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Molecular and Cellular Endocrinology Sep 2024Adrenocortical carcinoma (ACC) is a rare yet devastating tumour of the adrenal gland with a molecular pathology that remains incompletely understood. To gain novel...
Adrenocortical carcinoma (ACC) is a rare yet devastating tumour of the adrenal gland with a molecular pathology that remains incompletely understood. To gain novel insights into the cellular landscape of ACC, we generated single-nuclei RNA sequencing (snRNA-seq) data sets from twelve ACC tumour samples and analysed these alongside snRNA-seq data sets from normal adrenal glands (NAGs). We find the ACC tumour microenvironment to be relatively devoid of immune cells compared to NAG tissues, consistent with known high tumour purity values for ACC as an immunologically "cold" tumour. Our analysis identifies three separate groups of ACC samples that are characterised by different relative compositions of adrenocortical cell types. These include cell populations that are specifically enriched in the most clinically aggressive and hormonally active tumours, displaying hallmarks of reorganised cell mechanobiology and dysregulated steroidogenesis, respectively. We also identified and validated a population of mitotically active adrenocortical cells that strongly overexpress genes POLQ, DIAPH3 and EZH2 to support tumour expansion alongside an LGR4+ progenitor-like or cell-of-origin candidate for adrenocortical carcinogenesis. Trajectory inference suggests the fate adopted by malignant adrenocortical cells upon differentiation is associated with the copy number or allelic balance state of the imprinted DLK1/MEG3 genomic locus, which we verified by assessing bulk tumour DNA methylation status. In conclusion, our results therefore provide new insights into the clinical and cellular heterogeneity of ACC, revealing how genetic perturbations to healthy adrenocortical renewal and zonation provide a molecular basis for disease pathogenesis.
Topics: Humans; Adrenocortical Carcinoma; Adrenal Cortex Neoplasms; Tumor Microenvironment; Gene Expression Regulation, Neoplastic; Single-Cell Analysis; Intercellular Signaling Peptides and Proteins; Calcium-Binding Proteins; Membrane Proteins
PubMed: 38759836
DOI: 10.1016/j.mce.2024.112272 -
American Journal of Cancer Research 2024Adrenocortical carcinoma (ACC) is a malignant tumour that originates from the adrenal cortex. It is a highly aggressive cancer characterised by a poor prognosis with an... (Review)
Review
The effect of adjuvant mitotane therapy of the adrenocortical carcinoma on the endometrium and its clinical consequences in menstruating women. Literature review and authors' own experiences.
Adrenocortical carcinoma (ACC) is a malignant tumour that originates from the adrenal cortex. It is a highly aggressive cancer characterised by a poor prognosis with an annual incidence estimated to be up to 2 cases per million. In the adult population, ACC is diagnosed typically between 40 and 50 years of age, more often in women. Complete surgical resection of the tumour is the primary treatment method for ACC. Unfortunately, despite properly performed adrenalectomy, regional recurrences or distant metastases are detected in up to 90% of the patients. For that reason, adjuvant therapy is recommended. Mitotane is the most effective adrenal-specific agent used in adjuvant and palliative therapy. Two menstruating patients, after adrenalectomy due to ACC, during adjuvant mitotane therapy, have been included in the study. The study aimed to assess the effect of mitotane therapy on the endometrium and its clinical consequences, based on the analysis of these two cases and a review of the literature. It seems that menorrhagia may be expected during adjuvant mitotane therapy of ACC in menstruating women. Heavy uterine bleeding during menstruation may appear several months after the beginning of therapy. The likely mechanism for heavy menstrual bleeding is complex. Menorrhagia can occur due to the toxic effect of mitotane in the form of a haemorrhagic diathesis, while long-term treatment (over ten months) can lead to relative hypoestrogenism resulting in endometrial hyperplasia. Clinical signs of hypoestrogenism during mitotane treatment, have been described (including pre-puberty girls) and should be considered as a side-effect of the therapy. Menorrhagia may lead to severe anaemia, so this should be considered when planning mitotane treatment. Continuous gestagen therapy is helpful in the treatment of the above disorders. After over 60 years of experience with mitotane usage, knowledge about it is still insufficient, and further studies are required.
PubMed: 38726272
DOI: 10.62347/QKWF9884 -
Translational Andrology and Urology Apr 2024Adrenocortical carcinoma (ACC) is an extremely rare and highly invasive malignant tumor. However, there is currently no reliable method to predict the prognosis of ACC....
BACKGROUND
Adrenocortical carcinoma (ACC) is an extremely rare and highly invasive malignant tumor. However, there is currently no reliable method to predict the prognosis of ACC. Our objective is to construct a nomogram and a risk classification system to predict the 1-year, 3-year, and 5-year overall survival (OS) of ACC.
METHODS
We retrieved clinicopathological data of patients diagnosed with ACC in The Surveillance, Epidemiology, and End Results (SEER) database and divided them into training and validation cohorts with a 7:3 ratio. Simultaneously, we collected an external validation cohort from The First Affiliated Hospital of Naval Medical University (Shanghai, China). Univariate and multivariate Cox analyses were performed to identify relevant risk factors, which were then combined to develop a correlation nomogram. The predictive performance of the nomogram was evaluated using the concordance index (C-index), receiver-operating characteristic curve (ROC), and calibration curves. Decision curve analysis (DCA) was applied to assess the clinical utility of the nomogram. In addition, Kaplan-Meier survival curves were generated to demonstrate the variation in OS between groups.
RESULTS
The final nomogram consisted of five factors: age, T, N, M, and history of chemotherapy. Our prognostic model demonstrated significant discriminative ability, with C-index and the area under the receiver operating characteristic (AUC) values exceeding 0.70. Additionally, DCA validated the clinical utility of the nomogram. In the entire cohort, the median OS for patients in the low- and high-risk groups was 70 and 10 months, respectively.
CONCLUSIONS
A nomogram and a corresponding risk classification system were developed in order to predict the OS of patients diagnosed with ACC. These tools have the potential to provide valuable support for patient counseling and assist in the decision-making process related to treatment options.
PubMed: 38721297
DOI: 10.21037/tau-23-571 -
European Journal of Cancer (Oxford,... Jul 2024Adrenocortical carcinoma (ACC) is a rare cancer that arises sporadically or due to hereditary syndromes. Data on germline variants (GVs) in sporadic ACC are limited. Our...
BACKGROUND
Adrenocortical carcinoma (ACC) is a rare cancer that arises sporadically or due to hereditary syndromes. Data on germline variants (GVs) in sporadic ACC are limited. Our aim was to characterize GVs of genes potentially related to adrenal diseases in 150 adult patients with sporadic ACC.
METHODS
This was a retrospective analysis of stage I-IV ACC patients with sporadic ACC from two reference centers for ACC in Italy. Patients were included in the analysis if they had confirmed diagnosis of ACC, a frozen peripheral blood sample and complete clinical and follow-up data. Next generation sequencing technology was used to analyze the prevalence of GVs in a custom panel of 17 genes belonging to either cancer-predisposition genes or adrenocortical-differentiation genes categories.
RESULTS
We identified 18 GVs based on their frequency, enrichment and predicted functional characteristics. We found six pathogenic (P) or likely pathogenic (LP) variants in ARMC5, CTNNB1, MSH2, PDE11A and TP53 genes; and twelve variants lacking evidence of pathogenicity. New unique P/LP variants were identified in TP53 (p.G105D) and, for the first time, in ARMC5 (p.P731R). The presence of P/LP GVs was associated with reduced survival outcomes and had a significant and independent impact on both progression-free survival and overall survival.
CONCLUSIONS
GVs were present in 6.7 % of patients with sporadic ACC, and we identified novel variants of ARMC5 and TP53. These findings may improve understanding of ACC pathogenesis and enable genetic counseling of patients and their families.
Topics: Humans; Adrenocortical Carcinoma; Male; Female; Germ-Line Mutation; Middle Aged; Adrenal Cortex Neoplasms; Adult; High-Throughput Nucleotide Sequencing; Retrospective Studies; Aged; Genetic Predisposition to Disease; Young Adult; Biomarkers, Tumor; Aged, 80 and over
PubMed: 38714106
DOI: 10.1016/j.ejca.2024.114088 -
JCEM Case Reports May 2024Malignancies may induce clinical sequelae distant from the sites of the tumor. Such paraneoplastic phenomena are known to affect many organs, including the skin....
Malignancies may induce clinical sequelae distant from the sites of the tumor. Such paraneoplastic phenomena are known to affect many organs, including the skin. Vitiligo is a disorder of patchy depigmentation, appearing as white macules with distinct margins. Rarely, vitiligo has been reported as a paraneoplastic occurrence, in the settings of pituitary adenoma, thymoma, gastric carcinoma, and lymphoma. We now describe a man presenting with the abrupt onset of vitiligo on the hands coinciding with recurrence of adrenocortical carcinoma (ACC) in the abdomen. The vitiligo rapidly dissipated following resection of his cancer. We believe this to be the first report of paraneoplastic vitiligo associated with ACC. Endocrinologists typically manage ACC and should be aware of this link, as the de novo observation of vitiligo may signal the onset or recurrence of underlying tumor. Other practitioners that encounter patients with new vitiligo should add ACC to their differential diagnosis of potential underlying conditions.
PubMed: 38707658
DOI: 10.1210/jcemcr/luae070 -
Journal of Surgical Case Reports May 2024The adrenal haemangioma, a rare benign vascular tumour, is increasingly detected through abdominal imaging. Just over 70 surgical cases have been reported since 1955....
The adrenal haemangioma, a rare benign vascular tumour, is increasingly detected through abdominal imaging. Just over 70 surgical cases have been reported since 1955. Their potential large size and overlapping imaging features with adrenocortical carcinoma poses a diagnostic challenge. Adrenalectomy is often needed for a definitive diagnosis due to inconclusive imaging. We report the case of a 61-year-old female presenting with an incidental finding of a right-sided 9.5-cm adrenal mass on imaging. Due to the risk of adrenocortical carcinoma with inconclusive imaging findings, an open right adrenalectomy was performed. The patient was discharged after 6 days with no complications. Post-surgical histopathology confirmed a diagnosis of adrenal haemangioma with a secondary adrenal pseudocyst. The presence of an adrenal incidentaloma with discordant radiological features proves to be a diagnostic conundrum. Therefore, in the setting of contradictory radiology and concerning mass size, we recommend adrenalectomy for definitive diagnosis of an adrenal haemangioma.
PubMed: 38706490
DOI: 10.1093/jscr/rjae286 -
Oxford Medical Case Reports Apr 2024Ectopic adrenal tissue is a rare finding often encountered incidentally during histopathological examinations. The most common site is the genitourinary tract and...
Ectopic adrenal tissue is a rare finding often encountered incidentally during histopathological examinations. The most common site is the genitourinary tract and pelvis, and more frequently in males than females. Ectopic adrenal tissue is primarily found in neonates and is extremely rare in adults. Although it is an unexpected entity, pathologists should be aware of it because it may be confused with metastasis of clear cell renal carcinoma. To the best of our knowledge, only three cases of ectopic adrenal tissue in the mesosalpinx of the fallopian tube have been reported in the medical literature, making this case the fourth one. In our report, we discussed an ectopic adrenal tissue that was discovered incidentally in the mesosalpinx of an older female.
PubMed: 38680768
DOI: 10.1093/omcr/omae024 -
JCEM Case Reports May 2024Adrenal tumors with invasion into the inferior vena cava (IVC) are typically malignant. Here, we present a case of adrenocortical adenoma with protrusion into the IVC. A...
Adrenal tumors with invasion into the inferior vena cava (IVC) are typically malignant. Here, we present a case of adrenocortical adenoma with protrusion into the IVC. A 70-year-old man was referred to our hospital after his magnetic resonance imaging scan of the abdomen coincidently revealed a right adrenal tumor invading the IVC. We suspected an aggressive adrenal carcinoma and tumor resection was performed. However, all 3 existing pathological criteria (Weiss, modified Weiss, and Helsinki) suggested the tumor was benign. Immunohistochemistry for CD31 showed the tumor inside the central adrenal vein (CAV), right adrenal vein (RAV), and IVC was entirely covered with CD31-positive vascular endothelial cells. The CAV is known to sometimes lack smooth muscle in its walls and normal adrenocortical cells covered by endothelial cells sometimes protrude into the CAV from this gap. These findings suggest that this tumor likely protruded into the IVC by pushing against the CAV wall, rather than by invasion into the vascular wall. In the case with adrenal tumors protruding into the IVC, the fact that the tumor surface was covered by vascular endothelial cells was considered supportive of its benign nature.
PubMed: 38660484
DOI: 10.1210/jcemcr/luae043