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.