Adrenal Cortex Carcinoma

To our knowledge, this is the first report of a malignant adrenal tumor co-secreting steroid hormones with ACTH-dependent hypercortisolism, catecholamines and IGF-2. We faced obvious diagnostic and therapeutic challenges and encourage future studies to explore the complex interactions between cortical and chromaffin cells of the adrenal gland, that may have bidirectionally contributed to this patient's condition.

This study presents DLK1 as a novel biomarker in ACC with opportunities for use in the diagnosis, prognosis and longitudinal follow up of patients. DLK1, a marker of adrenocortical stem cells, is re-expressed in ACC, is measurable in patients' serum and is associated with increased malignancy.

In our cohort, the prevalence of adrenal tumours among patients with pathogenic and likely pathogenic APC mutations is at least twice to three times higher than the general population prevalence reported from international population-based studies. The hormonal functions of patients with pathogenic APC variants and adrenal tumours can be investigated with routine testing in further research.

The study highlights the diagnostic and prognostic significance of leptin receptor isoforms in adrenal tumors. Specifically, LepR1 may serve as a diagnostic marker for carcinomas, while LepR3&LepR6 have potential use as prognostic markers.

P=N/A, N=150, Not yet recruiting, Latin American Cooperative Oncology Group | Trial completion date: Aug 2025 --> Nov 2025 | Initiation date: Jun 2024 --> Sep 2024 | Trial primary completion date: Aug 2025 --> Nov 2025

At 1 and 3 months, CT and 18F-FDG-PET/CT showed a significant decrease in size and uptake of adrenal mass (40 × 20 mm and 19 × 10 mm and SUVmax 5.9 and 0.0). This report shows the interest of adrenal biopsy for well-selected cases to avoid unnecessary adrenal surgery.

We investigated the first PUMAH associated with severe Cushing's syndrome and concomitant androgen excess, suggesting pathogenic mechanisms involving KDM1A.

Overall, our results provide novel insights into adrenal homeostasis and molecular mechanisms potentially underlying early adrenocortical tumorigenesis and/or autonomous steroid secretion. Our cell atlas represents a powerful resource to investigate other adrenal-related pathologies.

It also allows exploration of pertinent treatment markers such as MDR-1, SOAT1, MGMT, MMR and SLFN11, and introduces the potential to repurpose agents like temozolomide for ACC therapy. ACC_CellMinerCDB provides the foundation for exploring larger preclinical ACC models.

P2, N=37, Active, not recruiting, Wuerzburg University Hospital | Recruiting --> Active, not recruiting | Trial primary completion date: Sep 2024 --> Dec 2024

P1, N=25, Active, not recruiting, Radionetics Oncology | Recruiting --> Active, not recruiting | Trial completion date: Apr 2024 --> Sep 2024 | Trial primary completion date: Apr 2024 --> Jul 2024

The histopathologic features and the immunohistochemical profile confirmed the diagnosis of metastatic carcinoma consistent with adrenal cortical origin. The diagnosis can be difficult (especially when no clinical data are provided), and an immunohistochemical battery is often useful in distinguishing this tumor from other tumors with similar cytomorphological features.

In addition, we developed 10 ACC patient-derived xenograft (PDX) and two humanized ACC-PDX models to test new therapeutics and examine the mechanism of mitotane action in combination with immunotherapy. These new preclinical models allow us to identify novel targets and test new therapeutics for our patients with adrenal cancer.

In addition to the metastatic disease, few cases with the mutations can be a biochemically silent PHEO/PGL. We concluded that the patient presented a metastatic abdominal paraganglioma associated with an SDHB mutation and we reinforced the need to perform genetic screening for all adrenal/extra-adrenal lesions characteristic of PHEO/PGL.

P2, N=82, Recruiting, National Cancer Institute (NCI) | N=34 --> 82

Cell Counting Kit-8 (CCK-8), colony formation, and Transwell assays confirmed that knockdown of ZFHX4-AS1 inhibited proliferation and migration of ACC cells. This study demonstrates that ZFHX4-AS1 has a reliable predictive value for the prognosis of ACC patients and is a promising biomarker.

This case highlights a patient with LFS with neoplasia of multiple endocrine organs including ACC, which is a classic finding, as well as papillary thyroid carcinoma and Cushing disease. Further investigation may be necessary to assess if patients with LFS are at a higher risk of various endocrine neoplasms in addition to the core malignancies classically described because this could affect future screening protocols.

P3, N=40, Completed, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia | Unknown status --> Completed | N=240 --> 40 | Trial completion date: Jun 2021 --> May 2024 | Trial primary completion date: Jun 2020 --> Feb 2024

This case report highlights the importance of pursuing genetic testing in patients with a history of multiple tumor types, particularly those with uncommon diagnoses. In this case, confirmation of LFS had important implications for personalized patient care, including identification of contraindicated treatment interventions and the imaging modalities necessary for vigilant follow-up screening.

SDHx and sporadic genetic clusters achieved the highest precisions of 73.1% and 72.7% respectively. Our state-of-the art findings highlight the promising nature of the challenging task of automated PPGL detection.

P2, N=120, Recruiting, UNICANCER | Not yet recruiting --> Recruiting

P=N/A, N=300, Recruiting, University of Roma La Sapienza

P2, N=109, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Jun 2025

The study emphasizes the potential importance of NCAPG, NCAPG2, and NCAPH in ACC, suggesting roles in tumor aggressiveness and diagnostic relevance. These genes could serve as therapeutic targets and markers for ACC, but further exploration into their molecular activities and validation studies is imperative to fully harness their diagnostic and therapeutic potential, advancing precision medicine approaches against this rare but lethal malignancy.

The possibility of untreated classic CAH with 21-OH deficiency causing functional adrenal cortical adenoma should be considered. When clinical diagnosis highly considers CAH and cannot rule out the influence of functional adrenal tumors' secretion function on 17-OHP, gene mutation analysis should be performed.

Patients should be diagnosed in large clinical centres with experience in this field. The treatment strategy should be individualised. Genetic testing for TP53 gene mutations is indicated in patients with ACC.

The authors review the role of imaging, imaging guidelines, and imaging features of tumors in the setting of LFS.

P2, N=21, Recruiting, West China Hospital | Trial primary completion date: Apr 2023 --> Dec 2023

The evolution was favorable after the excision of the tumor, with normalization of blood pressure. In resistant hypertension with café au lait spots may indicate pheochromocytoma, especially bilateral, suggesting an underlying genetic condition like NF1, warranting systematic screening.

Somatic mutations in PRKACA may correlate with the upregulation of LHCGR, which synergistically drives the accelerated growth of co-secretion tumors during pregnancy, thereby exacerbating disease progression.

P2, N=3, Completed, M.D. Anderson Cancer Center | Recruiting --> Completed | N=50 --> 3 | Trial completion date: Jan 2028 --> Jul 2024 | Trial primary completion date: Jan 2026 --> Jul 2024

P2, N=818, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: May 2033 --> May 2026 | Trial primary completion date: May 2033 --> May 2026

P2, N=818, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: May 2026 --> May 2033 | Trial primary completion date: May 2026 --> May 2033

P1/2, N=70, Active, not recruiting, Enterome | Trial completion date: Nov 2025 --> Oct 2024

P=N/A, N=397, Suspended, Dana-Farber Cancer Institute | Trial completion date: Jun 2024 --> Jun 2028 | Trial primary completion date: Jun 2024 --> Jun 2028

P1, N=30, Recruiting, Jonsson Comprehensive Cancer Center | Trial completion date: Jul 2025 --> Jul 2026 | Trial primary completion date: Jul 2024 --> Jul 2025

The NR4A family genes have the potential to serve as a diagnostic, prognostic, and immunological marker of human cancers.

Although endocan was expressed with a higher frequency in subjects with ACC and ACA, it was also expressed in subjects with normal adrenal cortex tissue. The percentage of cells expressed endocan in subjects with ACC was also significantly higher than in subjects with both ACA and normal adrenal cortex.

Using a multiparameter approach, we identified 45 genes that significantly influenced survival. Notably, many of these genes have protein interactions not previously implicated in ACC. These findings may lay the foundation for improved prognostication and future targeted therapies.

In previous case reports it has been proposed that GH-secreting adenomas contribute to CM1 by causing hypertrophy of soft tissue structures in the skull base, overcrowding the posterior fossa. Given that our patient had normal IGF-1 levels, there could be a different underlying mechanism that contributed to the concomitant occurrence of CM1 with the pituitary and adrenal tumors.

A simplified targeted-NGS approach seems the best routinely applicable first step towards somatic genetic characterisation of ACC for prognostic assessment. This approach proved to be particularly promising in low-stage cases, suggesting the need for more stringent surveillance and personalised treatment.

In the setting of metastatic adrenocortical cancer, there are limited therapy options such as mitotane and platinum-based chemotherapy with only low response rates. To the best of our knowledge, this is the first successful use of a long-term two-drug immunotherapy (48 weeks) in a patient with metastatic adrenocortical cancer and high mutational burden. Ipilimumab and nivolumab should be considered as a new therapy option in this patient group.