Introduction
Adrenocortical carcinoma (ACC) is an endocrine malignancy with an estimated incidence between 0.7 and 2.0 per million per year. Reference Rossella1 The prognosis is reserved, even for patients with early stage Reference Ammu, Ekta, Ghada and Ricardo2 and 5-year overall survival (OS) for non-metastatic ACC confined to adrenal gland is 60–80% but decreases to 35–50% for locally advanced disease. ACC has a bimodal age distribution, one peak before the age of 5 and the other between 40 and 60 years. Females have a slightly higher incidence (1.5 to 2.5 female-to-male ratio). Reference Rossella1 Most of the adult cases are sporadic, but this neoplasm can occur as part of hereditary syndromes such as Li-Fraumeni or Lynch syndrome. Reference Ammu, Ekta, Ghada and Ricardo2–Reference Martin, Olaf and Tobias4
Herein, we present a case of a young women diagnosed with a large functioning ACC that underwent a trimodality approach (surgery, radiotherapy and chemotherapy).
Case Description
A previously healthy 26-year-old woman presented to the endocrinologist for investigation of a suspected Cushing’s disease. Major complaints were weight gain (12 kg over the previous 12 months), facial acne and hirsutism. Physical examination evidenced a typical “moon” face, central obesity, purple striae on her thighs and abdomen. Hormonal evaluation showed hyperandrogenism and hypercortisolism.
An adrenal computed tomography (CT) revealed a 10 cm mass in the left adrenal gland. Patient was proposed for surgery, and a left open adrenalectomy was performed. Histology revealed a mass with 14x11x7cm, compatible with ACC, Fuhram nuclear grade IV, high mitotic index with abnormal mitoses, vascular and capsular invasion, extensive necrosis, presence of a tumoral thrombus in the left supradrenal vein and Ki-67 50–60%.
Postoperative CT scan showed a thickening of 1.9 cm in tumour bed compatible with residual disease. After multidisciplinary discussion, tumour was staged as a pT4cN0M0 R1 – stage III, and due to the high risk recurrence (positive margins, Ki-67>10%, capsular invasion, vascular thrombus and large size), adjuvant chemotherapy and radiotherapy (RT) were proposed. Fertility issues was further discussed with the patient and oocyte cryopreservation prior to the adjuvant treatment was decided.
Mitotane therapy was initiated, 1 month after surgery, with 1.5 g/day and increased gradually to 5 g/day.
For RT planning, a simulation CT was performed with the patient positioned supine. Free breathing axial images with 2.5-mm slice thickness were obtained. Treatment planning was performed using the Varian® Eclipse v 13.5.35. Clinical target volume (CTV) included tumour bed and postoperative CT thickening, and a planning target volume (PTV) was generated with an isotropic margin of 10 mm from the CTV. Prescribed dose to the PTV was 50.4 Gy on 28 fractions, 1.8 Gy per fraction. A volumetric-modulated arc therapy (VMAT) plan utilising 6-MV photons was created and left kidney, spinal cord and small bowel were chosen as the principal avoidance structures (dosimetric parameters are described in detail in Table 1). After informed consent regarding the possible toxic effects, radiation therapy was delivered, 8 weeks after surgery. For treatment delivery a Varian ® Trilogy CMF Millenium 120 linear accelerator was used, with 10 mm outer and 5-mm inner-thick MLC. Offline review of daily portal imaging was used for image guidance. Acute adverse effects reported were nausea and diarrhoea (grade 1 – CTCAE 5.0) that resolved soon after treatment. Patient was then assigned to follow-up.
Table 1. Dosimetric plan details
1 Constraint according reference Spalding et al., Med Phys 34, 521–529 (2007).
2 Constraint according reference RTOG 0436.
3 Constraint according reference RTOG 0822.
4 Constraint according reference RTOG 0623.
Six months after RT, lab tests showed normal androgen and cortisol levels; however, a positron emission tomography (PET) scan suggested metastatic involvement of pelvic and peritoneal lymph nodes (SUVmax= 13,1). Tumour board decided to start a chemotherapy regimen combining etoposide, doxorubicin and cisplatin with mitotane.
At the time of the last follow-up, (13 months after surgery), the patient received four cycles of chemotherapy, with reasonable tolerance, referring as side effects nausea and vomiting (grade 2 – CTCAE 5.0).
Discussion
Although the most common presentation of secretory ACC is a Cushing syndrome/hypercortisolism alone (45%), around 25% could present a mixed Cushing and virilisation syndrome (hypercortisolism and hyperandrogenism) similar to our case.
Workup must include imaging exams, especially a CT or magnetic resonance imaging to define loco-regional invasion and rule out metastases. Functional imaging with PET/CT could be important differentiating benign adenomas from malignant adenocarcinomas. Reference Ammu, Ekta, Ghada and Ricardo2 Histologic confirmation is not always possible because preoperative biopsy can be risky with a considerable chance of false-negative results.
The management of ACC is a challenging task. Treatment guidelines are based mainly on retrospective studies and non-randomised trials; therefore, the level of evidence is low. Reference Ammu, Ekta, Ghada and Ricardo2
Currently, complete surgical resection is considered the only potentially curative treatment. Reference Martin, Olaf and Tobias4 Still, even after complete resection, 5-years recurrence rate is up to 70%. Reference Margonis, Kim and Prescott5 Adjuvant treatment can decrease recurrences and improve survival; Reference Martin, Olaf and Tobias4 however, available evidence exploring adjuvant therapies is limited. Reference Gustavo and Bruno7
The use of mitotane in adjuvant setting is recommended in patients at high risk for recurrence (positive or unknown surgical margins, ruptured capsule, large size, high grade and Ki-67 >10%). Reference Rossella1–Reference Martin, Olaf and Tobias4 Additional cytotoxic therapy can be weighed in patients with specific adverse features (Ki-67 >30%, large tumour thrombus in the vena cava, stage IV, tumor spillage or R1/R2 resection). Reference Martin, Olaf and Tobias4 For early recurrence (within 6 months), systemic treatment is also recommended. Reference Fassnacht, Assie and Baudie6
Adjuvant RT has shown promising results in improving local control, but with no impact on overall survival (OS). Therefore, it is reasonable to associate RT with mitotane in selected high-risk patients (positive or unknown surgical margins, stage III disease, tumour spillage or high-grade ACC). Reference Martin, Olaf and Tobias4,Reference Fassnacht, Assie and Baudie6,Reference Srougi, Junior and Tanno8,Reference Jiawei, Ziye and Jing9
Due to the paucity of data in the literature, lack of randomised trials and mixed results on published studies, the clear indications for adjuvant RT are not fully understood. Yet, based on available data, there is reasonable consensus regarding the use of adjuvant RT in situations of close/positive margins. Reference Sara, Marilyne, Lina and Mouhammed3,Reference Martin, Olaf and Tobias4,Reference Gustavo and Bruno7–Reference Gharzai, Green and Griffith10
Ghrazai Reference Gharzai, Green and Griffith10 et al performed retrospective propensity-matched analysis on 39 patients who underwent postoperative adjuvant RT. The majority of patients were treated using intensity-modulated RT (IMRT) (92.3%), with a median radiation dose of 55 Gy. Authors concluded that adjuvant RT provides substantial improvements in locoregional control regardless of margin status.
Two recent meta-analysis addressing the role of adjuvant RT in ACC treatment with 238 and 184 patients, respectively, Reference Gustavo and Bruno7,Reference Jiawei, Ziye and Jing9 showed that RT in combination with mitotane has an acceptable tolerability and reduces the risk of local recurrence, but with no impact on distant recurrence or OS. However, these analyses were based on retrospective data from case series or small cohort studies with multiple biases, namely: different radiation doses, different or omitted treatment technique (majority treated with three-dimensional conformal RT, but 2-D RT and IMRT were also reported) and target volume details not provided (studies details are shown in Table 2). These parameters are particularly relevant because modern radiation techniques permit a more conformal dose distribution (specially in high-dose areas) allowing dose escalation and better coverage of potential high-risk areas resulting in potential benefits in tumour control with less toxic effects to adjacent normal structures.
Table 2. Retrospective studies of adjuvant radiation therapy
Abbreviation: 2DCRT – 2D conventional radiotherapy; 3DCRT – 3D conformal radiotherapy; Fup – follow-up, IMRT – intensity-modulated radiotherapy; NR – not reported; RT – radiotherapy.
Although there is limited evidence, guidelines from European Society of Medical Oncology, Reference Fassnacht, Assie and Baudie6 European Society of Endocrinology Reference Martin, Olaf and Tobias4 and National Comprehensive Cancer Network 11 consider adjuvant RT, mainly in association with mitotane, for selected high-risk patients.
Conclusion
ACC is a rare and aggressive tumour with a challenging approach and surgical resection is the mainstay treatment. Adjuvant therapy is essential to minimise the risk of postoperative recurrence in selected high risk patients, Reference Martin, Olaf and Tobias4,Reference Gharzai, Green and Griffith10 yet available evidence addressing this issue is limited. Indications for adjuvant RT and extent of the potential benefit of modern radiations techniques still not clear. Prospective, larger randomised trials will be essential to clarify these issues.
Acknowledgements
The authors thank Dra. Luísa Carvalho, Dr. Ângelo Oliveira, Dra. Carla Castro, Dra. Silvia Lopes and Dra. Dora Gomes for sharing their knowledge with us and for their valuable contributions along the path.
Financial Support
This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
Conflicts of interest
The authors declare none.
