly presents in the third or fourth decade of life. Female patients predominate with a ratio of approximately 2.5 women to each male patient. Men tend to be older, but women are more likely to have symptoms of hormonal excess (3.6 to 1). Nonfunctional tumors are fairly evenly distributed between the two sexes. Most patients with non- functional tumors present with abdominal pain or pressure. Less common manifestations include weight loss, fever, malaise, hematuria, left vari- cocele, and dyspnea.54 Another clinical finding suggestive of cancer is the presence of an adrenal mass in association with a breast carcinoma, os- teosarcoma, or brain tumor (Li-Fraumeni syndrome). Because of the in- sidious nature of the symptoms associated with this tumor, there is usu- ally a delay in the diagnosis. In one large series reported by Luton and coworkers,41 the average time from onset of symptoms to diagnosis was 8.7 months with a range of 0 to 53 months.
Those with functional tumors may present with a variety of signs and symptoms depending on the nature of their tumor. When biochemical testing is performed, approximately 80% of patients have elevated urinary dehydroepiandrosterone levels.63 The hormonal secretory pattern has been described.28,55 Pure hypercortisolism (Cushing’s syndrome) is ob- served in approximately 30% of patients. A pure virilizing tumor occurs in between 22%. Less common are feminizing tumors and those that only secrete aldosterone, accounting for 10% and 2.5%, respectively. Approxi- mately 35% of these cancers exhibit a mixed pattern of excess hormone production. In a patient with an adrenal mass, a pattern of mixed hor- monal secretion, feminizing signs, or the increased production of hormone precursors should raise the suspicion of malignancy. Although adreno- cortical cancer accounts for only 5% to 10% of cases of hypercortisolism, 40% of patients with Cushing’s syndrome and an adrenal mass have a malignant neoplasm. Thirty percent of virilizing tumors are malignant. Feminizing tumors in adult men are nearly always malignant. Pure al- dosterone-secreting adrenal neoplasms are infrequently malignant.
PATHOLOGY
Metastatic disease or invasion into a contiguous structure is the only absolute indicator of malignant disease. Local recurrence is not sufficient because benign tumors may recur due to tumor seeding as a result of capsule disruption during resection. Supportive criteria include a diam- eter greater than 5 cm and a weight in excess of 50 g. The average size of an adrenocortical cancer when diagnosed is 10 to 12 cm in diameter.61 As with many endocrine tumors, pathologic examination to establish the di- agnosis of cancer can be problematic. The gross appearance of an adrenal cortical cancer generally features areas of hemorrhage and necrosis (Fig. 1). Microscopic indicators of malignancy include architectural disorder, nuclear pleomorphism, a high mitotic index, hemorrhage, necrosis, and capsular or vascular invasion. A more thorough list of histologic features suggestive of malignancy is detailed in Table 1, although none are patho- gnomonic by and of themselves.
Flow cytometry may be a useful adjunct to pathologic evaluation when a diagnosis of malignancy is not possible based on histology alone, as an aneuploid pattern is associated with carcinomas.1,4 Cibas and col- leagues studied the DNA content of 43 adrenal cortical neoplasms includ- ing 13 cancers.12 DNA ploidy as determined by flow cytometry correlated with tumor size, mitotic rate and nuclear grade. It did not, however, cor- relate with clinical outcome. A cooperative group study of 22 adrenocor- tical cancers found 21 exhibited an aneuploid DNA pattern.8 Again, no correlation was found between flow cytometry findings and patient sur- vival.
Imaging studies may suggest malignancy. The presence of an irreg- ular border, adjacent lymphadenopathy, and heterogeneous pattern seen on CT suggest a malignant adrenal lesion. Fine-needle aspiration (FNA) or core needle biopsy of these lesions does not generally allow one to
Table 1. HISTOLOGIC FEATURES OF AN ADRENAL MASS SUGGESTIVE OF MALIGNANCY37,68
Diffuse architectural pattern with broad fibrous and trabecular bands
Foci of confluent necrosis
Hemorrhagic areas
Fibrosis and calcifications
Capsular invasion
Venous and sinusoidal invasion
Nuclear stage III or IV High mitotic index
Clear cells comprising more than 25% of the tumor
differentiate an adenoma from a carcinoma; therefore, it is not recom- mended for potentially resectable primary tumors. There may, however, be use for FNA in a patient with a history of a prior distant cancer to establish the presence of a-metastatic lesion in the adrenal gland.
MOLECULAR BIOLOGY
Because of the present difficulties differentiating benign from malig- nant lesions of the adrenal cortex, there have been some seminal efforts to identify specific markers at the molecular level. Comparative genomic hybridization analysis of eight adrenocortical cancers demonstrated losses in chromosomes 2, 11q, and 17p of four tumors, whereas gains occurred in chromosomes 4q and 5.34 These genetic changes were associated with an aneuploid DNA pattern and were not seen in small (<5 cm) adrenal adenomas. Previous cytometric studies in adrenocortical cancers showed loss of heterozygosity on chromosome 11p, 17p, and 13q.72 Karyotype analysis of two sporadic adrenocortical cancers showed alterations on chromosome 11p.27,40
Some have suggested the aberrant growth of some adrenal cortex neoplasms is the result of a position 179 mutation in the gip2 oncogene.42 Such a mutation in this inhibitory G protein (G12) is associated with an inhibition of adenylate cyclase and a reduction of cellular cyclic adenosine monophosphate (cAMP).70 In cultured human SW-13 human adrenal cor- tical adenocarcinoma cells, elevation in cAMP was related to a decrease in cell proliferation.48 We and others disputed the assertion that this mu- tation is important in the pathogenesis of adrenocortical neoplasms be- cause we found no such mutation in 85 tumors, including 29 cancers in our combined series.17,73
Recently, McNicol and colleagues reported overexpression of the p53 tumor suppressor gene in 4 of 34 adrenocortical adenomas and 22 of 42 carcinomas, by immunohistochemistry.47 Additionally, in one of four ad- enomas and 10 of 21 carcinomas, analysis by polymerase chain reaction- single strand conformational polymorphism (PCR/SSCP) suggested the presence of a mutation in exons 5-8 of the p53 gene. These findings were not confirmed by sequencing. Furthermore, there was no correlation be- tween p53 status and patient survival. In another recent report,20 17 ad- renocortical cancers from 16 patients were studied for expression of p53,
insulin-like growth factor (IGF), epidermal growth factor receptor (EGF- r), and proliferation markers PCNA and Ki-67. All tumors expressed PCNA and Ki-67 with median values of 59% and 14%, respectively, whereas p53 staining was negative in 88%, IGF negative in 82%, and EGF- r positive in 94%. No correlation was found between p53, IGF, EGF-r, or the proliferation markers and survival rate.
PREOPERATIVE EVALUATION AND PREPARATION
Initial preoperative preparation should include a full evaluation of the extent of disease. The most often used staging scheme was described by MacFarlane43 and later modified by Sullivan and colleagues58 (Table 2). Common sites of metastasis are the liver, lung, and bones. Other less com- mon sites of metastasis include the spleen, pancreas, small bowel, brain, ovary, orbit, peritoneum, pleura, skin, and the contralateral adrenal gland.41,54 Overall, 5- and 10-year survival rates are approximately 30% and 10%. In reports by the French Association of Endocrine Surgeons and the Italian Registry, tumor stage at initial operation had prognostic sur- vival implications (Fig. 2).15,28 Survival was not, however, influenced by patient age, gender, or whether the tumor exhibited hormone secretion.
Less than 50% of patients have resectable disease at presenta- tion.13,18,43,58 CT of the chest and abdomen should be used to examine for the presence of adenopathy, invasion of contiguous structures, or meta- static disease in the lungs or liver. MR imaging is particularly useful to evaluate the liver for metastases (Fig. 3) and the inferior vena cava for the presence of tumor thrombus. Tumor thrombus in the vena cava is not a contraindication to resection but cardiopulmonary bypass may be neces- sary if the tumor extends to the right atrium (Fig. 4).10 Adrenal malignan- cies measuring between 3 and 6 cm in diameter are well described and pose a diagnostic dilemma. Scintigraphy with NP59 (131I-6ß-iodomethyl- norcholesterol) has been suggested to distinguish benign from malignant small adrenal neoplasms seen by CT.35 For unilateral nonhypersecretory adrenal tumors, NP59 uptake that exceeds the normal appearing contra-
Table 2. STAGING CRITERIA OF ADRENAL CORTICAL CARCINOMA
T1: Tumor diameter ≤ 5 cm, no local invasion
T2: Tumor diameter > 5 cm, no local invasion
T3: Tumor of any size with local extension to but not involving any adjacent organs
T4: Tumor of any size with local invasion of adjacent organs
NO: No regional nodal involvement
N1: Positive regional lymph nodes
MO: No distant metastatic disease
M1: Distant metastatic disease
Stage |: T1NOMO
Stage II: T2NOMO
Stage III: T1 or T2N1M0, T3NOMO
Stage IV: Any T, Any N, M1, T3N1, T4
100
local cancers (n=83)
locoregional cancers (n=39)
P < 0.001
metastatic cancers (n=34)
Survival Rate (%)
80
60
53% (24)
40
(5)
(6)
24% (6)
20
(2)
0
1
2
3
4
5
6
7
8
9
10
Years
lateral adrenal gland suggests benignity, whereas decreased or absent NP59 uptake in a mass seen on CT should be considered worrisome. It is important not to perform a needle biopsy of a potentially resectable ad- renal cortical tumor that may be a cancer. Biopsy by FNA is not likely to distinguish a benign from malignant adrenal cortical neoplasm. Further- more, the risk of tumor mitigates any potential benefit of a preoperative
LV
RV
TCV
T
LA
diagnosis. Percutaneous biopsy may have a role in some patients in whom metastatic disease to the adrenal glands is suspected.9
If the adrenal tumor is deemed resectable by imaging studies, pre- operative preparation should include an assessment of contralateral kid- ney function. This is important because an adrenal tumor may invade the adjacent kidney or its vascular supply, requiring removal of the kidney. A normal serum creatinine with a normal appearance and dye excretion on CT of the contralateral kidney is sufficient. The patient should receive preoperative hydrocortisone. Because almost pure hypercortisolism oc- curs in 30% and mixed secretion patterns in approximately 35% of pa- tients,28 the contralateral adrenal gland may be suppressed. Preoperative treatment with mitotane may be indicated in two situations: metastatic disease and severe hypercortisolism. Mitotane controls Cushing’s syn- drome in up to 75% of patients37 and occasionally results in partial re- gression of the primary tumor and metastases. Symptoms of hypercorti- solism may also be controlled by the administration of ketoconazole (400 mg/day) that blocks the synthesis of steroids. Other agents such as me- tyrapone and aminoglutethimide have also been used. Prophylaxis against thromboembolism should be used in the form of low molecular weight heparin because these patients are at risk for pulmonary embolism. A French series of 80 patients included two patients who died from peri- operative pulmonary emboli.41
OPERATION
The adrenal glands may be approached by way of a variety of inci- sions. For small adrenal tumors, a laparoscopic adrenalectomy has become
the procedure of choice for most patients because it has been proven safe and is associated with a more rapid recovery than are open approaches.24 When dealing with potentially malignant adrenal tumors, one must place the priority on performing an appropriate cancer operation. Important tenets of oncologic surgery must be observed, including adequate expo- sure, intraoperative staging, and performing an en-bloc resection of intact tumor mass. The maximum size of an adrenal tumor that can technically be removed by way of the laparoscope is not the issue. Although it also occurs after open removal, local recurrence after laparoscopic removal of an intact adrenocortical tumor has been reported.62 If one suspects an ad- renal tumor is malignant based on its size or radiographic imaging, an open operation is warranted. Complete surgical excision is the only treat- ment that can offer the potential for cure. Complete resection is the best prognostic factor predicting long-term survival. In the Anderson series, median survival of patients with completely resected tumors is 46 months versus only 8.5 months if the tumors were incompletely resected (P < 0.005).38 Others report similar correlation with completeness of resection.75
The choice of incision is partially dependent on the size of the adrenal tumor, side, involvement of adjacent structure, patient body habitus, and surgeon preference. Adequate exposure is paramount for vascular control and to allow careful resection without fracture of the tumor. Anterior ab- dominal exposure by way of midline, bilateral subcostal, flank, or thoraco- abdominal incisions may be appropriate depending on the circum- stances.22 A posterior approach is generally ill advised because it does not allow full exploration of the abdomen for staging or resection of contigu- ous involved organs. Staging should include a careful evaluation of the primary tumor, examination for involvement of adjacent organs or ret- roperitoneal lymphadenopathy, and evaluation of the liver by inspection, palpation, and intraoperative ultrasonography.
The approach to a relatively small tumor in the left adrenal gland can be accomplished by reflecting the splenic flexure of the colon downward and dividing the lateral omental attachments to the transverse mesocolon. The adrenal can then be exposed by making an incision in the retroperi- toneum below the tail of the pancreas. For large adrenal tumors, it is usually necessary to rotate the spleen and pancreas medially to provide adequate exposure. This is accomplished by dividing the lienophrenic lig- aments to approach the avascular plane posterior to the spleen and tail of the pancreas. The anterior and lateral aspects of the adrenal gland are generally supplied by small blood vessels, but in the case of large malig- nant tumors, large collateral vessels may be encountered. The primary vascular supply, however, is located on the medial-inferior aspect cours- ing directly to the renal artery and vein. Accessory vessels may arise di- rectly from the aorta and vena cava. If direct invasion of the kidney is encountered, it may be resected en bloc with the adrenal gland and peri- nephric fat providing the surgeon has documented contralateral renal function. In the unusual setting of an absent contralateral kidney, we have performed partial nephrectomy of the upper pole. The tail of the pancreas and spleen may be resected if the adrenal tumor invades the pancreas.
For very large left adrenal gland tumor, a thoraco-abdominal incision may be necessary.14 For this approach, some recommend placing a roll beneath the left side to position in a semidecubitus position. The abdom- inal incision is made first to determine whether the thoracic extension is needed. The abdominal aspect of the incision may be either oblique or partially oblique with a vertical extension in a midline or paramedian midline incision. The thoracic aspect of the incision is a continuation of the abdominal incision across the costal arch into the eight or ninth inter- space. During closure, the costal cartilage tends to overlap so a segment is resected subperichondrially as the incision is made. The preserved peri- chondrium promotes solid union after firm approximation with nonab- sorbable suture. The diaphragm is then incised with care not to injure the phrenic nerve. Because the phrenic nerve fans out from the median por- tion of the hemidiaphragm, a radial incision may denervate a large por- tion of the diaphragm. An incision along the lateral subcostal margin is preferred.
The right adrenal gland may be approached through either a midline or a subcostal incision. The hepatic flexure of the colon is reflected infe- riorly and the duodenum is reflected medially by performing a Kocher maneuver. The inferiorolateral peritoneal attachments of the right lobe of the liver are then divided. The adrenal gland is then approached directly with the caveat that the adrenal vein is generally short and empties di- rectly into the vena cava. The possibility of involvement of the vena cava with tumor or tumor thrombus has hopefully been investigated with pre- operative imaging studies. En bloc resection with a portion of the wall of the vena cava may be needed. In cases with extensive intravenous tumor thrombus, cardiopulmonary bypass has been used. For very large right adrenal tumors, a thoraco-abdominal incision may be needed.19 For this approach, the patient is placed in the kidney position with the eleventh rib over a kidney rest on a flexed table. The patient is turned so the lower body is elevated by 10º to 20° and the chest is at a 45° angle to the table. The incision is carried through the external and internal oblique abdom- inal muscles and the rectus fascia and transversalis muscle. The eleventh rib is resected subperiosteally and the diaphragm and pleura incised.
After operation, normal principles of postoperative care apply. Intra- venous fluids are administered until the patient is able to resume oral alimentation. Serum electrolytes should be monitored. Pulmonary toilet is important to maintain expansion of the lung bases. Steroid hormone replacement is necessary as these patients have surgical or chemical in- duced primary adrenal insufficiency. One satisfactory regimen is to ad- minister hydrocortisone or cortisone in the early morning and afternoon. The usual initial daily dose is 25 mg of hydrocortisone (given as 15 mg in the morning and 10 mg in the afternoon) or 37.5 mg of cortisone (divided into doses of 25 and 12.5 mg).49 Patients should also receive a single daily dose of 0.1 to 0.2 mg fludrocortisone to replace the mineralocorticoid ac- tivity of aldosterone. The appropriate dosing should be guided based on the patient’s blood pressure, serum potassium, and plasma renin activ- ity.50,51
CHEMOTHERAPY
Resection of metastases is indicated25,36 and when feasible offers sub- stantial survival benefits over drug therapy.5,54 There is no proven che- motherapeutic regimen and toxicities are often severe and dose limiting.
Mitotane
Adjuvant treatment for resected adrenocortical cancers with mitotane (o,p’-DDD or 1,1-dichloro-2-[0-chlorophenyl]-2-[p-chlorophenyl] ethane) is controversial and the rarity of this tumor precludes extensive clinical trials to determine optimum therapy. Mitotane is an adrenal cytotoxic agent, although it can cause adrenal inhibition without cellular destruc- tion. The biochemical mechanism of its action is unknown. The Memorial Sloan-Kettering series reported no benefit from adjuvant mitotane che- motherapy in seven patients.54 Another small single institution retrospec- tive study also failed to show improved survival in patients receiving mitotane.66 This study can be faulted because the investigators did not report on blood levels. Others have shown that the therapeutic value of mitotane is dependent on achieving sufficiently high blood levels of the drug.26 Yet other experienced endocrine surgeons use it empirically, feel- ing the high risk of recurrence justifies therapy and claiming encouraging results.61
The lack of clear efficacy and its toxicities mitigate against the use of mitotane in the adjuvant setting. The side effects of mitotane are pre- dominantly gastrointestinal, neurologic, and cutaneous. Gastrointestinal disturbances occur in approximately 80% of patients and include anorexia, nausea and vomiting, and possibly diarrhea. Central nervous system side effects occur in approximately 40% of patients and may include depres- sion, lethargy, somnolence, vertigo, ataxia, and difficulty with speech. The skin rash that occurs in approximately 15% of patients does not appear to be dose related and may subside with continued treatment. Other effects include gynecomastia in men, leukopenia, thrombocytopenia, hy- percholesterolemia, hyperuricemia and hepatic dysfunction manifested by increases in serum levels of alkaline phosphatase, aspartate amino- transferase, alanine aminotransferase, and gamma glutamyl transferase. Low serum thyroxin may be noted but with normal thyroid stimulating hormone levels.
For unresectable metastatic disease, a trial of mitotane is warranted. In the Eastern Cooperative Oncology Group study, for the 22% of patients whose tumors responded to mitotane treatment, median survival was pro- longed to 50 months compared with 14 months for nonresponders.16 In this study, 19% of patients responded to Adriamycin chemotherapy but this agent was not effective as a second-line agent for patients who failed mitotane. A review of existing literature suggests the response rate to mitotane is approximately 35%.71 One study suggested that a minimum serum mitotane level of 10 µg/mL is critical to achieving efficacy. van Slooten and associates showed an increase in survival or tumor regression
in 57% of patients who had serum levels greater than 14 µg/mL with complete remission in one patient.64 No patient with a mitotane level less than 10 µg/mL, however, had a significant response to chemotherapy. Mitotane may have a role in the treatment of the hormonal toxicities of secretory adrenal tumors in that mitotane controls hormonal secretion in 75% of patients.41 Palliation of hypercortisolism may also be treated with ketoconazole or octreotide,52 and hyperaldosteronism may be treated with spironolactone.
Suramin
Suramin, a polysulfonated naphthylurea, when used as a treatment for HIV was noted to have adrenal toxicity leading to adrenocortical in- sufficiency.31,39 In experiments on Cynomolgus monkeys, suramin admin- istration led to lymphocytic infiltration and destruction of the adrenal cortex.21 These findings led to a preliminary trial showing some efficacy with the use of suramin as chemotherapy for adrenocortical cancer.57 In a German series, suramin was administered to 9 patients with metastatic adrenocortical cancer.69 Three patients achieved partial responses and two had stabilization of their disease, but four experienced disease progression while on therapy. More over, serious side effects were noted, including coagulopathy and thrombocytopenia in six patients, skin reactions in four patients, and polyneuropathies in two patients. The authors concluded that while suramin has antitumor activity in the treatment of adrenocor- tical cancer, its use is limited by the risk of serious complications. It should not be used as a first line agent and if used, serum levels should be closely monitored and maintained between 200 and 250 mg/L to limit toxicities.
Combination Chemotherapy
Combination chemotherapy may have efficacy in some patients, par- ticularly when combined with mitotane. P-glycoprotein, a product of the mdr-1 gene, mediates multi-drug resistance in cell culture.10 It is routinely expressed in adrenocortical cells.23 Mitotane partially reverses mdr-1/P- glycoprotein multi-drug resistance by reducing drug efflux from cells.3 Furthermore, the therapeutic benefit of cisplatin on adrenocortical cancer may be augmented when combined with mitotane.6 For mitotane failures, largely anecdotal experience or small series report responses in patients treated with doxorubicin, bischloroethylnitrosourea (BCNU), and cispla- tin, alone or in combination with other agents.60,65 Two reports on three patients documented responses to the combination of cisplatin and eto- poside.30,74 The overall response rate reported for the combination of 5-fluorouracil, doxorubicin, and cisplatin in 13 patients was 23%.56 We have treated one patient with the eight cycles of a combination of doxo- rubicin, vincristine, and etoposide to obtain complete remission of diffuse pulmonary, hepatic, and splenic metastases for over 15 months.
RADIATION THERAPY
Some investigators have suggested a role for adjuvant radiation ther- apy to the bed of resected adrenocortical cancers, but reports are largely anecdotal.44,45,53 Local recurrence is common but adjuvant radiotherapy has not been studied in a prospective manner. Furthermore, the devel- opment of secondary malignancies after irradiation for adrenal cancers has been reported in long-term survivors.2,44 External beam irradiation does, however, have an established role in the treatment of painful osseous metastases.45 In the series by Percapio and Knowlton, 11 patients received 18 courses of 30 to 40 Gy radiation for palliation of adrenocortical metas- tases.53 Five of these patients were treated for painful bone metastases and had relief of pain associated with radiographic evidence of healing. None required further local therapy except one patient required subsequent de- compression lumbar laminectomy for recurrent tumor 15 months after palliative lumbar spine irradiation.
CONCLUSIONS
Adrenocortical cancers are rare tumors that generally present late in their course. Although surgical resection offers the only potentially cu- rative therapeutic modality, less that half of these patients present at a stage where resection is possible for cure. Mitotane, alone or in combi- nation with other agents, remains the most effective chemotherapy but only 35% of patients respond to this treatment. Methods for early detec- tion and better systemic therapies are needed to impact favorably on the course of patients with adrenocortical cancer.
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