Adrenocortical Carcinoma

Introduction

Adrenocortical carcinoma (ACC) is a rare and highly lethal malignancy, representing 0.02% of all carcinomas. With an incidence of 2.5 cases per million individuals and generating a 5-year survival of less than 25% for advanced cancers, it remains a significant clinical challenge as effective systemic therapy options continue to evade clinicians and scientists [1, 2]. In general, patients present with advanced disease (20%-40% metastatic) owing to limited screening modalities, and the retroperitoneal location of the tumor which facilitates extensive invasion and growth before symptoms arise [3, 4]. Malignant tumors of the adrenal gland are increasingly detected in early stages because of the rise in diagnostic imaging modalities often performed for other indications. However, most patients will still present with advanced disease at their time of diagnosis. Below, we will review the management options for both early and advanced adrenocortical carcinomas. Tumors of the adrenal medulla, known as pheochromocytomas, will not be discussed in the below review owing to their unique physiology and separate embryologic origin.

Symptoms
Adrenocortical carcinoma (ACC) often presents at advanced stages due to the location of the tumors, which may not produce symptoms until a considerable mass is attained. In general, ACCs are classified as being functional (i.e a tumor capable of secreting cortisol, aldosterone, and/or androgens and estrogens) or non-functional, with thirty to fifty percent of malignant tumors being non-functional.  Non-functional tumors are most at risk for silent growth until they’ve reached a considerable size. On average, ACC impacts women twice as often as men, and women are more likely to show overt signs of functionality [5]. Tumors on the left or right side may present with pain from invasion into the retroperitoneal spinal nerves, otherwise symptoms will depend based on location of the tumor. Left sided tumors may present with dysphagia, dyspepsia, pancreatitis, or descending colon obstruction, while tumors on the right may present with duodenal outlet obstruction, right sided colon obstruction, and inferior vena cava obstructive symptoms (ankle edema, and DVT/PE for instance) [5]. Most commonly, a large mass may be identified by the patient or a primary care physician working up the recent development of cachexia or asthenia in the setting of new abdominal pain. Regardless of the location, renal function is often preserved unless an extensive infiltrative process has occurred [1].

Functional tumors (60%), however, may present earlier depending on symptoms attributable to autonomous hormone secretion. The majority of functional tumors, as mentioned previously, occur in young women, often younger than 40 years of age. Functional tumors can secrete one (65%) or multiple (35%) steroid hormones unique to the adrenal cortex. For those tumors that secrete aldosterone (1- 2.5%), patients may develop uncontrolled hypertension and refractory hypokalemia despite multi-modal therapy. Conn’s syndrome in adrenocortical carcinoma overall represents a rare subset of functional tumors [1, 5].

Cortisol secreting malignancies are the most common functional tumor, representing 30% of functional malignancies. In those with cortisol excess from adrenal cancer, Cushing’s syndrome may present more abruptly than is typically observed in patients with pituitary Cushing’s or autonomous adrenal adenomas. Cortisol excess may cause rapid weight gain, peripheral muscle wasting and weakness, insulin-dependent diabetes mellitus, uncontrolled hypertension, mood changes/ emotional lability (specifically depressed mood and anxiety), and classic physical exam findings including central adiposity with peripheral muscle wasting, moon faces, increased growth of the dorsocervical fat pad, and abdominal striae with weakened connective tissue (namely thinned dermal tissue) [5].

Perhaps most clinically striking are those patients with sex-hormone secreting tumors. Sex-hormone secreting tumors represent 32% of functional malignancies, and have the greatest association with malignancy, with 70-80% of identified tumors being malignant [3, 5]. These particular tumors are separated into two groups, virilizing or feminizing based on their hormone profile. In virilizing tumors (22%), which  secrete one or a combination of dehydroepiandrosterone (DHEA), its sulfate derivative (DHEAS), testosterone, or androstenedione, patients may experience male patterned baldness, acne, hirsutism, deep voice, the development of male stereotypic muscle mass and adipose tissue distribution, and irregular menses or amenorrhea in reproductive age females. Feminizing tumors  (10%) are associated with advanced bone age, female hair distribution, gynecomastia, and at times irregular menses in women of any age distribution. Subtle personality changes may also be present. While not all virilizing or feminizing tumors may be malignant, it should be noted that virtually all feminizing tumors in male patients are malignant [3, 5].

• Screening

Unfortunately, screening protocols do not exist for early detection of adrenocortical carcinomas. Except in the case of individuals with inherited mutations in TP53 or CHEK 2 (Li-Fraumeni syndrome), insulin-like growth factor-2 (IGF-2) mutations (Beckwith-Wiedeman Syndrome), and those patients with Carney Complex, there are no particular subsets of patients more inclined to develop adrenal tumors [6]. Routine laboratory testing and cross-sectional imaging is not recommended [4, 5].

• Diagnosis

The diagnosis of adrenocortical carcinoma is based on a combination of suspicion from modern imaging modalities and post-operative pathologic assessment. Due to the aggressiveness of the tumors, concerns for disrupting the tumor capsule, and challenges in differentiating benign from malignant lesions in small tissue samples, percutaneous biopsy is usually deferred and is not recommended [3-5]. As mentioned previously, adrenal tumors and adrenocortical carcinoma may be found incidentally on computed tomography (CT) scans, often obtained to evaluated other pathology or unrelated symptoms. It should be noted however that asymptomatic adrenocortical carcinomas are a rarer presentation of disease [1, 4]. If an adrenal mass is identified on CT or magnetic resonance imaging (MRI) scans, the first step in pursuing a diagnosis involves obtaining serum and urine chemistries to evaluate tumor functionality and exclude pheochromocytoma [4]. Typically, serum aldosterone and renin levels are obtained, serum ACTH and cortisol, serum DHEA and DHEAS, as well as serum and urine metanephrines. Serum estrogens are not typically evaluated unless there is clinical concern for feminizing functional tumor biology, owing to its exceptionally low incidence [4, 5]. Elevation in any of the aforementioned hormones above reference range is indicative of a functional tumor. For those with normal cortisol levels and either low or normal ACTH levels, or in those patients with clinical suspicion for Cushing’s syndrome, we recommend continuing testing further with a low dose, and if necessary, a high dose dexamethasone suppression test and 24-hour urine cortisol [1, 3, 7].

Most routine cross-sectional imaging studies will not have the resolution to delineate subsets of adrenal pathology [8]. As such, we recommend obtaining a dedicated CT scan with thin, 3-5mm helical collimation, with and without intravenous contrast to assess the enhancement characteristics, wash out, and vascular anatomy which may be pathognomonic for disease. Oral contrast may also be necessary. Dedicated MRI (specifically chemical shift MRI, or CSI) can also be obtained and offers greater tissue contrast, though studies evaluating its ability to detect adrenal pathology (specifically to differentiate benign from malignant lesions) are more limited [8]. Typically, adrenal pathology is evaluated on MRI through the use of T1 and T2 weighted density, gadolinium enhancement, and chemical shift characteristics. Lastly, scintigraphy with radionuclide fluorine -18 fluorodeoxyglucose positron emission tomography (FDG-PET) can add diagnostic value in differentiating benign (typically non-enhancing) from malignant (FDG-avid) lesions [5].  

The following needs to be considered when evaluating an adrenal lesion identified incidentally. First, adrenal incidentalomas occur in 5-7% of the population, with the vast majority being benign nonfunctional adenomas [8].  Of the subset of individuals with adrenal incidentalomas, 4-7% will harbor a malignancy (adrenocortical or adrenal metastasis). A clinician’s index of suspicion for adrenocortical carcinoma should rise in patients presenting with symptoms related to steroid excess, those without a known history of malignancy, and those with bilateral disease as 10% of adrenal cortical carcinomas will have bilateral involvement at presentation [1, 3, 5]. In general, a size cut-off of 4 centimeters (cm) is suspicious for a primary or secondary adrenal malignancy as 5-15% of tumors >4cm will harbor malignancy. It should be noted that 90% of adrenocortical carcinomas are greater than 4cm at the time of presentation [1, 5].

With CT imaging, ACCs often appear larger (>4cm), with irregular margins, central necrosis and calcifications (30%), heterogenous, and display a rapid growth pattern if followed with serial imaging. Benign lesions (adenomas) are typically lipid rich and have densitometry of <10 Hounsfield units (HU) on non-contrast enhanced imaging, a feature which may differentiate benign from malignant lesions (sensitivity 71%, specificity 98%) [8]. Malignant lesions will also display delayed contrast washout due to irregular capillary development within the tumor. This may necessitate delayed repeat CT imaging in ten minutes and up to one hour to fully process delays. On both CT and MRI, malignancies will vigorously enhance owing to the higher water to lipid content. Additionally, adjacent adenopathy, concurrent metastases to the liver or lung, and features of invasion will be suggestive of malignancy. Other clinical findings highly suggestive of malignancy include rapid onset of disease, abdominal pain or abdominal mass, inferior vena cava obstruction or infiltration, mixed hormone secretion, mild androgenic changes, feminizing syndrome, and elevated inactive steroid hormone precursors (pregnenolone and aldosterone precursors including 18-hydroxylated compounds, which may be identified on serum or urine testing) [5].

After surgical resection, the final diagnosis of adrenocortical carcinoma is made by pathologic examination of the tumor specimen. Consensus guidelines include evaluation of the tumor specimen by an expert adrenal histopathologist for those tumors difficult to qualify. All specimens should be evaluated for steroidogenic factor expression (SF1) to differentiate adrenal versus non-adrenocortical origin. Ki67 index should also be included, as this will provide important prognosticating information. Lastly, all pathology reports should include a Weiss score, with the exact mitotic count, exact Ki67 index, resection status, pathologic tumor stage (including invasion through the capsule and/or surrounding tissue and organs), and lastly nodal status [4]. With this information provided, increased confidence in the diagnosis and prognosis can be achieved, both of which will guide recommendations for further systemic or local treatment options.

Pathologic features of malignancy (as defined by the Weiss criteria for malignancy) include high nuclear grade, mitotic rate >5 per 50 high power fields (hpf), atypical mitoses, eosinophilic tumor cell cytoplasm (>70% of tumor cells), diffuse architectural pattern (>33% of tumor) with broad fibrous and trabecular bands, foci of confluent necrosis, venous invasion, sinusoidal invasion, and capsular invasion [9]. Typically, 3 or more of the aforementioned pathologic features correlates well with malignancy and will be seen in tumors in excess of 6cm. For tumors between 3-6cm in diameter, capsular invasion may not be encountered, additionally tumors may exhibit weak mitotic activity. In this setting immunohistochemistry can be useful. Malignant tumors express vimentin in 80-90%, IGF-2 in 90%, with synaptophysin and MIB-1 also commonly identified in malignant tumor expression profiles. Lastly, malignant tumors are typically monoclonal in nature, which can help to differentiate these tumors from benign adenomas, which are typically polyclonal [1, 5, 9, 10].

As mentioned previously, if adrenocortical carcinoma is suspected, percutaneous biopsy is not recommended. However, if the patient’s clinical history is suggestive of adrenal metastasis (for instance, in a patient with co-existing known malignancy or known stage IV disease),  biopsy may provide valuable information [1, 4]. For those with suspected metastatic adrenocortical carcinoma, surgery is controversial and usually not recommended. Often, patients are better palliated with medical therapy alone [1, 4]. In patients with suspected stage IV adrenocortical carcinoma, percutaneous biopsy of the primary tumor may provide histopathologic information to aid in informing systemic treatment modalities.

• Staging

Adrenocortical carcinomas are staged using the tumor-node-metastasis (TNM) classification system. T1 involves tumors <5 cm, <50gm. T2 involves tumors >5cm, >50gm. T3 tumors exhibit gross or pathologic invasion into adjacent periadrenal fat and/or vascular and lymphatic invasion. Lastly, T4 tumors include those with invasion into adjacent organs, or those with venous tumor thrombus in the inferior vena cava or renal vein. N0 includes those tumors without nodal involvement, N1 with any number of positive lymph nodes. M0 describes the absence of distant metastases, while M1 tumors involve any evidence of distant metastatic spread. Using these criteria, Stage I tumors are less than 5cm (less than 50gm) and exhibit no local extension, lymph node involvement, or distant metastases (T1N0M0). Stage II tumors are greater than 5cm (>50gm) and similarly have no features of local invasion or lymph node involvement (T2N0M0). Stage III tumors can be any size and/or locally advanced (T1-T4) and demonstrate local lymph node involvement (T1-4N1M0). Stage IV tumors include all tumors with metastatic spread to distant organs (T1-4N1M1). Of note, the combination of tumor stage and proliferation index are used to estimate clinical prognosis [1].

For stage I and II tumors, 5-year survival approaches 60-80%, However, detection of tumors at this stage is rare unless discovered incidentally [1]. Stage III disease incurs a 5-year survival of 30-50%, with stage IV disease typically less than 25% [1, 11]. These prognostic values unfortunately do not change with the addition of adjuvant therapies, as a tumor response to mitotane therapy in advanced cancers is only seen in 13-30% and is typically temporary [11]. With adjuvant therapy (systemic, radiation, or a combination thereof) patients will experience improved recurrence-free survival, however overall survival is not impacted [12].

• Treatment

The mainstay of treatment for ACC involves early surgical excision, as this represents the only means of cure. For any patient with Stage I to Stage III disease, upfront surgical resection is recommended with attempted en bloc or R0 resection. Owing to the rare nature of ACCs and importance of R0 resection, we recommend referral to experienced centers or surgeons (defined as performing >10 adrenalectomies annually). If access to a tertiary referral center is not possible, referral to those surgeons experienced in multi-visceral resection would also be ideal. This practice reduces the risk of inadequate resection or tumor capsule disruption, both of which are associated with poor prognosis and local tumor seeding [1, 4].

While some centers perform laparoscopic adrenalectomy for ACC, this remains highly controversial [13, 14]. Due to the grave consequences of inadequate resection, the typically thin and friable tumor capsule, and the risk of local tumor seeding with capsule rupture, we recommend an open surgical approach [1]. We perform open resections via a midline or lateral subcostal approach which can be extended across midline if necessary. Improved exposure, if particularly challenging, can be achieved by extending a midline incision along the subcostal margin or the later. Thoracoabdominal incisions may be preferrable for tumors with significant superior posterior extension, for instance, in the retrohepatic space. Intravenous tumor thrombus (vena cava or renal vein) is not a contraindication to surgical excision and may be removed with adjunct use of cardiopulmonary bypass, if available [1]. Improved surgical access for such tumors can be accomplished via sternotomy, if necessary. Young patients with oligometastases can be considered for surgical resection of the primary tumor and metastasectomy, for instance in a patient with a solitary liver metastasis [5]. For particularly large tumors, or those with major vascular involvement, CT imaging in combination with MRI can provide a surgical road map and cue the operating surgeon to areas where significant hemorrhage may occur without judicious intraoperative dissection.

As mentioned previously, the mainstay of therapy involves en bloc excision of all involved viscera, while ideally maintaining a healthy uninvolved contralateral kidney. Invasion into the liver requiring formal resection is rare, and usually a cleavage plane will exist between the tumor and liver parenchyma. Similarly, invasion of the adjacent kidney is rare, but nephrectomy is typically warranted to achieve adequate margins and facilitate aorto-caval exposure and lymph node clearance, particularly when the renal hilar vasculature is involved [1, 5]. Lymphadenectomy of grossly involved nodes should be performed and can include the aortocaval, portal, splenic, and renal regional lymph nodes. Lymphadenectomy is associated with improved short-term survival in patients with gross adenopathy at diagnosis [1].

For those with suspected major intravenous thrombus, pre-operative MRI, doppler flow studies, and right atrial echography can help to determine the extent of tumor thrombus. Removal of this thrombus, as mentioned previously, can be accomplished via cardiopulmonary bypass, or by total hepatic vascular isolation, venotomy, and threading a large fogarty catheter into the right atrium (if necessary). Invasion into the caval wall usually is an indicator that curative resection is less likely, but nevertheless can be addressed with partial caval wall excision (wedge resection), or segmental caval excision with bypass grafting [5].

For all surgical candidates, a pre-operative hormone assessment must be performed to identify those with cortisol excess. Even those patients with subclinical Cushing’s syndrome will demonstrate some hypothalamus-pituitary-adrenal (HPA) axis suppression, and as such will require glucocorticoid replacement in the post-operative period to avoid adrenal insufficiency. In patients with Cushing’s syndrome, we recommend “stress dose” steroids given intra-operatively (typically dosed by the Anesthesiologist after the adrenal vein is ligated, or after the tumor is removed) and continued for twenty-four hours before starting a steroid taper. We recommend co-managing the patient closely with Endocrinologists to avoid adrenal insufficiency postoperatively. Typically, a dose of 50 milligrams (mg) hydrocortisone can be given intravenously (IV) at the time of tumor excision and then continued at 50mg IV every 8 hours for 24 hours. After that time, the dose can be tapered over the course of days to weeks pending the patient’s clinical condition. An example of a  typical hydrocortisone taper includes 20mg of oral hydrocortisone dosed every morning, with another 10mg hydrocortisone dosed every afternoon, tapering by 5 to 10mg every one to two weeks. Patients require close monitoring and follow up in the outpatient setting, as many will require a prolonged taper over potentially months to a year [1, 3].

Adjuvant chemotherapy with Mitotane, a pesticide derivative of DDT (dichlorodiphenyltrichloroethane) with adrenocorticolytic properties, is recommended for those at highest risk for recurrence (Ki67 index >10%, >20 mitoses per hpf, intraoperative tumor capsule disruption or spillage, tumors with lymphatic or vascular invasion). Mitotane therapy is typically associated with significant side effects, including adrenal insufficiency, and as such is only tolerated in 60-70% of patients. For young patients, those with a reasonable life expectancy, and high-grade tumor biology, five years of mitotane therapy is recommended and is associated with improved disease-free recurrence and overall survival. For those with completely resected and low-grade tumors, the role of adjuvant mitotane remains unclear [1, 3, 4].

Adjuvant mitotane therapy is recommended to begin no later than three months after surgery and is dosed at initially 0.5 grams (gm) twice daily and increased as needed up to 6 gm/day over 4 to 12 weeks for a goal of serum mitotane concentrations of 14 -20 mcg/mL. Serum concentrations should be monitored every 3 to 4 weeks. In settings where serum mitotane concentrations may not be available, dosing should be increased to 6–8 gm/day for patients with high risk for local recurrence, though many patients will not tolerate doses in excess of 2 gm/day. Serum monitoring can usually be accomplished, even in areas where testing is not typically performed, by inquiring with local pharmaceutical companies who may offer monitoring as a part of an orphan drug program [15].

Patients treated with mitotane need frequent monitoring of their serum electrolytes, as they may develop severe hyperkalemia and other electrolyte abnormalities after initiating treatment. Serum sodium, potassium, ACTH, and 24-urinary free cortisol are typically monitored. Empiric replacement with glucocorticoid is recommended (initially 30- 40 mg daily hydrocortisone divided into twice daily doses) as the precise timing of adrenal insufficiency after initiating mitotane is unknown. Additionally, patients should be instructed to take “stress dose” level steroids when acutely ill and should be educated on the signs and symptoms of adrenal insufficiency. Medical alert bracelets are also recommended, if available. Lastly, practitioners should anticipate an increase in cortisol replacement therapy to two to three times their initial replacement dose over time. Treatment with fludrocortisone (aldosterone replacement) is not usually necessary until later in treatment and can be initiated when patients demonstrate hypokalemia and symptoms of postural hypotension [1, 3-5].

Radiotherapy in combination with mitotane in the adjuvant setting is controversial. In some European centers, it is utilized in patients with surgical margins which are unable to be assessed pathologically or are frankly positive. In several retrospective studies, the addition of locoregional radiation therapy in patients with high-risk features for recurrence did improve local recurrence rates. As such, radiotherapy for tumors with high-risk features for local recurrence is recommended to begin within three months of surgery [1, 4].

Several clinical trials exist evaluating the role of combination adjuvant cytotoxic chemotherapy with cisplatin, etoposide, and mitotane, or streptozosin and mitotane in children and adults with local-regionally advanced disease. Neoadjuvant treatment with cytotoxic chemotherapy has also been explored. Prior studies are inconclusive about whether cytotoxic chemotherapy provides any therapeutic benefit, as such we would not recommend routine use of cytotoxic chemotherapy except in patients with advanced (stage III or stage IV) disease or stage I and II disease with pathologic features associated with high risk of recurrence [4, 15].

Of the available cytotoxic chemotherapy regimens, a combination of etoposide (100 mg per square meter of body-surface area on days 2 to 4), doxorubicin (40 mg per square meter on day 1), and cisplatin (40 mg per square meter on days 3 and 4) (EDP) was found to be superior to other chemotherapeutic regimens, including combination streptozocin and mitotane [16]. In the seminal publication of EDP cytotoxic chemotherapy for ACC, 148 patients were recruited to each arm of an international phase III clinical trial and were noted to have an overall improved progression-free survival of 5.0 months in the treatment group compared to 2.1 months in the safety control group [16]. This article published in the New England Journal of Medicine in 2012 represents the first major advance in systemic therapy for adrenocortical carcinoma [16].

• Surveillance

Surveillance after resection is typically accomplished with timed serial imaging studies. This is recommended every three months for two to three years, and then every four to six months for five years. Typically, a CT of the chest, abdomen, and pelvis is required with intravenous contrast. PET CT can be added as an adjunct, though studies evaluating its utility are limited. Biochemical testing can also be performed every three to four months but is complicated in patients receiving mitotane therapy who may have falsely elevated biochemical profiles as a consequence of therapy [1, 4].

• Controversies

The main controversy surrounding the treatment of adrenocortical carcinoma involves minimally invasive surgical resection for small suspected adrenal cancers or indeterminate nodules. Several studies evaluating minimally invasive approaches at major referral centers describe inferior oncologic outcomes [13, 14, 17, 18]. This may be in part due to surgeon experience, which for most would be extremely limited given the rarity of adrenocortical carcinomas. Additionally, the use of laparoscopy is shown to be associated with inferior oncologic outcomes (secondary to inadequate resection), tumor fracture or capsule rupture causing local or intraperitoneal tumor seeding, and port site recurrences [13]. Because the majority of evidence available on adrenalectomy for adrenocortical carcinoma is poor quality (limited series, retrospective, or based on consensus/ expert opinion), we recommend against laparoscopic resection for any known or suspected malignancy [1, 4].  In these scenarios, with a median survival of 25 months and 25% 5 year survival, the inherent risk to the patient does not weigh in favor of laparoscopic excision [19].

Another area of controversy surrounds the concept of surgical debulking of advanced disease. Debulking functional adrenocortical carcinomas may provide some benefit to patients [20]. In general, patients with stage IV disease treated with operative intervention have a shorter life expectancy than those initially palliated with medical therapy [4]. However, some patients experience hormone excess to the point of precluding initiation chemotherapy [20]. In these cases, operative debulking may play a role in palliating the patients’ symptoms and facilitating treatment with chemotherapy [1].

• Summary and Recommendations
  • Adrenocortical carcinomas are rare and highly lethal tumors that benefit from treatment at experienced referral centers.
  • All adrenal tumors require a pre-operative biochemical assessment, including serum ACTH, cortisol, aldosterone, renin, dehydroepiandrosterone (DHEA), DHEAS, testosterone, androstenedione, estrogens and estrogen precursors, as well as plasma metanephrines to rule out the possibility of pheochromocytoma.
  • Dexamethasone suppression testing and 24-hour urine cortisol levels may be necessary to establish a diagnosis of cortisol excess in patients with normal morning cortisol levels and/or normal to low ACTH levels, particularly in patients with clinical symptoms concerning for hypercortisolism.
  • Clinical syndromes with feminizing features are highly concerning for malignancy, particularly in male patients.
  • Cross sectional imaging by CT with 3-5 mm “thin cuts” with and without intravenous contrast, or MRI with and without gadolinium, can help differentiate benign from malignant tumors as well as aid in surgical planning.
  • Tumors suspicious for malignancy, indeterminate by cross-sectional imaging and greater than 4cm, or those with growth rates >1cm/ year, should be strongly considered for surgical excision to rule out malignancy.
  • We recommend AGAINST pre-operative percutaneous biopsy for tumors suspicious or indeterminate for adrenal cortical carcinoma.
  • For any Stage I to Stage III adrenocortical carcinomas, upfront surgical resection is recommended after appropriate biochemical evaluation.
  • Attempted R0 resection can and should involve multi-visceral resection if necessary. Care to avoid tumor capsule rupture is paramount.
  • Adjuvant mitotane therapy should be initiated three months post-operatively in patients with high-risk features for recurrence, as defined by Ki67 index >10%, >20 mitoses per hpf, intraoperative tumor capsule disruption or spillage, and those tumors with lymphatic or vascular invasion (Stage 3 disease).
  • Adjuvant radiotherapy is recommended in those patients at high risk for recurrence within 3 months of surgery.

1. References

1.         Vaidya, A., M. Nehs, and K. Kilbridge, Treatment of Adrenocortical Carcinoma. Surg Pathol Clin, 2019. 12(4): p. 997-1006.

2.         Else, T., et al., Adrenocortical carcinoma. Endocr Rev, 2014. 35(2): p. 282-326.

3.         Shariq, O.A. and T.J. McKenzie, Adrenocortical carcinoma: current state of the art, ongoing controversies, and future directions in diagnosis and treatment. Ther Adv Chronic Dis, 2021. 12: p. 20406223211033103.

4.         Fassnacht, M., et al., European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol, 2018. 179(4): p. G1-G46.

5.         Orlo, C.H., TEXTBOOK OF ENDOCRINE SURGERY. 2016, NEW DELHI: JAYPEE.

6.         Brondani, V.B., et al., High Prevalence of Alterations in DNA Mismatch Repair Genes of Lynch Syndrome in Pediatric Patients with Adrenocortical Tumors Carrying a Germline Mutation on TP53. Cancers (Basel), 2020. 12(3).

7.         Vaidya, A., et al., The Evaluation of Incidentally Discovered Adrenal Masses. Endocr Pract, 2019. 25(2): p. 178-192.

8.         Elsayes, K.M., et al., Mimics, pitfalls, and misdiagnoses of adrenal masses on CT and MRI. Abdom Radiol (NY), 2020. 45(4): p. 982-1000.

9.         Mete, O., et al., Diagnostic and Prognostic Biomarkers of Adrenal Cortical Carcinoma. Am J Surg Pathol, 2018. 42(2): p. 201-213.

10.       Aubert, S., et al., Weiss system revisited: a clinicopathologic and immunohistochemical study of 49 adrenocortical tumors. Am J Surg Pathol, 2002. 26(12): p. 1612-9.

11.       Altieri, B., et al., Next-generation therapies for adrenocortical carcinoma. Best Pract Res Clin Endocrinol Metab, 2020. 34(3): p. 101434.

12.       Else, T., et al., Adjuvant therapies and patient and tumor characteristics associated with survival of adult patients with adrenocortical carcinoma. J Clin Endocrinol Metab, 2014. 99(2): p. 455-61.

13.       Saunders, B.D. and G.M. Doherty, Laparoscopic adrenalectomy for malignant disease. Lancet Oncol, 2004. 5(12): p. 718-26.

14.       Miller, B.S., et al., Resection of adrenocortical carcinoma is less complete and local recurrence occurs sooner and more often after laparoscopic adrenalectomy than after open adrenalectomy. Surgery, 2012. 152(6): p. 1150-7.

15.       Bednarski, B.K., et al., Borderline resectable adrenal cortical carcinoma: a potential role for preoperative chemotherapy. World J Surg, 2014. 38(6): p. 1318-27.

16.       Fassnacht, M., et al., Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med, 2012. 366(23): p. 2189-97.

17.       Kiernan, C.M. and J.E. Lee, Minimally Invasive Surgery for Primary and Metastatic Adrenal Malignancy. Surg Oncol Clin N Am, 2019. 28(2): p. 309-326.

18.       Mazzaglia, P.J. and M.P. Vezeridis, Laparoscopic adrenalectomy: balancing the operative indications with the technical advances. J Surg Oncol, 2010. 101(8): p. 739-44.

19.       Creamer, J. and B.D. Matthews, Laparoscopic adrenalectomy for cancer. Surg Oncol Clin N Am, 2013. 22(1): p. 111-24, vi-vii.

20.       Jasim, S. and M.A. Habra, Management of Adrenocortical Carcinoma. Curr Oncol Rep, 2019. 21(3): p. 20.