PERSONALIZED CARE OF PATIENTS WITH ADRENOCORTICAL CARCINOMA: A COMPREHENSIVE APPROACH
Barbra S. Miller, MD1; Tobias Else, MD2; on behalf of the AACE Adrenal Scientific Committee
ABSTRACT
A concerted effort has been made in the past decade to better differentiate benign from malignant adrenocortical tumors. Of those tumors found to be adrenocortical carci- nomas (ACCs) and through the use of multiple modalities including biochemical, radiologic, and genomic analysis, significant strides have been made in understanding what drives ACC development, how various treatments may result in different outcomes, which ACCs are more likely to respond to various treatments, and overall prognosis. While most patients will have recurrence of their ACC and succumb to their disease, the disease course is highly vari- able; it is therefore imperative that each patient is treated with individualized attention paid to their particular ACC. This article highlights and discusses specific, important, and many times subtle features that may impact the evalu- ation, management, treatment selection, and outcome of patients with ACC. (Endocr Pract. 2017;23:705-715)
Abbreviations:
ACC = adrenocortical carcinoma; CT = computed tomography; XRT = external beam radiation therapy
Submitted for publication December 18, 2016
Accepted for publication April 18, 2017
From the 1Division of Endocrine Surgery, Department of Surgery and 2Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Hospital and Health Systems, Ann Arbor, Michigan.
Address correspondence to Dr. Barbra S. Miller; Assistant Professor, Division of Endocrine Surgery; Section of General Surgery, Department of Surgery; University of Michigan, 2920F Taubman Center, 1500 E. Medical Center Drive, Ann Arbor, MI 48109.
E-mail: barbram@umich.edu
Published as a Rapid Electronic Article in Press at http://www.endocrine practice.org. DOI:10.4158/EP161719.RA
To purchase reprints of this article, please visit: www.aace.com/reprints. Copyright @ 2017 AACE.
INTRODUCTION
Over the past decade significant focus has been placed on better understanding the differences in adrenocortical carcinoma (ACC) among different patients - from what drives tumor development to how various treatments may result in different outcomes depending on the mutations responsible for unregulated growth, as well as the impact of varying mutations that may exist within different areas of a single tumor. While identification of specific properties of a tumor that can be targeted in certain ways to achieve remis- sion has been successful in a few types of malignancies, the complexity of halting tumor growth is far from well understood. While a certain mutation within a malignant tumor may be identified as a potential target for treatment, one needs to consider the complexity of signaling networks that often provide alternative or compensatory mecha- nisms to fuel tumor growth and metastasis (e.g., additional downstream mutations). However, with the successes that have been achieved, this avenue of investigation and effort should be pursued as it may unlock numerous novel thera- pies for many malignancies.
ACC is a very rare and aggressive malignancy with an incidence of 0.7 to 2 per million per year (1-3), but data are scant, and the prevalence has been documented to be as high as 2.9 to 4.2 per million per year in children in Brazil due to the high prevalence of the R337H low-penetrance allele of TP53 (4-6). ACC in children with Li-Fraumeni syndrome occurs most often before the age of 4, and more than 50% of all ACCs in children are associated with a TP53 germ- line mutation (7). Historically, about 20 to 30% of ACCs are found incidentally after imaging obtained for investiga- tion of another problem (8), although this percentage may increase as the number of abdominal and chest computed tomography (CT) scans performed is expected to grow at a fast rate in the future. The remaining ACC patients present with signs of hormone excess or symptoms of local tumor
growth. Excess cortisol production has been associated with worse outcome in some studies (9,10). Most ACCs are diagnosed at an advanced stage, but this is changing as well with improvement in earlier diagnosis. Some early studies report 49% of patients presenting at stage 4. More recent studies report 25 to 30% of patients presenting with metastatic disease (11,12). This is likely related to more nonfunctional tumors being incidentally discovered. The overall 5-year survival for stage 1 and 2 patients has been reported to be as high as 65% using the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program database, 44% for stage 3, and 7% for stage 4 patients (3). Staging in children follows a modi- fied system (Table 1). Younger patients (<3 years) and patients with a complete resection without tumor spill have a significantly better prognosis (13). While most patients will have recurrence of ACC and succumb to their disease, the disease course is highly variable, so it is imperative that each patient is treated with individualized attention given to their particular tumor.
The remainder of this article highlights and discusses specific important and many times subtle features that may impact personalized evaluation, management, treatment selection, and outcome of patients with ACC (Fig. 1).
DIAGNOSIS
The cornerstone of diagnosis of ACC relies on appro- priate radiologic and biochemical evaluation. Usual radio- logic investigation of an adrenal mass includes an adrenal protocol CT scan to assess a number of important char- acteristics. Calculation of washout percentage should not be performed if the tumor is heterogeneous (Fig. 2) (14-19). Magnetic resonance imaging (MRI) is an alterna-
tive modality (20). Assessment for tumor involvement of the vena cava or other adjacent organs impacts the deci- sion for and extent of surgery. In some cases, a tumor may appear to involve the vena cava on CT imaging, leading the tumor to be deemed unresectable in some scenarios, but MRI may provide clearer definition of the margins of the tumor and adjacent organs, often allowing a plane to be identified between the tumor and adjacent organ indi- cating a less likely chance of invasion. A final method for assisting in differentiation of benign from potentially malignant tumors, as this knowledge may alter the opera- tive approach, is positron emission tomography with CT (PET/CT) imaging; however, specificity for differentiat- ing benign from malignant tumors is not perfect at 90% (21-25). 11C-Metomidate PET/CT can distinguish tumors of adrenal origin from those of nonadrenal origin, which is helpful when entertaining a diagnosis of metastatic disease to the adrenal gland, but it cannot reliably distinguish benign adrenal tumors from ACC (26).
Biochemical evaluation of adrenal tumors follows a standard approach. Knowledge of hormone excess or lack thereof impacts future management during surveillance and treatment and is utilized in a personalized fashion. Knowledge of initial hormone secretion patterns can be utilized as part of long-term surveillance for tumor recur- rence or progression. A suggested plan for initial biochemi- cal evaluation of patients with an adrenal tumor is listed in Table 2. More recently, steroid intermediaries have been shown to be produced in excess in some ACC patients and may become part of the future of biochemical evaluation of these patients. For example, serum 11-deoxycortisol is normally about 1% of total cortisol. In patients with ACC, 11-deoxycortisol may be significantly elevated due to downstream enzyme deficiencies in ACC. One must
| Table 1 Staging Systems for Adult and Pediatric ACC | ||||||||
|---|---|---|---|---|---|---|---|---|
| Adult | Pediatric | |||||||
| ENSAT staging system | Pediatric staging system - Michalkiewicz et al (12) | |||||||
| Stage | T | N | M | Stage | Resection status | Weight | Adrenal hormone levels | M |
| 1 | T1 | N0 | M0 | 1 | R0 | <100 g or <200 cm3 | Normal | |
| 2 | T2 | N0 | M0 | 2 | R0 | >100 g or >200 cm3 | Normal | |
| 3 | T3-4 | N0 | M0 | 3 | R0 | Failure to normalize | ||
| T1-4 | N1 | M0 | R1, R2 or unresectable, any tumor spill, or + RLN | |||||
| 4 | T1-4 | N0 or N1 | Any M1 | 4 | Any distant metastasis | |||
Abbreviations: ENSAT = European Network for the Study of Adrenal Tumors; M = metastasis; N = nodal involvement; R0 = complete resection; R1 = microscopic residual disease; R2 = gross residual disease; T = tumor; + RLN-metastasis to retroperitoneal lymph nodes.
Initial Diagnosis
Full Biochemical Evaluation Staging CT (chest, abdomen, pelvis)
Stage 1-3
Stage 4
Mitotane and chemotherapy
Unresectable
Resectable
Consider neoadjuvant therapy
Unresectable
Resectable
Open adrenalectomy with en-blocresection of adjacent involved organs and lymph nodes
Surgery with plan for treatment of metastatic sites of disease, XRT +/- mitotane and/or additional chemotherapy
Unresectable
Resectable
Mitotane + chemotherapy
☒ Surveillance
Complete Resection (RO)
Incomplete Resection (R1 or R2)
Progression
Consider XRT, RFA, other modalities for palliation
Stage 1 or 2
Stage 3
2nd line chemotherapy, consider XRT, RFA, other modalities for palliation
Continue therapy
Consider Reoperation
Ki67<10%
KI67 >10%
Surveillance
Consider ADIUVO trial
Mitotane consider XRT
Mitotane XRT
Mitotane XRT
Stable disease/response
Progression
Consider mutation assessment for targeted therapy, clinical trials
Surveillance<
Stable Disease
Progression
Palliative care
Progression
VC
TT
| Table 2 Biochemical Evaluation of Adrenal Tumors | |
|---|---|
| Initial Evaluation | |
| Routine | Consider |
| Aldosterone | 17-OH progesterone |
| Renin | 17-OH pregnenolone |
| Metanephrine and normetanephrineª | 11-Deoxycortisol |
| 1-mg DST with 8:00 AM ACTH, cortisol | Progesterone |
| 24-hour urine free cortisolb | Androstenedione, estradiol, FSH, LH |
| DHEA-S | |
| Testosterone (total or bioavailable) | |
Abbreviations: ACTH = adrenocorticotropic hormone; DHEA-S = dehydroepiandrosterone sulfate; DST = dexameth- asone suppression test; FSH = follicle-stimulating hormone; LH = luteinizing hormone.
a Either plasma or 24-h urine studies
b Obtain if DST suggests inappropriate suppression of cortisol
remember to convert 11-deoxycortisol units to the same as those for cortisol prior to calculating a percentage. No offi- cial cut-off is suggested at this point, and more investigation is needed prior to making this a routine test to order. Urine steroidobolomics has become an emerging field in which benign adrenal tumors can reliably be differentiated from ACC. Metabolites of serum 11-deoxycortisol found in the urine, such as tetrahydro-11-deoxycortisol (THS) seem to be most promising (27,28). Urine androgens and androgen precursors have also shown to be useful to follow as tumor markers. While highly promising, this test is not yet widely available due to the need for gas chromatography/mass spectrometry. In addition to its application for the differen- tial diagnosis of benign tumors versus ACC, measurement of steroid hormones and intermediaries might also open up new avenues for surveillance and tumor progression (e.g., by using individual steroid hormone profiles).
SURGICAL TREATMENT OF ACC
Surgical resection in those patients presenting with resectable nonmetastatic disease remains the mainstay of ACC treatment. Each resection should be tailored to the individual patient’s tumor and comorbidities. A careful assessment of the tumor and its surrounding structures should be made. If an adrenal mass is indeterminate by imaging characteristics, the surgeon should treat the tumor as a presumed ACC until proven otherwise, as a resection for ACC is quite different than a resection performed for a benign adrenal tumor (29). At a minimum, CT of the chest, abdomen, and pelvis should be obtained if ACC is in the differential diagnosis after initial imaging and biochemical
evaluation. As ACCs can grow rapidly and progress from resectable to unresectable or develop distant metastases in short intervals, it is prudent to ensure imaging has been obtained no longer than 1 month before surgery. Changes found on the most recent imaging may change the over- all treatment plan. Needle biopsy is not recommended for tumors presumed to be of adrenal origin (as opposed to metastatic disease to the adrenal from another site) as differentiation between benign and malignant adreno- cortical tumors is difficult and often not achieved, while penetrating the tumor capsule and potentially seeding the needle tract with tumor cells is possible and undesirable. Although still debated, oncologic principles of resection of ACC are best followed using a traditional open surgi- cal approach (30-37). Focus has shifted to understanding if performing a lymphadenectomy at the time of initial resection affects outcome. Data are conflicting at this time (38-43). Consideration for neoadjuvant treatment of borderline resectable ACCs has been postulated and may be found to be worthwhile after data from additional ongo- ing studies is analyzed. After several months of treatment, response to therapy can be assessed, and surgery can be considered (44). For many years, those with synchronous metastatic disease did not undergo surgical resection of the primary tumor other than for palliative reasons to try to reduce hormone secretion, severe pain, bleeding, or obstruction. New data suggests that resection of the prima- ry tumor along with any resectable synchronous metasta- ses or at least a plan to locally treat nonresectable meta- static tumor in some manner can result in acceptable long- term outcomes in highly selected patients (45). Similarly, patients who develop recurrent disease after resection with curative intent are more willingly offered reoperation than in the past. High-grade tumors, tumors with a high Ki-67 index, cortisol-secreting tumors, and time to recurrence less than 12 months after initial resection along with qual- ity of the initial resection are markers suggesting re-oper- ation may not be worthwhile and that continued disease progression with new sites of disease can be expected in the near future (46-48). A detailed review of intra-opera- tive details from the initial resection must be performed as tumor/capsule rupture and extent of resection will provide insight into the prediction of future disease course. Review of imaging at 3-month intervals also gives insight into the tempo of disease and potential for longer survival after reresection. Heated intra-operative peritoneal extracorpo- real chemotherapy (HIPEC) is offered at select centers to highly selected patients where imaging suggests all disease can be resected or eradicated by various techniques (49). The long-term benefit of this procedure in ACC patients is under active investigation. Sites of disease not amenable to surgical resection may be treated by various modalities including external beam radiation therapy (XRT), single- beam radiation therapy (SBRT), radiofrequency ablation, transcatheter arterial chemo-embolization, and high-inten-
sity focused ultrasound. Each modality has advantages, disadvantages, and complications that must be considered in the context of the individual patient and the particular tumor site being treated, along with consideration of the effect on surrounding structures and ability to treat the area in the future.
ADJUVANT AND PALLIATIVE CHEMOTHERAPY AND CARE
Aside from surgical resection, mitotane has been a cornerstone of treatment for adrenal cancer in those with metastatic disease. During mitotrane treatment, cortisol levels and thyroid and liver function should be monitored (50,51). Mitotane used as adjuvant therapy has been asso- ciated with a significant reduction in risk of recurrence and possibly death based on an international multicenter retrospective trial. Additional trials, such as the ADIUVO trial are studying the effectiveness of mitotane in patients at low- to intermediate-risk of cancer recurrence after cura- tive resection of stage 1 to 3 low-grade ACC. Pregnancy while on mitotane can present a problem. There is no consensus on the advisability of pursuing pregnancy while harboring a diagnosis of ACC, even if without evidence of disease depending on time since resection. Available litera- ture advises against the use of mitotane while pregnant, but there have been no reports of birth defects if mothers took mitotane for a short time while pregnant. It seems as though mitotane does not cross the placenta well as concentrations from maternal and fetal circulations differ significantly (52-56). Other chemotherapeutic agents such as etoposide, doxorubicin, and cisplatin used in those with metastatic ACC have been found to have effect against some adrenal cancers; however, most adrenal cancers remain resistant to the vast majority of chemotherapy regimens. Mitotane, etoposide, doxorubicin, and cisplatin may also be used in the treatment of pediatric ACC. A number of trials have
been conducted attempting to define the appropriate situa- tions in which to employ various chemotherapeutic agents. The volume of distribution of mitotane is high and clear- ance is low as it is a very lipophilic drug, with fatty tissue concentrations 200-fold higher than plasma concentra- tions. Target plasma levels should remain between 14 and 20 µg/L to be considered therapeutic (57-61). As mito- tane levels and tolerance of side effects can be difficult to predict, a pharmacokinetic model to assist in dosing and attainment of therapeutic levels in the most efficient manner has been developed (62). The model had an overall error margin of 14%. It allows for adaptive dosing based on individual plasma levels considering individual patient characteristics including age, sex, body mass index, body surface area, lean body mass, and renal function. Genetic factors are also presumed to impact mitotane levels, includ- ing a recent finding that a polymorphism in the CYP2B6 enzyme is associated with higher plasma concentrations after 3 months of treatment (63). Close monitoring of multiple organ systems is required while on mitotane as illustrated in Table 3, in addition to providing the patient with supplemental steroids. As mitotane is a very potent inducer of CYP3A4 in the gut, supraphysiologic doses of hydrocortisone replacement therapy are necessary. In addi- tion, this enzyme induction makes patients prone to other drug-drug interactions. Medication metabolism pathways should be carefully reviewed prior to and during therapy.
Additional agents useful in the treatment of patients with hormone-producing tumors include medications to address the specific hormone produced in excess. Options for control of excess cortisol production include mito- tane, mifepristone, metyrapone, ketoconazole, and etomi- date. Metyrapone or mifepristone is usually preferred to control severe excess cortisol production as efficacy is greater and control is quicker. Mitotane is useful in an adjuvant setting, but if tumor burden and excess cortisol production progresses, mitotane is deemed ineffective,
| Table 3 Laboratory Testing to Assess Therapeutic Effects of Mitotane and Effects on Other Organ Systems | |
| Therapy: Monthly blood draws until therapeutic, then every 3 months | Mitotane Cortisola |
| ACTHª 24-hour urine free cortisola | |
| Organ systems: | Complete blood count |
| Every 3 months | Liver function tests (AST, ALT, alkaline phosphatase, GGT, bilirubin) |
| Lipid panel | |
| Renin | |
| Thyroid function studies | |
| Males: testosterone, LH, FSH | |
| Abbreviations: ACTH = adrenocorticotropic hormone; ALT = alkaline transaminase; AST = aspartate trans- aminase; DHEA-S = dehydroepiandrosterone sulfate; DST = dexamethasone suppression test; FSH = folli- cle-stimulating hormone; GGT = gamma-glutamyl transferase; LH = luteinizing hormone. a Interpret with caution given effect of mitotane on cortisol levels and cortisol metabolism. | |
and metyrapone is initiated for control of cortisol excess. Other means are employed to attempt to control tumor growth if available and the patient’s performance status permits. Mineralocorticoid excess may be controlled with spironolactone or eplerenone. Hyperandrongenemia may be treated with spironolactone. For the rare male patient with estrogen excess and significant gynecomastia, estro- gen receptor antagonists such as tamoxifen, raloxifene or aromatase inhibitors (anastrozole, letrozole, or exemes- tane) may be used (2).
In the past, XRT was not found to impact the outcome of ACC patients in a particularly beneficial manner (64-67). More recently, several studies have re-evaluated the use of XRT and reveal a benefit in patients with ACC by decreas- ing local recurrence after initial surgical resection (68, 69). Decrease in local recurrence has also been shown when comparing 20 ACC patients matched for tumor stage who did and did not receive XRT to the tumor bed after under- going R0 resection (70). Patients who have undergone laparoscopic resection, an R1 resection, or whose tumor capsule was violated during surgery (with or without gross tumor spillage) are at highest risk for local recurrence. Any notation in the operative report of attempted separation of tumor adherent to an adjacent organ or vessel should also lead to suspicion of increased risk for local tumor recur- rence. Those having undergone an R2 resection should be expected to have local progression and can be treated with XRT +/- palliative mitotane and/or chemotherapy depend- ing on the clinical scenario. Surgeon input into radiothera- py planning is important as the surgeon can provide critical information regarding the extent of the field to be radiated having first-hand knowledge regarding the conduct of the resection, findings not well communicated in the operative note, and any particular areas of concern. Areas of routine lymphatic drainage from the adrenal gland should also be covered by the field to be treated. In general, radiotherapy after adrenalectomy is well tolerated with minimal side effects. The timing of adjuvant radiotherapy is debatable but is most often begun about 4 to 6 weeks after initial surgical resection. Institution of mitotane for several weeks prior to initiation of XRT may also have a beneficial effect on radiotherapy outcomes, although gastro-intesti- nal side effects of nausea may be increased during radio- therapy (71). The use of XRT in a palliative setting can be successful in decreasing tumor size and aiding in control of hormone excess when resection cannot be performed. SBRT is also an option for palliative radiotherapy of lung lesions and other discrete lesions elsewhere in the body including isolated bone metastases to prevent a debilitat- ing fracture. While overall survival was not significantly impacted in many older studies, that may be changing, and clinicians must begin to think of a time when we will have agents that can better control distant metastatic disease. At that time, local tumor control and prevention of tumor recurrence in the tumor bed or retroperitoneum, which are areas difficult to access during reoperative surgery due to
scar tissue, will become highly important and likely signif- icantly impact outcome.
In select situations, such as a patient with a border- line resectable tumor requiring an extensive multivisceral resection where an R0 status is unlikely to be achieved, or in a patient with significant intravascular tumor throm- bus, neoadjuvant chemotherapy may enhance the ability to perform an R0 resection, convert an unresectable tumor into a resectable tumor, and/or significantly decrease the amount of intravascular tumor thrombus. Neoadjuvant chemotherapy may also provide additional therapeutic benefit in those patients expected to undergo nephrectomy at the time of surgery. While an infrequent occurrence, if residual kidney function is too compromised to permit administration of nephrotoxic mediations after surgery, an opportunity to provide systemic chemotherapy may have been missed. However, in our group’s experience, the inability to proceed with adjuvant or palliative chemo- therapy postnephrectomy (or post-XRT) has been exceed- ingly rare. In those patients who do not undergo en-bloc nephrectomy and are administered XRT to the tumor bed and relevant nodal basins after resection because the ipsi- lateral kidney is usually unable to be excluded from the radiation field due to natural postadrenalectomy migration superiorly, it eventually has limited to no function.
GENOMIC AND PROTEOMIC ANALYSIS FOR PERSONALIZED CARE OF STAGE 4 ACC PATIENTS
Investigation into the genomic, proteomic, and other “-omic” features of ACC has moved at a rapid pace over the past decade. Currently generated from retrospective studies of ACC, this research has begun to lead to a signifi- cant increase in the understanding of the molecular biology of ACC and has led to significant advances in identification of mutations leading to the development of ACC (Table 4) along with identification of factors having clinical impact. A number of clinical applications have resulted from infor- mation gained using these emerging analytical methods. First, they can allow for determination of tumor aggres- siveness and prediction of disease course. This can then be used to inform clinical decisions about treatment rang- ing from watchful waiting to initial aggressive therapy. Second, certain general molecular signatures allow for the prediction of recurrence and progression, opening up new avenues for therapeutic trials (e.g., exploration of demeth- ylating drugs in the unfavorable group of hypermethyl- ated tumors). Third, results from individual tumor analysis can be used to determine potentially targetable molecu- lar changes allowing for a truly personalized therapeutic approach (72,73).
While promising, such rapid data generation must be viewed with caution before translating results directly to clinical care. Molecular data need to be carefully inte- grated into a patient’s treatment plan including taking
| Table 4 Identified Mutations in ACC | ||||
|---|---|---|---|---|
| Gene | Genetic Alteration | Gene Function | Germline/Somatic | Associated Syndrome |
| APC | Inactivating mutations | Negative regulator of Wnt/ß-catenin signaling | Germline/somatic | Familial adenomatous polyposis |
| ATRX | Inactivating mutation | Chromatin remodeling, telomere lengthening | Somatic | |
| CCNE1 | Amplifications | Regulator of CDK2 in G1/S cell cycle transition | Somatic | |
| CDK4 | Amplifications | Oncogene, inhibits RB phosphorylation | Somatic | |
| CDKN2A | Inactivating mutations, deletions | Tumor suppressor gene, acts through p53 and RB activation | Somatic (~15%) | |
| CTNNB1 | Activating mutation | Encodes ß-catenin | Somatic (15-20%) | |
| DAXX | Inactivating mutations | Chromatin remodeling, telomere lengthening | Somatic | |
| MDM2 | High-level amplification | E3 ubiquitin ligase negative regulator of p53 protein | Somatic | |
| MENIN | Inactivating mutations | Transcriptional regulator/ chromatin remodeling | Germline/somatic | Multiple endocrine neoplasia 1 |
| MLH1 | Inactivating mutations | Mismatch repair | Germline/somatic | Lynch syndrome |
| MSH2 | Inactivating mutations | Mismatch repair | Germline/somatic | Lynch syndrome |
| PMS2 | Inactivating mutations | Mismatch repair | Germline/somatic | Lynch syndrome |
| NF1 | Premature translation termination | Negative regulator or Ras signal transduction pathway | Germline/somatic | Neurofibromatosis type 1 |
| PRKAR1A | Inactivating mutation | Regulatory subunit of protein kinase A | Somatic | Carney complex |
| RB1 | Inactivating mutations, deletions | Encodes RB, negative regulator of cell cycle | Somatic | |
| RPL22 | Inactivating mutations | Encodes 60S ribosomal protein L22 | Somatic | |
| TERF2 | Inactivating mutations | Telomere specific protein/ telomere protection | Somatic | |
| TERT | Activated by high-level amplification | Reverse transcriptase of telomerase complex | Somatic (14%) | |
| TP53 | Inactivating mutations | Encodes p53 | Germline Somatic (15-20%) | Li-Fraumeni Syndrome |
| ZNRF3 | Inactivating mutations and deletions | E3 ubiquitin ligase, negative regulator of Wnt/ß-catenin signaling | Somatic (~20%) | |
| Abbreviations: ACC = adrenocortical carcinoma; CDK = cyclin-dependent kinase; RB = retinoblastoma. | ||||
into consideration prior treatment and individual physiol- ogy and comorbidities. It is important to keep in mind the shortcomings of molecular analysis derived from a single sample taken from within what is usually a large tumor. Heterogeneity as regards to different molecular changes found throughout the tumor and the ability to definitive- ly identify genetic changes as clinically important driver mutations as opposed to innocent bystanders and passenger mutations is difficult at best.
Through the efforts of large-scale molecular profiling by the European Network for the Study of Adrenal Tumors
(ENSAT) and The Cancer Genome Atlas (TCGA) (74) consortia, several common molecular alterations previous- ly identified in older studies have been confirmed, and new alterations have emerged. A significant number of ACCs harbor genetic alterations impairing the p53 pathway and others activate the ß-catenin pathway. Although activating mutations in ß-catenin and inactivating mutations in adeno- matous polyposis coli (as in familial adenomatous polypo- sis) have been known for some time, new mutations in the ubiquitin ligase ZNFR3 as a common driver of ß-catenin signaling have more recently been identified. Several other
mutations impacting cell cycle progression have been iden- tified in ACCs, including in ATRX and MENIN.
Until recently, it was not clear that ACC developed via an adenoma to carcinoma sequence, but this has become evident based on histopathologic identification of malig- nancy clearly developing within adenomas for some tumors (75). Investigation is underway to better understand how to account for this variation in the histopathologic and molecular analysis of these tumors, as sampling error may misinform clinical decision making.
Evidence from molecular profiling studies can be used to differentiate benign from malignant adrenocor- tical tumors and identify more aggressive subtypes of ACC leading to shorter recurrence free survival and over- all survival. The following approaches using complex molecular data for prognostication have been employed: (1) several groups have proposed and validated the use of gene expression information from 2 genes, BUB1B and PINK1, to recapitulate the information gained from that when using the entire transcriptome (75-77); (2) miRNome analysis has led to the identification of 3 ACC subgroups, all associated with different outcomes and useful for prog- nostication of disease course (78); (3) somatic alterations of driver genes are present in more than half of ACCs, and these ACCs are associated with worse outcomes (79,80); and (4) hypermethylation of the CpG islands located in regulatory (promoter) regions of the genes (i.e., CpG island methylator phenotype [CIMP]) is associated with poor outcome (74,79-81). In summary, ACCs with a more favor- able prognosis have low methylation rates, lower mutation rates, and very few mutations of ACC driver genes. Large- scale molecular analyses are often costly, labor intensive, and require significant time to perform and analyze. A chal- lenge for the future lies in the derivation of assays avoiding these shortcomings to allow for wider clinical application and greater cost effectiveness.
Several studies have explored the possibility of molecular genotyping and phenotyping of different tumor entities to provide individual actionable targets for tumor therapy. While these are exciting and promising approach- es, success in these studies has been limited to a small frac- tion of patients with ACC or other tumors. With the emer- gence of several academically and commercially available tests for molecular analysis, the true impact on patient care will hopefully be determined in the not too distant future. More studies specifically focusing on patients with ACC are needed.
In addition to identification of somatic mutations, tumor and patient analysis often includes the investigation of indi- vidual patients’ germline DNA. Current studies reveal that approximately 5 to 15% of cancer patients are found to have predisposing germline mutations. At least 5% of all ACCs arise in patients with Li-Fraumeni syndrome (TP53 muta-
tions) or Lynch syndrome (MLH1, MSH2, MSH6, PMS2). These results further underscore the importance of includ- ing genetic counseling as part of the routine evaluation and management of patients with ACC. Evaluation for muta- tions in at least the TP53 and Lynch syndrome genes (and possibly MEN1, APC, and others) is recommended for all patients. Identification of one of these germline mutations leads to provision of appropriate surveillance for other associated tumors and testing of family members at risk. Although large-scale molecular landscape analysis has deepened the insight into molecular changes of ACC, they have not produced any molecular markers for diagnosis, prognosis, or follow-up. Determination of useful markers, likely using TCGA and ENSAT analysis as a basis, will be a matter for future prospective studies. Of all molecular analytical markers, only testing for germline variants has found widespread use.
CONCLUSION
Although ACC is an extremely rare malignancy and our understanding of the disease process has been limited for many years, the creation of multi-institutional and inter- national collaborative groups such as France’s COMETE, Europe’s ENSAT, TCGA project, and the new multicon- tinent American Australian Asian Adrenal Alliance (A5) has been a driving force behind the now rapidly advanc- ing basic science and clinical care we see for patients with ACC. Much work still needs to be done to realize the goal of characterizing the biology of each ACC, understanding its interactions with and impact upon the patient’s physiologic milieu, and defining the molecular targets for treatment to ultimately provide truly personalized patient manage- ment. In the setting of care provided by a multidisciplinary team, improved elucidation of the unique features of each individual patient’s tumor identified during the diagnostic phase, considered during the surgical phase of treatment, and accounted for when selecting other adjuvant therapies will slowly translate into better outcomes for patients with ACC in the future.
ACKNOWLEDGMENT
The authors would like to acknowledge the involve- ment of and feedback from the remaining members of the Adrenal Scientific Committee: Dr. Karel Pacak (chair), Dr. Aaron Vinik, Dr. Maria Fleseriu, Dr. Richard Auchus, Dr. Amir Hamrahian, Dr. Carl Malchoff, Dr. Phyllis Speiser, Dr. Hans Ghayee, Dr. Christian Koch, and Dr. Anand Vaidya.
DISCLOSURE
The authors have no multiplicity of interest to disclose.
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