Differentiating Benign from Malignant Adrenocortical Tumors by a Single Morphological Parameter—a Clinicopathological Study on 837 Adrenocortical Neoplasias

AbstractThe morphological differentiation between benign and malignant adrenocortical tumors is an ongoing problem in diagnostic pathology. In recent decades the complex scoring systems have been widely used to calculate the probability of malignancy in adrenocortical tumors on the basis of a variety of histomorphological parameters. We herewith present a substantially simplified method to diagnose adrenocortical carcinoma by a single histomorphological parameter on a consecutive series of more than 800 adrenocortical tumors. Between January 2000 and May 2019, altogether 2305 adrenalectomies for of all types of diseases were removed, approximately 98% by minimally invasive approaches. After exclusion of pheochromocytomas, adrenal ganglioneuromas, adrenal metastases, Cushing’s disease related specimens, and Conn’s adenomas, the present series finally consisted of 837 adrenocortical tumors. All tumors were analyzed by experienced pathologists of a single institution using standard histopathological methods (Hematoxylin-Eosin and Ki67 stained sections). Clinical and histopathologic data were prospectively collected and retrospectively analyzed. Clinically, 385 patients had 420 functioning tumors (FT), and 417 had non-functioning adrenal tumors (NFT). The mean size of FT was 3.8 ± 1.4 cm (range 0.5–16 cm) and for NFT 4.5 ± 1.6 cm (range 1.5–18 cm). Histomorphologically, 32 adrenal tumors were classified as adrenocortical carcinoma (ACC; 3.8%). In all 32 cases (tumor size 9.1 ± 4.0 cm, range 3–18 cm), confluenting tumor necrosis could be demonstrated. The remaining 805 tumors (control group) completely lacked this highly reproducible single morphological feature. Ki67 levels above 10% were found in 31 of 32 ACCs and never in adrenocortical adenomas (ACA). With a mean follow-up of 8.2 years, 24 out of 32 patients primarily diagnosed as ACC developed distant metastases (75.0%), whereas all patients in the control group remained free of local or distant recurrence. We conclude that a single morphological parameter (confluenting tumor necrosis) is sufficient to predict a poor clinical course in adrenocortical tumors. The histomorphological diagnosis of this parameter is straightforward and highly reproducible.

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

Cancers ◽

10.3390/cancers13225693 ◽

2021 ◽

Vol 13 (22) ◽

pp. 5693

Author(s):

Carmina Teresa Fuss ◽

Katharina Other ◽

Britta Heinze ◽

Laura-Sophie Landwehr ◽

Armin Wiegering ◽

...

Keyword(s):

Clinical Outcome ◽

Protein Expression ◽

Chemokine Receptor ◽

Adrenocortical Carcinoma ◽

Distant Metastases ◽

Adrenal Tumors ◽

Mrna Levels ◽

Primary Tumors ◽

Adrenocortical Tumors ◽

Adrenocortical Adenomas

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.

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Matrix metalloproteinase type 2 (MMP2) is selective expressed in adrenocortical carcinoma but not in adrenal adenoma: An immunohistochemical study

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.14534 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 14534-14534

Author(s):

P. Sperone ◽

M. Volante ◽

A. Berruti ◽

E. Bollito ◽

E. Frangipane ◽

...

Keyword(s):

Differential Diagnosis ◽

Solid Tumors ◽

Adrenocortical Carcinoma ◽

Adrenal Adenoma ◽

Disease Free Survival ◽

Scoring Systems ◽

Immunohistochemical Localization ◽

Adrenocortical Tumors ◽

Adrenocortical Adenomas ◽

Histological Criteria

14534 Background: Adrenocortical carcinoma (ACC) is a very rare disease which account for no more than 0.2% of all malignancies, and its differential diagnosis from adrenocortical adenomas (ACA) is based on the application of different scoring systems, which, however, lack a sensitivity and specificity of 100%. Little is known on the mechanisms leading to the malignant phenotype in adrenocortical tumors; among alternative mechanisms, metalloproteinases (MMPs) have been demonstrated in solid tumors, including endocrine ones, to be implicated in malignant progression and metastatization. Our aim was to investigate metalloproteinase 2 (MMP2) expression in adrenocortical tumors. Methods: A series of 33 ACC and 23 ACA was retrospectively collected from a large series of adrenocortical lesions, and the diagnosis was reviewed independently by three investigators (MV, EB, MP) according to the Weiss histological criteria. MMP2 was determined by immunohistochemistry and the results scored by semi-quantitative analysis, based on the intensity of the staining and the percentage of tumor cells positive. Immunohistochemical results were compared to clinico-pathological parameters, such as sex, age, hormonal secretion, and outcome. Results: MMP2 expression was detected in 1/23 ACA (4%), and in 25/33 ACC (76%) (X-square test p < 0.001). MMP2 immunohistochemical pattern in ACC was focal to moderate to strong in 10, 12 and 3 cases, respectively. In addition, moderate to strong MMP2 expression, as compared to low or negative immunostaining, correlated with shorter disease-free survival (p = 0.012) and poor outcome (p = 0.07). No correlation were found comparing MMP2 expression and other clinico-pathological parameters. Conclusions: As reported in a variety of solid tumors, our data indicates a possible role of MMP2 in the malignant evolution of adrenocortical tumors, and its immunohistochemical localization may be a potential useful tool in the differential diagnosis of benign versus malignant adrenocortical lesions. In addition, a strong immunohistochemical MMP2 expression seems to be related to a poor prognosis in ACC. No significant financial relationships to disclose.

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A Critical Appraisal of Contemporary and Novel Biomarkers in Pheochromocytomas and Adrenocortical Tumors

Biology ◽

10.3390/biology10070580 ◽

2021 ◽

Vol 10 (7) ◽

pp. 580

Author(s):

Marina Tsoli ◽

Kosmas Daskalakis ◽

Eva Kassi ◽

Gregory Kaltsas ◽

Apostolos V. Tsolakis

Keyword(s):

Hormone Secretion ◽

Predictive Biomarkers ◽

High Specificity ◽

Scoring Systems ◽

Tumor Grade ◽

Adrenal Tumors ◽

Significant Heterogeneity ◽

Adrenocortical Tumors ◽

Specificity And Sensitivity ◽

Micro Rnas

Pheochromocytomas/Paragangliomas (PPGLs) and adrenocortical tumors are rare neoplasms with significant heterogeneity in their biologic and clinical behavior. Current diagnostic and predictive biomarkers include hormone secretion, as well as histopathological and genetic features. PPGL diagnosis is based on biochemical measurement of catecholamines/metanephrines, while histopathological scoring systems have been proposed to predict the risk of malignancy. Adrenocortical tumors are mostly benign, but some can be malignant. Currently, the stage of disease at diagnosis and tumor grade, appear to be the most powerful prognostic factors. However, recent genomic and proteomic studies have identified new genetic and circulating biomarkers, including genes, immunohistochemical markers and micro-RNAs that display high specificity and sensitivity as diagnostic or prognostic tools. In addition, new molecular classifications have been proposed that divide adrenal tumors in distinct subgroups with different clinical outcomes.

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Evaluation of plasma insulin-like growth factor binding protein-2 as a marker for adrenocortical tumors

Acta Endocrinologica ◽

10.1530/eje.0.1440029 ◽

2001 ◽

pp. 29-36 ◽

Cited By ~ 30

Author(s):

N Boulle ◽

E Baudin ◽

C Gicquel ◽

A Logie ◽

J Bertherat ◽

...

Keyword(s):

Growth Factor ◽

Complete Remission ◽

Metastatic Disease ◽

Adrenocortical Carcinoma ◽

Control Group ◽

Insulin Like Growth Factor ◽

Metastatic Tumors ◽

Factor Binding ◽

Adrenocortical Tumors

OBJECTIVE: Recent studies have pointed to the role of the IGF system in the pathogenesis of adrenocortical tumors, and it was shown recently that malignant adrenocortical tumors exhibit a high insulin-like growth factor binding protein (IGFBP)-2 content. Circulating markers specific for adrenocortical carcinoma are needed and the aim of this study was to evaluate plasma IGFBP-2 as a marker for these malignant tumors. METHODS: Plasma IGFBP-2 was determined in 51 patients referred to our institutions for adrenocortical tumors. Fifteen patients were in complete remission (group 1), eight patients had preoperative localized tumors (group 2) and 28 patients had metastatic tumors (group 3). Thirty-six healthy volunteers constituted a control group. RESULTS: There was no significant difference in plasma IGFBP-2 concentration between healthy controls and patients with complete remission or localized tumors. In contrast, patients with metastatic disease had significantly higher IGFBP-2 plasma levels than the control group (P<0.001). IGFBP-2 levels in patients with metastatic disease were inversely correlated with survival (R2=0.308; P=0.0026). In patients with localized tumors, there was no correlation between plasma IGFBP-2 concentration and tumor size or histological features. Analysis of individual IGFBP-2 concentrations showed that five patients (17.8%) with metastatic tumors had normal IGFBP-2 levels and two patients (13.3%) in complete remission had high plasma IGFBP-2 levels. The influence of nutrition, hormone secretion and treatment on IGFBP-2 levels was examined. Nutritional status was evaluated by determining IGF-I levels and was found to be normal in 16 patients (61.5%) with high IGFBP-2 levels, suggesting that malnutrition was not responsible for the high IGFBP-2 concentrations in these patients. IGFBP-2 levels did not differ significantly according to tumor secretion or mitotane treatment. In a follow-up study, plasma IGFBP-2 concentration remained stable in patients with complete remission or stabilized disease and was a late marker of tumor progression in patients with progressive metastatic disease. CONCLUSIONS: These results indicate that plasma IGFBP-2 is elevated in patients with malignant adrenocortical tumors and that the major factor affecting IGFBP-2 levels in these patients is tumor stage. However, plasma IGFBP-2 was less sensitive than expected for a tumor marker, which may limit its value in the diagnosis and follow-up of adrenocortical carcinoma.

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Germline EGFR variants are over-represented in adolescents and young adults (AYA) with adrenocortical carcinoma

Human Molecular Genetics ◽

10.1093/hmg/ddaa268 ◽

2020 ◽

Author(s):

Sara Akhavanfard ◽

Lamis Yehia ◽

Roshan Padmanabhan ◽

Jordan P Reynolds ◽

Ying Ni ◽

...

Keyword(s):

Young Adults ◽

Adrenocortical Carcinoma ◽

Kinase Inhibitor ◽

Mapk Pathway ◽

Adolescents And Young Adults ◽

Control Group ◽

Precision Oncology ◽

Sequencing Data ◽

Germline Variants ◽

Mutant Cells

Abstract Adrenocortical Carcinoma (ACC) is a rare endocrine tumor with poor overall prognosis and 1.5-fold overrepresentation in females. In children, ACC is associated with inherited cancer syndromes with 50–80% of childhood-ACC associated with TP53 germline variants. ACC in adolescents and young adults (AYA) is rarely due to germline TP53, IGF2, PRKAR1A and MEN1 variants. We analyzed exome sequencing data from 21 children (<15y), 32 AYA (15-39y), and 60 adults (>39y) with ACC, and retained all pathogenic, likely pathogenic, and highly prioritized variants of uncertain significance. We engineered a stable lentiviral-mutant ACC cell line, harboring an EGFR variant (p.Asp1080Asn) from a 21-year-old female without germline-TP53-variant and with aggressive ACC. We found that 4.8% of the children (P = 0.004) and 6.2% of AYA (P < 0.0001), all-female participants, harbored germline EGFR variants, compared to only 0.3% of the control group. Expanding our analysis to the RTK-RAS-MAPK pathway, we found that the RTK genes have the highest number of highly prioritized germline variants in these individuals amongst all three arms of this pathway. We showed EGFR mutant cells migrate faster and are characterized by a stem-like phenotype compared to wild type cells. While EGFR inhibitors did not affect the stemness of mutant cells, Sunitinib, a multireceptor tyrosine kinase inhibitor, significantly reduced their stem-like behavior. Our data suggest that EGFR could be a novel underlying germline predisposition factor for ACC, especially in the Childhood-AYA (C-AYA) population. Further clinical validation can improve precision oncology management of this disease, which is known to have limited therapeutic options.

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Sepsis Diagnostics: Intensive Care Scoring Systems Superior to MicroRNA Biomarker Testing

Diagnostics ◽

10.3390/diagnostics10090701 ◽

2020 ◽

Vol 10 (9) ◽

pp. 701

Author(s):

Fabian Link ◽

Knut Krohn ◽

Anna-Maria Burgdorff ◽

Annett Christel ◽

Julia Schumann

Keyword(s):

Intensive Care ◽

Scoring Systems ◽

Digital Pcr ◽

Absolute Quantification ◽

Medical Problem ◽

Control Group ◽

Multiple Parameters ◽

Sepsis Diagnosis ◽

Intensive Care Patients ◽

Healthy Control

Sepsis represents a serious medical problem accounting for numerous deaths of critically ill patients in intensive care units (ICUs). An early, sensitive, and specific diagnosis is considered a key element for improving the outcome of sepsis patients. In addition to classical laboratory markers, ICU scoring systems and serum miRNAs are discussed as potential sepsis biomarkers. In the present prospective observational study, the suitability of miRNAs in sepsis diagnosis was tested based on proper validated and normalized data (i.e., absolute quantification by means of Droplet Digital PCR (ddPCR)) in direct comparison to classical sepsis markers and ICU scores within the same patient cohort. Therefore, blood samples of septic intensive care patients (n = 12) taken at day of admission at ICU were compared to non-septic intensive care patients (n = 12) and a healthy control group (n = 12). Our analysis indicates that all tested biomarkers have only a moderate informative power and do not allow an unequivocal differentiation between septic and non-septic ICU patients. In conclusion, there is no standalone laboratory parameter that enables a reliable diagnosis of sepsis. miRNAs are not superior to classical parameters in this respect. It seems recommendable to measure multiple parameters and scores and to interpret them with regard to the clinical presentation.

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Radiofrequency ablation of adrenal tumors and adrenocortical carcinoma metastases

Cancer ◽

10.1002/cncr.11084 ◽

2003 ◽

Vol 97 (3) ◽

pp. 554-560 ◽

Cited By ~ 180

Author(s):

Bradford J. Wood ◽

Jame Abraham ◽

Julia L. Hvizda ◽

H. Richard Alexander ◽

Tito Fojo

Keyword(s):

Radiofrequency Ablation ◽

Adrenocortical Carcinoma ◽

Adrenal Tumors

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O-024 Endoscopic management of the unexplained infertility, what does it add?

Human Reproduction ◽

10.1093/humrep/deab126.004 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

S Gordts

Keyword(s):

Pregnancy Rate ◽

Cellular Proliferation ◽

Unexplained Infertility ◽

Endoscopic Management ◽

Control Group ◽

Consecutive Series ◽

Infertile Patient ◽

Tubal Patency ◽

Spontaneous Pregnancy ◽

Visualization Techniques

Abstract text Endoscopic management of the unexplained infertility, what does it add? Stephan Gordts [email protected] Unexplained infertility “strictu sensu” is not a diagnosis, but a description of a status where no causal factor is identified in a couple trying to conceive for at least one year. The more parameters are assessed, the more likely to identify an etiology, the less likely becomes “unexplained” infertility. Limiting the fertility exploration to indirect visualization techniques like ultrasound, HSG or HycoSy involves the risk of missing existing pathologies. Uterus Uterine volumetric abnormalities can be detected by indirect techniques, but information is lacking on the visualization of the endometrium in case of chronic endometritis and the presence of endometrial defects and hypervascularization areas as seen in patients with adenomyosis. Tubo-ovarian Even with the increased accuracy of indirect visualization techniques, lesions of minimal endometriosis and tubo-ovarian adhesions are not detected (Table). Tubal normality constitutes not only normal tubal patency but also normal tubal function. The importance of subtle tubal lesions is underestimated. Hydatid of Morgagni are detected in 38.1% in patients with infertility versus only in 16,7% in fertile women (Gupta et al. JMIG 2017).Removal of these lesions resulted in a spontaneous pregnancy rate of 58.7% versus 20.6 in the non-treated group (Rasheed et al. EJOG Repr. 2011). Endometriosis In a series of 107 patients with unexplained infertility and 3 failed IVF cycles (Agni Pantou et al. J. Clin. Med. 2019)laparoscopy revealed the presence of endometriosis in 57.97%, peri-adnexal adhesions in 23.3% and was normal in 18.69%. Also, in a group of patients with 3 failed IVF cycles and unexplained infertility (Xiaoming Yu et al.Medicine 2019) laparoscopy showed endometriosis in 57.7%, tubal abnormalities in 31.1% and adhesions in 33.3%. Laparoscopic correction of these pathologies did not only result in a spontaneous pregnancy rate of 35% but resulted also in a higher pregnancy rate after IVF compared to the non-treated control group. Unexplained infertility hides frequently undiagnosed endometriosis. Endometrial BCL6 levels, a proto-oncogene where overexpression is associated with increased cellular proliferation and progesterone resistance, are increased in patients with endometriosis. In case of elevated BCL6 in patients with unexplained infertility, laparoscopy confirmed the presence of endometriosis in 93.8% (Evans-Hoeker et al. 2016). Abnormal BCL6 expression in a population with unexplained infertility reduced the chance of having a successful IVF treatment in 74% of the population (Almquist et al. Fertil Steril 2017). Transvaginal Hydro Laparoscopy Direct endoscopic visualization remains important but due to the invasiveness, diagnostic standard laparoscopy is frequently postponed or omitted in the exploration of the infertile patient. The technique of transvaginal hydro-laparoscopy allows in a minimal invasive way the inspection of the pelvis. In a consecutive series of 2288 patients without obvious pelvic pathology, findings were normal in 49.3%, endometriosis was diagnosed in 15.9% and tubal pathology in 14.5% of the patients (Gordts et al. FVV 2021). The rate of failed access was 1% and the complication rate 0.74%. Causing a minimal ovarian trauma, treatment of these early endometriotic lesions resulted in a spontaneous pregnancy rate of 73.2%. Conclusion The inappropriate use of “unexplained infertility” by omitting the diagnostic endoscopy in the exploration of the infertile patient, can hide undiagnosed and treatable pathology, jeopardizing possibilities for patients for a spontaneous conception and can be responsible for reduced pregnancy rates after IVF.

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Fascin-1 Is a Novel Prognostic Biomarker Associated With Tumor Invasiveness in Adrenocortical Carcinoma

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2018-01717 ◽

2018 ◽

Vol 104 (5) ◽

pp. 1712-1724 ◽

Cited By ~ 6

Author(s):

Giada Poli ◽

Carmen Ruggiero ◽

Giulia Cantini ◽

Letizia Canu ◽

Gianna Baroni ◽

...

Keyword(s):

Disease Free Survival ◽

Tumor Stage ◽

Labeling Index ◽

University Hospital ◽

Adrenal Tumors ◽

Adrenocortical Cancer ◽

Tumor Spread ◽

Adrenocortical Tumors ◽

Tumor Invasiveness ◽

Ki67 Labeling Index

Abstract Context Novel tumor markers are urgently needed to better stratify adrenocortical cancer (ACC) patients and improve therapies for this aggressive neoplasm. Objective To assess the diagnostic and prognostic value of the actin-bundling protein fascin-1 (FSCN1) in adrenocortical tumors. Design, Setting and Participants A local series of 37 malignant/37 benign adrenocortical tumors at Careggi University Hospital and two independent validation ACC cohorts (Cochin, TCGA) from the European Network for the Study of Adrenal Tumors were studied. Main Outcome Measures FSCN1 expression was quantified by immunohistochemistry, Western blot and quantitative RT-PCR in ACC specimens; overall and disease-free survival associated with FSCN1 expression were assessed by Kaplan-Meier analysis and compared with that of Ki67 labeling index and tumor stage. Results Despite the low diagnostic power, in the Florence ACC series, FSCN1 immunohistochemical detection appeared as an independent prognostic factor, also refining results obtained with staging and Ki67 labeling index. The robust prognostic power of FSCN1 levels was further confirmed in two independent ACC cohorts. A positive correlation was found between FSCN1 and steroidogenic factor-1 (SF-1), with a substantially higher expression of both factors in ACCs at advanced stages and with at least one of the three Weiss score parameters associated with invasiveness. Moreover, we demonstrated FSCN1 role in promoting cell invasion in a human ACC cell line only in the case of increased SF-1 dosage. Conclusions These findings show that FSCN1 is a novel independent prognostic marker in ACC and may serve as a potential therapeutic target to block tumor spread.

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Serum biomarkers and clinical characteristics of patients with Hodgkin lymphoma

Vojnosanitetski pregled ◽

10.2298/vsp160705018s ◽

2018 ◽

Vol 75 (9) ◽

pp. 911-917

Author(s):

Olivera Simonovic ◽

Milena Todorovic ◽

Biljana Mihaljevic ◽

Tatjana Stoimenov-Jevtovic ◽

Ivan Petkovic ◽

...

Keyword(s):

Progressive Disease ◽

Clinical Status ◽

Scoring Systems ◽

Control Group ◽

Newly Diagnosed ◽

Risk Patients ◽

Tumor Environment ◽

Prognostic Scoring Systems ◽

The Relationship

Background/Aim. In classical Hodgkin?s lymphoma (cHL) the existing prognostic scoring systems do not include markers that adequately reflect the interaction of malignant Hodgkin and Reed-Sternberg (HRS) cells and tumor environment. The aim of this study was to determine the relationship between serum Galectin-1 (Gal-1) and soluble CD163 (sCD163) and the clinical status of patients with cHL, with special emphasis on the presence of relapse, progression, or resistance to the therapy applied. Methods. The research included 79 patients of whom 63 were patients with cHL, and the control group of 16 healthy volunteers. The study group of 63 patients with cHL included a subgroup of newly diagnosed patients without therapy, newly diagnosed patients with therapy, patients with relapse and progression of the disease and primary refractory patients during 2014 and 2015. Results. Analysis of the levels of sCD163 and Gal-1 within a group of patients suffering from cHL showed that the values of both molecules were higher in relapsed patients and the subgroup with progressive disease comparing to the subgroup of newly diagnosed patients without therapy or patients with therapy onset. Conclusion. Determination of Gal-1 and sCD163 levels is simple and reliable analysis that can contribute to the identification of high-risk patients with cHL and deserves inclusion in current prognostic scoring systems.

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