Adrenocortical Carcinoma A Clinician’s Perspective
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Aymen Elfiky, MD, MA, MPH, MSC
KEYWORDS
· Adrenocortical carcinoma · Adrenal cortex tumors · Rare malignancies · Mitotane
· Platinum-based chemotherapy
Key points
· Adrenocortical carcinoma (ACC) diagnosis management often requires a multidisciplinary approach.
. Most cases are sporadic, although specific cancer syndromes have been identified with increased inci- dence of ACC.
. Approximately 60% of ACC tumors are functional and present with signs and symptoms related to production of excess hormones.
· Careful consideration should be given to the clinical context and manifestations of an adrenal tumor before obtaining pathology specimens.
. Although multidisciplinary approaches to ACC may result in long-term disease control and survival, conventional chemotherapy is not curative and newer targeted therapies have not yielded any signif- icant impact on disease trajectory.
ABSTRACT
W ithin the category of orphan diseases and rare malignancies, adrenocortical carci- noma (ACC) represents an aggressive en- tity with high mortality and morbidity. While localized tumors which are diagnosed early can be cured with surgical intervention, there are prog- nostic factors which predict for micrometastases and consequent recurrent and advanced disease. In such cases, mitotane and cytotoxic chemo- therapy have been utilized with a modest degree of benefit. The poor prognosis of recurrent and advanced ACC has underscored the interest in nuanced characterization of ACC cases to guide the personalized use of immunotherapeutic and novel targeted therapies.
Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy of the adrenal cortex
with an annual US incidence of approximately 1 to 2 new cases per million population.1,2 Overall, ACC carries a poor prognosis, with the most consistent prognostic factor being the tumor stage at the time of diagnosis.3 Unfortunately, retrospective studies have reported a 5-year sur- vival rate of 24% for stage III and 0% for stage IV disease.4
ACC diagnosis (see also Pinto and Barletta, Ad- renal Tumors, Surgical Pathology Clinics, 2015, Volume 8, Issue 4) and management often requires a multidisciplinary approach, frequently involving a medical oncologist, an endocrine surgeon, an endocrinologist, a pathologist (preferably one with endocrine expertise), and other disciplines. Approximately 80% of patients with localized dis- ease will recur after complete resection.5-7 With re- gard to recurrent or advanced disease, ACC is modestly responsive to standard cytotoxic chemotherapies, although various combina- tions have shown palliative benefit. Radiation and ablative techniques have been used with variable benefit depending on the clinical scenario.
OVERVIEW
Disclosures: None.
Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Lank Center for Genitourinary Oncology, 450 Brookline Avenue, Boston, MA 02215, USA
E-mail address: Aymen_Elfiky@dfci.harvard.edu
http://dx.doi.org/10.1016/j.path.2015.07.002
1875-9181/15/$ - see front matter @ 2015 Elsevier Inc. All rights reserved.
PATHOGENESIS
Most cases are sporadic, although specific cancer syndromes have been identified with increased inci- dence of ACC (Table 1). Sporadic cases have been proposed to develop through a sequence of genetic defects that are progressively acquired, ultimately resulting in malignant transformation.8-11 TP53 is a frequently mutated gene in ACC and has been impli- cated in approximately one-third of sporadic ACC cases; loss of heterozygosity (LOH) at the 17p13 locus has been a frequent associated finding. Similarly, overexpression of insulinlike growth factor (IGF)-II, whose gene is located on chromo- some 11, has been associated with sporadic ACC cases resulting from LOH at the 11p15 locus. 12,13
Constitutive activation of beta-catenin in the Wnt signaling pathway as a result of activating so- matic mutation of the CTNNB1 gene has been identified as a frequent alteration in malignant adrenocortical tumors.14 Wnt/beta-catenin pathway activation has been shown to be an inde- pendent predictor of less favorable disease-free and overall survival in patients with resected pri- mary adrenal carcinoma.15 Using present day exome sequencing techniques and nucleotide polymorphism arrays, a spectrum of mutations can be revealed in any given sporadic case. Although each such finding is not clinically action- able, we do appreciate that such genetic features can help differentiate patients with ACC with poor or good outcomes.
CLINICAL
Approximately 60% of ACC tumors are functional and present with signs and symptoms related to production of excess hormones. Cushing syn- drome is a notable cause of morbidity and is the most frequent presentation in 45% of cases as compared with a mixed Cushing and virilization
syndrome characterized by both glucocorticoid and androgen excess in 25%. 16,17 Glucocorticoid excess causes weight gain, fatigue, muscle weak- ness, and insomnia progressing over the course of months. Feminization and hyperaldosteronism occur in fewer than 10% of cases.16 Virilization alone manifests in fewer than 10% of cases, but in the context of an adrenal lesions, this finding tends to be most suggestive of ACC.
In contrast, nonfunctioning ACCs include those with normal or subclinical production of hormones. These tumors are usually discovered incidentally when imaging is obtained for other reasons or as a consequence of a local mass effect or metastatic disease progression.
DIFFERENTIAL CONSIDERATIONS
Careful consideration should be given to the clin- ical context and manifestations of an adrenal tumor before obtaining pathology specimens. Suspicion of pheochromocytoma, for example, must be approached by biochemical testing as opposed to biopsy. Findings of hyperaldosteron- ism, hyperandrogenism, or Cushing syndrome provide added insight into the differential of an adrenal tumor. In attempting to rule out an ACC, cytology from a specimen obtained by fine- needle aspiration (FNA) is typically not adequate to distinguish between a benign mass and ACC (see also Pinto and Barletta, Adrenal Tumors, Sur- gical Pathology Clinics, 2015, Volume 8, Issue 4). Instead, FNA of an adrenal mass is more useful to characterize a metastatic lesion if there is suffi- cient suspicion that a different primary malig- nancy has metastasized to the adrenal gland.18
Several markers, such as alpha-inhibin, Melan A, and SF-1, can confirm the primary adrenal origin of a tumor (see also Pinto and Barletta, Adrenal Tu- mors, Surgical Pathology Clinics, 2015, Volume 8, Issue 4), but to distinguish ACC from a benign
| Table 1 Cancer syndromes associated with increased incidence of ACC | |
|---|---|
| Syndrome | Characteristics |
| Li-Fraumeni syndrome | Inactivating mutations of the TP53 tumor suppressor gene on chromosome 17p with risk of breast cancer, soft tissue and bone sarcoma, brain tumors, and ACC. |
| Beckwith-Wiedemann syndrome | Abnormalities in 11p15 with risk of Wilms tumor, neuroblastoma, hepatoblastoma, and ACC. |
| Multiple endocrine neoplasia type 1 (MEN1) | Inactivating mutations of the MEN1 gene on chromosome 11q. With risk of parathyroid, pituitary, and pancreatic neuroendocrine tumors, adrenal adenomas, and carcinomas. |
Abbreviation: ACC, adrenocortical carcinoma.
adrenal lesion, an experienced pathologist is required to use the microscopic Weiss criteria. 19-22 The 5 criteria used in the updated/modified Weiss system include the following:
· Greater than 6 mitoses/50 high-power fields
· ≤25% clear tumor cells in cytoplasm
· Abnormal mitoses
· Necrosis
· Capsular invasion
Each criterion is scored 0 when absent, or 2 for the first 2 criteria and 1 for the last 3 when pre- sent; the threshold for malignancy is a total score ≥3.21
Other immunohistochemical criteria can be used to provide added insight into the malignant potential of ACC, although specific cutoff criteria have not been consistently validated. The Ki-67 proliferation index of malignant lesions can vary from 1.5% to 10.0%,23 but when considered in the context of other factors, such as stage, pa- tient age, and comorbidities, it can be used to tailor treatment decisions. In contrast, ACC often overexpresses TP53, IGF-2, and cyclin E23; how- ever, such findings do not provide added insight on which to base management decisions. Most recently, PD-L1 expression has been evaluated in malignant ACC samples.24 Although PD-L1 positivity was noted in both tumor cells and tumor-infiltrating mononuclear cells, there was no significant association with higher stage at diagnosis Union for International Cancer Control (UICC) or European Network for the Study of Ad- renal Tumors (ENSAT), higher tumor grade, excessive hormone secretion, or overall survival (OS).24
TREATMENT AND PROGNOSIS
Malignant ACC is a rare and often very aggressive disease, and therefore distinction from benign cortical adrenal tumors and medullary based tumors is critical (see also Pinto and Barletta, Ad- renal Tumors, Surgical Pathology Clinics, 2015, Volume 8, Issue 4). Although multidisciplinary ap- proaches to ACC may result in long-term disease control and survival, conventional chemotherapy is not curative and newer targeted therapies have not yielded any significant impact on disease trajectory.
Platinum-based chemotherapies form the cornerstone of first-line ACC therapy, which have response rates ranging from 11% to 48%, affected in part by patient selection.25,26 Specifically, the combination of etoposide/doxorubicin/cisplatin chemotherapy given in conjunction with mitotane
offers the current standard approach based on a Phase III clinical trial result.27 Despite no differ- ences in OS being found, this study provides the most robust evidence for the systemic treatment of advanced ACC. Emerging genomic insights as well as immunotherapeutic strategies provide optimism in realizing novel therapeutics and improved patient outcomes.
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