Case Report: Complete Necrosis of a Large Adrenocortical Cancer and Liver Metastases Achieved by Selective Arterial Embolization: A Case Study and Review of Literature.

There is very limited experience regarding the interventional radiological treatment of adrenocortical cancer (ACC). We present the case of a 57-year-old female patient with a large, potentially unresectable left-sided ACC and two hepatic metastases. Both liver tumors were effectively treated by trans-arterial embolization (TAE), followed by TAE of the bulky primary tumor as a life-saving intervention necessitated by severe intratumoral bleeding. Surgical removal of the primary tumor revealed complete necrosis. The patient is considered tumor free after 3.5 years. To the best of our knowledge, this is the first report to show that even a primary ACC may be completely ablated by selective embolization, and the fourth to prove the curative potential of liver TAE for ACC metastases. This case highlights the potential of selective embolization in ACC treatment.

Case Report: Exceptional Response to Second Line Temozolomide Therapy in a Patient With Metastatic Adrenocortical Carcinoma.

Background: In a recently published retrospective case series, Temozolomide was found active as second line approach in advanced ACC patients. The disease control rate obtained, however, was short-lived. We report here an ACC patient with extensive metastatic disease who obtained a remarkable long lasting response with this alkylating agent. Case Presentation: a 22-year-old female patient with ACC presented at our Medical Oncology Department in poor general condition due the presence of extensive metastatic pulmonary involvement. The disease had progressed to etoposide, doxorubicin and cisplatin plus mitotane therapy. Second line temozolomide therapy was prescribed leading to a progressive improvement of patient general conditions. The disease restaging after 12 cycles revealed a complete response of lung lesions and the patient was free from progression for 14+ months. Conclusion: Temozolomide therapy could be exceptionally efficacious in the management of ACC patients. The molecular mechanisms of sensitivity and resistance to this drug should be carefully studied, in order to select the patients destined to obtain a significant clinical benefit to the drug.

Clinical Prognostic Factors in Patients With Metastatic Adrenocortical Carcinoma Treated With Second Line Gemcitabine Plus Capecitabine Chemotherapy.

Gemcitabine plus Capecitabine (Gem/Cape) is a frequently adopted second line chemotherapy for metastatic adrenocortical carcinoma (ACC), but only a minority of patients is destined to obtain a clinical benefit. The identification of baseline predictive factors of efficacy is relevant. We retrospectively analyzed clinical data from 50 consecutive patients with metastatic progressing ACC treated between 2011 and 2019. Patients received intravenous Gemcitabine and oral Capecitabine on a metronomic schedule. Previous mitotane therapy was maintained. Clinical benefit (partial response + stable disease) at 4 months was 30%, median progression-free survival (PFS) and disease-specific survival (DSS) from Gem/Cape start were 3 and 8 months, respectively. Among clinical variables evaluated before the start of Gem/Cape, presence of ECOG performance status ≥1 [HR 6.93 95% confidence interval (CI) 0.03-0.54, p.004] and neutrophil-to-lymphocyte ratio (NLR) ≥5 [HR 3.88, 95% (CI) 0.81-0.90, p.003] were independent indicators of poor PFS at multivariate analysis. Conversely, surgery of primary tumor, the presence of lung or lymph-node metastases, blood mitotane level, anemia, and the Advanced Lung cancer Inflammation index (ALI) failed to be independently associated. This study confirms that the Gem/Cape schedule is modestly active in heavily pretreated ACC patients (28% received at least two previous chemotherapy lines). NLR and performance status (PS) are easily available clinical parameters that are helpful to identify patients not likely to derive significant advantage from Gem/Cape chemotherapy.

Clinical Score Predicting Overall Survival After Surgery for Synchronous Metastatic Adrenocortical Carcinoma: A Surveillance, Epidemiology, and End Result-Based Study.

Surgery remains the only potential option for prolonging survival in synchronous metastatic adrenocortical carcinoma (ACC). The purpose of this study is to identify patients who may benefit from adrenalectomy. Using the Surveillance, Epidemiology, and End Results (SEER) database (2010-2015), we identified synchronous metastatic ACC patients who underwent adrenalectomy. Cox regression analysis was performed to identify prognostic factors associated with overall survival. A clinical scoring system was created to predict survival after surgery. Sixty-two patients underwent adrenalectomy for synchronous metastatic ACC. Median age was 54.5 years. Median overall survival was 12 months. In univariable analysis revealed that age 65≥years, tumor stage: T3/4, multiple metastases, liver metastases, and no chemotherapy were associated with poor survival. In the multivariable Cox analysis, liver metastases (P = .017) and no chemotherapy (P = .039) remained independent predictors of worse prognosis. A clinical scoring system including of 1-point each for the 2 predictors demonstrated good discrimination in predicting survival after adrenalectomy (3-year survival: 45.9% for 0 points and 0% for 1 or 2 points; P < .001, area under the curve = .78). Prolonged survival after adrenalectomy combined with chemotherapy can be potentially achieved in synchronous metastatic ACC patients without liver metastases. Patients with liver metastases should be carefully evaluated for surgery.

Risk factors associated with positive resection margins in patients with adrenocortical carcinoma.

BACKGROUND: Positive resection margins are associated with worse survival after surgery for adrenocortical carcinoma (ACC). We aimed to identify risk factors for positive margins post-resection. METHODS: The NCDB was queried for ACC patients from 2006 to 2015. Patients with positive versus negative resection margins post-surgery were compared using Chi-square tests. Survival based on adjuvant treatment was assessed using Kaplan-Meier curves. RESULTS: 1,973 patients with ACC were identified, 217 (11.0%) with positive margins. Multivariable analysis identified extra-adrenal extension (HR 4.92, p < 0.001), lymph node metastases (HR 2.64, p = 0.001), and distant metastases (HR 1.53, p = 0.03) as risk factors for positive margins. No significant difference in margin status existed between patients who had an open versus minimally invasive procedure (p = 0.6). Positive margin patients receiving adjuvant radiation (p = 0.007) or combined chemo-radiation (p = 0.001) had the longest survival. CONCLUSION: No modifiable risk factors were identified, but patients with positive margins receiving adjuvant radiation or chemo-radiation had the longest survival.

Features of synchronous versus metachronous metastasectomy in adrenal cortical carcinoma: Analysis from the US adrenocortical carcinoma database.

BACKGROUND: Adrenocortical carcinoma is a rare, aggressive cancer. We compared features of patients who underwent synchronous versus metachronous metastasectomy. METHODS: Adult patients who underwent resection for metastatic adrenocortical carcinoma from 1993 to 2014 at 13 institutions of the US adrenocortical carcinoma group were analyzed retrospectively. Patients were categorized as synchronous if they underwent metastasectomy at the index adrenalectomy or metachronous if they underwent resection after recurrence of the disease. Factors associated with overall survival were assessed by univariate analysis. RESULTS: In the study, 84 patients with adrenocortical carcinoma underwent metastasectomy; 26 (31%) were synchronous and 58 (69%) were metachronous. Demographics were similar between groups. The synchronous group had more T4 tumors at the index resection (42 vs 3%, P < .001). The metachronous group had prolonged median survival after the index resection (86.3 vs 17.3 months, P < .001) and metastasectomy (36.9 vs 17.3 months, P = .007). Synchronous patients with R0 resections had improved survival compared to patients with R1/2 resections (P = .008). Margin status at metachronous metastasectomy was not associated with survival (P = .452). CONCLUSION: Select patients with metastatic adrenocortical carcinoma may benefit from metastasectomy. Patients with metachronous metastasectomy have a more durable survival benefit than those undergoing synchronous metastasectomy. This study highlights need for future studies examining differences in tumor biology that could explain outcome disparities in these distinct patient populations.

Disease-free interval and tumor functional status can be used to select patients for resection/ablation of liver metastases from adrenocortical carcinoma: insights from a multi-institutional study.

BACKGROUND: Adrenocortical carcinoma (ACC) is an aggressive malignancy that frequently metastasizes to the liver. Given the limitations of systemic therapy in this setting, we sought to determine characteristics associated with a two-fold increase in survival with resection/ablation compared to that reported with chemotherapy alone (∼12 months). METHODS: Patients who underwent resection/ablation at our institutions for ACC liver metastases were identified. Those who survived 12-24 months after metastasectomy were excluded, as the aim was to characterize patients who most clearly benefited from these procedures. Clinicopathologic and treatment characteristics were assessed for associations with survival. RESULTS: Sixty-two patients met inclusion criteria, of whom 44 survived >24 months and 18 survived <12 months. Patients with extended survival were less likely to have functioning tumors (p = 0.047), had fewer liver metastases (p = 0.047), and a longer disease-free interval (DFI) (median 17.6 vs 2.3 months, p < 0.0001). On multivariable analysis, DFI (OR = 1.33, 95% CI = 1.12-1.58) and non-functioning tumor (OR = 0.13, 95% CI = 0.13-0.56) were independently associated with prolonged survival. CONCLUSION: Metastasectomy/ablation should be considered for patients with ACC liver metastases. DFI and tumor functional status may be useful in selecting optimal candidates for these procedures.

Successful treatment of metastatic adrenocortical carcinoma in the spine: A case report and literature review.

RATIONALE: Adrenocortical carcinoma is a rare aggressive type of cancer whose prognosis is poor, particularly for metastatic entities. Metastatic adrenocortical carcinoma in the spine is a rare disease with no standard curative managements yet. The objective of this study is to report a very rare case of spinal metastases of adrenocortical carcinoma successfully managed by combination of cement augmentation, radiotherapy together with adjuvant programmed cell death 1 (PD-1) therapy. The management of these unique cases has yet to be well-documented. PATIENT CONCERNS: A 42-year-old woman presented with a 3-month history of continuous and progressive back pain. The patient, who had been diagnosed of right pheochromocytoma, received surgical treatment of right adrenalectomy 14 months ago in another hospital, followed by no further treatment. DIAGNOSIS: Magnetic resonance imaging of spine showed vertebral pathological fracture of L1, spinal cord compression secondary to the epidural component of the L1 mass, with increased metastatic marrow infiltration of the right L1 vertebral body, which presented as a solid tumor. Postoperative pathology confirmed the diagnosis of spinal metastases of adrenocortical carcinoma. INTERVENTIONS: The patient underwent cement augmentation via a posterior approach, radiotherapy, radiofrequency ablation of psoas major muscle occupying lesions, right chest wall, liver and kidney recess together with adjuvant PD-1 therapy. OUTCOMES: The patient's neurological deficits improved significantly after the surgery, and the postoperative period was uneventful at the 6-month and 1-year follow-up visit. There were no complications associated with the operation during the follow-up period. LESSONS: Combined efforts of specialists from orthopedics, urology, interventional radiology, radiotherapy, pathology, endocrinology, and medical oncology led to the successful diagnosis and management of this patient. Metastatic adrenocortical carcinoma of the spine, although rare, should be part of the differential diagnosis when the patient has a history of adrenal carcinoma and presents with back pain, myelopathy, or radiculopathy. We recommend the posterior approach for total excision of the spinal metastatic adrenocortical carcinoma when the tumor has caused neurological deficits. Osteoplasty by cement augmentation, radiotherapy, and targeted PD-1 therapy may also be good choices for treatment.

Evaluating the effectiveness of computed tomography-guided 125I seed interstitial implantation in patients with secondary adrenal carcinoma.

AIM: This study aimed to evaluate the feasibility, safety, and clinical efficacy of computed tomography (CT)-guided 125 I seed interstitial implantation in patients with secondary adrenal carcinoma. MATERIALS AND METHODS: Twenty patients with secondary adrenal carcinoma received CT-guided 125 I seed interstitial implantation. A three-dimensional treatment planning system was used to calculate the dose distribution before 125 I seed interstitial implantation. CT scans were performed every 2 months after the treatment to evaluate local therapeutic efficacy according to the Response Evaluation Criteria in Solid Tumors. RESULTS: The mean follow-up time was 23.65 months (5-102 months). The mean maximum tumor diameter was 34.16 ± 18.94 mm at the beginning of follow-up and 14.42 ± 24.07 mm at the end of follow-up. Eleven patients had complete response (CR), seven had partial response (PR), one had stable disease, and one had progressive disease. Local control rate (CR + PR) was 90% (18/20). The median survival time was 19 months (5-71 months). The 1-, 2-, 3-, and 5-year overall survival rates were 83.70%, 46.8%, 20.80%, and 20.80%, respectively. CONCLUSION: CT-guided 125 I radioactive seed interstitial implantation may be a feasible, safe, effective, and minimally invasive treatment for secondary adrenal carcinoma.

Nivolumab in Metastatic Adrenocortical Carcinoma: Results of a Phase 2 Trial.

CONTEXT: Systemic treatment of metastatic adrenocortical carcinoma (ACC) remains limited to chemotherapy and mitotane. Preliminary evidence suggesting that antitumor immune responses can be elicited in ACC has fostered interest in checkpoint inhibitors such as anti-PD-1 nivolumab. OBJECTIVE: The primary endpoint was objective response rate according to the response evaluation criteria in solid tumors. Secondary endpoints were progression-free survival (PFS), overall survival, and safety. DESIGN: Single-arm, multicenter, phase 2 clinical trial with two-stage design. SETTING: Comprehensive cancer center. PATIENTS: Ten adult patients with metastatic ACC previously treated with platinum-based chemotherapy and/or mitotane as well as patients who declined front-line chemotherapy. INTERVENTION: Nivolumab (240 mg) IV every 2 weeks. RESULTS: Ten patients with metastatic ACC were enrolled between March and December 2016. The median number of doses of nivolumab administered was two. Three patients only received one treatment [one died of disease progression, one discontinued due to adverse events (AEs), one withdrew after beginning treatment]. The median PFS was 1.8 months. The median follow-up was 4.5 months (range, 0.1 to 25.6 months). Two patients had stable disease for a duration of 48 and 11 weeks, respectively. One patient had an unconfirmed partial response but discontinued the study due to an AE. Most AEs were grade 1/2. The most common grade 3/4 treatment-related AEs were aspartate aminotransferase and alanine aminotransferase elevations, mucositis, and odynophagia. CONCLUSION: Nivolumab demonstrated modest antitumor activity in patients with advanced ACC. The nivolumab safety profile was consistent with previous clinical experience without any unexpected AEs in this population.

Endovascular Treatment of Inferior Vena Cava Thrombosis in Metastatic Malignancy: A Case Report and Review of Literature.

Inferior vena cava (IVC) thrombosis is a specific form of thromboembolism that occurs at a rate of 1.5% in all patients hospitalized with a deep vein thrombosis. Malignant IVC thrombosis may occur due to compression from a tumor mass or metastasis or may also occur through tumor invasion of the venous vasculature. Obstruction of the IVC can lead to IVC syndrome, marked by ascites, lower extremity edema, and even congestive hepatic failure. We present a case of extensive IVC thrombosis in a 69-year-old female with metastatic adrenal cell carcinoma, presenting with severe bilateral lower extremity edema and ascites. Computed tomography showed IVC compression by the caudate lobe due to a metastatic liver mass and extensive clot burden of the IVC extending from the renal veins to the right atrium (RA). She underwent percutaneous IVC stenting with 4 stents placed in tandem from the IVC to the RA. Her hospital course was complicated by gastrointestinal bleed requiring clipping, acute liver failure, and hypophysitis due to trial therapy. Although her IVC symptoms were partially relieved with percutaneous intervention, her acute liver failure worsened and she was ultimately transitioned to hospice care.

Sorafenib Toxicity Mimicking Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS) Syndrome

Sorafenib is an oral multikinase inhibitor approved by the United States Food and Drug Administration for the treatment of advanced hepatocellular and renal cell carcinoma. Cases of sorafenib-induced Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome have been reported in the literature. DRESS syndrome is a potentially fatal, drug-induced hypersensitivity reaction that occurs 2-8 weeks after drug exposure. DRESS syndrome presents with generalized morbilliform eruption, facial edema, eosinophilia, and end-organ damage. We present the first reported case of sorafenib toxicity mimicking DRESS syndrome in a patient with metastatic adrenocortical carcinoma presenting with fever, morbilliform rash, and transaminitis in the absence of eosinophilia three days following initiation of sorafenib therapy. It is critical that clinicians are equipped to accurately diagnose DRESS syndrome due to its high mortality rate and the morbidity associated with prolonged steroid therapy. J Drugs Dermatol. 2019;18(5):468-469.

Operative Management of Recurrent and Metastatic Adrenocortical Carcinoma: A Systematic Review.

Metastatic adrenocortical carcinoma (ACC) is associated with a poor 5-year survival rate and high rate of recurrence. Outcomes after resection for patients with limited disease remain poorly described. We conducted a PubMed search for articles published between 1950 and 2017 using the terms "ACC," "recurrence," and "surgery." Patients with metastatic ACC at any anatomic site who had undergone surgical resection were included. Thirteen studies met the criteria. Patients were grouped according to the recurrence site. Pulmonary metastasectomy was reported in 50 patients with moderate complications and without perioperative mortality. Disease recurrence rates range from 25 to 42 per cent, with median overall survival of 40 to 50 months. Hepatic metastasectomy was reported in 108 patients with a single perioperative mortality. Disease recurrence rates range from 65 to 100 per cent, with median disease-free survival (DFS) and OS of five to nine months and 22 to 76 months. Peritoneal cytoreduction and heated intraperitoneal chemotherapy have been reported for 10 patients with minimal morbidity and without perioperative mortality. The disease recurrence rate was 70 per cent, with DFS of 19 months. For selected patients with recurrent ACC in the lungs, liver, or peritoneum, metastasectomy is safe and can be associated with prolonged survival. However, subsequent disease recurrence is common, and patients should be counseled accordingly.

Pembrolizumab for metastatic adrenocortical carcinoma with high mutational burden: Two case reports.

RATIONALE: In the setting of metastatic or locally advanced adrenocortical carcinoma, a limited number of therapies are available and their efficacy is generally below modest. The backbone of treatment remains surgery, even for metastatic disease, whenever it is possible, and mitotane. Chemotherapy can be used with limited results. A small subset of patients with adrenocortical carcinoma may have high mutational burden and harbor mutations in mismatch-repair genes. PATIENT CONCERNS: We report a 40-year old and a 28-year-old female patients with metastatic adrenocortical carcinoma refractory to multiple treatments. DIAGNOSIS: Next-generation sequencing detected high mutational burden (>10 mutations/megabase) in both patients, one of them with MSH2 mutation. INTERVENTIONS: They were treated with pembrolizumab (100 to 200 mg every 3 weeks). OUTCOMES: The patient harboring a MSH2 mutation experienced a long-term complete response after pembrolizumab, while the patient with high mutational burden and absence of mismatch repair deficiency did not have any response. LESSONS: To the best of our knowledge, this is the first report in the literature of a durable complete response after pembrolizumab in a patient with metastatic adrenocortical carcinoma. Differences in therapy sequencing, possibly abscopal effect related to multiple previous radiotherapy exposition, predictive values of high mutational burden and mutations in mismatch-repair genes are discussed.

A Phase II Trial of Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy for Recurrent Adrenocortical Carcinoma.

BACKGROUND: Recurrent adrenocortical carcinoma (ACC) is an aggressive disease with few options offering durable survival benefit. Despite metastasectomy, recurrence is common. Cytoreduction and intraperitoneal chemotherapy have offered improved survival in other advanced cancers. We sought to evaluate the use of cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of recurrent intraperitoneal ACC. METHODS: A phase II, single institution clinical trial was approved for patients with radiographic evidence of resectable ACC limited to the peritoneum. Patients underwent treatment if optimal cytoreduction was deemed possible at exploratory laparotomy. Primary outcome was intraperitoneal progression-free survival. Secondary outcomes were treatment-related morbidities and overall survival. RESULTS: Sixty-three patients were evaluated, of whom 11 met eligibility criteria. Nine patients underwent cytoreduction and HIPEC, including one patient who recurred and was re-treated (n = 10 treatments). One patient could not be optimally cytoreduced for HIPEC and therefore did not receive intraperitoneal chemotherapy. There was no perioperative mortality; perioperative comorbidities were limited to Clavien-Dindo grade 2 or 3 and included hematologic, infectious, and neurologic complications. Seven patients experienced disease recurrence and two patients died of disease during follow-up (median 24 mo). Intraperitoneal progression-free survival was 19 mo, and median overall survival has not yet been reached. CONCLUSIONS: Cytoreduction and HIPEC can be performed safely in selected patients. Patients with recurrent ACC confined to the peritoneal cavity can be considered for regional therapy in experienced hands. However, disease recurrence is common, and other treatment options should be explored.

Adjuvant and Neoadjuvant Therapy, Treatment for Advanced Disease, and Genetic Considerations for Adrenocortical Carcinoma: An Update from the SSO Endocrine and Head and Neck Disease Site Working Group.

This is the second of a two-part review on adrenocortical carcinoma (ACC) management. While margin-negative resection provides the only potential cure for ACC, recurrence rates remain high. Furthermore, many patients present with locally advanced, unresectable tumors and/or diffuse metastases. As a result, selecting patients for adjuvant therapy and understanding systemic therapy options for advanced ACC is important. Herein, we detail the current literature supporting the use of adjuvant mitotane therapy, consideration of adjuvant radiation therapy, and utility of cytotoxic chemotherapy in patients with advanced disease. Ongoing investigation into molecular targeted agents, immunotherapy, and inhibitors of steroidogenesis for the treatment of ACC are also highlighted. Lastly, the importance of genetic counseling in patients with ACC is addressed as up to 10% of patients will have an identifiable hereditary syndrome.

Phrenicoabdominal venotomy for tumor thrombectomy in dogs with adrenal neoplasia and suspected vena caval invasion.

OBJECTIVE: To describe a technique for tumor thrombectomy by phrenicoabdominal venotomy in dogs with adrenal neoplasia and suspected caval invasion and to report complications and outcomes associated with the procedure. STUDY DESIGN: Retrospective case series. ANIMALS: Eight client-owned dogs with invasive adrenal tumors. METHODS: Medical records of dogs diagnosed with adrenal tumors with extension of thrombus into the phrenicoabdominal vein (PAV) and vena cava were reviewed. Cases where phrenicoabdominal venotomy without cavotomy for thrombus resection was performed were included. Data collected from the medical records included signalment, clinical signs, physical examination findings, diagnostic imaging results, preoperative laboratory testing, surgical technique, surgical and postoperative complications and outcome. RESULTS: Phrenicoabdominal venotomy was successful in removal of vena caval thrombosis in 7 of 8 dogs. In one case, an attempt was made to remove a large vena caval thrombus through a distended PAV resulting in fragmentation of the thrombus and the need to extend the incision into the vena cava. In all dogs, complete removal of tumor thrombus was achieved. Two dogs died in the perioperative period, one from cardiopulmonary arrest and a second from bronchopneumonia and pancreatitis. The remaining 6 dogs were discharged from the hospital. CONCLUSION: Thrombectomy through a phrenicoabdominal venotomy may obviate the need for a cavotomy in a subset of dogs with invasive adrenal neoplasia.