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Pathologic and Clinical Prognostic Factors in ACC

Staging and Prognostic Stratification

Pathologic and clinical prognostic factors in adrenocortical carcinoma (ACC) are features associated with recurrence risk and survival after diagnosis. In ACC, prognostic assessment extends beyond the basic identification of malignancy to include anatomic stage, completeness of resection, histopathologic aggressiveness, hormonal phenotype, and selected patient-related clinical variables.123 These factors are used to estimate relapse risk after surgery, frame expectations in advanced disease, and support stratification in registries, observational studies, and clinical trials.45

The most consistently supported prognostic framework is stage-based stratification, particularly with ENSAT staging, but outcomes vary substantially within the same stage. This has led to greater emphasis on additional modifiers such as nodal status, margin status, Ki-67 or mitotic activity, and cortisol excess, as well as composite systems such as GRAS and S-GRAS.67589 In routine practice, these variables are generally interpreted together rather than as isolated determinants.

The evidence base remains limited by the rarity of ACC. Most prognostic data derive from retrospective single-center cohorts, multicenter registry studies, or post hoc model development analyses spanning long treatment eras with variable pathology review, endocrine definitions, surgical approaches, and nodal assessment.101112 As a result, many factors are directionally informative at the population level but are not sufficiently precise for deterministic prediction in an individual patient, and many proposed molecular or blood-based biomarkers remain investigational.119

Diagnostic and prognostic context

ACC is biologically heterogeneous, with outcomes ranging from prolonged survival after complete resection of localized tumors to rapid progression in metastatic or biologically aggressive disease.131415 Prognostic stratification therefore has implications for postoperative surveillance, consideration of adjuvant therapy, interpretation of treatment outcomes, and risk adjustment in research cohorts.15

Across both historical series and contemporary registries, extent of disease at presentation remains the dominant determinant of outcome.161713 This is a reliable and durable finding, but stage alone does not fully explain prognosis because patients with similar anatomic disease burden may differ substantially according to pathologic grade, hormonal excess, age, performance status, and resection completeness.104 Clinically, stage anchors prognostic discussions, but additional clinicopathologic features are needed for more meaningful risk stratification.

Major prognostic domains

Stage and anatomic extent

ENSAT stage is the most reproducible prognostic factor in ACC, and survival worsens markedly with regional extension, lymph node involvement, or distant metastases.181920 In advanced disease, retrospective data further suggest that metastatic burden, including the number of involved organs, helps distinguish outcomes within stage IV disease and underlies modified ENSAT approaches.211022

Features of locally aggressive growth also appear prognostically adverse. Venous invasion, large-vessel extension, tumor thrombus, and adjacent organ invasion are repeatedly associated with shorter recurrence-free and overall survival after surgery.232425 This signal is fairly consistent, although definitions and ascertainment vary across studies; practically, such findings support viewing apparently localized tumors as high-risk rather than truly favorable disease.

Surgical and nodal factors

Among patients undergoing resection, completeness of surgery is one of the strongest comparative prognostic variables. R0 resection is consistently associated with better outcomes than R1 or R2 resection, and the adverse effect of residual disease appears graded.142627 This is one of the more reliable observations in the literature; in management terms, margin status remains central to postoperative counseling and adjuvant treatment discussions.

Nodal disease is likewise an adverse prognostic feature, and greater nodal burden may identify additional risk among surgically treated patients.282930 By contrast, whether lymphadenectomy itself improves survival is less certain because nodal sampling is inconsistent and heavily influenced by operative selection and institutional practice.31 The practical implication is that documented nodal positivity is informative, whereas absence of sampled nodal disease may be less reassuring when node evaluation was limited.

Transitioning from anatomic and operative factors to tumor biology, histopathologic markers provide much of the additional prognostic refinement after surgery.

Histopathology and proliferative activity

Among pathologic variables, proliferative markers are the most consistently useful beyond stage. High mitotic activity has long been associated with poor survival, and Ki-67 is now the most widely used postoperative marker for recurrence and mortality risk.3233634 Although thresholds such as 10% or 20% are commonly applied, external validation suggests that risk may increase along a continuum rather than at a single biologically fixed cutoff.9 Clinically, Ki-67 is reliable for broad risk stratification, but exact threshold-based decisions should be interpreted with caution across institutions.

Other adverse histopathologic features include necrosis, atypical mitoses, capsular and venous invasion, poor differentiation, and higher Weiss-family scores.23353612 Tumor size and volume often correlate with outcome, but their independent contribution is less consistent once stage and proliferative activity are considered.3738 The practical message is that pathology can refine postoperative prognosis meaningfully, while interobserver variability and differences in reporting limit strict portability of individual scoring systems.

Hormonal phenotype and clinical presentation

Hormonal activity, especially cortisol excess, is one of the clearest clinical adverse prognostic features in adult ACC.394041 Retrospective cohorts and meta-analytic data suggest that cortisol-secreting tumors are associated with shorter disease-free and overall survival, and mixed secretory phenotypes may identify particularly aggressive disease.4243 This association appears reasonably consistent, although some of the effect may reflect both tumor biology and morbidity from hypercortisolism; clinically, cortisol excess is generally treated as a high-risk feature rather than a descriptive biochemical subtype alone.

Older age, poorer performance status, symptom burden, frailty-related body-composition measures, and some metabolic factors have also been linked to inferior outcomes.444546 These markers are less specific for intrinsic tumor biology and may partly capture treatment tolerance, comorbidity, or more advanced presentation. Their main value is in global risk estimation and comparative research rather than replacing tumor-centered prognostic factors.

Composite models and emerging biomarkers

Because no single variable adequately captures prognosis, several composite models combine stage with biologic and clinical features. GRAS and S-GRAS frameworks, along with postoperative nomograms incorporating age, stage, nodal status, tumor size, secretion pattern, and resection status, show moderate ability to discriminate recurrence and survival after adrenalectomy.4774889 These models are more useful than isolated biomarkers for structured risk estimation, but substantial unexplained variability remains.

A wider range of candidate biomarkers has been proposed, including inflammatory indices, serum albumin, body-composition measures, and molecular features such as SGK1, VAV2, immune-related signatures, TP53-associated variants, and multi-omics classifiers.495051525354 Some studies suggest incremental prognostic value, but most derive from limited retrospective datasets or exploratory analyses without consistent external validation.1112 Blood-based inflammatory markers are of interest, yet they may be confounded by cortisol excess and remain insufficiently established for routine ACC decision-making.55565758 Indirect evidence from other malignancies supports biologic plausibility but does not establish clinical utility in ACC.59

Prognostic assessment across disease settings

The relative importance of prognostic factors changes by clinical setting. In localized resectable ACC, recurrence risk after surgery is driven mainly by stage, margin status, nodal involvement, proliferative activity, and cortisol secretion.476061 These factors are reasonably reproducible across retrospective cohorts, but recurrence remains common even after apparently curative surgery; prognostic assessment is therefore more useful for estimating relapse risk than for assuming durable cure.

In advanced or metastatic ACC, prognosis is influenced more strongly by tumor burden, number of metastatic sites, ECOG performance status, hormonal excess, and treatment-response variables during systemic therapy.216222 This shift is supported by registry and treatment-series data, although heterogeneity in systemic therapy limits direct comparisons. In practice, advanced-disease prognostic models complement rather than replace standard therapeutic decision-making.

Pediatric ACC is usually considered separately from adult prognostic frameworks. Age, tumor volume, stage, and secretion pattern may carry different weights, and pediatric-adapted models appear more appropriate than direct transfer of adult scores.636465 Because pediatric evidence is based on small populations, these findings are informative but still constrained in generalizability.

Limitations and role in management

Across the literature, prognostic factors in ACC are better suited to stratification than to precise individualized prediction. Variability in pathology review, endocrine classification, surgical technique, nodal evaluation, and adjuvant treatment exposure limits direct comparison among cohorts and weakens the certainty of many reported associations.101112 A practical consequence is that concordant high-risk features increase confidence in poor-risk classification, whereas isolated weak or exploratory markers should be interpreted conservatively.

In current management, conventional clinicopathologic variables remain the most actionable prognostic tools. They inform surveillance intensity, adjuvant therapy discussions, and design or interpretation of clinical studies, whereas newer molecular classifiers remain primarily research instruments pending broader validation and standardization.1358

Included Articles

  • PMID 1413845: In a 41-patient surgical series, survival was strongly associated with disease extent: 5-year actuarial survival was 45% after curative resection for local or regional disease, versus 10% at 1 to 2 years for patients with distant metastases. Sex, age, functional status, tumor weight, and OP’DDD use were not significant prognostic factors in this cohort.16
  • PMID 1564827: A small retrospective flow-cytometry study of adrenal cortical tumors found DNA aneuploidy in 2 of 2 evaluable adrenocortical carcinomas and in none of 17 evaluable adenomas; both aneuploid ACC cases died within 1 year, suggesting possible prognostic value of DNA ploidy.66
  • PMID 2325710: In a single-center series of 105 patients with adrenocortical carcinoma, prognosis was poor, with median survival of 14.5 months and 22 percent five-year survival. Age over 40 years and distant metastases at diagnosis were the main adverse prognostic factors, while regional disease shortened disease-free interval after curative surgery.17
  • PMID 2919718: In a retrospective series of 42 adrenocortical carcinomas, mitotic rate was the strongest pathologic predictor of overall survival. Tumors with more than 20 mitoses per 50 high-power fields had markedly shorter median survival than those with 20 or fewer, while atypical mitoses, capsular invasion, tumor size, and weight showed only marginal associations.32
  • PMID 8318407: This study evaluated flow-cytometric nuclear DNA content in adrenocortical tumors and found that ploidy patterns in ACC were associated with outcomes: diploid carcinomas had shorter survival, while hypo/hyperdiploid carcinomas had longer disease-free survival. DNA content was not associated with histologic indices or clinical parameters.67
  • PMID 8678951: In this adrenalectomy series of Cushing syndrome, the subgroup with cortisol-secreting adrenocortical carcinoma had uniformly poor outcomes: all five patients died within 2 years after surgery, and most primary tumors were not resectable. The report highlights markedly worse survival for ACC than for benign adrenal causes of hypercortisolism.68
  • PMID 10025460: In a retrospective series of 46 patients undergoing curative resection for primary ACC, larger tumor size, higher mitotic count, and intratumoral hemorrhage independently correlated with worse overall survival. Combining these pathologic factors separated patients into progressively worse postoperative risk groups.37
  • PMID 10915011: In this single-center surgical series of Cushing’s syndrome, all five patients with adrenocortical carcinoma had far advanced tumors at operation and died within two years, highlighting the very poor prognosis associated with advanced cortisol-secreting ACC.69
  • PMID 11571723: In this retrospective ACC cohort diagnosed since 1980, extent of disease at presentation was the clearest prognostic discriminator: long-term survivors had significantly less extensive disease, while age, sex, tumor size, and hormonal functionality did not distinguish longest from shortest survivors overall.13
  • PMID 11844815: In a retrospective ACC cohort, disease-specific survival was strongly associated with metastatic presentation and adverse morphologic features including venous, capsular, and adjacent organ invasion, necrosis, high mitotic rate, and atypical mitoses. Survival worsened markedly as the number of adverse histologic parameters increased, while mdm-2 overexpression also showed prognostic significance.23
  • PMID 15757066: In a 17-patient single-institution ACC series, median survival declined sharply by Icard stage, from 67 months in stage II to 13 months in stage III and 3 months in stage IV. Worse overall survival was associated with older age, distant metastasis, nonoperative management, positive margins, and venous invasion.18
  • PMID 15844468: In a retrospective pediatric ACC series, worse outcome was associated with age over 33 months, disease duration of 7 months or less, right-sided tumors, systemic hypertension, tumor weight over 250 g, and absent p53 immunoreactivity. Composite clinical and clinicopathologic indices outperformed Weiss-based histology for prognostic separation in this cohort.63
  • PMID 17062775: In metastatic ACC, survival was poor and heterogeneous, with median survival of 20 months after first metastasis. Across derivation and validation cohorts, the number of involved tumoral organs at first metastasis and a high primary-tumor mitotic rate above 20 per 50 high-power fields independently predicted worse survival.21
  • PMID 18187873: In a 17-patient resected ACC series, a Ki67/MIB1 labeling index of 7% or higher was associated with significantly shorter disease-free survival after primary tumor resection, supporting Ki67 as a recurrence-risk marker. Higher Weiss score also correlated with worse disease-free and overall survival.33
  • PMID 18973179: A large US registry analysis found poor survival after ACC resection, with 5-year overall survival of 38.6%. Worse prognosis was associated with older age, poor differentiation, positive margins, and nodal or distant metastases, whereas tumor size was not associated with survival.35
  • PMID 19198016: In a 17-patient retrospective ACC series, estrogen receptor nuclear positivity was observed in 8 tumors and was associated on univariate analysis with lower stage, fewer metastases at presentation, and better 1- and 5-year survival. However, multivariate analysis identified tumor stage, not ER status, as the only independent prognostic factor.70
  • PMID 20592067: In metastatic ACC treated with first-line mitotane plus platinum-based chemotherapy, median overall survival was about 1 year and objective response was 27.3%. On multivariable analysis, achieving a plasma mitotane level of at least 14 mg/L and an objective response to platinum were independent predictors of longer survival.62
  • PMID 21134533: In a retrospective series of 57 patients undergoing curative-intent resection for ACC, large vessel extension into the renal vein or inferior vena cava was associated with markedly worse overall and recurrence-free survival. Multivariable analysis identified large vessel extension, along with stage III or IV disease, as an independent adverse prognostic factor.24
  • PMID 22526034: In a retrospective ACC cohort, CT-based morphometric measures of frailty and body composition, especially lower psoas muscle density, lower lean psoas muscle area, and higher intra-abdominal fat, were associated with worse overall survival and improved prognostic discrimination beyond stage alone.44
  • PMID 23055545: In a large adrenocortical tumor cohort, low SGK1 protein expression in ACC was associated with worse overall survival, with prognostic value independent of ENSAT stage and glucocorticoid secretion. The study also linked reduced SGK1 expression to ACTH-independent cortisol-secreting tumors.50
  • PMID 23343838: In a 24-patient retrospective ACC series, overall survival was strongly associated with disease extent: earlier T stage, lymph node negativity, absence of distant metastases, and lower overall stage correlated with longer survival, while stage IV disease had particularly short mean survival.19
  • PMID 23444945: This retrospective single-center study developed and internally validated a clinicopathologic ACC prognostic score for metastasis or local recurrence using five variables: non-isolated-hyperandrogenic functional pattern, tumor size greater than 7.5 cm, T3/T4 primary tumor, microscopic venous invasion, and mitotic index above 5 per 50 high-power fields.71
  • PMID 24086089: A large tertiary-center ACC cohort showed strongly stage-dependent survival, with median overall survival decreasing from 24.1 years in stage I to 0.89 years in stage IV. Older age, hormonally functioning tumors, advanced stage, and incomplete resection were associated with worse outcomes, while positive margins and advanced stage increased local recurrence risk.14
  • PMID 24268504: In adults with completely resected R0 ACC, clinically overt hypercortisolism at diagnosis was independently associated with worse recurrence-free and overall survival after adjustment for age, sex, stage, and adjuvant mitotane. Adjuvant mitotane’s association with reduced progression did not appear to differ by cortisol secretory status.39
  • PMID 24566897: In a 72-patient adult ACC cohort, carrying at least one less frequent TP53 genotype variant across four analyzed polymorphisms was associated with significantly worse overall survival than common homozygous genotypes, and this association remained significant in multivariable analysis alongside established clinicopathologic factors.72
  • PMID 26013141: In a 72-patient single-institution ACC cohort, median survival was 36 months, with 1-, 5-, and 10-year survival of 52.5%, 41.1%, and 16.4%. Multivariable analysis identified lymph node metastases as an adverse prognostic factor and postoperative mitotane therapy as a favorable prognostic factor for survival.28
  • PMID 26038209: This review emphasizes ACC prognostic stratification using ENSAT staging, proposed modified ENSAT grouping, and GRAS parameters. It highlights stage, resection status, Ki-67 or grade, age, and symptom or hormone-related presentation as key factors associated with recurrence-free and overall survival.1
  • PMID 26191527: This review emphasizes ENSAT staging as the recommended framework for ACC prognosis and treatment planning, with prognosis further refined by resection status and tumor grade. Ki-67 and mitotic count are highlighted as key pathological prognostic markers, and stage-specific survival declines sharply with advanced disease.2
  • PMID 26234285: In a multicenter cohort of 84 patients undergoing ACC resection, elevated preoperative inflammatory indices were associated with worse outcomes: NLR greater than 5 independently predicted shorter disease-specific survival, while PLR greater than 190 was associated with shorter recurrence-free survival. These routine blood-based markers may complement conventional prognostic assessment after surgery.49
  • PMID 26259571: This review emphasizes that stage at diagnosis is the dominant prognostic factor in ACC, while highlighting limitations of the ENSAT system, especially within stage IV. It identifies Ki-67 as the most useful currently available marker for recurrence and survival risk after resection and discusses proposed refinement of advanced-stage stratification.6
  • PMID 26392430: In a large ENSAT registry cohort of stage III-IV ACC, a modified ENSAT classification separating stage III from stage IVa, IVb, and IVc by number of involved organs better stratified overall survival. Prognosis was also independently associated with age, tumor- or hormone-related symptoms, resection status, and higher grade defined by Weiss score and/or Ki-67.10
  • PMID 26408728: In a SEER-based surgical ACC cohort, lymph node dissection was infrequent, but nodal positivity carried prognostic value. More than one positive lymph node was associated with worse cancer-specific survival, suggesting nodal burden may help refine postoperative risk stratification.29
  • PMID 26546184: In a multicenter cohort of 265 patients undergoing ACC resection, postoperative complications were associated with worse overall survival, with infectious complications showing an independent and particularly strong adverse association. Hormone-secreting tumors and a thoraco-abdominal approach were linked to higher postoperative morbidity.73
  • PMID 26676275: This invited commentary highlights a postoperative nomogram for patients undergoing intended curative resection of adrenocortical carcinoma, using tumor size, lymph node metastases, and incomplete microscopic resection to estimate recurrence-free and overall survival. It frames individualized risk stratification as potentially useful for guiding adjuvant treatment decisions.74
  • PMID 26676603: A multicenter curative-intent resection cohort developed internally validated nomograms for recurrence-free and overall survival in ACC. Key adverse prognostic factors included tumor size at least 12 cm, nodal positivity, cortisol secretion, capsular invasion, advanced stage, and R1 margin status.47
  • PMID 26810939: In a multicenter retrospective cohort of resected adult ACC, cortisol-secreting tumors were independently associated with shorter recurrence-free survival after adjustment for patient and disease factors, while not remaining an independent predictor of overall survival. The study also found higher postoperative morbidity in cortisol-secreting ACC, supporting cortisol secretion as a clinically relevant adverse prognostic feature.42
  • PMID 26984275: In a single-centre retrospective ACC cohort, survival worsened markedly by ENSAT stage and by resection margin status, with macroscopically positive margins associated with particularly poor outcomes. Ki-67 above 10% and a pathologic urinary steroid profile showed trends toward shorter survival but were not statistically significant predictors in this series.75
  • PMID 27504106: In a retrospective single-center ACC series, advanced ENSAT stage independently predicted recurrence after R0 resection, while positive resection margins independently predicted mortality. Larger tumor size and higher Ki-67 were associated with worse outcomes on univariate analysis, and isolated hyperandrogenism was linked to better prognosis than cortisol-secreting disease.60
  • PMID 27633419: In a multicenter surgical ACC cohort, actual long-term survival after resection was uncommon, with 27% surviving at least 5 years and 7% at least 10 years. Early mortality was associated with cortisol secretion, metastatic disease, positive margins, capsular invasion, and vena cava involvement, while some 10-year survivors still had nodal or distant metastases or R1 resection.76
  • PMID 27957799: This multicenter pediatric high-risk ACC study found that distant metastases were the dominant adverse prognostic factor, while tumor volume greater than 200 cm3 independently predicted shorter progression-free survival and remained the only significant prognostic factor among localized tumors. Having two or more risk factors was associated with more aggressive disease behavior.64
  • PMID 28009746: In a multi-institutional cohort after curative-intent ACC resection, conditional disease-free survival improved substantially with time already spent recurrence-free, indicating that prognosis is dynamic rather than fixed at surgery. Capsular invasion and functional tumors were independently associated with worse disease-free survival, while adverse baseline features showed the largest conditional survival gains over follow-up.77
  • PMID 28662713: A small retrospective surgical series found that preoperative neutrophil-to-lymphocyte ratio was higher in malignant than benign adrenal tumors, and that ACC had the highest ratio. Within ACC, an NLR of at least 5 was associated with significantly worse overall survival, suggesting a potential prognostic marker requiring further validation.55
  • PMID 28738949: In a multicenter cohort of patients undergoing curative-intent ACC resection, perioperative allogenic blood transfusion was independently associated with shorter recurrence-free and overall survival. Stage IV disease and hormonal hypersecretion also remained independent adverse prognostic factors, while transfused patients more often had larger, more locally advanced tumors and more complications.78
  • PMID 28895102: In resected nonmetastatic ACC with lymph nodes examined, nodal positivity independently predicted worse overall survival, and positive margins also remained prognostic. Among node-negative cases, assessment of at least four lymph nodes was associated with better survival and higher detection of occult nodal involvement than examination of one to three nodes.30
  • PMID 28911143: In a multicenter ACC cohort, high VAV2 expression correlated with shorter progression-free and overall survival and showed low intratumoral heterogeneity. Combining VAV2 with Ki67 improved separation of low-, intermediate-, and high-risk groups, including among patients with R0 resection.51
  • PMID 29475877: This review summarizes prognostic stratification in ACC, emphasizing ENSAT stage as the main survival determinant, with modified ENSAT refining advanced disease categories. It also highlights tumor grade, especially Ki-67 proliferation index and mitotic count, margin status, and emerging molecular classifications as contributors to heterogeneous outcomes.4
  • PMID 29500765: In a national cohort of 1553 patients undergoing ACC resection, both microscopically and macroscopically positive surgical margins were independently associated with worse overall survival versus negative margins, with a graded adverse effect. Median survival was 58 months for negative margins, 22 months for microscopic positivity, and 14 months for macroscopic positivity.26
  • PMID 29726479: In a retrospective Polish series of 66 adults with ACC, worse overall survival was independently associated with older age, ENSAT stage IV, and macroscopically positive margins, while mitotane treatment was associated with better survival. Higher Ki67 and mitotic indices correlated with poorer outcomes in univariate analyses, and recurrence after curative surgery remained frequent even in stage II and III disease.79
  • PMID 29968693: This editorial summarizes prognostic factors in ACC from a 66-patient retrospective Polish series, highlighting worse outcomes with advanced ENSAT stage, R2 resection, older age, and higher Ki-67 or mitotic index. It also notes differing predictors for overall versus recurrence-free survival and supports routine reporting of Ki-67 and mitotic index.80
  • PMID 29982685: A large NCDB analysis found worse overall survival in ACC with older age, higher Charlson-Deyo comorbidity score, high tumor grade, stage IV disease, absence of surgery, and lymphadenectomy on multivariable analysis. Median survival was markedly longer in stage I-III than stage IV disease, underscoring stage and clinicopathologic factors as major prognostic determinants.81
  • PMID 30221891: This review summarizes prognostic stratification in ACC by integrating clinical, pathologic, and molecular factors. It highlights ENSAT and modified ENSAT staging, resection status, age, cortisol excess, mitotic count, and especially Ki-67 as major determinants of recurrence and overall survival.3
  • PMID 30325179: A systematic review and meta-analysis found that cortisol-secreting ACC is associated with worse overall survival and higher recurrence risk even in analyses adjusted for tumor stage, whereas androgen secretion was not clearly associated with survival. The findings support hormonal functional status, especially cortisol excess, as a prognostic stratification factor.40
  • PMID 31471770: In a retrospective single-center cohort of 66 patients with resected ACC, Ki-67 was an independent postoperative prognostic marker, with values above 20% associated with worse overall survival and values above 3% associated with shorter recurrence-free survival. The study suggests different Ki-67 cutoffs may stratify risk of death versus rapid relapse after primary surgery.34
  • PMID 31626211: This review emphasizes marked biological heterogeneity in ACC and summarizes prognostic signals linked to worse outcomes, including overt hypercortisolism after radical resection, older age, mass-effect symptoms, adverse resection status, high mitotic activity, elevated Ki-67, and high SF1 expression, alongside molecular alterations associated with aggressive behavior.15
  • PMID 31646101: In retrospective ACC cohorts, high tumor PDL1 mRNA expression was heterogeneous and independently associated with longer postoperative disease-free survival in nonmetastatic patients, despite no clear correlation with standard clinicopathologic prognostic variables. PDL1-high tumors also showed gene-expression features consistent with a cytotoxic but partially exhausted local immune response.52
  • PMID 32438344: A nationwide South Korean ACC registry found ENSAT stage strongly stratified survival, with 5-year overall survival falling from 91.7% in stage 1 to 30.3% in stage 4. Additional adverse prognostic features included lymph node involvement, venous, sinusoidal, and capsular invasion, large tumor size, and cortisol secretion.20
  • PMID 32705677: In a National Cancer Database cohort of 897 patients undergoing margin-negative curative-intent resection for localized ACC, lymph node examination was uncommon and did not confer a survival benefit. However, nodal positivity, especially a higher number of positive nodes, identified worse prognosis and supports more granular nodal staging.31
  • PMID 33221947: In a 57-patient resection cohort, elevated preoperative inflammatory ratios showed prognostic associations in ACC: high PLR was linked to shorter recurrence-free survival, while both high NLR and high PLR were associated with shorter overall survival on univariate analysis. The study highlights these blood-based markers as possible adjunct prognostic factors but notes limited ability to adjust for competing variables.56
  • PMID 33416409: In a retrospective single-center cohort of 48 ACC patients, preoperative neutrophil-lymphocyte ratio above 3.9 was associated on univariate analysis with worse disease-specific and overall survival, and with higher ENSAT stage, Ki-67, and Weiss score. Its prognostic effect was not independent after multivariable adjustment.57
  • PMID 33521844: A retrospective multi-institutional and single-center analysis suggests that diabetes mellitus and post-diagnosis hyperglycemia are associated with worse ACC outcomes, including more recurrent or persistent disease and inferior overall survival. In one cohort, mean serum glucose above 110 mg/dL was linked to markedly higher all-cause mortality after adjustment for selected covariates.45
  • PMID 33532879: This commentary summarizes evidence that a cumulative GRAS score based on tumor grade, resection status, age 50 years or older, and preoperative hormone hypersecretion symptoms stratifies overall survival after ACC resection, with a three-tiered version also separating disease-free survival.7
  • PMID 33609384: In a single-centre resected ACC cohort, older age, higher ENSAT stage, cortisol secretion, nodal involvement, and possibly higher Ki-67 were associated with worse postoperative survival. Published nomograms showed inconsistent prognostic performance, whereas conditional survival provided more dynamic survival estimates for patients who had already survived after surgery.82
  • PMID 33626208: A multi-omics prognostic model for adult ACC integrating FASN, fibronectin, TFRC, and TSC1 identified a high-risk group with shorter overall survival and remained independently prognostic in multivariable analysis. In a real-world cohort, the model slightly outperformed Ki-67 and correlated with higher stage, T stage, and N stage.53
  • PMID 34277297: A small retrospective ACC cohort found shorter recurrence-free and overall survival associated with secretory tumors, cortisol or androgen excess, Ki-67, mitotic rate, Modified Weiss score, and a composite high-risk variable incorporating ENSAT stage III, mitotic rate at least 10 per 50 HPF, or Ki-67 at least 20. Multivariable analysis identified tumor functional status as the main predictor of recurrence-free survival and the composite recurrence-risk variable as the main predictor of overall survival.83
  • PMID 34445989: In a retrospective cohort of 71 patients with ACC undergoing primary resection, higher preoperative serum albumin was associated with better survival outcomes, with albumin independently predicting overall survival and showing borderline significance for recurrence-free survival. The study suggests routine preoperative albumin may aid postoperative risk stratification alongside established factors such as stage and Ki-67.54
  • PMID 34740271: In a 45-patient single-center ACC cohort, shorter overall survival was independently associated with tumor volume greater than 400 cm3, Weiss score above 5, and p53 overexpression, while melan-A expression and Ki-67 of 4% or less were linked to longer survival. The study also reiterates the prognostic importance of ENSAT stage.84
  • PMID 34850906: This review emphasizes that prognosis in adrenocortical carcinoma is shaped by stage, resection status, Ki-67, and cortisol excess, while noting that clinicopathologic factors alone still misclassify outcomes in a substantial minority of patients. It highlights genomic profiling as an additional layer for risk stratification and more personalized management.11
  • PMID 36178218: In a 73-patient surgical ACC cohort, independent prognostic factors were mitotic activity and hormonal activity for recurrence-free survival, and mitotic activity plus ENSAT stage for overall survival. Higher recurrence or death risk was associated with mitotic count over 20, Ki-67 above 12, classic histologic variant, pathologic mitoses, aldosterone excess, and ENSAT stage IV.85
  • PMID 36193775: This systematic review of 733 pediatric adrenocortical tumor cases found that a modified pediatric S-GRAS score correlated with overall survival. Favorable factors included age under 4 years, androgen-only hormone production, and lower-risk stage and grade patterns, supporting pediatric-specific risk stratification rather than direct transfer of adult models.65
  • PMID 36246926: In a retrospective single-centre ACC cohort, poorer overall survival was associated with ENSAT stage III-IV disease, Ki-67 greater than 10%, non-R0 resection, and hormonally active tumors, especially cortisol-secreting phenotypes. Hormonal activity remained an independent prognostic factor in multivariate analysis.61
  • PMID 36952130: In a multicenter retrospective cohort of 79 surgically treated conventional ACCs, microscopic tumor necrosis emerged as the strongest individual Weiss parameter for prognosis, independently predicting worse overall and disease-free survival and shorter time to recurrence, including after complete resection.36
  • PMID 37498296: In a TCGA-based pan-cancer analysis, higher NCAPD2 expression in adrenocortical carcinoma was associated with more advanced clinical stage and worse overall and disease-specific survival. The study suggests NCAPD2 as a potential prognostic biomarker in ACC, though the evidence is exploratory and not ACC-specific.86
  • PMID 37640703: In a pan-cancer genomic analysis, adrenocortical carcinomas with core histone mutations were associated with significantly shorter progression-free and overall survival than histone-wildtype ACC. Core histone mutations were also enriched in the poor-prognosis CoC3 molecular subtype of ACC.87
  • PMID 37690343: This review emphasizes ENSAT stage and the GRAS framework as the best validated clinical prognostic tools in ACC, highlighting adverse effects of nodal involvement, incomplete resection, high Ki-67, older age, and cortisol excess on recurrence and survival. It also summarizes stage-specific relapse and overall survival estimates.5
  • PMID 37945477: A large multicenter retrospective ACC study found that hormonal secretory subtype carries prognostic information: mixed cortisol/androgen secretion was independently associated with worse overall survival, while cortisol secretion was associated with worse disease-free survival after R0 resection. Higher Ki-67, older age, and advanced stage also predicted poorer outcomes.43
  • PMID 37950078: A pan-cancer analysis identified CDK6 expression as a prognostic marker in adrenocortical carcinoma, with higher expression associated with worse overall survival in a 77-patient ACC cohort and a hazard ratio of 1.806.88
  • PMID 37953139: A large National Cancer Database study validated a prognostic model for surgically treated ACC that estimates 5- and 10-year overall survival using age, comorbidity, insurance status, tumor size, pathologic T/N/M category, margin status, and adjuvant chemotherapy and radiation. Model discrimination was moderate in validation, with AUCs of 0.70 for 5-year and 0.72 for 10-year survival.48
  • PMID 38384443: A large retrospective referral-center cohort identified mortality predictors in adult ACC, with advanced ENSAT stage, larger tumor size, incomplete resection, higher Ki-67, steroid hypersecretion, and adverse histopathologic features linked to worse survival. Weiss, modified Weiss, and Helsinki scores also showed strong prognostic stratification.12
  • PMID 38571632: A SEER-based study of 426 adults with ACC found tumor size to be an independent prognostic factor, with tumors larger than 8.5 cm associated with worse cancer-specific and overall survival after adjustment for age, metastasis, surgery, and other covariates.38
  • PMID 38626660: In a multicenter retrospective ACC cohort, survival differed markedly by stage, with median overall survival of 87.3 months in stage 2, 25.8 months in stage 3, and 13.3 months in stage 4 disease. In nonmetastatic patients, older age, higher Ki-67, worse ECOG performance status, and hormonal activity were independent adverse prognostic factors.46
  • PMID 38721297: A SEER-based prognostic nomogram for ACC, externally validated in a Chinese cohort, used age, T stage, N stage, M stage, and chemotherapy history to estimate 1-, 3-, and 5-year overall survival. The derived risk classification separated low- and high-risk groups with markedly different median overall survival.89
  • PMID 39041556: In a single-center retrospective surgical cohort, ACC with venous tumor thrombus was usually advanced at presentation and was associated with substantially worse outcomes than ACC without thrombus, including shorter median survival and recurrence time and lower 3-year overall survival and 2-year recurrence-free survival.25
  • PMID 39080085: A retrospective study of 42 resected ACC cases found that a lower fibrinogen change value, defined as a smaller drop from preoperative to 1-month postoperative fibrinogen, was associated with higher stage, higher Ki-67, and independently shorter relapse-free survival, but not overall survival.90
  • PMID 39427460: In a large NCDB cohort of adults undergoing curative-intent resection for nonmetastatic ACC, positive surgical margins were independently associated with substantially worse overall survival than R0 resection, with median survival 22.9 versus 78.8 months and adjusted hazard ratio 1.89. The adverse prognostic effect of R1/R2 status appeared to lessen over time as adjuvant therapy use increased.27
  • PMID 39432022: A 2024 systematic review and meta-analysis found that hormonally active ACC is associated with worse prognosis, including inferior overall survival and disease-free survival versus nonsecreting tumors. Cortisol-secreting ACC specifically also showed increased hazards of death and recurrence, supporting hormone secretion as an adverse prognostic feature.41
  • PMID 39950976: This study validates machine learning models built from S-GRAS variables in adults with resected ACC to predict 5-year overall mortality and 1-year and 3-year disease progression. It supports S-GRAS-based individualized prognostic stratification and provides an externally validated web tool for clinical risk estimation.8
  • PMID 40100700: In an international pediatric ACC cohort, pretreatment inflammation-based blood indices were evaluated as prognostic markers, with monocyte-to-lymphocyte ratio of at least 0.28 and stage IV disease independently associated with worse overall survival after multivariable adjustment. The study suggests these markers may aid risk stratification in pediatric ACC but require further validation.91
  • PMID 40810251: This multicenter external validation study found that the S-GRAS score provides moderate discrimination and good calibration for recurrence-free and overall survival after adrenalectomy in ACC. Spline modeling of Ki-67 improved prognostic precision, while additional clinical variables added little and substantial recurrence variability remained unexplained.9
  • PMID 41510077: In a single-center retrospective Chinese ACC cohort, preoperative neutrophil-to-lymphocyte ratio above 3.9 independently predicted worse disease-specific survival alongside higher Ki-67 and advanced ENSAT stage. Cortisol-secreting cases had higher NLR, suggesting hypercortisolism can confound interpretation of this inflammatory prognostic marker.58
  • PMID 41790725: A multicenter ENSAT study in 418 patients with advanced ACC receiving systemic therapy found that tumor burden, cortisol excess, ECOG performance status, and neutrophil-to-lymphocyte ratio independently predicted worse overall survival. An integrated ENSAT Risk Score using these variables also stratified time to progression and treatment response across mitotane, EDP-based, and second-line regimens.22
  • PMID 32977754: A multicenter retrospective study in castration-resistant prostate cancer found higher pretreatment neutrophil-to-lymphocyte ratio to be independently associated with shorter overall survival during abiraterone or enzalutamide treatment. For ACC, the article is only indirectly relevant and supports cautious interest in inflammatory markers without providing ACC-specific validation.59

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