Cancers

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11 pages, 453 KiB

Open AccessArticle

Outcomes after Surgical Treatment of Metastatic Disease in the Adrenal Gland; Valuable for the Patient?

by Madelon J. H. Metman, Charlotte L. Viëtor, Auke J. Seinen, Annika M. A. Berends, Patrick H. J. Hemmer, Michiel N. Kerstens, Richard A. Feelders, Gaston J. H. Franssen, Tessa M. van Ginhoven and Schelto Kruijff

Cancers 2022, 14(1), 156; https://doi.org/10.3390/cancers14010156 - 29 Dec 2021

Cited by 7 | Viewed by 1866

Abstract

The adrenal glands are common dissemination sites for metastasis of various solid tumors. Surgical treatment is often recommended because targeted therapies and immunotherapy are frequently ineffective for adrenal metastasis. We report the experience with short-term and long-term surgical outcomes of patients undergoing surgery [...] Read more.

The adrenal glands are common dissemination sites for metastasis of various solid tumors. Surgical treatment is often recommended because targeted therapies and immunotherapy are frequently ineffective for adrenal metastasis. We report the experience with short-term and long-term surgical outcomes of patients undergoing surgery for adrenal metastasis in two hospitals. A retrospective, multicenter study was performed to analyze patient characteristics, tumor-related data, perioperative outcomes, and oncological outcomes. Postoperative complications that occurred within 30 days were scored according to the Clavien Dindo classification. Metastatic adrenalectomy was performed in 95 patients. We observed an increase from an average of 3 metastatic adrenalectomies per year between 2001–2005 to 10 between 2015–2019. The most frequent underlying malignancies were colorectal and lung cancer. In 55.8%, minimal invasive adrenalectomy was performed, including six conversions to open surgery. A total of 37.9% of patients had postoperative complications, of which ileus or gastroparesis, wound problems, pneumonia, and heart arrhythmias were the most occurring complications. Improved cancer care has led to an increased demand for metastatic adrenalectomy over the past years. Complication rates of 37.9% are significant and cannot be neglected. Therefore, multidisciplinary teams should weigh the decision to perform metastatic adrenalectomy for each patient individually, taking into account the drawbacks of the described morbidity versus the potential benefits. Full article

(This article belongs to the Special Issue Malignant Adrenal Tumors – from Bench to Bedside)

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13 pages, 2629 KiB

Open AccessArticle

Expression of the Chemokine Receptor CCR7 in the Normal Adrenal Gland and Adrenal Tumors and Its Correlation with Clinical Outcome in Adrenocortical Carcinoma

by Carmina Teresa Fuss, Katharina Other, Britta Heinze, Laura-Sophie Landwehr, Armin Wiegering, Charis Kalogirou, Stefanie Hahner and Martin Fassnacht

Cancers 2021, 13(22), 5693; https://doi.org/10.3390/cancers13225693 - 14 Nov 2021

Cited by 1 | Viewed by 1757

Abstract

Background: The chemokine receptor CCR7 is crucial for an intact immune function, but its expression is also associated with clinical outcome in several malignancies. No data exist on the expression of CCR7 in adrenocortical tumors. Methods: CCR7 expression was investigated by qRT-PCR and [...] Read more.

Background: The chemokine receptor CCR7 is crucial for an intact immune function, but its expression is also associated with clinical outcome in several malignancies. No data exist on the expression of CCR7 in adrenocortical tumors. Methods: CCR7 expression was investigated by qRT-PCR and immunohistochemistry in 4 normal adrenal glands, 59 adrenocortical adenomas, and 181 adrenocortical carcinoma (ACC) samples. Results: CCR7 is highly expressed in the outer adrenocortical zones and medulla. Aldosterone-producing adenomas showed lower CCR7 protein levels (H-score 1.3 ± 1.0) compared to non-functioning (2.4 ± 0.5) and cortisol-producing adenomas (2.3 ± 0.6), whereas protein expression was variable in ACC (1.8 ± 0.8). In ACC, CCR7 protein expression was significantly higher in lymph node metastases (2.5 ± 0.5) compared to primary tumors (1.8±0.8) or distant metastases (2.0 ± 0.4; p < 0.01). mRNA levels of CCR7 were not significantly different between ACCs, normal adrenals, and adrenocortical adenomas. In contrast to other tumor entities, neither CCR7 protein nor mRNA expression significantly impacted patients’ survival. Conclusion: We show that CCR7 is expressed on mRNA and protein level across normal adrenals, benign adrenocortical tumors, as well as ACCs. Given that CCR7 did not influence survival in ACC, it is probably not involved in tumor progression, but it could play a role in adrenocortical homeostasis. Full article

(This article belongs to the Special Issue Malignant Adrenal Tumors – from Bench to Bedside)

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Review

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24 pages, 1376 KiB

Open AccessReview

How to Differentiate Benign from Malignant Adrenocortical Tumors?

by Charlotte L. Viëtor, Sara G. Creemers, Folkert J. van Kemenade, Tessa M. van Ginhoven, Leo J. Hofland and Richard A. Feelders

Cancers 2021, 13(17), 4383; https://doi.org/10.3390/cancers13174383 - 30 Aug 2021

Cited by 15 | Viewed by 5406

Abstract

Adrenocortical carcinoma (ACC) is a rare cancer with a poor prognosis. Adrenal incidentalomas are, however, commonly identified in clinical practice. Discrimination between benign and malignant adrenal tumors is of great importance considering the large differences in clinical behavior requiring different strategies. Diagnosis of [...] Read more.

Adrenocortical carcinoma (ACC) is a rare cancer with a poor prognosis. Adrenal incidentalomas are, however, commonly identified in clinical practice. Discrimination between benign and malignant adrenal tumors is of great importance considering the large differences in clinical behavior requiring different strategies. Diagnosis of ACC starts with a thorough physical examination, biochemical evaluation, and imaging. Computed tomography is the first-level imaging modality in adrenal tumors, with tumor size and Hounsfield units being important features for determining malignancy. New developments include the use of urine metabolomics, also enabling discrimination of ACC from adenomas preoperatively. Postoperatively, the Weiss score is used for diagnosis of ACC, consisting of nine histopathological criteria. Due to known limitations as interobserver variability and lack of accuracy in borderline cases, much effort has been put into new tools to diagnose ACC. Novel developments vary from immunohistochemical markers and pathological scores, to markers at the level of DNA, methylome, chromosome, or microRNA. Molecular studies have provided insights into the most promising and most frequent alterations in ACC. The use of liquid biopsies for diagnosis of ACC is studied, although in a small number of patients, requiring further investigation. In this review, current diagnostic modalities and challenges in ACC will be addressed. Full article

(This article belongs to the Special Issue Malignant Adrenal Tumors – from Bench to Bedside)

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15 pages, 1033 KiB

Open AccessReview

The Immunotherapy Landscape in Adrenocortical Cancer

by Guillaume J. Pegna, Nitin Roper, Rosandra N. Kaplan, Emily Bergsland, Katja Kiseljak-Vassiliades, Mouhammed Amir Habra, Yves Pommier and Jaydira Del Rivero

Cancers 2021, 13(11), 2660; https://doi.org/10.3390/cancers13112660 - 28 May 2021

Cited by 9 | Viewed by 4027

Abstract

Adrenocortical carcinoma (ACC) is a rare cancer of the adrenal gland that is frequently associated with excess production of adrenal hormones. Although surgical resection may be curative in early-stage disease, few effective therapeutic options exist in the inoperable advanced or metastatic setting. Immunotherapies, [...] Read more.

Adrenocortical carcinoma (ACC) is a rare cancer of the adrenal gland that is frequently associated with excess production of adrenal hormones. Although surgical resection may be curative in early-stage disease, few effective therapeutic options exist in the inoperable advanced or metastatic setting. Immunotherapies, inclusive of a broad array of immune-activating and immune-modulating antineoplastic agents, have demonstrated clinical benefit in a wide range of solid and hematologic malignancies. Due to the broad activity across multiple cancer types, there is significant interest in testing these agents in rare tumors, including ACC. Multiple clinical trials evaluating immunotherapies for the treatment of ACC have been conducted, and many more are ongoing or planned. Immunotherapies that have been evaluated in clinical trials for ACC include the immune checkpoint inhibitors pembrolizumab, nivolumab, and avelumab. Other immunotherapies that have been evaluated include the monoclonal antibodies figitumumab and cixutumumab directed against the ACC-expressed insulin-like growth factor 1 (IGF-1) receptor, the recombinant cytotoxin interleukin-13-pseudomonas exotoxin A, and autologous tumor lysate dendritic cell vaccine. These agents have shown modest clinical activity, although nonzero in the case of the immune checkpoint inhibitors. Clinical trials are ongoing to evaluate whether this clinical activity may be augmented through combinations with other immune-acting agents or targeted therapies. Full article

(This article belongs to the Special Issue Malignant Adrenal Tumors – from Bench to Bedside)

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19 pages, 768 KiB

Open AccessReview

Tumor Microenvironment in Adrenocortical Carcinoma: Barrier to Immunotherapy Success?

by Natalia Georgantzoglou, Stefania Kokkali, Gerasimos Tsourouflis and Stamatios Theocharis

Cancers 2021, 13(8), 1798; https://doi.org/10.3390/cancers13081798 - 9 Apr 2021

Cited by 17 | Viewed by 3468

Abstract

Adrenocortical carcinoma is a rare malignancy with aggressive behavior, with up to 40% of patients presenting with metastases at the time of diagnosis. Both conventional chemotherapeutic regimens and novel immunotherapeutic agents, many of which are currently being tested in ongoing clinical trials, have [...] Read more.

Adrenocortical carcinoma is a rare malignancy with aggressive behavior, with up to 40% of patients presenting with metastases at the time of diagnosis. Both conventional chemotherapeutic regimens and novel immunotherapeutic agents, many of which are currently being tested in ongoing clinical trials, have yielded modest results so far, bringing the need for a deeper understanding of adrenal cancer behavior to the forefront. In the recent years, the tumor microenvironment has emerged as a major determinant of cancer response to immunotherapy and an increasing number of studies on other solid tumors have focused on manipulating the microenvironment in the favor of the host and discovering new potential target molecules. In the present review we aim to explore the characteristics of adrenocortical cancer’s microenvironment, highlighting the mechanisms of immune evasion responsible for the modest immunotherapeutic results, and identify novel potential strategies. Full article

(This article belongs to the Special Issue Malignant Adrenal Tumors – from Bench to Bedside)

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Other

Jump to: Research, Review

23 pages, 1478 KiB

Open AccessSystematic Review

Adrenocortical Carcinoma in Childhood: A Systematic Review

by Maria Riedmeier, Boris Decarolis, Imme Haubitz, Sophie Müller, Konstantin Uttinger, Kevin Börner, Joachim Reibetanz, Armin Wiegering, Christoph Härtel, Paul-Gerhardt Schlegel, Martin Fassnacht and Verena Wiegering

Cancers 2021, 13(21), 5266; https://doi.org/10.3390/cancers13215266 - 20 Oct 2021

Cited by 18 | Viewed by 3478

Abstract

Adrenocortical tumors are rare in children. This systematic review summarizes the published evidence on pediatric adrenocortical carcinoma (ACC) to provide a basis for a better understanding of the disease, investigate new molecular biomarkers and therapeutic targets, and define which patients may benefit from [...] Read more.

Adrenocortical tumors are rare in children. This systematic review summarizes the published evidence on pediatric adrenocortical carcinoma (ACC) to provide a basis for a better understanding of the disease, investigate new molecular biomarkers and therapeutic targets, and define which patients may benefit from a more aggressive therapeutic approach. We included 137 studies with 3680 ACC patients (~65% female) in our analysis. We found no randomized controlled trials, so this review mainly reflects retrospective data. Due to a specific mutation in the TP53 gene in ~80% of Brazilian patients, that cohort was analyzed separately from series from other countries. Hormone analysis was described in 2569 of the 2874 patients (89%). Most patients were diagnosed with localized disease, whereas 23% had metastasis at primary diagnosis. Only 72% of the patients achieved complete resection. In 334 children (23%), recurrent disease was reported: 81%—local recurrence, 19% (n = 65)—distant metastases at relapse. Patients < 4 years old had a different distribution of tumor stages and hormone activity and better overall survival (p < 0.001). Although therapeutic approaches are typically multimodal, no consensus is available on effective standard treatments for advanced ACC. Thus, knowledge regarding pediatric ACC is still scarce and international prospective studies are needed to implement standardized clinical stratifications and risk-adapted therapeutic strategies. Full article

(This article belongs to the Special Issue Malignant Adrenal Tumors – from Bench to Bedside)

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9 pages, 1334 KiB

Open AccessPerspective

Reactive Oxygen Species: A Promising Therapeutic Target for SDHx-Mutated Pheochromocytoma and Paraganglioma

by Katerina Hadrava Vanova, Chunzhang Yang, Leah Meuter, Jiri Neuzil and Karel Pacak

Cancers 2021, 13(15), 3769; https://doi.org/10.3390/cancers13153769 - 27 Jul 2021

Cited by 3 | Viewed by 2373

Abstract

Pheochromocytoma (PHEO) and paraganglioma (PGL) are rare neuroendocrine tumors derived from neural crest cells. Germline variants in approximately 20 PHEO/PGL susceptibility genes are found in about 40% of patients, half of which are found in the genes that encode succinate dehydrogenase (SDH). Patients [...] Read more.

Pheochromocytoma (PHEO) and paraganglioma (PGL) are rare neuroendocrine tumors derived from neural crest cells. Germline variants in approximately 20 PHEO/PGL susceptibility genes are found in about 40% of patients, half of which are found in the genes that encode succinate dehydrogenase (SDH). Patients with SDH subunit B (SDHB)-mutated PHEO/PGL exhibit a higher likelihood of developing metastatic disease, which can be partially explained by the metabolic cell reprogramming and redox imbalance caused by the mutation. Reactive oxygen species (ROS) are highly reactive molecules involved in a multitude of important signaling pathways. A moderate level of ROS production can help regulate cellular physiology; however, an excessive level of oxidative stress can lead to tumorigenic processes including stimulation of growth factor-dependent pathways and the induction of genetic instability. Tumor cells effectively exploit antioxidant enzymes in order to protect themselves against harmful intracellular ROS accumulation, which highlights the essential balance between ROS production and scavenging. Exploiting ROS accumulation can be used as a possible therapeutic strategy in ROS-scavenging tumor cells. Here, we focus on the role of ROS production in PHEO and PGL, predominantly in SDHB-mutated cases. We discuss potential strategies and approaches to anticancer therapies by enhancing ROS production in these difficult-to-treat tumors. Full article

(This article belongs to the Special Issue Malignant Adrenal Tumors – from Bench to Bedside)

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