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The Weiss system for evaluating adrenocortical neoplasms: 25 years later
Abstract
The evaluation and categorization of adrenocortical neoplasms remain among the most challenging areas in adrenal pathology. The Weiss system, first introduced 25 years ago, provides specific guidelines for differentiating adrenocortical adenoma from adrenocortical carcinoma and is considered the standard for determining malignancy in tumors of the adrenal cortex. Considerable advances in the understanding of the pathology of adrenocortical neoplasia have occurred since delineation of the Weiss system, offering alternative approaches to the contemporary assessment of adrenocortical tumors.
... Several studies have determined that tumor grade, resection status, age, and preoperative symptoms of hormone hypersecretion can have an impact on ACC prognosis. [10][11][12][13][14][15][16] These factors (grade [G], resection status [R], patient age [A], and preoperative symptoms [S] of hormone hypersecretion) have been demonstrated retrospectively to have individual prognostic value in stages III-IV ACC, and in 2015 these factors were collectively referred to as the ''GRAS'' parameters by the European Network for the Study of Adrenal Tumors (ENSAT). [10][11][12][13][14][15][16] The utility of combining the individual GRAS parameters into a cumulative GRAS score for further stratification of ACC patient prognosis was recently assessed by Liang et al. 11 for 65 patients with stages I-III ACC in a singlecenter study using a three-tiered system (GRAS score B 1, 2, C 3). ...
... [10][11][12][13][14][15][16] These factors (grade [G], resection status [R], patient age [A], and preoperative symptoms [S] of hormone hypersecretion) have been demonstrated retrospectively to have individual prognostic value in stages III-IV ACC, and in 2015 these factors were collectively referred to as the ''GRAS'' parameters by the European Network for the Study of Adrenal Tumors (ENSAT). [10][11][12][13][14][15][16] The utility of combining the individual GRAS parameters into a cumulative GRAS score for further stratification of ACC patient prognosis was recently assessed by Liang et al. 11 for 65 patients with stages I-III ACC in a singlecenter study using a three-tiered system (GRAS score B 1, 2, C 3). These early findings require validation with a larger multi-institutional cohort for patients with all stages (I-IV) of surgically resectable ACC. ...
... Of the 265 patients in the US-ACCG database, 243 (91.7%) had sufficient data available to calculate a GRAS score and were included in our analysis. A sum GRAS score was calculated for each patient meeting the criteria by adding one point for each of the following GRAS categories: G (grade: C 3 Weiss criteria met 12 (Table 1) or Ki67 C 20% on the final pathology report), R (resection status: a microscopically [R1] or macroscopically [R2] positive final surgical margin at the index operation), A (age of C 50 years at the index operation), and S (symptoms: preoperative symptoms of hormone hypersecretion) ( Table 2). ...
Background:
Adrenocortical carcinoma (ACC) is a rare but aggressive malignancy, and many prognostic factors that influence survival remain undefined. Individually, the GRAS (Grade, Resection status, Age, and Symptoms of hormone hypersecretion) parameters have demonstrated their prognostic value in ACC. This study aimed to assess the value of a cumulative GRAS score as a prognostic indicator after ACC resection.
Methods:
A retrospective cohort study of adult patients who underwent surgical resection for ACC between 1993 and 2014 was performed using the United States Adrenocortical Carcinoma Group (US-ACCG) database. A sum GRAS score was calculated for each patient by adding one point each when the criteria were met for tumor grade (Weiss criteria ≥ 3 or Ki67 ≥ 20%), resection status (micro- or macroscopically positive margin), age (≥ 50 years), and preoperative symptoms of hormone hypersecretion (present). Overall survival (OS) and disease-free survival (DFS) by cumulative GRAS score were analyzed by the Kaplan-Meier method and log-rank test.
Results:
Of the 265 patients in the US-ACCG database, 243 (92%) had sufficient data available to calculate a cumulative GRAS score and were included in this analysis. The 265 patients comprised 23 patients (10%) with a GRAS of 0, 52 patients (21%) with a GRAS of 1, 92 patients (38%) with a GRAS of 2, 63 patients (26%) with a GRAS of 3, and 13 patients (5%) with a GRAS of 4. An increasing GRAS score was associated with shortened OS (p < 0.01) and DFS (p < 0.01) after index resection.
Conclusion:
In this retrospective analysis, the cumulative GRAS score effectively stratified OS and DFS after index resection for ACC. Further prospective analysis is required to validate the cumulative GRAS score as a prognostic indicator for clinical use.
... In cases with metastases, either regional or distant, the diagnosis of malignant adrenocortical tumors is evident. However, in cases with only local disease, the Weiss score, consisting of several histopathological criteria, is still the gold standard to separate benign from malignant adrenocortical tumors [11,12]. The European Network for the Study of Adrenal Tumors (ENSAT) classification (Table 1) is the currently used staging system for ACC [13] and has an accuracy of 83% in predicting 3-year cancer-specific mortality [8]. ...
... The Weiss score is currently the most widely used scoring system for ACC and represents the gold standard [12,65,67]. It consists of nine domains, which can all be scored with either zero points or one point (Table 2). ...
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.
... μg/dL (32.7-276), 17-OHprogesterone 9.41ng/mL (1.0), and testosterone 2169.62ng/mL (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). ...
... Functional ACTs are presumed to cause suppression of the contralateral adrenal gland [3]. Modified Weiss criteria is an established method for the diagnosis of ACC [8,9]. ...
Adrenal tumors can arise either from cortex or from medulla; both the regions being structurally and functionally different. They are categorized as functional (hormone-secreting) or silent and as either benign or malignant. Adrenocortical Carcinoma (ACC) are rare tumors that have a bimodal distribution, although most adult ACC are non-functional, in pediatric age group, nearly 95% are functional Our case report is presented because of its rarity consisting of our patient with virilising signs at the age of one and a half years.
... Oncocytic adrenal neoplasms are a rare type of adrenal tumor that was first described in 1986. 1 They are composed of eosinophilic cells with abundant granular cytoplasm, resulting from the accumulation of mitochondria. Their clinical characteristics remain poorly understood due to their rarity, and little is known about their long-term outcomes. ...
Background: Oncocytic adrenal neoplasms, defined by ≥90 % of oncocytic cells, are rare. The significance of oncocytic changes within an adrenal neoplasm remains unclear.
Methods: A retrospective study of adults who underwent adrenalectomy at a large center identified pure oncocytic neoplasms on final pathology (1997-2022). Neoplasms were categorized based on Lin-Weiss-Bisceglia system as malignant, benign, or of uncertain malignant potential. Analysis was performed using Fisher exact, Kruskal-Wallis tests, and Kaplan-Meier analysis.
Results: Among a total of 33 patients, 24% had benign, 36% malignant, and 39% neoplasm of uncertain malignant potential. None of the benign neoplasms recurred, while 50% of the malignant neoplasms recurred (median of 40 months). Two of 13 neoplasms initially thought to be of uncertain malignant potential recurred as distant metastatic adrenocortical carcinoma at 11 and 25 months, over a median follow-up duration of 31 months. Ki67% was available for 20 patients: median (IQR) Ki67% was 5 (1, 5) for benign, 10 (6, 15) for malignant, and 6.5 (5, 10) for neoplasms of uncertain behavior, P = 0.05. Recurred neoplasms had higher Ki67% at initial resection compared to cases that did not recur.
Conclusion: While oncocytic adrenal neoplasms are rare, a significant proportion are malignant or have malignant potential. Judicious follow-up is required for oncocytic adrenal neoplasms of uncertain malignant potential, as they can recur as metastatic adrenocortical carcinoma. Ki67% should always be obtained in cases of malignancy or uncertain malignant potential as it can predict recurrence. Larger studies are needed to evaluate the appropriate follow-up protocols for these neoplasms.
... A histological analysis showed that the tumor was mostly composed of clear cells with a clear margin (Fig. 3A, B). The tumor met none of the nine parameters of the Weiss criteria (39). An immunohistochemical analysis revealed that most part of the tumor showed positive immunoreactivity for steroidogenic enzymes (40), including 3 β-hydroxysteroid dehydrogenase (3β-HSD) type 2, CYP21 A, CYP11B1, and CYP11B2 (Fig. 3C-F). ...
Many cases of primary aldosteronism (PA) in patients who developed hypokalemia-induced rhabdomyolysis and underwent adrenalectomy for aldosterone-producing adenoma (APA) have been reported; however, the immunohistopathological and molecular features remain unknown. We herein report the case of a 28-year-old woman with PA who presented with hypokalemia-induced rhabdomyolysis and underwent adrenalectomy for unilateral APA. An immunohistochemical analysis revealed that most adenoma cells were positive for steroidogenic enzymes, including CYP11B2. A genetic analysis revealed a somatic mutation in the KCNJ5. These findings suggest a strong aldosterone production capacity in our patient's adenoma, which was presumably related to her severe hyperaldosteronism and the resultant hypokalemia-induced rhabdomyolysis.
... One criterion seems to be emerging: tumor grade, assessed by counting mitoses in the tumor and/or by Ki-67 immunohistochemistry, which quantifies the proportion of cells in mitosis. Highgrade tumours appear to be associated with a poor prognosis (8). ...
Adrenocortical adenocarcinoma (ACA) is a rare malignancy that develops at the expense of the adrenal cortex. The key to its treatment lies in surgery, with complete resection of a localized form offering the best chance of cure. This article presents the case of a 68-year-old man treated for adrenocortical adenocarcinoma at the Hassan 2 University Hospital in Fez. The patient, with no notable pathological history, consulted for dizziness and abdominal pain, leading to the discovery of a malignant adrenal mass on radiological evaluation. A successful left laparotomy adrenalectomy was performed, confirming, by pathological analysis, a Weiss score 4 adenocarcinoma. Immunohistochemical results showed expression of cytokeratin AE1/AE3, while other markers were absent. The article highlights the efficacy of surgery in the treatment of localized forms of this rare tumor, while highlighting diagnostic challenges and the need for international coordination in adrenocortical adenocarcinoma research and care.
... In fact, in a recent study of 705 adrenal tumors > 4 cm, 31% were benign adenomas and surgical procedures were performed in 55% of thèse even without presence of hormonal excess, consistent with others finding similar results [13]. Confident identification of ACC through adrenal biopsy has limitations and concern of needle track seeding has been raised [14], and therefore adrenalectomy becomes necessary. The therapeutic approach might be altered by additional information supporting a benign etiology for the mass. ...
Purpose
Distinguishing stage 1–2 adrenocortical carcinoma (ACC) and large, lipid poor adrenal adenoma (LPAA) via imaging is challenging due to overlapping imaging characteristics. This study investigated the ability of deep learning to distinguish ACC and LPAA on single time-point CT images.
Methods
Retrospective cohort study from 1994 to 2022. Imaging studies of patients with adrenal masses who had available adequate CT studies and histology as the reference standard by method of adrenal biopsy and/or adrenalectomy were included as well as four patients with LPAA determined by stability or regression on follow-up imaging. Forty-eight (48) subjects with pathology-proven, stage 1–2 ACC and 43 subjects with adrenal adenoma >3 cm in size demonstrating a mean non-contrast CT attenuation > 20 Hounsfield Units centrally were included. We used annotated single time-point contrast-enhanced CT images of these adrenal masses as input to a 3D Densenet121 model for classifying as ACC or LPAA with five-fold cross-validation. For each fold, two checkpoints were reported, highest accuracy with highest sensitivity (accuracy focused) and highest sensitivity with the highest accuracy (sensitivity focused).
Results
We trained a deep learning model (3D Densenet121) to predict ACC versus LPAA. The sensitivity-focused model achieved mean accuracy: 87.2% and mean sensitivity: 100%. The accuracy-focused model achieved mean accuracy: 91% and mean sensitivity: 96%.
Conclusion
Deep learning demonstrates promising results distinguishing between ACC and large LPAA using single time-point CT images. Before being widely adopted in clinical practice, multicentric and external validation are needed.
... Histologic diagnosis of ACC was carried out by two independent reference pathologists on tumor tissue removed at surgery. Tumor specimens were evaluated according to the Weiss scoring system, in which the presence of three or more criteria highly correlates with malignant behavior [12]. The Ki67 labeling index (LI) was estimated on digitalized glass slides, after immunohistochemical staining with antihuman Ki67 antibody (1:40 dilution, MIB-1, Dako, Carpinteria, CA, USA). ...
Adrenal cortical carcinoma (ACC) is an uncommon neoplasm with variable prognosis. Several histologic criteria have been identified as predictors of malignancy in adrenal cortical tumors. The Weiss score is the system most widely employed for diagnostic purposes, but also possesses prognostic value. We aim to determine the relative impact of each Weiss parameter on ACC patient survival. A multicenter retrospective analysis was conducted on a series of 79 conventional ACCs surgically treated at the Florence and Utrecht centers of the European Network for the Study of Adrenal Tumors (ENSAT). Weiss classification was recapitulated using principal component analysis (PCA). The Kaplan–Meier and Cox multivariate regression analyses were applied in order to estimate the prognostic power of Weiss versus other clinical parameters. PCA reduced the nine Weiss parameters to the best fitting 4-component model, each parameter clustering with a single component. Necrosis and venous invasion clustered together with the highest scores, thus establishing the most relevant component (Component 1) to explain Weiss distribution variability. Only Component 1 significantly predicted overall survival (OS, log-rank = 0.008) and disease-free survival (DFS, log-rank < 0.001). When considering the prognostic power of Weiss parameters, necrosis alone could independently assess OS (log-rank = 0.004) and DFS (log-rank < 0.001) at both the Kaplan–Meier and multivariate Cox regression analyses [hazard ratio (HR) = 7.8, 95% confidence interval [CI] = 1.0–63.5, p = 0.05, and HR = 12.2, 95% CI = 1.6–95.0, p = 0.017, respectively]. The presence of necrosis significantly shortened time to survival (TtS) and time to recurrence (TtR), 57.5 [31.5–103.5] vs 34 [12–78] months (p = 0.05) and 57.5 [31.5–103.5] vs 7 [1.0–31.5] months (p < 0.001), respectively. Our study suggests that, of the Weiss parameters, necrosis is the most powerful adverse factor and the best predictor of OS and DFS in ACC patients.
... The microscopic Weiss criteria is the best validated approach to differentiate between benign and malignant adrenal tumors. The 5 criteria used in updated Weiss system include (1) number of mitoses per 50 high-power field, (2) percentage of clear cells, (3) abnormal mitoses, (4) necrosis, and (5) capsular invasion [9]. A total score of ≥3 supports malignancy. ...
We report a case of a 58-year-old woman with a history of hypertension diagnosed at aged 35 years, on 5 antihypertensive agents and a history of intermittent spontaneous hypokalemia, was found to have a 6-cm left adrenal mass on computed tomography scan of the abdomen. The unenhanced computed tomography attenuation of the adrenal mass was −16 Hounsfield units (HU). The biochemical evaluation showed potassium of 2.8 mEq/L (SI unit, mmol/L) (reference range, 3.5-5.0), plasma aldosterone concentration of 61.3 ng/dL (SI unit, 1701 pmol/L) with plasma renin activity of 0.4 ng/mL/h (SI unit, μg/L/h). An overnight 1-mg dexamethasone suppression test showed nonsuppressible serum cortisol of 10.8 μg/dL (SI unit, 298 nmol/L). Dehydroepiandrosterone sulfate and ACTH were measured at 24.5 μg/dL (age-adjusted, 26-200) (SI unit, 0.66 μmol/L; 0.70-5.43) and <5 pg/mL (SI unit, < 1.1 pmol/L), respectively. Left adrenalectomy was performed and hydrocortisone therapy was initiated. Postoperatively and thereafter, her blood pressure was controlled with no antihypertensive agent. Seven months later, hydrocortisone therapy was stopped once her cortisol level had normalized. Pathology showed adrenal cortical neoplasm of uncertain malignant potential with associated lipomatous and myelolipomatous metaplasia. This is a rare case of aldosterone and cortisol co-secreting adrenal cortical neoplasm of uncertain malignant potential with lipomatous and myelolipomatous metaplasia. Although the majority of cases of myelolipoma are benign and nonfunctioning, this case emphasizes the importance of thorough hormonal and morphologic evaluation of the tumor.
... An examination was performed on multiple frozen sections. Weiss histological criteria [2] were applied: diffuse architecture greater than 1/3 of the lesion: no; clear cell tumour component ≤ to 25%: no; nuclear G3/G4 (Fuhrman's grading): yes; mitotic count >5/50 high power field (HPF): yes (7 mitoses/50 HPF), (fig. 2); atypical mitotic figures: yes; necrosis: yes; venous inva-sion: no; sinusoidal invasion: no; capsular invasion: yes. ...
... 37,73 They usually occur before 5 years of age and show a remarkably increased frequency in the Brazilian population, as the incidence is almost 15 times higher than that of the United States and Europe. 56,[74][75][76] In children, ACC is often part of genetic syndromes [eg, Li-Fraumeni syndrome (LFS)] and most cases are hormonally active, presenting with increased secretion of androgens (virilization; up to 80% of cases), glucocorticoids (Cushing syndrome; 14%), estrogens (feminization and gynecomastia; 7%), and aldosterone (hypertension, hypokalemia; 1% to 4%). 26 The histopathologic distinction between benign and malignant lesions in the pediatric population is even more challenging than in the adult setting, considering that many more cases share misleading features and discordant clinicpathologic correlations. This discrepancy is particularly evident when applying the Weiss system, thus leading, in 2003, to the development of a scoring system tailored for the pediatric population, the Wieneke index. ...
Adrenal cortical carcinoma (ACC) is a rare and aggressive malignancy that poses challenging issues regarding the diagnostic workup. Indeed, no presurgical technique or clinical parameters can reliably distinguish between adrenal cortical adenomas, which are more frequent and have a favorable outcome, and ACC, and the final diagnosis largely relies on histopathologic analysis of the surgical specimen. However, even the pathologic assessment of malignancy in an adrenal cortical lesion is not straightforward and requires a combined evaluation of multiple histopathologic features. Starting from the Weiss score, which was developed in 1984, several histopathologic scoring systems have been designed to tackle the difficulties of ACC diagnosis. Dealing with specific histopathologic variants (eg, Liss-Weiss-Bisceglia scoring system for oncocytic ACC) or patient characteristics (eg, Wieneke index in the pediatric setting), these scores remarkably improved the diagnostic workup of ACC and its subtypes. Nevertheless, cases with misleading features or discordant correlations between pathologic findings and clinical behavior still occur. Owing to multicentric collaborative studies integrating morphologic features with ancillary immunohistochemical markers and molecular analysis, ACC has eventually emerged as a multifaceted, heterogenous malignancy, and, while innovative and promising approaches are currently being tested, the future clinical management of patients with ACC will mainly rely on personalized medicine and target-therapy protocols. At the dawn of the new Fifth World Health Organization classification of endocrine tumors, this review will tackle ACC from the pathologist's perspective, thus focusing on the main available diagnostic, prognostic, and predictive tissue-tethered features and biomarkers and providing relevant clinical and molecular correlates.
... 14 The modified Weiss criteria are a well-established technique for ACC diagnosis. 14,15 Age at diagnosis is a significant prognostic factor, with children under the age of two years having a favorable result. Children above the age of two are said to have a survival rate of only 29%, 16 However, our case is 6 years old, and she is alive and well 1 year after the operation. ...
Adrenocortical cancers in childhood are very rare tumors. They are categorized as functional (hormone-secreting) or silent and as either benign or malignant. They have a bimodal distribution. Although in most adults they are non-functional, in the pediatric age group they may present as hormonal active or as an active tumor presenting with either virilizing forms or Cushing’s syndrome or both sometimes. In children, due to the rapid development of symptoms, they come to attention early. However, if not diagnosed and treated early, they can develop into serious medical conditions. We present here a 6-year-old girl complaining of voice changes (deepening), extremely overweight, excessive hair growth over her body, and clitoromegaly for one year. Abdominal ultrasound and computed tomography revealed a well-defined adrenal mass with a slightly heterogeneous appearance and heterogeneous-contrast enhancement containing some necrotic areas. The patient was discharged one week after unilateral right adrenalectomy in good condition, and oral medications were given along with high-dose corticosteroid medications, which were reduced gradually. All the symptoms disappeared 6 months after the operation.
... In contrast to adrenocortical adenomas (ACAs), adrenocortical carcinomas (ACCs) are rare and usually very aggressive tumors. The differential diagnosis between ACC and ACA, despite being driven by a few clinical and imaging characteristics, relies mainly on the histopathologic criteria that comprise the Weiss system and Ki-67 expression [3]. However, tumor morphological features are poorly specific, and there can be considerable overlap between ACA and ACC that contribute to diagnostic inaccuracy. ...
The differential diagnosis between adrenocortical adenomas (ACAs) and adrenocortical carcinomas (ACCs) relies on unspecific clinical, imaging and histological features, and, so far, no single molecular biomarker has proved to improve diagnostic accuracy. Similarly, prognostic factors have an insufficient capacity to predict the heterogeneity of ACC clinical outcomes, which consequently lead to inadequate treatment strategies. Angiogenesis is a biological process regulated by multiple signaling pathways, including VEGF and the Ang–Tie pathway. Many studies have stressed the importance of angiogenesis in cancer development and metastasis. In the present study, we evaluated the expression of VEGF and Ang–Tie pathway mediators in adrenocortical tumors (ACTs), with the ultimate goal of assessing whether these molecules could be useful biomarkers to improve diagnostic accuracy and/or prognosis prediction in ACC. The expression of the proteins involved in angiogenesis, namely CD34, VEGF, VEGF-R2, Ang1, Ang2, Tie1 and Tie2, was assessed by immunohistochemistry in ACC (n = 22), ACA with Cushing syndrome (n = 8) and non-functioning ACA (n = 13). ACC presented a significantly higher Ang1 and Ang2 expression when compared to ACA. Tie1 expression was higher in ACC with venous invasion and in patients with shorter overall survival. In conclusion, although none of these biomarkers showed to be useful for ACT diagnosis, the Ang–Tie pathway is active in ACT and may play a role in regulating ACT angiogenesis.
... Using several pathologic features, the Weiss system can sensitively and specifically identify malignant adrenal neoplasms. [13][14][15] However, unlike conventional adrenocortical tumors, adrenocortical oncocytic neoplasms are characterized by a low proportion of clear cells, diffuse tumor architecture, and high nuclear grade; thus, the application of Weiss criteria tends to classify these tumors as malignant adrenocortical carcinomas. 3,10 For adrenocortical oncocytic neoplasms, the Lin-Weiss-Bisceglia criteria are used instead. ...
Background: Adrenal masses are common incidental findings, most of which are benign and non-functional. Malignant adrenal tumors, however, differ from their benign counterpart and confer poor prognosis. In addition, the oncocytic variants of these tumors present challenges to clinicians owing to their unique biologic behavior and rarity.
Case presentation: We present a case report of a 61-year-old male with a T2N0M0 adrenocortical oncocytic neoplasm of the right adrenal gland. The patient complained of worsening right upper quadrant abdominal pain and was diagnosed with a right adrenal mass after an abdominal CT-scan examination two weeks before. Subsequently, the patient underwent open adrenalectomy due to a history of abdominal surgery. Due to unique oncocytic biologic behavior, we used the Lin–Weiss–Bisceglia criteria to predict a malignancy instead of the Weiss system. We only found one malignant criterion, which showed a small tumor invasion on the vascular bed on one histopathological section. Thus, we diagnosed it as malignant adrenocortical oncocytic neoplasm. Furthermore, the PET Scan showed no residual mass or pathological metabolic activity on the tumor bed and metastatic sign.
Conclusions: The diagnosis of the malignant oncocytic adrenal case is based on the histopathological criteria. Based on this case, we suggest a thorough histopathological examination to determine malignant criteria in adrenal neoplasm cases.
... 8 Based on the Lin-Weiss-Bisceglia criteria, they may be classified as benign, with undetermined malignant potential, or malignant. 9 We present a case of OAN with undetermined malignant potential in a patient with autonomous cortisol secretion. ...
Increasing incidence of adrenal incidentalomas with hypercortisolemia not associated with overt features of Cushing's syndrome has led to the evolution of the term autonomous cortisol secretion. Oncocytic adrenocortical neoplasms (OANs) are rare adrenal cortex neoplasms with only 250 reported cases worldwide. We present a woman in her 30s with menometrorrhagia, weight gain and increasing abdominal girth who was found to have a large right adrenal mass on abdominal CT scan. Serum cortisol was not suppressed after 1 mg dexamethasone (31.5 µg/dL) and adrenocorticotrophic hormone was not detectable (<1.0 pg/mL). She underwent right adrenalectomy under glucocorticoid coverage. Hypertension, weight, visceral adiposity and menometrorrhagia improved postoperatively. Histopathology with immunohistochemistry showed OAN with undetermined malignant potential. These kinds of tumours can only be definitively diagnosed postsurgically using the Lin-Weiss-Bisceglia system. Although they have better prognosis compared with adrenocortical carcinomas and do not require chemotherapy, patients should be closely monitored to identify recurrence promptly.
... Adrenal malignancies are generally large and very few are small. Some pathologists also report that size is the most important criterion for the differential diagnosis of benign or malignant adrenal masses (9). Based on these results and the lack of biochemical and imaging methods to make benign/malignant separation definitively in adrenal tumor, they recommend surgical excision in all nonfunctioning adrenal incidentalomas, taking into account that they encounter a high level of malignity (10). ...
Purpose: Laparoscopic adrenalectomy, which was performed successfully for the first time in 1992, has become the preferred method in adrenal surgery especially in adrenal diseases. In this study, our aim is to compare the demographic and operative data of laparoscopic and open adrenalectomies performed in the general surgery clinic of our hospital. Methods: The records of the patients who were operated in hospital due to a surrenal mass between August 2006 and December 2012 have been retrospectively assessed. Demographic characteristics of the patients, such as age, sex, the size and location of tumors were included. Surgical indications were classified in terms of their radiologic and biochemical investigations. Type of the surgery (lateral transperitoneal laparoscopic or open approach), the incision used in these surgeries (midline, subcoastal and paramedian), the length of operation, the length of hospital stay, postoperative complications and the final pathology results were all examined. Results: During the afformentioned period, adrenalectomy was performed in 106 patients. Eighty of these patients (%75,4) were operated by open and 26 of them (%24,6) by lateral transperitoneal laparoscopic surgery. Subcostal incision was used 61 of 80 patients (% 82,4), whereas 17 patients (% 22,9) were operated by midline incision and 2(% 2,7) were by paramedian incision. No mortality was encountered. Operation time was statistically significantly shorter in the open group (p<0,0166). Duration of hospital stay was statistically significantly longer in open group (p<0,0083). Hospital stay time was statistically significantly longer in midline incision group (p<0,0083). Except for the weight of masses, statistically significant difference was not found between two groups (laparascopic and open surgery) in demographic and operative features (age,gender,side,pathological diagnose,size of mass) releated to postoperative complications. Conclusion: In carefully selected group of patients laparoscopic adrenalectomy offered lesser postoperative hospital stay than the open adrenalectomy. The longer operative time can be decreased when more experience is gained in laparascopic adrenalectomy. Laparoscopic adrenalectomy should be preferred in adrenal disease as the gold standard in centers with completed learning curve.
... The histologic diagnosis of ACC was performed by the referent pathologist (G.N.) on the tumor tissue removed at the surgery. The tumor specimens were evaluated according to the Weiss System, where the presence of three or more criteria correlates highly with malignant behavior [37]. ...
Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis when metastatic and scarce treatment options in the advanced stages. In solid tumors, the chemokine CXCL12/CXCR4 axis is involved in the metastatic process. We demonstrated that the human adrenocortex expressed CXCL12 and its cognate receptors CXCR4 and CXCR7, not only in physiological conditions, but also in ACC, where the receptors’ expression was higher and the CXCL12 expression was lower than in the physiological conditions. In a small pilot cohort of 22 ACC patients, CXCL12 negatively correlated with tumor size, stage, Weiss score, necrosis, and mitotic activity. In a Kaplan–Meier analysis, the CXCL12 tumor expression significantly predicted disease-free, progression-free, and overall survival. In vitro treatment of the primary ACC H295R and of the metastatic MUC-1 cell line with the PPARγ-ligand rosiglitazone (RGZ) dose-dependently reduced proliferation, resulting in a significant increase in CXCL12 and a decrease in its receptors in the H295R cells only, with no effect on the MUC-1 levels. In ACC mouse xenografts, tumor growth was inhibited by the RGZ treatment before tumor development (prevention-setting) and once the tumor had grown (therapeutic-setting), similarly to mitotane (MTT). This inhibition was associated with a significant suppression of the tumor CXCR4/CXCR7 and the stimulation of human CXCL12 expression. Tumor growth correlated inversely with CXCL12 and positively with CXCR4 expression, suggesting that local CXCL12 may impair the primary tumor cell response to the ligand gradient that may contribute to driving the tumor progression. These findings indicate that CXCL12/CXCR4 may constitute a potential target for anti-cancer agents such as rosiglitazone in the treatment of ACC.
... Therefore, it is no surprise that pediatric adrenal cortical neoplasms appear to behave differently than histologically similar tumors in the adult population. Pathological criteria for malignancy in the adult population are well-established and routinely employed in clinical practice [113,114]. In contrast, definitive pathological criteria for malignancy in pediatric adrenal cortical neoplasms remain uncertain and are still subject to ongoing discussions. ...
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.
... Adrenocortical carcinomas were diagnosed using modified Weiss criteria and some of the features of malignant tumors are illustrated in Fig. 1. In addition, the Lin-Weiss-Bisceglia system was used for oncocytic adrenocortical tumors [14][15][16][17][18]. Tumors with a score of 3 under the Weiss system, and those fulfilling 1 to 4 minor criteria under the Lin-Weiss-Bisceglia system were classified as "borderline" in this study. ...
Molecular characterization of adrenocortical carcinomas (ACC) by The Cancer Genome Atlas (TCGA) has highlighted a high prevalence of TERT alterations, which are associated with disease progression. Herein, 78 ACC were profiled using a combination of next generation sequencing ( n = 76) and FISH ( n = 9) to assess for TERT alterations. This data was combined with TCGA dataset ( n = 91). A subset of borderline adrenocortical tumors ( n = 5) and adrenocortical adenomas ( n = 7) were also evaluated. The most common alteration involving the TERT gene involved gains/amplifications, seen in 22.2% (37/167) of cases. In contrast, “hotspot” promoter mutations (C > T promoter mutation at position -124, 7/167 cases, 4.2%) and promoter rearrangements (2/165, 1.2%) were rare. Recurrent co-alterations included 22q copy number losses seen in 24% (9/38) of cases. Although no significant differences were identified in cases with and without TERT alterations pertaining to age at presentation, tumor size, weight, laterality, mitotic index and Ki67 labeling, cases with TERT alterations showed worse outcomes. Metastatic behavior was seen in 70% (28/40) of cases with TERT alterations compared to 51.2% (65/127, p = 0.04) of cases that lacked these alterations. Two (of 5) borderline tumors showed amplifications and no TERT alterations were identified in 7 adenomas. In the borderline group, 0 (of 4) patients with available follow up had adverse outcomes. We found that TERT alterations in ACC predominantly involve gene amplifications, with a smaller subset harboring “hotspot” promoter mutations and rearrangements, and 70% of TERT -altered tumors are associated with metastases. Prospective studies are needed to validate the prognostic impact of these findings.
... Adrenal malignancies are generally large and very few are small. Some pathologists also report that size is the most important criterion for the differential diagnosis of benign or malignant adrenal masses (9). Based on these results and the lack of biochemical and imaging methods to make benign/malignant separation definitively in adrenal tumor, they recommend surgical excision in all nonfunctioning adrenal incidentalomas, taking into account that they encounter a high level of malignity (10). ...
... adrenal tumor (Ki67 proliferation index, overexpression of TP53, IGF-2, and cyclin E) however, they are not sufficiently discriminatory. (31,32). ...
Introduction: Functional adrenocortical carcinoma is very uncommon. Aldosterone producing adrenocortical carcinoma (APAC) is rare malignancy with incidence of less than 10% among adrenal tumor. The diagnosis of APAC is done based on clinical findings, radiological features, and hormonal assay. Most of the cases of APAC were in isolated case reports since 1955. Due to the rarity of the disease the clinicopathological details is less known. The impact of the functional varieties of the adrenal malignancy on disease prognosis is less explored. We present here a case report of an APAC surgically managed in our institution and review of the published data on APAC. Methods: A case history, clinical and treatment details of an APAC in 40 years gentleman is presented. Online search of the literature on APAC was done and details were extracted to construct database for statistical analysis. The summary measures were done in mean, median, or range after testing for normality. Kaplan Meier analysis and Cox regression proportional hazard analysis were done to evaluate the survival and the survival covariates respectively. Abstract-Introduction: Functional adrenocortical carcinoma is very uncommon. Aldosterone producing adrenocortical carcinoma (APAC) is rare malignancy with incidence of less than 10% among adrenal tumor. The diagnosis of APAC is done based on clinical findings, radiological features, and hormonal assay. Most of the cases of APAC were in isolated case reports since 1955. Due to the rarity of the disease the clinicopathological details is less known. The impact of the functional varieties of the adrenal malignancy on disease prognosis is less explored. We present here a case report of an APAC surgically managed in our institution and review of the published data on APAC. Methods: A case history, clinical and treatment details of an APAC in 40 years gentleman is presented. Online search of the literature on APAC was done and details were extracted to construct database for statistical analysis. The summary measures were done in mean, median, or range after testing for normality. Kaplan Meier analysis and Cox regression proportional hazard analysis were done to evaluate the survival and the survival covariates respectively. mean age of the study population was 45.7±15 years. APAC is more common in female than male gender. Muscle weakness, headache, and hypertension were the common clinical features. Hypokalemia (mean-2.3±0.5 meq/l), high plasma aldosterone level (median 45 ng/dl), Low plasma renin activity (median-0.25 ng/ml/hr) were the biochemical abnormalities observed in the study cases. Majority of the disease were in stage II (38.7%) at presentation, followed by stage I (21.5%). The median disease free survival was 25 months and overall survival was 36 months. Age at Conclusion: Aldosterone producing adrenocortical carcinoma is one of the rare types of functional adrenal malignancy. Any suspected case should undergo thorough clinical, radiological and biochemical evaluation. Surgery is the mainstay treatment and adjuvant therapy has no conclusive role in disease free survival. A large cases series and multicenter study could further add scientific evidence for management of the APAC.
... Although several different scoring systems have been proposed to assess the malignant potential in adrenocortical neoplasms, the Weiss score remains the most utilized tool in distinguishing benign from malignant adrenocortical neoplasms [3]. This score counts nine histopathologic criteria: eosinophilic ("dark") cytoplasm in more than 75% of tumor cells, a "patternless" diffuse architecture, necrosis, nuclear atypia, mitotic index above 5 per 50 high-power fields, atypical mitoses, sinusoidal, venous, and capsular invasion [4]. An adrenocortical neoplasm is classified as malignant when it meets three or more of these criteria [5]. ...
Adrenal cortical carcinoma (ACC) is a rare cancer with poor prognosis that needs to be distinguished from adrenocortical adenomas (ACAs). Although, the recently developed transcriptome analysis seems to be a reliable tool for the differential diagnosis of adrenocortical neoplasms, it is not widely available in clinical practice. We aim to evaluate histological and immunohistochemical markers for the distinction of ACCs from ACAs along with assessing their prognostic role. Clinical data were retrospectively analyzed from 37 patients; 24 archived, formalin-fixed, and paraffin-embedded ACC samples underwent histochemical analysis of reticulin and immunohistochemical analysis of p27, p53, Ki-67 markers and were compared with 13 ACA samples. Weiss and Helsinki scores were also considered. Kaplan−Meier and univariate Cox regression methods were implemented to identify prognostic effects. Altered reticulin pattern, Ki-67% labelling index and overexpression of p53 protein were found to be useful histopathological markers for distinguishing ACAs from ACCs. Among the studied markers, only pathological p53 nuclear protein expression was found to reach statistically significant association with poor survival and development of metastases, although in a small series of patients. In conclusion, altered reticulin pattern and p53/Ki-67 expression are useful markers for distinguishing ACCs from ACAs. Immunohistopathology alone cannot discriminate ACCs with different prognosis and it should be combined with morphological criteria and transcriptome analysis.
... Histologic diagnosis was performed by the reference pathologist on tumor tissue removed at surgery (n = 18). Tumor specimens were evaluated according to the Weiss score system in which the presence of three or more criteria highly correlates with malignant behavior [30,31]. The Ki67 labelling index (Ki67) was evaluated as a proliferation marker to assess ACC prognosis using the anti-human Ki67 antibody (1:40 dilution, clone name MIB-1, Dako, Carpenteria, CA, USA). ...
Adrenocortical carcinoma (ACC), a rare and aggressive neoplasia, presents poor prognosis when metastatic at diagnosis and limited therapies are available. Specific and sensitive markers for early diagnosis and a monitoring system of therapy and tumor evolution are urgently needed. The liquid biopsy represents a source of tumor material within a minimally invasive blood draw that allows the recovery of circulating tumor cells (CTCs). CTCs have been recently shown to be detectable in ACC. In the present paper, we evaluated the prognostic value of CTCs obtained by size-filtration in a small pilot cohort of 19 ACC patients. We found CTCs in 68% of pre-surgery and in 38% of post-surgery blood samples. In addition, CTC clusters (CTMs) and cancer associated macrophages (CAMLs) were detectable in some ACC patients. The median number of CTCs significantly decreased after the mass removal. Finally, stratifying patients in high and low pre-surgery CTC number groups, assuming the 75th percentile CTC value as cut-off, CTCs significantly predicted patients’ overall survival (log rank = 0.005), also in a multivariate analysis adjusted for age and tumor stage. In conclusion, though preliminary and performed in a small cohort of patients, our study suggests that CTC number may represent a promising marker for prognosis and disease monitoring in ACC.
... Tumor weight should be determined after other organs are removed and adipose tissue is trimmed as much as possible without affecting the histological assessment of invasive growth. (13,14). Furthermore, knowledge of the morphological type can assist with future diagnostic assessments if there is recurrence. ...
Complete resection of adrenal cortical carcinoma (ACC) with or without adjuvant therapy offers the best outcome. Recurrence is common and in individual cases the long term outcome is difficult to predict, making it challenging to personalize treatment options. Current risk stratification approaches are based on clinical and conventional surgical pathology assessment. Rigorous and uniform pathological assessment may improve care for individual patients and facilitate multi-institutional collaborative studies.
The International Collaboration on Cancer Reporting (ICCR) convened an expert panel to review ACC pathology reporting. Consensus recommendations were made based on the most recent literature and expert opinion. The data set comprises 23 core (required) items. The core pathological features include: diagnosis according to the current World Health Organization (WHO) classification, specimen integrity, greatest dimension, weight, extent of invasion, architecture, percentage of lipid rich cells, capsular invasion, lymphatic invasion, vascular invasion, atypical mitotic figures, coagulative necrosis, nuclear grade, mitotic count, Ki-67 proliferative index, margin status, lymph node status and pathological stage. Tumors were dichotomized into low grade (<20 mitoses per 10 mm²) and high grade (>20 mitoses per 10 mm²). Additional noncore elements that may be useful in individual cases included several multifactorial risk assessment systems (Weiss, modified Weiss, Lin-Weiss-Bisceglia, reticulin, Helsinki, and AFIP scores/algorithms).
This data set is now available through the ICCR website with the hope of better standardizing pathological assessment of these relatively rare but important malignancies.
... Таким образом, в дальнейшем при выявлении у аденомы с низким содержанием жира атипичных КТ-признаков, например, неоднородности контрастирования, целесообразно включать онкоцитарную опухоль в дифференциальную диагностику. Окончательный диагноз основывается на гистологическом и иммуногистохимическом анализе послеоперационного материала, однако существуют трудности морфологической диагностики, так как классификация Weiss не применима в случае адренокортикальных онкоцитом [27]. В связи с этим в 2004 г. была разработана модифицированная система Lin-Weiss-Bisceglia (LWB) для оценки степени злокачественности адренокортикальных онкоцитом, которая включила: (1) большие критерии: частота митозов >5 на 50 полей, любые нетипичные митозы или венозная инвазия; (2) малые критерии [большой размер (>10 см и/или вес >200 г), некроз, инвазия капсулы или синусов]; (3) морфологические критерии онкоцитарных клеток (преимущественно клетки с эозинофильно-гранулярной цитоплазмой, высоким ядерно-цитоплазматическим соотношением и диффузным архитектурным рисунком) [28]. ...
Cushings syndrome accounts for approximately 2030% of endogenous hypercortisolism cases, and adrenal involvement can be either unilateral or bilateral. Cushings syndrome due to bilateral adrenal tumors is extremely rare. Adrenal oncocytomas are another rare cause of endogenous hypercortisolism: about 13 cases are described in the literature. Oncocytomas are rare epithelial neoplasms, characterized by abnormally excessive accumulation of defective mitochondria in the cytoplasm of cells, and make up 1.8% of all adrenal neoplasms. We describe a 58-year old patient with Cushings syndrome and bilateral adrenal tumors. Multispiral computed tomography of the adrenals showed signs suspicious of lipid-poor atypical adenomas or malignant tumors. Surgical treatment was the method of choice, and the larger tumor was excised first. Due to the absence of remission of endogenous hypercortisolism the excision of the second tumor was performed. Morphological and immunohistochemical examination confirmed the diagnosis of bilateral oncocytic adrenocortical tumors with uncertain malignant potential. Cases of bilateral hormone-producing adrenal oncocytomas have not been described in the literature.
... Some clinical variables show prognostic potential: the Weiss score is the internationally acknowledged pathologic scoring system to differentiate between malignant and benign tumors. The Weiss score is a nine-point scoring system, in which a score of three or higher corresponds to a high probability of malignancy [3,4]. A Weiss score greater than six has been found to correspond to poor prognosis [5]. ...
Adrenocortical carcinoma (ACC) has an incidence of about 1.0 per million per year. In general, survival of patients with ACC is limited. Predicting survival outcome at time of diagnosis is a clinical challenge. The aim of this study was to develop and internally validate a clinical prediction model for ACC-specific mortality. Data for this retrospective cohort study were obtained from the nine centers of the Dutch Adrenal Network (DAN). Patients who presented with ACC between 1 January 2004 and 31 October 2013 were included. We used multivariable Cox proportional hazards regression to compute the coefficients for the prediction model. Backward stepwise elimination was performed to derive a more parsimonious model. The performance of the initial prediction model was quantified by measures of model fit, discriminative ability, and calibration. We undertook an internal validation step to counteract the possible overfitting of our model. A total of 160 patients were included in the cohort. The median survival time was 35 months, and interquartile range (IQR) 50.7 months. The multivariable modeling yielded a prediction model that included age, modified European Network for the Study of Adrenal Tumors (mENSAT) stage, and radical resection. The c-statistic was 0.77 (95% Confidence Interval: 0.72, 0.81), indicating good predictive performance. We developed a clinical prediction model for ACC-specific mortality. ACC mortality can be estimated using a relatively simple clinical prediction model with good discriminative ability and calibration.
... The reference standard of this study was the formal pathologic report regarding the adrenalectomy specimens. The pheochromocytoma of the adrenal gland scaled score and modified Weiss system were used for pathologic diagnosis [18,19]. ...
Purpose:
To investigate the performance of modified criteria to distinguish pheochromocytoma from adrenal adenoma by using adrenal protocol computed tomography (CT).
Methods:
We retrospectively included consecutive 199 patients who underwent adrenal CT and surgically proven pheochromocytoma (n = 66) or adenoma (n = 133). Two independent radiologists analyzed two CT criteria for pheochromocytoma. Conventional criteria were as follows: (a) lesion attenuation on unenhanced CT > 10 Hounsfield unit (HU); (b) absolute percentage washout < 60%; and (c) relative percentage washout < 40%. Modified criteria were as follows: (a) conventional criteria or (b) one of the following findings: (i) lesion attenuation on unenhanced CT ≥ 40 HU, (ii) 1-min enhanced CT ≥ 160 HU, (iii) 15-min enhanced CT ≥ 70 HU, , or (iv) intralesional cystic degeneration seen on both 1-min and 15-min enhanced CT. We analyzed area under the curve (AUC) and inter-reader agreement.
Results:
Proportion of pheochromocytoma was 33.2% (66/199). AUC of modified criteria was consistently higher than that of conventional criteria for distinguishing pheochromocytoma from adenoma (reader 1, 0.864 versus 0.746 for raw data set and 0.865 versus 0.746 for internal validation set; reader 2, 0.872 versus 0.758 for raw data set and 0.872 versus 0.757 for internal validation set) (p < 0.05 for all comparisons). Inter-reader agreement was excellent in interpreting any criteria (weighted kappa > 0.800).
Conclusion:
Our modified criteria seem to improve diagnostic performance of adrenal CT in distinguishing pheochromocytoma from adrenal adenoma.
... The diagnosis of ACC was based on the Weiss scoring system, and a score of >3 was considered malignant. [7] For tumor staging, the European Network for the Study of Adrenal Tumors (ENSAT) system was used. The following baseline hormonal evaluations were performed in the patients as per the ENSAT recommendations and institution's practice: fasting blood glucose, serum potassium, cortisol, corticotropin (ACTH), 24-h urinary free cortisol, fasting serum cortisol at 8 AM, adrenal androgens (dehydroepiandrosterone sulfate and testosterone), and serum estradiol in men and postmenopausal women. ...
... Modified Weiss criteria is an established method for the diagnosis of ACC. [22,23] Out of nine histological criteria, three findings are required to make the diagnosis of ACC [21] and our case fulfilled five Weiss criteria. The morphology was characteristic of ACC. ...
Context: Adrenal tumors can arise either from cortex or from medulla; both the regions being structurally and functionally different. Current knowledge on childhood adrenocortical tumors (ACTs), the management approach, and the outcome is limited due to limited number of cases and studies. Neuroblastoma is a neoplasm of the neural crest origin and 50% arise from adrenal medulla. Pheochromocytoma (PCC) is an exciting and rare neoplasm in childhood. Aims: To evaluate the clinical presentation, spectrum of pathology, and management of adrenal tumors in children. Subjects and Methods: The study was conducted in a tertiary care pediatric institute over 5 years on children with intra-abdominal solid tumors. Adrenal tumors were diagnosed on radiological studies and postoperatively confirmed by histopathology. Results: Sixty-three patients were operated for intra-abdominal solid tumors, and Wilms tumor (39) was the most common finding. Of 11 cases of adrenal tumors confirmed by histopathology, eight were adrenal neuroblastoma, one 14-month-old female baby was detected as PCC, while two female children presented with the features of Cushing syndrome and virilization at the age of 3 and 7 years. Postoperatively, one of them was found to be adrenal adenoma and one was found to be adrenocortical carcinoma. Conclusions: ACTs are rare and potentially fatal in childhood. Complete surgical resection is the mainstay of therapy in adrenal tumors and is curative for associated hypertension. Neuroblastoma was the third common intra-abdominal solid tumor after Wilms tumor and retroperitoneal teratoma. The patient with PCC contributed to “Rule of 10s” because of the absence of hypertension and childhood occurrence.
Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy with limited treatment options and poor prognosis, with a 5-year survival rate of about 15 %. This study used whole genome sequencing to characterize the genomic landscape of five patients, one of them with both primary and metastatic samples. Key driver mutations were detected, including APC, JAK1, RFWD3 as well as other genes. Notably, a primary tumor harbored a RAD51 biallelic deleterious translocation, associated with homologous recombination deficiency signature. Large-scale copy neutral loss of heterozygosity (LOH) was identified in four tumors, three had TP53 mutations, with structural variants impacting genes as RB1, CDKN2A, and NF1. A genomic signature specific to mismatch repair was observed in a sample with MHS6 mutation. Two tumors presented novel fusions at TERT locus, including TERT::ZNF521. Comparative analysis between conventional and oncocytic ACC subtypes revealed no significant differences in mutation load, microsatellite instability, or specific gene enrichment. This comprehensive WGS analysis broadens the spectrum of genomic alterations in ACC, highlighting potential
molecular targets and differences across subtypes that may Inform future therapeutic strategies.
Objective
Adrenal cortical carcinoma (ACC) is a rare malignancy with a generally poor but heterogeneous prognosis, especially depending on the tumour stage at diagnosis. Identification of somatic gene alterations combined with clinical/histopathological evaluation of the tumour can help improve prognostication. We applied a simplified targeted-NGS panel to characterise the mutational profiles of ACCs, providing potentially relevant information for better patient management.
Design and Methods
Thirty frozen tumour specimens from a local ACC series were retrospectively analysed by a custom-NGS panel (CDKN2A, CTNNB1, DAXX, MED12, NF1, PRKAR1A, RB1, TERT, TP53, ZNRF3) to detect somatic prioritized single-nucleotide variants. This cohort was integrated with 86 patients from the ACC-TCGA series bearing point-mutations in the same genes and their combinations identified by our panel. Primary endpoints of the analysis on the total cohort (113 patients) were overall (OS) and progression-free (PFS) survival, and hazard-ratio (HR) for the different alterations grouped by the signalling pathways/combinations affected.
Results
Different PFS, OS and HR were associated to the different pathways/combinations, being NF1 + TP53 and Wnt/β-catenin + Rb/p53 combined mutations the most deleterious, with a statistical significance for progression HR which is retained only in low-(I/II) stages - NF1+TP53 combination: HR = 2.96[1.01-8.69] and HR = 13.23[3.15-55.61], all and low stages, respectively; Wnt/β-catenin + Rb/p53 combined pathways: HR = 6.47[2.54-16.49] and HR = 16.24[3.87-68.00], all and low-stages, respectively.
Conclusions
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.
Determination of body composition (the relative distribution of fat, muscle, and bone) has been used effectively to assess the risk of progression and overall clinical outcomes in different malignancies. Sarcopenia (loss of muscle mass) is especially associated with poor clinical outcomes in cancer. However, estimation of muscle mass through CT scan has been a cumbersome, manually intensive process requiring accurate contouring through dedicated personnel hours. Recently, fully automated technologies that can determine body composition in minutes have been developed and shown to be highly accurate in determining muscle, bone, and fat mass. We employed a fully automated technology, and analyzed images from a publicly available cancer imaging archive dataset (TCIA) and a tertiary academic center. The results show that adrenocortical carcinomas (ACC) have relatively sarcopenia compared to benign adrenal lesions. In addition, functional ACCs have accelerated sarcopenia compared to non-functional ACCs. Further longitudinal research might shed further light on the relationship between body component distribution and ACC prognosis, which will help us incorporate more nutritional strategies in cancer therapy.
Adrenocortical epithelial neoplasms represent a diverse spectrum of tumors originating in the adrenal cortex, such as adrenal cortical carcinomas (ACCs) and adrenal cortical adenomas (ACAs), which are rare but clinically significant tumors. The aim of this article is to report the clinical case of a 29-year-old patient who was affected by an adrenocortical epithelial neoplasm with intense cellular pleomorphism. Surgical treatment was performed urgently to resolve the initial condition, and the diagnosis was aided by imaging and anatomopathological methods.
Objectives:
To investigate performance of adrenal computed tomography (CT)-derived multivariate prediction models in differentiating adenomas with cortisol hypersecretion from the other subtypes.
Methods:
This retrospective study included 127 patients who underwent adrenal CT and had a surgically proven adrenal adenoma. Adenoma subtypes were defined according to biochemical test results: group A, overt cortisol hypersecretion; group B, mild cortisol hypersecretion; group C, aldosterone hypersecretion; and group D, non-function. Two independent readers analyzed size, attenuation, and washout properties of adenomas, and performed quantitative and qualitative analyses for assessing contralateral adrenal atrophy. Actual and internally validated areas under the curves (AUCs) of adrenal CT-derived multivariate prediction models for differentiating adenomas with cortisol hypersecretion from the other subtypes were assessed.
Results:
In differentiating group A from the other groups, the actual and internally validated AUCs of the prediction model were 0.856 (95% confidence interval [CI]: 0.786, 0.926) and 0.853 (95% CI: 0.702, 1.000) for reader 1, respectively, and 0.901 (95% CI: 0.845, 0.956) and 0.900 (95% CI: 0.787, 1.000) for reader 2, respectively. In differentiating group B from group C and D, the actual and internally validated AUCs of the prediction model were 0.777 (95% CI: 0.687, 0.866) and 0.760 (95% CI: 0.522, 0.969) for reader 1, respectively, and 0.783 (95% CI: 0.690, 0.875) and 0.765 (95% CI: 0.553, 0.977) for reader 2, respectively.
Conclusions:
Adrenal CT may be useful in differentiating adenomas with cortisol hypersecretion from the other subtypes.
Advances in knowledge:
Adrenal CT may benefit in adrenal adenoma subtyping.
We explored the application of TFE3 immunostaining and TFE3 mRNA expression in the differential diagnosis and prognostication of adrenal cortical tumors and distinction of the latter from clear cell renal cell carcinoma (ccRCC) which show significant morphologic overlap. TFE3 immunostaining was performed on a large cohort of samples including 40 adrenal cortex tissues, 95 adrenocortical adenoma (ACA), 11 adrenocortical carcinoma (ACC), 53 ccRCC, and 18 pheochromocytomas. TFE3 was compared with other immunomarkers melan-A, inhibin-α, synaptophysin, chromogranin A, CAIX and CD10. One hundred percent normal adrenal cortices and 94% ACA were strongly and diffusely stained for TFE3 while no ACC showed diffuse staining. TFE3 is thus useful in distinguishing ACA from ACC. TFE3 is also useful in separating ACC from ccRCC as 64% ACC showed partial, while only 7% of ccRCC showed partial TFE3 staining. Only 1 pheochromocytoma showed focal weak TFE3 staining. Results also demonstrated superiority of TFE3 over other commonly used immunomarkers. TFE3 gene rearrangement testing by fluorescence in situ hybridization showed no rearrangement in 6 TFE3 positive adrenal tumors. TFE3 mRNA were analyzed by the Cancer Genome Atlas database and we found TFE3 mRNA expression correlated with overall patient survival in ACC. Our study showed usefulness of TFE3 in distinguishing ACA from ACC, and ACC from ccRCC. TFE3 is superior over other commonly used immunomarkers for adrenal tumors. In addition, decreased TFE3 immunoexpression and TFE3 mRNA expression may carry poor prognostic implication in adrenal tumors.
Background and aims:
Superior imaging techniques have increased the recognition of adrenal pathology. Distinguishing benign from malignant adrenocortical tumors is not always easy. Several criteria and immunohistochemical markers have been discovered which help to differentiate between adrenocortical adenoma (ACA) and adrenocortical carcinoma (ACC). Our aim here was to evaluate the diagnostic and prognostic role of steroidogenic factor-1 (SF-1) in adult adrenocortical tumors (ACT) diagnosed using the Weiss criteria. In this cohort, we have also analyzed Ki67 and p53 expression and the extent of agreement between SF-1 and Ki-67.
Methodology:
This was a retrospective, observational study comprising 24 cases of adult ACT over 10 years. Immunohistochemical staining for SF-1, Ki67, and p53 was done in all the cases, and the results correlated with the morphological diagnosis made using Weiss criteria.
Results:
SF-1 was 100% sensitive and 80% specific as a marker of malignancy. Increased SF-1 expression correlated with worse survival. There was a moderate degree of agreement between Ki-67 labeling-index and SF-1 as a marker of malignancy with the kappa coefficient being 0.75. The sensitivity of p53 was lower than Ki67 in diagnosing ACC.
Conclusion:
In adult ACTs, SF-1 has diagnostic significance and prognostic implication. SF-1 is a crucial, dosage-dependent survival factor in ACC. There is a moderate extent of agreement between Ki-67 and SF-1 as a marker of malignancy.
The Weiss scoring system is the most popular system used in the histologic diagnosis of adrenocortical carcinoma (ACC) and includes assessment of diffuse architecture; clear cells; nuclear grade; mitotic rate; atypical mitotic figures; necrosis; and venous, sinusoidal, or capsular invasion. However, it presents several limitations, including classification of borderline adrenal tumors (Weiss score of 3) or oncocytic and myxoid adrenal tumors. Oncocytic adrenocortical tumors demonstrate cells with eosinophilic cytoplasm, clear cells <25% of tumor volume, high-grade nuclear atypia, and diffuse architecture—all features diagnostic of ACC based on the Weiss scoring system and thus potentially misclassified. Oncocytic adrenocortical tumors are thus classified based on the Lin-Weiss-Bisceglia system that includes (1) major criteria (mitotic rate >5 mitoses/50 high-power fields, atypical mitoses, venous invasion) and (2) minor criteria (tumor size >10 cm or mass >200 g, necrosis, capsular invasion, sinusoidal invasion). The presence of any one major criterion is diagnostic of the oncocytic ACC, and the presence of at least one minor criterion indicates oncocytic neoplasm of uncertain malignant potential. The absence of any major or minor criteria is diagnostic of adrenocortical oncocytoma. Here we present a case of oncocytic ACC.
Das Nebennierenrindenkarzinom (ACC) ist eine sehr seltene maligne Erkrankung, die mit einer infausten Prognose vergesellschaftet ist. In Zeiten apparativ geprägter Medizin treten suspekte Befunde der Nebenniere gehäufter auf als je zuvor. Diese Nebennierenraumforderungen, die zumeist bei Bildgebungen auffallen, die aus anderen Gründen indiziert waren, werden Nebenniereninzidentalome genannt und sind meist benigne Befunde. Dennoch wird es angesichts dieser steigenden Zahl an Inzidentalomen immer wichtiger, die Entität der gefundenen Raumforderung schnell zu sichern, um die entsprechende Therapie einleiten zu können. Somit sollen das Zeitfenster bis zur Krebstherapie verkleinert und gleichsam unnötige chirurgische Eingriffe bei Patient*innen mit benignen Nebennierentumoren vermieden werden. Um die diagnostischen Schritte weiter zu verbessern, wurde in der vorliegenden Arbeit eine bioinformatische Regressionsanalyse an Steroidhormonkonzentrationen von ACC-Patient*innen und Kontrollen durchgeführt und der diagnostische Wert der berechneten Steroidsignaturen untersucht. Dabei zeigte sich im geschlechtsspezifischen Modell jeweils eine 6-Steroid-Signatur mit bester Trennschärfe zwischen benignen und malignen NN-Befunden. So konnte mit der 6-Steroid-Signatur in der männlichen Patientengruppe mit einer Sensitivität von 80% und Spezifität von 97%, in der weiblichen Patientinnengruppe mit einer Sensitivität von 78% und Spezifität von 97% die Diagnose richtig zugewiesen werden. Im Rahmen der targeted Metabolomics Untersuchung konnten Tumor-assoziierte Stoffwechselalterationen aufgezeigt werden. Eine Plasma-Metabolit-Signatur zur Differenzierung von ACCs und Nebennierenadenomen, welche die gängige Diagnostik bei der Abklärung von unklaren Nebennierentumoren erleichtern könnte, erscheint jedoch angesichts der großen Anzahl an zu bestimmenden Metaboliten - auch unter ökonomischen Gesichtspunkten - zu diesem Zeitpunkt noch nicht mit der Routine-Patient*innenversorgung vereinbar.
Adrenocortical carcinoma (ACC) is one of the deadliest endocrine malignancies and telomere maintenance by activated telomerase is critically required for ACC development and progression. Because telomerase reverse transcriptase (TERT) and regulator of telomere elongation helicase 1 (RTEL1) play key roles in telomere homeostasis, we determined their effect on ACC pathogenesis and outcomes. Analyses of TCGA and GEO datasets showed significantly higher expression of RTEL1 but not TERT in ACC tumors, compared to their benign or normal counterparts. Furthermore, gains/amplifications of both TERT and RTEL1 genes were widespread in ACC tumors and their expression correlated with their gene copy numbers. Higher expression of either TERT or RTEL1 was associated with shorter overall and progression-free survival (OS and PFS) in the TCGA ACC patient cohort, and higher levels of both TERT and RTEL1 mRNA predicted the shortest patient OS and PFS. However, multivariate analyses showed that only RTEL1 independently predicted patient OS and PFS. Gene set enrichment analysis further showed enrichments of wnt/β-catenin, MYC, glycolysis, MTOR, and DNA repair signaling pathways in ACC tumors expressing high TERT and RTEL1 mRNA levels. Taken together, TERT and RTEL1 promote ACC aggressiveness synergistically and may serve as prognostic factors and therapeutic targets for ACC.
Adrenocortical cancer (ACC) is among the most aggressive endocrine tumours with an overall poor prognosis. Morbidity and mortality can be secondary to tumour-related steroid hormone excess and/or tumour growth and metastases. This potentially poor outcome explains why the early detection of adrenocortical malignancy is paramount for the investigation of adrenal masses, alongside exclusion of hormone excess. The diagnosis of adrenocortical carcinoma relies on careful investigations of clinical, endocrine, and imaging features before surgery, and histopathological examination after tumour removal. Appropriate management and follow-up by an expert multidisciplinary team is critical to improve prognosis and drive progress for this rare cancer.
Context.—
Lesions in the genitourinary (GU) organs, both benign and malignant, can demonstrate overlapping morphology, and practicing surgical pathologists should be aware of these potential pitfalls and consider a broad differential diagnosis for each specific type of lesion involving the GU organs. The following summary of the contents presented at the 6th Annual Chinese American Pathologists Association (CAPA) Diagnostic Course (October 10–11, 2020), supplemented with relevant literature review, exemplifies the common diagnostic challenges and pitfalls for mass lesions of the GU system of adults, including adrenal gland, with emphasis on immunohistochemical and molecular updates when relevant.
Objective.—
To describe the common mass lesions in the GU system of adults, including adrenal gland, with emphasis on the diagnostic challenges and pitfalls that may arise in the pathologic assessment, and to highlight immunohistochemical workups and emerging molecular findings when relevant.
Data Sources.—
The contents presented at the course and literature search comprise our data sources.
Conclusions.—
The diagnostic challenges and pitfalls that arise in the pathologic assessment of the mass lesions in the GU system of adults, including adrenal gland, are common. We summarize the contents presented at the course, supplemented with relevant literature review, and hope to provide a diagnostic framework to evaluate these lesions in routine clinical practice.
Adrenocortical carcinoma (ACC) is a rare malignancy, with an estimated annual incidence of 0.7–2 cases per million and a median overall survival of 3–4 years. Hormone-secreting ACCs represent most cases; of these, only a small minority presents with virilisation alone. Early diagnosis is key to increase the chances of a better outcome. Here, we report a case of a 41-year-old woman who presented with menstrual irregularities, hirsutism and virilising symptoms, associated with abdominal discomfort and constitutional symptoms. On physical examination, there was a palpable mass in the right upper quadrant. Laboratory workup revealed elevated serum androgens. The imaging study showed a 163×110×122 cm right adrenal mass with features consistent with ACC and suggested potential hepatic invasion. Our patient underwent surgical resection, and the histopathological findings confirmed the diagnosis. She was referred to a specialised centre for follow-up and adjuvant therapy.
Introduction: Adrenal gland tumors are rare. Asymptomatic adrenal tumours are found in 2-10% of the population worldwide, out of which, adrenocortical carcinomas(ACC) have an incidence of 0.5-2 cases/million population/year. ACC accounts for 0.05% -0.2% of all malignancies with a bimodal age distribution, in the first two decades and then in the fifth decade. They can be asymptomatic and diagnosed as Incidentalomas or present with signs and symptoms of hormone imbalance. Materials and methods: In this 2 year hospital-based retrospective case series from June,2018 to May,2020 , 5 cases of adrenal gland tumors diagnosed in the Department of Pathology , GMCH, were retrieved from the archives and reviewed. Each case was analyzed with respect to age , sex, site and tumor characteristics. Results: In this 2-year period, 5 cases of adrenal tumors were found. The age range of the patients was 8-54 years. Out of 5 cases,2 cases were male and 3 cases were female. Out of 5 cases of , 4 were on the left side and 1 was on the right side.2 out of the 5 cases were diagnosed as Adrenocortical carcinoma(low grade), 1 as Phaeochromocytoma and 2 as Adrenocortical Adenoma. Conclusion: Adrenal gland tumors are rare, so the pathologic classification and determination of prognosis are very challenging.
Adrenocortical carcinoma (ACC) is a rare malignancy that is associated with a dismal prognosis. Pan-genomic studies have demonstrated the involvement of ATRX and ZNRF3 genes in adrenocortical tumorigenesis. Our aims were to evaluate the protein expression of ATRX and ZNRF3 in a cohort of 82 adults with ACC and to establish their prognostic value. Two pathologists analyzed immuno-stained slides of a tissue microarray. The low protein expression of ATRX and ZNRF3 was associated with a decrease in overall survival (OS) (p = 0.045, p = 0.012, respectively). The Cox regression for ATRX protein expression of >1.5 showed a hazard ratio (HR) for OS of 0.521 (95% CI 0.273–0.997; p = 0.049) when compared with ≤1.5; for ZNRF3 expression >2, the HR for OS was 0.441 (95% CI, 0.229–0.852; p = 0.015) when compared with ≤2. High ATRX and ZNRF3 protein expressions were associated with optimistic recurrence-free survival (RFS) (p = 0.027 and p = 0.005, respectively). The Cox regression of RFS showed an HR of 0.332 (95%CI, 0.111–0.932) for ATRX expression >2.7 (p = 0.037), and an HR of 0.333 (95%CI, 0.140–0.790) for ZNRF3 expression >2 (p = 0.013). In conclusion, low protein expression of ATRX and ZNRF3 are negative prognostic markers of ACC; however, different cohorts should be evaluated to validate these findings.
Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy of the adrenal cortex. This study characterizes a single-institution cohort of children treated for ACC, and explores the relationship between clinical outcomes of ACC and germline TP53 mutation status. We performed a retrospective chart review of 23 consecutive pediatric patients with ACC treated at The Hospital for Sick Children, Toronto, Canada, between 1977 and 2017. Clinical, biochemical, radiologic, pathologic, and genetic data were collected for each patient. ACC diagnosis followed a bimodal age distribution of 0 to 6 (n=17) and 12+ (n=6) years, with a female:male ratio of 3.6:1. Ten of 20 patients tested for germline TP53 status carried a pathogenic (9) or likely pathogenic (1) variant, including all but 1 male patient. Only 3 patients died of ACC-related causes, each 5 months post-diagnosis. When treated with resection and combination chemotherapy, carriers of germline TP53 mutations may respond more favorably than their wild-type counterparts. In addition, the survival of patients reported in our cohort with high-stage ACC was appreciably greater than previously described (100.0% for stage II, 50.0% for stage III, and 42.9% for stage IV), favoring aggressive intervention in these patient populations.
Das Nebennierenrindenkarzinom (Adrenocortical Cancer, ACC) ist eine seltene Erkrankung mit schlechter Prognose vor allem in fortgeschrittenen Tumorstadien. Diese Studie untersucht ein großes Kollektiv (n=114) an Patienten mit fortgeschrittenem ACC, die mit einer Gemcitabin (Gem)-basierten Therapie behandelt wurden. Hier zeigte sich eine moderate Wirksamkeit mit einem „clinical benefit“ (definiert als ein progressionsfreies Überleben von vier oder mehr Monaten) bei 18% der Patienten und einer guten Verträglichkeit (schwerwiegende unerwünschte Ereignisse bei 11% der Patienten). Als mögliche prädiktiver Marker für die Gem-Wirksamkeit und prognostische Marker für das Gesamt-Überleben wurden die große Untereinheit M1 der Ribonukleotidreduktase (RRM1) und der Transmembrantransporter human Equilibrative Nucleosie Transporter 1 (hENT1) untersucht. Keiner der Marker hatte einen prädiktiven Vorhersagewert auf das Ansprechen auf die Gem-basierte Therapie oder das progressionsfreie Überleben nach Beginn der Gem-basierten Therapie. Für die Untersuchung des prognostischen Werts wurden weitere Gewebe untersucht (hENT1 und RRM1 mRNA: 30 ACC, 20 adrenokortikale Adenome (ACA) and 21 normale Nebennieren (nNN), Gewebe für hENT1-Proteinuntersuchung: 303 ACC von 262 Pateinten, 51 ACA, 18 nNN, für RRM1-Proteinuntersuchung: 279 ACC von 238 Patienten, 45 ACA, 12nNN). Es fand sich signifikant weniger hENT1-mRNA und häufiger eine negative hENT1-Protein-Membranfärbung (hENT1m) in ACCs als in ACAs und nNN und tendenziell häufiger negatives hENT1m in Metastasen im Vergleich zu Primärtumoren und Rezidiven. Patienten mit negativem hENT1m hatten ein kürzeres krankheitsspezifisches Überleben und progressionsfreies Überleben unabhängig von der Therapie als Patienten mit positivem hENT1m. Die RRM1-Expression korrelierte nicht mit den Überlebenszeiten unabhängig von der Therapie. Zusammenfassend zeigt eine Gem-basierte Therapie bei Patienten mit fortgeschrittenem ACC eine moderate Wirksamkeit und einer guten Verträglichkeit. Weder hENT1 noch RRM1 eignen sich als prädiktive Markert für die Wirksamkeit einer Gem-basierten Therapie. hENT1 könnte ein möglicher prognostischer Marker für das ACC sein.
Although the relationship between pathologic features and clinical outcome is well established in adult adrenocortical neoplasms, the prognostic value of these features in pediatric adrenocortical neoplasms (PACN) is unclear. In a series of PACNs from 54 Brazilian children, the authors retrospectively investigated the prognostic value of histologic classification, ploidy, proliferative index, and size (as tumor weight or greatest diameter). Histologic classification was most predictive of clinical behavior: there were no failures in 11 adenomas, 5 failures in 27 low-grade carcinomas, and 9 failures in 16 high-grade carcinomas (P = .0003). Tumor weight was predictive of failure in tumors weighing ≥ 100 versus < 100 g (P = .04), and a trend was found toward failure among tumors measuring ≥ 5 cm, as opposed to those < 5cm (P = .07). Proliferative index was marginally related to failure (P = .05 at < 11% vs. ≥ 11% and .07 at < 10% vs. ≥ 10%), and ploidy was not significantly predictive of outcome (P = .25). Histologic type and tumor weight were the most reliable predictors of outcome in PACN.
The gene expression profiles of benign and malignant adrenocortical tumors are different.
Genomewide gene expression profiling and validation.
Tertiary medical center.
Eighty-five patients with benign adrenocortical tumors (n = 74) and adrenocortical carcinoma (n = 11).
Real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) in 89 adrenocortical tissue samples (11 malignant and 78 benign). The criteria for differentially expressed genes between benign and malignant adrenocortical tumors were a false discovery rate of less than 5% and an adjusted P < .01. Genes differentially expressed by 8-fold higher or lower were validated by RT-PCR.
The diagnostic accuracy of differentially expressed genes as determined by the area under the receiver operating characteristic curve (AUC).
We found 37 genes differentially expressed by 8-fold higher or lower. Fifteen genes were downregulated and 22 were upregulated in adrenocortical carcinoma. Of the 37 genes, 29 differentially expressed by microarray correlated with the gene expression levels by quantitative RT-PCR (P < or = .01). Of the 37 genes validated by RT-PCR, 22 were significantly differentially expressed between benign and malignant adrenocortical tumors (P < .05). Five of these 22 genes had an AUC of 0.80 or greater (the AUC for IL13RA2 was 0.90; HTR2B, 0.87; CCNB2, 0.86; RARRES2, 0.86; and SLC16A9, 0.80), indicating high diagnostic accuracy for distinguishing benign from malignant adrenocortical tumors.
We identified 37 genes that are dysregulated in adrenocortical carcinoma, and several of the differentially expressed genes have excellent diagnostic accuracy for distinguishing benign from malignant adrenocortical tumors.
The differentiation between malignant and benign adrenocortical tumors is often difficult, and better markers are required. Because the genetic background of adrenocortical tumors is poorly characterized, we used comparative genomic hybridization (CGH) to screen for DNA sequence copy number changes in 8 sporadic primary adrenocortical cancers and 14 adenomas. There was a strong relationship between the number of genetic aberrations detected using CGH and both tumor size and malignancy. No alterations were seen in the smaller adenomas (< 5 cm), whereas the two largest adenomas (5 cm each) and seven of the eight cancers (7-20 cm) showed an increased number of genetic alterations. The presence of genetic aberrations detected using CGH was associated with an aneuploid DNA pattern. In the cancers, losses most often involved the chromosomal regions 2, 11q, and 17p (four of eight tumors), whereas gains took place at chromosomes 4 and 5 (four of eight tumors). In conclusion, our data indicate that genetic changes may help to define the malignant potential of adrenocortical tumors. Furthermore, the CGH results implicate several chromosomal regions that may contain genes with an important role in the development of adrenocortical cancers.
To review the cytomorphologic features of adrenocortical carcinoma (ACC), correlate them with histology and compare them with the cytomorphologic features of very similar renal cell carcinoma (RCC) on fine needle aspiration (FNA) smears.
Cytomorphologic features in 7 cases of ACC in FNA smears were analyzed and compared with those in 10 cases of RCC. Five cases of ACC and five of RCC were later confirmed on histopathology. Parameters analyzed pertained mainly to architectural, cytoplasmic and nuclear features.
The presence of cells in sheets with a central, thin-walled vascular core (endocrine vascular pattern); monomorphic cell population; eccentric nuclei; focal dramatic anisonucleosis; and focal spindling with crushing was a prominent feature of ACC in contrast to RCC, which showed mainly an acinar pattern with only a focal endocrine pattern, well-defined cytoplasmic angles and projections, and cytoplasmic vacuolations; pleomorphism, if present, was gradual and seen uniformly in all the cells. Univariate analysis using the chi 2 test showed the presence of endocrine architecture; focal dramatic anisonucleosis; crushed spindle fragments; eccentric nuclei; and absence of cytoplasmic vacuolizations as significant differentiating features in favor of ACC (P < .05).
A cytomorphologic comparison of ACC with RCC showed that differentiation is possible by a set of statistically significant features that not only have diagnostic value but, as with crushed spindle fragments, also have prognostic significance.
Adrenocortical carcinoma (ACC) is a rare neoplasm with poor prognosis. Discerning ACCs from benign adenomas histologically may be difficult if invasion into surrounding tissues or metastases are missing.
In order to establish molecular markers for malignancy, we analyzed seven normal adrenals, three massive macronodular ACTH-independent adrenocortical hyperplasias (MMAHs), 30 adrenocortical adenomas (ACAs) and ten ACCs.
All tissues were studied for the presence of alterations in the p53 tumor suppressor gene using the PAb 1801 antibody, which detects mutant p53 protein and the pYNZ22 microsatellite marker to show loss of heterozygosity (LOH) at 17p, for expression of the proliferation-associated antigen Ki67 using the MIB1 antibody, for the rate of apoptotic tumor cells with the TdT-mediated dUTP biotin nick end labeling (TUNEL) method, and for LOH of 11q13 (menin gene locus) with the D11S956 microsatellite marker.
0/3 MMAH, 1/28 ACA and 3/10 ACC revealed immunopositive staining for p53. LOH for pYNZ22 was observed in 1/3 MMAH, 1/23 informative ACA and 6/6 informative ACC. The rate of apoptotic cells was significantly higher in ACC (P<0.0001 by ANOVA) than in ACA but there was some overlap between groups. The Ki67 index (% immunopositive cells) was 1.9+/-1.30% (mean+/-s.d.) in normal adrenals, 3.47+/-1.37% in MMAH, and 2.11+/-1.01% in ACA. ACC had the highest Ki67 index of 11.94+/-7.58% distinguishing all ACC from the ACA and MMAH studied with a cut-off level of 5%. LOH for 11q13 was detected in 2/3 MMAH, 5/26 ACA and 6/8 ACC.
We conclude that a Ki67 index above 5% is a sensitive and specific indicator of ACC and may be useful in the differentiation of adenomas from carcinomas.
Genetic alterations, such as loss of heterozygosity (LOH) at the 17p13 and 11p15 loci and overexpression of the insulin-like growth factor (IGF)-II gene, are associated with the malignant phenotype in sporadic adrenocortical tumors. A high risk of recurrence after surgery for adrenocortical tumors is predicted in cases with regional invasion or distant metastases. However, patients with localized tumors also have a high risk of recurrence. Reliable prognostic markers are required to identify subjects at high risk of recurrence. The aim of this study was to assess the prognostic value of three molecular markers (17p13 LOH, 11p15 LOH, and overexpression of the IGF-II gene) by assessing disease-free survival in a large series of adult patients with sporadic adrenocortical tumors. Adult patients (114) were prospectively followed up from diagnosis of the disease to June 1999 or to death. Malignancy was initially diagnosed in 18 patients (McFarlane stage III: n = 1 and stage IV: n = 17). The remaining 96 patients with localized adrenal disease at diagnosis (stage I: n = 60 and stage II: n = 36) were at risk of recurrence. Histological grade was assessed according to Weiss criteria, and tumors were classified into two groups (Weiss score <or=3 and Weiss score >or=4). Tumor samples were analyzed for LOH at the 17p13 and 11p15 loci and for IGF-II gene mRNA content. 17p13 LOH was a strong predictor of shorter disease-free survival in univariate analysis (P = 0.001; relative risk, 27), as were histological grade (Weiss score >or=4; P = 0.00001; relative risk, 15), 11p15 LOH (P = 0.004; relative risk, 9), tumor size (size >5 cm; P = 0.006; relative risk, 18), and overexpression of the IGF-II gene (P = 0.01; relative risk, 5). In a Cox proportional hazards regression model, histological grade (P = 0.04; relative risk, 4.2) and 17p13 LOH (P = 0.009; relative risk, 21.5) were independently associated with recurrence. Molecular markers, particularly 17p13 LOH, are predictive of long-term outcome in patients with sporadic adrenocortical tumors. In patients who have undergone curative surgery, routine assessment of these tumor markers is a useful complement to histological scoring for predicting recurrence and guiding decisions for subsequent follow-up and management.
Context.—The behavior of adrenocortical tumors (ACTs) is usually difficult to establish in childhood, and the role of immunomarkers in predicting outcome has not yet been elucidated.
Objective.—To investigate the relationship between clinical, pathologic, and immunohistochemical findings and prognosis in a series of children with ACTs.
Patients and Methods.—Clinical data were evaluated retrospectively in 33 children with ACTs, including age at diagnosis, sex, time between first symptoms and diagnosis, clinical signs and symptoms, tumor position, and follow-up. Histologic sections were reviewed, each tumor was classified, and staging was performed according to previously published criteria. Immunohistochemical analysis of p53, Ki-67, c-Erb-B2, and Bcl-2 was performed according to previously published techniques.
Results.—Sixty-four percent (n = 21) of the patients were female, and the age at diagnosis in the cohort ranged from 2 to 96 months. Virilization alone affected 70% (n = 23) of the patients, and 18 patients had stage 1 disease, 9 had stage 2 disease, and 3 each had stage 3 and stage 4 disease. Female sex and stage 1 and stage 2 disease were associated with good outcome. None of the histopathologic criteria evaluated correctly predicted outcome. Only tumors with a volume exceeding 200 mL were associated with malignant behavior. Because only a small number of tumors expressed the antigens, results of these immunohistochemical tests were considered inconclusive.
Conclusion.—In this sample of pediatric ACTs, the clinical and surgical parameters are the most important prognostic factors, while the immunohistochemical markers evaluated were not predictive of outcome.
Forty-one patients with adrenal cortical tumors were evaluated retrospectively for the presence of histologic and non-histologic features associated with malignant behavior. The patients who survived operation were followed at least five years. The association of these features with subsequent metastasis was examined by both parametric and nonparametric statistical methods. Twelve criteria were statistically significant in predicting subsequent metastasis. The most significant of these were: clinical evidence of weight loss, broad fibrous bands traversing the tumor, a diffuse growth pattern, vascular invasion, tumor cell necrosis, and tumor mass. The tendency toward metastasis for each tumor was expressed in indices that correlated well with diagnoses made by conventional histologic means, but were more accurate in predicting subsequent clinical behavior than nonquantitative methods of evaluation.
The prognostic significance of morphologic parameters was evaluated in 103 patients with renal cell carcinoma diagnosed during 1961--1974. Pathologic material was classified as to pathologic stage, tumor size, cell arrangement, cell type and nuclear grade. Four nuclear grades (1--4) were defined in order of increasing nuclear size, irregularity and nucleolar prominence. Nuclear grade was more effective than each of the other parameters in predicting development of distant metastasis following nephrectomy. Among 45 patients who presented in Stage I, tumors classified as nuclear grade 1 did not metastasize for at least 5 years, whereas 50% of the higher grade tumors did so. Moreover, among Stage I tumors there was a significant difference in subsequent metastatic rate between nuclear grades 1 and 2. There was an apparent positive relationship between cell type and metastatic rate; clear cell tumors were less aggressive than predominantly granular cell tumors (metastatic rate 38% versus 71%). This relationship in part a function of the nuclear grade: only 5% of grade 3 and 4 tumors consisted of clear cells, whereas such high grades were seen in 57% of granular cell tumors. The size of the primary correlated well with the stage at the time of surgery. However, with the exception of extremely large and small tumors, the size was not useful in predicting the subsequent course of patients treated for Stage I tumors. Nuclear grade was the most significant prognostic criterion for the outcome of Stage I renal cell carcinoma.
OBJECTIVE: To determine the specific cytomorphologic criteria for diagnosing benign adrenal cortical nodule (BACN) by fine needle aspiration (FNA). STUDY DESIGN: The smears from 162 adrenal FNA biopsies were reviewed. A diagnosis of BACN was rendered in 50 cases (31%). The cytologic features of BACN were compared to those of primary and metastatic malignant tumors of the adrenal gland, and the size of BACN as measured by computed tomography was recorded. RESULTS: Bubbly, vacuolated, lipid background; large, cohesive tissue fragments with a syncytial nesting arrangement admixed with sinusoidal endothelial cells; and abundant oval, round, bare nuclei are the three cytomorphologic features most often seen in BACN. The combination of these three features was observed in 40 cases (89%) of BACN and was seen in 4 cases of metastatic carcinoma (6%) in which there was also coexisting adrenal cortical hyperplasia None of the other primary or metastatic malignancies showed this combination of cytomorphologic features. The mean size of BACN was 2.5 cm, with a standard deviation of 1 cm and a range of 1-5 cm. The sizes of the four metastatic carcinomas with coexisting adrenal cortical hyperplasia were 6.5, 6, 5 and 1.5 cm, respectively (mean, 4.8). CONCLUSION: Our data suggest that combined cytologic features of bare nuclei; bubbly, vacuolated background; and large, cohesive tissue fragments with sinusoidal endothelial cells in a small adrenal nodule (<3.5 cm) are highly specific to FNA diagnosis of BACN.
We studied three cases of adrenocortical neoplasms that were detected incidentally after radiological examination of the abdomen. These cases did not demonstrate any clinical evidence of adrenocortical abnormalities, such as virilization. Macroscopically, the tumors were light to dark tan on cut surface. Light-microscopic examination revealed compact cells with abundant lipid-sparse eosinophilic cytoplasm and occasional enlarged nuclei. In one case, ultrastructural observation demonstrated abundant mitochondria. Immunohistochemical examination of all of the adrenocortical steroidogenic enzymes showed that none of the cases had immunoreactivity. No mitotic activity and no vascular invasion was observed. The postoperative course were uneventful. The follow-up interval varied from 8 to 27 months. These three neoplasms apparently represent the first reported cases of adrenocortical oncocytoma. They can be considered true nonfunctioning adrenocortical neoplasms because steroidogenic enzymes required for corticosteroid biosynthesis were not expressed in the tumor cells.
Oncocytic tumors of the adrenal cortex are very uncommon. Arriving at the correct diagnosis is important and the use of mES-13 immunohistochemical testing or ultrastructural analysis can support their recognition. However, once the diagnosis is established, trying to predict their biologic behavior is even more important. The Weiss system, considered to be predictive of the biologic behavior of conventional (nononcocytic) adrenocortical tumors, has been recently reviewed in the context of its possible application to the oncocytic tumor variant, along with the introduction of the size and weight parameter. Definitional criteria (mainly cells with eosinophilic and granular cytoplasm, high nuclear grade, diffuse architectural pattern) common to all types of oncocytic tumors are outlined, and proposed major criteria (high mitotic rate, atypical mitoses, venous invasion) and minor criteria (large size and huge weight, necrosis, capsular invasion, sinusoidal invasion) for distinguishing malignant tumors are discussed. As a starting point for this discussion, a case of uncertain malignant potential is presented. The authors’ proposed working rules for diagnostic categorization of such tumors are defined, with the presence of 1 major criterion indicating malignancy, 1 to 4 minor criteria indicating uncertain malignant potential (borderline), and the absence of all major and minor criteria indicative of benignancy.
Distinction of adrenocortical carcinoma from benign adrenocortical lesions by standard criteria is often difficult. In order to search for additional diagnostic parameters, a series of 25 adrenocortical tumors, 8 adenomas, 14 primary carcinomas, 1 metastasis, and the 2 adrenocortical carcinoma cell lines SW13 and NCI-H295 were analyzed by the approach of comparative genomic hybridization (CGH). Except for the two smallest adenomas, all tumors showed chromosomal imbalances with a high incidence of chromosomal gains, most frequently involving chromosomes or chromosome arms 5, 7, 8, 9q, 11q, 12q, 14q, 16, 17q, 19, 20, and 22q. The only significant loss of material concerned the distal part of 9p. Furthermore, 21 high-level amplifications were identified in 15 different regions of the genome. The consensus regions of recurrent gains and the focal high-level amplifications allowed identification of a series of chromosomal subregions containing candidate proto-oncogenes of potential pathogenic function in adrenocortical tumors: 1p34.3–pter, 1q22–q25, 3p24–pter, 3q29, 7p11.2–p14, 9q34, 11q12–11q13, 12q13, 12q24.3, 13q34, 14q11.2–q12, 14q32, 16p, 17q24–q25, 19p13.3, 19q13.4, and 22q11.2–q12. A subset of the CGH data was independently confirmed by interphase cytogenetics. Interestingly, the adenomas larger than 4 cm contained gained material of regions also overrepresented in carcinomas. In addition, several chromosomal gains, in particular the high-level amplifications, were exclusive for the malignant status of the tumors. These data indicate that the larger adrenal lesions need to be carefully considered in the diagnosis of adrenocortical tumors, and that genetic aberrations might provide useful markers for a better diagnostic differentiation. Genes Chromosomes Cancer 28:145–152, 2000. © 2000 Wiley-Liss, Inc.
Differentiation between benign and malignant tumors of the adrenal cortex was studied by means of seven histologic parameters. Each separate criterion was significantly different in two groups, one consisting of patients without metastases within 10 years after operation and one of patients with metastatic tumors. Discrimination on the basis of single parameters in individual patients, however, was of little value. When a histologic index was calculated using the same parameters but after “weighing,” a much better discrimination was obtained. The histologic index and, to a lesser degree, the mitotic activity seems to be related to the survival time of the patients with adrenal cortical carcinoma. The authors conclude that the calculation of a histologic index based on a summation of different parameters makes it possible to differentiate between malignant and benign adrenal cortical tumors. As single parameters, tumor weight and mitotic activity have the highest discriminating value.
Morphologic features (abnormal mitoses, necrosis, vascular and capsular invasion, broad fibrous bands, cellular pleomorphism, size) previously suggested to be predictors of malignant behavior in adrenal cortical tumors were assessed individually in 23 (17 benign, 6 malignant) pediatric and 42 (29 benign, 13 malignant) adult tumors. Of these features, size was the only predictor of malignancy in pediatric tumors. All pediatric tumors weighing more than 500 g were malignant and all but one weighing less than 500 g were benign. The remaining features were present in both benign and malignant pediatric tumors, and pediatric benign tumors were significantly more likely to have mitoses (P <0.01), necrosis (P <0.001), broad fibrous bands (P <0.005), and moderate to severe pleomorphism (P <0.01) than were adult benign tumors. The authors conclude that pediatric tumors are more likely to be benign than previously thought, and that size is the only morphologic predictor of their biologic behavior.
Adrenocortical tumors, especially cancers, remain challenging both for their diagnosis and prognosis assessment. The aim of this article is to identify molecular predictors of malignancy and of survival.
One hundred fifty-three unilateral adrenocortical tumors were studied by microarray (n = 92) or reverse transcription quantitative polymerase chain reaction (n = 148). A two-gene predictor of malignancy was built using the disease-free survival as the end point in a training cohort (n = 47), then validated in an independent validation cohort (n = 104). The best candidate genes were selected using Cox models, and the best gene combination was validated using the log-rank test. Similarly, for malignant tumors, a two-gene predictor of survival was built using the overall survival as the end point in a training cohort (n = 23), then tested in an independent validation cohort (n = 35).
Unsupervised clustering analysis discriminated robustly the malignant and benign tumors, and identified two groups of malignant tumors with very different outcome. The combined expression of DLG7 and PINK1 was the best predictor of disease-free survival (log-rank P approximately 10(-12)), could overcome the uncertainties of intermediate pathological Weiss scores, and remained significant after adjustment to the Weiss score (P < 1.3 x 10(-2)). Among the malignant tumors, the combined expression of BUB1B and PINK1 was the best predictor of overall survival (P < 2 x 10(-6)), and remained significant after adjusting for MacFarlane staging (P < .005).
Gene expression analysis unravels two distinct groups of adrenocortical carcinomas. The molecular predictors of malignancy and of survival are reliable and provide valuable independent information in addition to pathology and tumor staging. These original tools should provide important improvements for adrenal tumors management.
Forty-one patients with adrenal cortical tumors were evaluated retrospectively for the presence of histologic and non-histologic features associated with malignant behavior. The patients who survived operation were followed at least five years. The association of these features with subsequent metastasis was examined by both parametric and nonparametric statistical methods. Twelve criteria were statistically significant in predicting subsequent metastasis. The most significant of these were: clinical evidence of weight loss, broad fibrous bands traversing the tumor, a diffuse growth pattern, vascular invasion, tumor cell necrosis, and tumor mass. The tendency toward metastasis for each tumor was expressed in indices that correlated well with diagnoses made by conventional histologic means, but were more accurate in predicting subsequent clinical behavior than nonquantitative methods of evaluation.
Fine-needle aspiration biopsy of 50 adrenal masses from 48 patients was performed between 1984 and 1991. The series consisted of 28 males and 20 females, with an age range of 12 months to 79 years (mean age, 55 years). Clinical and/or pathologic follow-up was available in 37 patients. Fine-needle aspiration was diagnostic in all 29 malignant cases having follow-up, with no false-positive diagnoses. There were six primary malignancies (three neuroblastomas, two pheochromocytomas, and one adrenal cortical carcinoma) and 23 metastatic lesions. Of these, the lung was the most frequent primary malignancy (60%), followed by melanoma and renal cell carcinoma (8.6% each). The remaining nonmalignant fine-needle aspiration diagnoses were adrenal cortical neoplasms (most likely adenoma), adrenal cortical hyperplasia, myelolipoma, benign adrenal tissue, and abscess. Based on clinical follow-up, three other adrenal adenomas were not diagnosed by fine-needle aspiration. Six biopsy specimens (12%) were insufficient for diagnosis. Ancillary studies including electron microscopy and/or immunocytochemistry were performed on 13 malignant aspirates and provided additional confirmation of the cytology diagnosis in 12 cases. This study confirms that fine-needle aspiration is a sensitive and highly specific procedure for the evaluation of primary and metastatic malignancies involving the adrenal gland. The technique is less useful in the workup of benign processes but, in some instances, can provide specific diagnostic information.
Ultrasonically guided fine-needle biopsies were performed from 28 adrenal lesions in 28 patients. In 15 patients adrenal enlargement was an incidental finding. In 17 of 18 (94%) patients with metastatic spread combined cytological and histological examination disclosed secondary malignancy, and in 4 of 5 patients with primary neoplastic disease the combined microscopic examination concluded primary neoplasia. However, it was not possible to classify these lesions as being of a malignant or a benign nature. A false positive diagnosis of a hepatocellular carcinoma of the clear cell type was made in one case. In all 5 patients with non-neoplastic adrenal lesions cytological and histological examinations concluded non-neoplastic disease. Electron microscopy was of special benefit in two cases of a non-Hodgkin's lymphoma and a pheochromocytoma. Using ultrasonically guided biopsies it is possible to differentiate between adrenal lesions due to metastatic spread and adrenal lesions due to primary neoplasia or non-neoplastic disease. Compared to other imaging techniques ultrasonically guided punctures of adrenal masses is a simple procedure giving important diagnostic information.
Adrenocortical carcinoma (ACC), a very rare tumor in children in the United States, is apparently more common among Brazilian children. We reviewed the medical records of 40 children whose disease was diagnosed between 1966 and 1987. There were 12 boys and 28 girls; their median age was 3.9 years (range, 1 day to 15.7 years). Virilization was the most common clinical sign (37 of 40); other signs included abdominal mass, deepened voice, plethora, hypertension, seizures (seven patients) and, rarely, weight loss (two patients). The median time between first signs or symptoms and diagnosis was 1.4 years (range, 3 days to 5 years). Four of 33 tumors were classified as benign according to the Weiss, van Slooten, or Hough systems (tumor tissue was unavailable for seven patients). Tumors were completely resected in 26 of 38 patients; of those, 17 are in continuous complete remission, five relapsed, and four have been lost to follow-up. One patient, who had local recurrence, has been in a third complete remission for 18+ months after tumor resection and chemotherapy (cisplatin and etoposide). Of the remaining 14 patients, 11 died of progressive disease, the diagnosis was confirmed at autopsy in two, and one has been lost to follow-up. Univariate analysis disclosed that age greater than or equal to 3.5 years at diagnosis, interval of greater than or equal to 6 months between first symptoms and diagnosis, tumor weight greater than 100 g, tumor size greater than 200 cm3, and high levels of urinary 17-ketosteroids (17-KS) and 17-hydroxycorticosteroids (17-OH) were associated with an unfavorable outcome. Multivariate analysis disclosed that only a tumor size greater than 200 cm3 independently identifies those patients with an unfavorable prognosis. Among the variables known before surgery, age, and the interval between first symptoms and diagnosis were important predictors of outcome. Our data suggest that some children with ACC and certain clinical characteristics are at high risk of primary treatment failure and, therefore, are good candidates for investigational adjuvant therapy.
There are currently no well-established pathologic prognostic factors helpful in distinguishing low versus high grade adrenocortical carcinomas. The effect of 11 pathologic parameters on survival was investigated in 42 cases of adrenocortical carcinoma. Only one variable, mitotic rate, had a strong statistical association with patient outcome. The 21 patients with carcinomas with greater than 20 mitoses per 50 high power fields (hpf) had a median survival of 14 months, whereas the 21 patients with carcinomas with less than or equal to 20 mitoses had a median survival of 58 months (p less than 0.02). The presence of atypical mitoses, capsular invasion, tumor weight greater than 250 g, and size greater than 10 cm each showed a marginal statistical association with poor survival (p less than 0.06), whereas other features assessed, such as nuclear grade, presence of necrosis or of venous or sinusoidal invasion, character of the tumor cell cytoplasm, or architectural pattern, showed no statistical significance in predicting survival. It is proposed that adrenal cortical carcinomas with greater than 20 mitoses be designated high grade, whereas tumors with less than or equal to 20 mitoses be designated low grade.
Adrenocortical carcinoma is an unusual tumor that tends to be larger than 100 g at diagnosis. Malignant adrenocortical tumors of less than 50 g have been reported rarely. We studied a small adrenocortical carcinoma that weighed 40 g and metastasized 3 1/2 years following bilateral adrenalectomy. The malignancy of adrenocortical tumors is frequently difficult to determine. Two recent studies have proposed histologic criteria for determining the malignancy of adrenal cortical tumors. Since the tumor we studied was initially judged to be benign, we sought to determine whether an extensive evaluation of this tumor using these recent criteria could have identified the tumor's potential for metastasizing. Careful application of these criteria indicated that the tumor was either a borderline lesion or a definitely malignant lesion. This emphasizes the need to approach systematically all adrenal neoplasms with regard to determining their malignant potential. Documenting small adrenocortical carcinomas also should help in setting criteria for evaluating adrenal masses discovered incidentally by sensitive radiologic methods.
Differentiation between benign and malignant tumors of the adrenal cortex was studied by means of seven histologic parameters. Each separate criterion was significantly different in two groups, one consisting of patients without metastases within 10 years after operation and one of patients with metastatic tumors. Discrimination on the basis of single parameters in individual patients, however, was of little value. When a histologic index was calculated using the same parameters but after "weighing," a much better discrimination was obtained. The histologic index and, to a lesser degree, the mitotic activity seems to be related to the survival time of the patients with adrenal cortical carcinoma. The authors conclude that the calculation of a histologic index based on a summation of different parameters makes it possible to differentiate between malignant and benign adrenal cortical tumors. As single parameters, tumor weight and mitotic activity have the highest discriminating value.
The cytologic appearance of fine needle aspiration (FNA) specimens emanating from both symptomatic and incidental masses of the adrenal glands in 22 patients who attended a large cancer institution from 1976 to 1981 is described. Eligibility for the study required thorough clinical and radiologic follow-up for at least two years following the initial cytologic diagnosis. Histologic and ultrastructural correlations were performed when possible. Nine patients were found to have benign lesions, including five adrenal cysts, two adenomas, one nodular hyperplasia and one adrenal myelolipoma. Thirteen patients had malignant lesions, of which six were primary adrenal tumors, either neuroblastoma (two) or adrenocortical carcinoma (four). The overall sensitivity of FNA in detecting the presence of malignancy was 85%, while the number of patients correctly classified for all adrenal masses was 90%. The test was 100% specific for malignant lesions. It is concluded that FNA of adrenal masses is a safe and simple procedure with a high degree of accuracy. Its use appears to be especially justified in those patients with primary neoplasms of nonadrenal sites, in whom silent adrenal lesions are detected during radiologic surveys for metastatic disease. Fifteen of the patients fell into this category, yet over half (53%) of them were shown to have benign adrenal lesions, treatable with a conservative approach.
A series of 43 adrenocortical tumors was analyzed using nine histologic features. Mitotic activity, especially with atypical forms, and venous invasion correlated best with metastasizing or recurring tumors; however, no single criterion was useful alone. The combination of the following nine criteria was most useful in distinguishing malignant from benign tumors: nuclear grade III or IV; mitotic rate greater than 5/50 high-power fields; atypical mitoses; clear cells comprising 25% or less of the tumor; a diffuse architecture; microscopic necrosis; and invasion of venous, sinusoidal, and capsular structures. None of the 24 tumors with two or less of these criteria metastasized or recurred, while all but one of the 19 tumors with four or more of these criteria either recurred or metastasized.
Percutaneous aspiration biopsy of solid adrenal masses was performed without complication in 14 patients. CT guidance of 20-22 gauge needles was used in all but one of the biopsies. Diagnostic cytologic material was recovered in 13 (93%) of the 14 cases. The diagnoses were primary and metastatic neoplasms (10 cases), benign adenomas (two cases), and a mycotic abscess. Twelve additional aspirations were performed of surgically resected or autopsy specimens in six normal adrenals, one adenoma, three adrenal cortical carcinomas, a pheochromocytoma, and a sarcoma arising in the adrenal stoma. Percutaneous aspiration of solid adrenal masses is recommended as a safe, reliable alternative to open surgical biopsy for both benign and malignant adrenal disease.
The prognostic significance of morphologic parameters was evaluated in 103 patients with renal cell carcinoma diagnosed during 1961--1974. Pathologic material was classified as to pathologic stage, tumor size, cell arrangement, cell type and nuclear grade. Four nuclear grades (1--4) were defined in order of increasing nuclear size, irregularity and nucleolar prominence. Nuclear grade was more effective than each of the other parameters in predicting development of distant metastasis following nephrectomy. Among 45 patients who presented in Stage I, tumors classified as nuclear grade 1 did not metastasize for at least 5 years, whereas 50% of the higher grade tumors did so. Moreover, among Stage I tumors there was a significant difference in subsequent metastatic rate between nuclear grades 1 and 2. There was an apparent positive relationship between cell type and metastatic rate; clear cell tumors were less aggressive than predominantly granular cell tumors (metastatic rate 38% versus 71%). This relationship in part a function of the nuclear grade: only 5% of grade 3 and 4 tumors consisted of clear cells, whereas such high grades were seen in 57% of granular cell tumors. The size of the primary correlated well with the stage at the time of surgery. However, with the exception of extremely large and small tumors, the size was not useful in predicting the subsequent course of patients treated for Stage I tumors. Nuclear grade was the most significant prognostic criterion for the outcome of Stage I renal cell carcinoma.
Percutaneous needle biopsy of adrenal masses was performed in 21 patients. Adrenal cysts, metastases, primary tumors, and a myelolipoma were diagnosed with a success rate of 81 per cent. No complications were encountered. We concluded that percutaneous biopsy of adrenal masses is very useful in the management of selected patients.
Although many histologic criteria have been utilized to help distinguish benign from malignant adrenocortical tumors, it still may be difficult to assess the biologic potential of a given tumor. We evaluated 19 adenomas and 15 primary carcinomas with the avidin-biotin complex peroxidase method utilizing formalin-fixed, paraffin-embedded tissues with monoclonal antibodies for proliferating cell nuclear antigen (PC10) and Ki-67 (MIB 1) to determine if staining for these antigens could be used to help differentiate benign from malignant adrenocortical neoplasms. We also evaluated whether these markers could be used as prognostic indicators. Labeling indices for both PCNA and Ki-67 were determined by enumerating 1000 tumor cells, and expressed as a percentage of cells with nuclear staining. A PCNA and a Ki-67 score was obtained by the product of the staining intensity (0-3+) and the extent of nuclear staining, expressed as an estimate of the percentage of cells staining. Both PCNA and Ki-67 score and labeling index were correlated with mitotic counts, histologic diagnosis, and clinical outcome. Follow-up period for patients ranged from 4 months to 12 years with a mean of 25 months. Mitotic counts correlated with histologic diagnosis and clinical outcome. Both Ki-67 score and labeling index were significantly higher in malignant than in benign tumors, and correlated with mitotic counts and clinical outcome. There was a strong correlation between Ki-67 score and labeling index, indicating that Ki-67 score may be a more rapid and equally accurate method of estimating proliferative index of a tumor. PCNA score and labeling index did not correlate with histologic diagnosis or clinical outcome.(ABSTRACT TRUNCATED AT 250 WORDS)
To determine the efficacy of fine needle aspiration (FNA) in the diagnosis of primary and metastatic lesions of the adrenal gland in conjunction with the radiologic size of the lesion.
One hundred eighty-eight FNA biopsies performed between 1988 and 1992 with a diagnostic rate of 86% (161 cases) were reviewed and correlated with the radiologically (computed tomography, ultrasound) measured size of the lesion and follow-up.
Eighty-one cases (43%) were primary adrenal lesions, and 80 (43%) were metastatic tumors. Three large cell lymphomas and two adrenal histoplasmoses were also noted. The most common primary site of metastatic tumors was the lung; these 55 cases (29%) included 47 adenocarcinomas and 3 small cell, 2 large cell and 3 squamous cell carcinomas. The other metastatic tumors were 5 melanomas, 7 renal cell carcinomas and 1 mixed müllerian tumor. The size of the metastatic tumors averaged 5.1 +/- 2.5 cm (+/- SD) and ranged from 1.5 to 10 cm in greatest diameter. Benign cortical nodules (61 cases, 32%) were the most common primary adrenal lesion, followed, in decreasing frequency, by 11 cortical neoplasms/carcinomas, 5 pheochromocytomas and 1 myelolipoma. The benign cortical nodules/adenomas measured an average of 2.4 +/- 0.8 cm in greatest diameter and ranged from 1 to 4 cm. The cortical neoplasm/carcinoma sizes ranged from 4 to 12 cm.
These data suggest that FNA in conjunction with the radiologically measured size of adrenal lesions is a specific and sensitive method of evaluating primary and metastatic lesions of the adrenal gland. It is also an important diagnostic tool in cancer staging, obviating open surgical procedures for many patients.
Cytopathologic smears and/or imprints of human adrenal cortex (9 cases) and its disorders were examined, including adrenocortical nodule (3 cases), adrenocortical adenoma (23 cases), carcinoma (8 cases), and renal cell carcinoma (6 cases). Immunocytochemistry directed against 3 beta-hydroxysteroid dehydrogenase and adrenal-4-binding protein (Ad4BP), a transcription factor in steroidogenesis, was also performed. There were no cytologic differences between normal adrenal and adrenocortical nodules. Large nuclei with prominent nucleoli were observed predominantly in adrenocortical neoplasms. Cellular atypia or pleomorphism and the degree of cohesiveness were unreliable criteria in differentiating between adrenocortical adenoma and carcinoma. Mitosis and necrotic materials were observed only in adrenocortical carcinoma. These cytologic findings were considered contributory, but not diagnostic when evaluating adrenocortical disorders because of marked intra-tumoral heterogeneity. There were no reliable cytologic criteria in differentiating adrenocortical and renal cell carcinoma. Immunocytochemistry of 3 beta-hydroxysteroid dehydrogenase and especially Ad4BP was demonstrated to aid greatly in the differential diagnosis between these carcinomas by identifying adrenocortical parenchymal cells.
To evaluate the indications for and complications, accuracy, and techniques of percutaneous adrenal biopsy performed from 1982 through 1991 at the authors' institution.
Two hundred seventy-seven percutaneous adrenal biopsies were performed in 270 patients (175 male and 102 female patients, aged 31-84 years). Imaging studies and histories were reviewed, and each patient's case was followed up for at least 1 year after the biopsy. A patient was excluded from the study only if follow-up data could not be obtained.
The accuracy of percutaneous adrenal biopsy was 90% (249 of 277 biopsies). In the first 5 years of the study, the accuracy was 85% (87 of 102 biopsies); in the latter 5 years it was 93% (163 of 175 biopsies). The sensitivity was 81%, and the specificity was 99%. The positive predictive value was 99%, and the negative predictive value was 80%. The complication rate was 2.8%.
Percutaneous biopsy is a safe, accurate procedure for the diagnosis of pathologic conditions of the adrenal glands. The most common indication for a biopsy is the presence of an adrenal mass in a patient with lung cancer.
Although the relationship between pathologic features and clinical outcome is well established in adult adrenocortical neoplasms, the prognostic value of these features in pediatric adrenocortical neoplasms (PACN) is unclear. In a series of PACNs from 54 Brazilian children, the authors retrospectively investigated the prognostic value of histologic classification, ploidy, proliferative index, and size (as tumor weight or greater diameter). Histologic classification was most predictive of clinical behavior: there were no failures in 11 adenomas, 5 failures in 27 low-grade carcinomas, and 9 failures in 16 high-grade carcinomas (P = .0003). Tumor weight was predictive of failure in tumors weighing > or = 100 versus < 100 g (P = .04), and a trend was found toward failure among tumors measuring > or = 5 cm, as opposed to those < 5 cm (P = .07). Proliferative index was marginally related to failure (P = .05 at < 11% vs. > or = 11% and .07 at < 10% vs. > or = 10%), and ploidy was not significantly predictive of outcome (P = .25). Histologic type and tumor weight were the most reliable predictors of outcome in PACN.