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Diagnosis, treatment, and survival analysis of adrenocortical carcinomas: a multicentric study
Pedro Souteiro 1,2,3 D . Sara Donato4 . Claudia Costa5 . Catarina A. Pereira6 · Joana Simões-Pereira 4,7,8 . Joana Oliveira5 . Sandra Belo1 . Ana Paula Santos5 . Helena Cardoso 6 . Valeriano Leite 4,7,8 . Davide Carvalho 1,2,3 . Isabel Torres 5
Received: 13 September 2019 / Accepted: 14 November 2019 C Hellenic Endocrine Society 2019
Abstract
Introduction Current guidelines specify controversial areas in adrenocortical carcinomas (ACC), such as optimal follow-up time after remission and identification of prognostic markers. We aim to address these topics by analyzing four reference centers in our country.
Methods Cross-sectional multicentric study of 69 patients (mean age: 51.7 ± 16.7 years-old; women, 72.5%). Kaplan-Meier survival curves and Cox regression analysis were used to calculate overall survival and its predictors.
Results Thirty-eight individuals (55.0%) had hormonal autonomous production, and 40.6% of the patients presented with metastasis. Surgery was performed in 84.1% of them. Most of these patients (72.4%) were then assigned to adjuvant therapy, while 27.6% were actively surveilled. Among patients undergoing surgery, those who achieved transient remission presented a longer survival time (66 months) than those who never reached the disease-free status (21 months) (p = 0.021). One patient presented with recurrence more than 7 years after complete tumor resection. The lowest overall survival was observed in patients (n = 11) assigned to palliative care since diagnosis (9 months). Tumor stage was identified as the only independent predictor of survival in our cohort (p = 0.006). Five-year survival was 67% for tumors confined to the adrenal space (stage I/II), 56% for locally advanced disease (stage III), and 0% for metastatic disease (stage IV).
Conclusion This study reinforces the dismal prognosis of ACC, the need for long-term follow-up, and tumor stage as the most important survival predictor. Reviewing medical records in such rare conditions is an opportunity to identify insufficiencies and to improve medical care.
Keywords Adrenocortical carcinoma · Adrenalectomy · Mitotane
☒ Pedro Souteiro pedrobsouteiro@gmail.com
1 Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário de São João, Porto, Portugal
2 Faculty of Medicine, Universidade do Porto, Porto, Portugal
3 Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
4 Department of Endocrinology, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal
5 Department of Endocrinology, Instituto Português de Oncologia do Porto Francisco Gentil, Porto, Portugal
6 Department of Endocrinology, Centro Hospitalar Universitário do Porto, Porto, Portugal
7 NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal
8 Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal
Introduction
Adrenocortical carcinomas (ACC) are rare tumors with an estimated incidence of between 1 and 2 cases per million per year [1, 2]. The majority of these neoplasms exhibit functional autonomy associated with a clinical syndrome of hormonal excess, such as hypercortisolism and hyperandrogenism [3]. Nonfunctioning tumors usually present as abdominal discom- fort or back pain caused by a mass effect [3]. ACC has an ominous prognosis with a median overall survival of about 3- 4 years [4, 5]. The advanced stage at diagnosis, with nearly 40% of cases being detected in patients already presenting with metastases, plays an important role in explaining this dismal scenario [6]. However, more recent series have report- ed that ACC patients are being increasingly diagnosed at ear- lier stages of the disease [7].
The recent Clinical Practice Guidelines on the Management of Adrenocortical Carcinomas in Adults pub- lished by the European Society of Endocrinology (ESE) in collaboration with the European Network for the Study of Adrenal Tumors (ENSAT) provided valuable insights into this aggressive carcinoma and established a standard of care for these patients [4]. Nonetheless, the above document also un- derlines certain areas of incertitude that remain to be clarified, such as the role of mitotane adjuvant therapy in low/interme- diate-risk patients after complete resection, the identification of reliable prognostic markers, and the time of follow-up in patients with long-standing remission.
The aim of this contemporary multicentric study was to characterize the epidemiology, diagnosis, and treatment of ACC patients followed in four referral centers over the last 15 years and to compare these variables with older series on this topic. Another objective was to identify prognostic factors in our cohort and to describe overall survival outcomes.
Methods
Study design and participants
This is a 15-year (from January 2004 to December 2018) retrospective observational study conducted in a cohort of 69 patients diagnosed with ACC and followed at four different centers: Instituto Português de Oncologia de Lisboa Francisco Gentil (Lisbon, Portugal), Instituto Português de Oncologia do Porto Francisco Gentil (Porto, Portugal), Centro Hospitalar Universitário de São João (Porto, Portugal), and Centro Hospitalar Universitário do Porto (Porto, Portugal). Patients’ medical records were reviewed in order to obtain clinical, demographic, biochemical, and imaging data.
All patients were initially evaluated by computed tomogra- phy (CT), and tumor size was defined as the largest axial plane diameter. Pathology records were also reviewed to assess for
Ki-67 proliferative index, resection margins, and the nine fea- tures of the Weiss score (high nuclear grade, high mitotic rate, atypical mitotic figures, low percentage of clear cells within the tumor, diffuse architecture, presence of necrosis, and ve- nous, sinusoid, or capsule invasion) [8]. Only patients with at least four of these high-suspicion criteria were classified as ACCs and enrolled in the present study. A Ki-67 threshold of 10% was used to classify tumors as low or highly prolifer- ative, as suggested by the ESE/ENSAT guidelines [4]. Resection margin status was classified as follows: R0, com- plete resection; R1, microscopic residual tumor; R2, macro- scopic residual tumor; and Rx, presence of residual tumor could not be assessed.
Tumor staging was reported according to ENSAT: stage I, tumors confined to the adrenal gland 5 cm or less in size; stage II, tumors confined to the adrenal gland more than 5 cm in size; stage III, tumors invading the surrounding fat, adjacent organs (such as the kidney, pancreas, spleen, and liver or large blood vessels) or nearby lymph nodes; and stage IV, tumors with metastases to distant sites [9]. Patients were considered disease-free after surgery if there was no evidence of macro- scopic residual disease in the surgical report, histopathological analysis, or postoperative imaging.
Mitotane was usually administered at a starting dose of 1 g/ day and then according to patient tolerance, until reaching a total dose of 3 g-4 g/day. After reaching this threshold, toler- ability and/or mitotane blood levels (aiming at levels between 14 and 20 mg/L) dictate further adjustments.
Statistical analyses
Categorical variables were expressed as frequencies and per- centages and were compared with the chi-square test or Fisher’s exact test, as appropriate. Normal distribution was evaluated using the Shapiro-Wilk test or skewness and kurto- sis. Continuous variables were presented as means and stan- dard deviations and compared using Student’s t-test or me- dians and interquartile ranges (IQR) for variables with skewed distributions. Survival curves were generated using the Kaplan-Meier method, and they were compared by log-rank test. A Cox regression analysis was used to assess in univar- iate and multivariate analyses, the different predictors of over- all survival. Reported p values are two-tailed, and p < 0.05 was considered significant. Analyses were performed with the use of SPSS Statistics 25®.
Results
Diagnosis
The baseline characteristics of our cohort are depicted in Table 1. Patients were mostly females (n = 50; 72.5%), and
mean age at diagnosis was 51.7 ± 16.7 years. Suspected hor- monal hypersecretion (n = 24; 34.8%), abdominal/back pain (n = 22; 31.9%), and adrenal incidentaloma (n = 20; 29.0%) were the most frequent clinical presentations. Individuals di- agnosed during the work-up with an incidentaloma were more frequently males (OR = 4.72; p = 0.030) and had significantly smaller tumors than those presenting with other clinical sce- narios (7.69 ± 3.65 vs. 12.0 cm; p = 0.001).
Regarding the assessment of functional status, 11 patients (15.9%) were not tested for hormonal excess at baseline. Glucocorticoid excess was the most frequently screened by clinicians (n = 55; 79.7%), followed by catecholamines (n = 45; 65.2%), sex steroids (n = 42; 60.9%), and aldosterone (n = 41; 59.4%). Among the screened patients (n = 58), most (n = 38; 65.5%) exhibited hormonal hypersecretion, with cortisol autonomous secretion being the most frequent feature (n = 29), associated (n = 8) or not (n = 21) with hyperandrogenism.
| Baseline characteristics | n (%) |
|---|---|
| Female sex | 50 (72.5%) |
| Age - mean ± SD (years) | 51.7 ±16.7 |
| Clinical presentation | |
| Suspicion of hormonal hypersecretion | 24 (34.8%) |
| Abdominal/back pain | 22 (31.9%) |
| Adrenal incidentaloma | 20 (29.0%) |
| Constitutional symptoms | 13 (18.8%) |
| Unknown | 2 (2.90%) |
| Other | 1 (1.45%) |
| Tumor size (cm) | 10.7 ±5.02 |
| Functional status | |
| Nonfunctional | 20 (29.0%) |
| Glucocorticoids only | 21 (30.4%) |
| Androgens only | 8 (11.6%) |
| Glucocorticoids and androgens | 8 (11.6%) |
| Aldosterone | 1 (1.45%) |
| Not evaluated | 11 (15.9%) |
| Tumor staging | |
| I | 2 (2.90%) |
| II | 28 (40.6%) |
| III | 11 (15.9%) |
| IV | 28 (40.6%) |
| Metastases location | |
| Lungs | 19 (67.9%) |
| Liver | 14 (50.0%) |
| Lymph nodes | 10 (35.7%) |
| Bones | 5 (17.9%) |
| Kidney | 1 (3.57%) |
| Spleen | 1 (3.57%) |
| Brain | 1 (3.57%) |
Metastases (stage IV disease) were common at diagnosis (n =28; 40.6%). Lungs (n = 19; 67.9%) were the most frequently involved organ. The remaining patients presented at stage I (2.9%), stage II (40.6%), and stage III (15.9%). Fifteen pa- tients (21.7%) had been previously diagnosed with other types of tumor: breast cancer (n = 3); brain tumor (n = 2); thyroid papillary cancer (n = 2); uterine cervix cancer (n = 2); and hematological malignancy (n = 2) or other (n = 4).
Treatment
Diagram 1 summarizes the treatment of enrolled patients. A total of 58 individuals (84.1%) underwent surgery as primary treatment. Laparotomy was the preferred approach (n = 47; 81.0%), while the remaining patients (n = 11; 19%) underwent a laparoscopic procedure. Those in the last subgroup were diagnosed with smaller lesions (p = 0.003) and presented at earlier stages (p < 0.001). Regarding pathologic assessment, the Weiss score was mentioned in the histopathologic report of nine patients (15.5%), with a mean score of 6.00 ± 1.94. Among the nine Weiss score features, the presence of necrosis (n=45; 77.6%) and mitotic rate (n = 38; 65.5%) were the most frequently reported, contrasting with the percentage of clear cells within the tumor (n = 17; 29.3%) and the presence of sinusoidal invasion (n = 13; 22.4%). The Ki-67 proliferative index was reported in 29 patients (50.0%), with 32.8% of them having a Ki-67 above 10%. Resection margin status was distributed as follows: R0 (n = 21; 36.2%), R1 (n = 8; 13.8%), R2 (n= 11; 19.0%), and Rx (n = 29; 31.0%).
Among operated patients, 42 (72.4%) were assigned to adjuvant therapy, but only 39 initiated it since three individ- uals deceased or were lost to follow-up shortly after surgery. Mitotane, either in monotherapy (n = 24) or combined with other treatment modalities (n = 15), was the most common adjuvant therapy. In 16 patients, active surveillance was un- dertaken after surgery. Eleven patients (15.9%) were initially
1,0
Stage I
0,8
Overall Survival
0,6
Stage II
0,4
+
+
1
Stage III
0,2
Stage IV
1
0,0
0
25
50
75
100
125
150
175
200
Months
assigned to a palliative strategy due to extensive stage IV disease and/or poor performance status.
Adjuvant mitotane was initiated on average 2.45 ± 1.86 months after surgery and was maintained for 27.0 ± 27.9 months. The median maximum dose of mitotane was 4.00 (1.63) grams. Overall, 26 patients (60.5%) had mitotane blood levels regularly checked, but only nine of them (34.6%) reached therapeutic levels due to the drug intolerance of the remaining individuals. Among those treated with chemother- apy, etoposide + cisplatin (EP) or etoposide + doxorubicin + cisplatin (EDP) regimens were administered in 60% and 40% of the patients, respectively, for 4.2 ± 1.81 cycles. Radiotherapy was pursued in 11 patients and was directed to the adrenal bed in most cases (n = 10; 90.9%), with a mean dose of 38.7 ± 16.5 Gy. In one patient, palliative radiotherapy targeted painful vertebral metastases.
Outcomes and survival analysis
After surgery, 33 patients (56.9%) were classified as disease- free, while 25 patients (43.1%) showed residual disease. Concerning the first group, 19 patients (57.6%) remained disease-free during a median follow-up time of 27.2 (IQR 75.4) months, whereas the remaining 14 patients (42.4%) re- curred after a median time of 22.4 months (IQR 20.7). In one patient, recurrence occurred more than 7 years after the surgi- cal procedure. Recurrences were managed with mitotane (n = 10), a second surgery (n = 8), chemotherapy (n = 5), and/or radiotherapy (n = 3), and the median survival time of these patients was 66.1 months (95% confidence interval [CI] 46.5- 85.8). Three out of these 14 patients, despite experiencing disease relapse, were surgically managed, and they were disease-free at their last visit (median follow-up after recur- rence detection of 39.9 months). Regarding patients with re- sidual disease after surgery, they had a significantly lower median survival time (21.1 months; 95% CI 16.1-26.0) than those who remained disease-free for some time despite having late recurrence (p = 0.021). Patients assigned to some form of palliative care had lower survival than the two other sub- groups (median survival time of 9.23 months; 95% CI 1.16- 17.3; p < 0.001).
Predictive factors for overall survival were studied, as shown in Table 2. In the univariate analysis, older age (p = 0.009) and an advanced tumor stage (p < 0.001) were signif- icantly correlated with lower survival. A positive trend effect on survival was detected in patients in whom the ACC was diagnosed during the adrenal incidentaloma work-up (p = 0.050). After including these variables in a multivariate re- gression model, tumor stage was identified as the only inde- pendent predictor of survival in our cohort (p = 0.006). Figure 1 represents Kaplan-Meier estimates of overall survival according to tumor stage (log-rank test p < 0.001). Five-year survival is 67% for tumors confined to the adrenal space (stage
| Variables | Univariate analysis | Multivariate analysis | ||||
|---|---|---|---|---|---|---|
| HR | 95% CI | p value | HR | 95% CI | p value | |
| Sex (male) | 0.88 | 0.40-1.94 | 0.748 | |||
| Age | 1.03 | 1.01-1.05 | 0.009* | 1.02 | 0.99-1.04 | 0.159 |
| Incidentaloma | 0.41 | 0.17-0.99 | 0.050 | 0.45 | 0.17-1.19 | 0.104 |
| Hypercortisolism | 1.45 | 0.69-3.01 | 0.330 | |||
| Resection status | 0.635 | |||||
| R0 | 1 | |||||
| R1 | 2.20 | 0.63-7.65 | 0.215 | |||
| R2 | 1.49 | 0.50-4.45 | 0.475 | |||
| Rx | 1.58 | 0.60-4.16 | 0.351 | |||
| Tumor stage | <0.001* | 0.006 | ||||
| I/II | 1 | 1 | ||||
| III | 1.63 | 0.54-4.86 | 0.384 | 1.85 | 0.61-5.62 | 0.276 |
| IV | 7.57 | 3.14-18.2 | <0.001* | 4.92 | 1.85-13.1 | 0.001 |
| Ki67>10% | 6.07 | 0.77-48.1 | 0.088 | |||
HR, hazard ratio; CI, confidence interval
*statistically significant (p <0.05)
I/II), 56% for locally advanced disease (stage III), and 0% for metastatic disease (stage IV).
Discussion
The demographic characteristics of our series overlap with others previously described, namely, a peak incidence be- tween 40 and 60 years, with females being more often affected than males (around 3:1 in our cohort) [2, 10]. Our data also confirms that the majority (66%) of the ACC present function- al autonomy and that this is often the clinical presentation that leads to the diagnosis [10]. Hypercortisolism, with or without concomitant hyperandrogenism, was the most common hor- monal abnormality. However, in our study, a higher percent- age of ACC was diagnosed during the work-up of an adrenal incidentaloma when compared with older series (29% vs. 10- 15%) [4]. This finding can probably be explained by the in- creasingly widespread availability of imaging methods and its better resolution. Interestingly, we found that patients diag- nosed with ACC as an incidental finding had significantly smaller tumors, reflecting an early diagnosis before other symptomatic manifestations became apparent. Additionally, they were more frequently males, possibly because the easily recognized virilization features in women lead to a prompt investigation of hormonal hypersecretion. We have verified that 80% of the individuals of our cohort were equally divided between stage II (~40%) and stage IV (~40%) disease, which
Active surveillance (n=16; 27.6%)
Surgery (n=58; 84.1%)
Deceased/LFU (n=3; 2.38%)
Adjuvant treatment (n=42; 72.4%)
Mitotane (n=24; 57.1%)
Mitotane + CTX (n=5; 11.9%)
Mitotane + RT (n=10; 23.8%)
Symptomatic treatment (n=4; 36.4%)
Mitotane + CTX (n=4; 36.4%)
Palliative care (n=11; 15.9%)
Mitotane (n=1; 9.09%)
CTX (n=1; 9.09%)
RT (n=1; 9.09%)
is a recent recognizable trend in the literature. Although older series stated that the majority of patients had metastasis (stage IV) at diagnosis [11, 12], more recent studies report that a larger subset of patients usually present at stage II [7, 13, 14], most likely reflecting the aforementioned improved ac- cess to and quality of imaging studies. Regarding the surgical approach applied, a small subset of our patients with smaller lesions and presenting at an earlier stage underwent a laparo- scopic procedure. Current guidelines confirm that smaller tu- mors without any evidence of local invasion could be reason- ably approached by this technique [4].
We have identified some limitations that may compromise the general care of ACC patients and that can be regarded as valuable learning points. About 15% of our cohort did not go through baseline hormonal assessment as recommended. The Weiss score was described only in 16% of the pathology re- ports. An effort to implement its widespread use should be undertaken considering its diagnostic (a score > 3 indicates ACC diagnosis) and even prognostic usefulness [15, 16]. A similar effort should be made regarding the Ki-67 proliferative index considering that it was reported in only 50% of our cohort and that it has implications in the management of ACC (e.g., a Ki-67 above 10% favors the use of mitotane even in patients with complete resection) [4, 17]. Moreover, mitotane blood level measurement was routinely assessed in 60% of the patients enrolled in this treatment. Previous studies have shown that mitotane levels can predict patients’ out- comes and help to manage drug toxicity [18, 19]. The ESE/ ENSAT guidelines state that starting mitotane within 6 weeks after surgery is the ideal timing and that it should not be
postponed for more than 3 months [4]. In our cohort, we have identified a time lag of 2.5 months, suggesting that earlier mitotane introduction after surgery should be pursued. Finally, the retrospective design of our study can be regarded itself as a limitation, as well the lack of data on postoperative hormonal assessment.
As concerns patient outcomes, we observed that among patients undergoing surgery, those who achieved transient re- mission presented a longer survival time (66 months) than those who never reached disease-free status (21 months). The lowest overall survival was observed in the group of patients assigned to palliative care since diagnosis (9 months). The median time to relapse was 22 months, matching previous publications on this topic [20, 21]. Three patients that present- ed with recurrence during their follow-up were again surgical- ly managed and had no evidence of residual disease at their last visit. This suggests that pursuing the disease-free status could be indicated in patients with a feasible complete resec- tion and a good performance status. Despite the ESE/ENSAT guidelines recommendation that follow-up imaging should be undertaken for at least 5 years after complete resection, there are no published studies to specifically clarify whether this surveillance should be continued after this period [4]. The majority of the authors of these recommendations felt uncom- fortable with completely withholding imaging studies after 5 years and preferred to continue annual surveillance for at least another 5 years. In the present study, we have identified one patient who presented with recurrence 7 years after remission had been attained, reinforcing the hypothesis that a 5-year follow-up may not suffice.
Univariate analysis of prognostic factors identified older age and later disease stage as potential variables associated with re- duced overall survival in our cohort, while the diagnosis of an ACC during the work-up of an adrenal incidentaloma reached a borderline significant correlation with improved survival. Despite a tendency toward shorter survival in patients with a Ki-67 above the 10% threshold, statistical significance was not reached for this parameter (p = 0.088). After adjusting for con- founding factors, multivariate analysis identified disease stage as the only independent predictor of survival as patient’s age and ACC diagnosis during the investigation of an incidentaloma lost their significance. This can probably be explained by the fact that these last two variables mirror disease stage only at diagnosis and are not true predictors per se: older patients are diagnosed at more advanced stages, and those referred due to an adrenal incidentaloma have a more precocious diagnosis. Tumor staging has been consistently identified as the single most important prognostic factor in ACC [9, 22, 23]. Other variables such as Ki-67 immunostaining, hypercortisolism, and resection status have also been recognized as potential determinants of survival in other series [24-27].
In conclusion, this study provides some additional insights into ACC hot topics, namely, the present-day shift toward ACC diagnosis at earlier stages of the disease and, during the evaluation of an adrenal incidentaloma, the need for care- ful follow-up even beyond the first 5 years after complete resection, and the identification of tumor stage as the most important survival prognostic factor. Additionally, reviewing of case series of such rare diseases as ACC is a good oppor- tunity to identify restraints in the management of patients that may put optimal medical care at risk.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflicts of interest.
Ethical approval The study was approved by the Centro Hospitalar Universitário de São João ethics committee, a member of the National Ethics Committee for Clinical Research (authorization number 113/19). All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional research com- mittee and with the 1964 Declaration of Helsinki and its later amend- ments or comparable ethical standards.
Informed consent Authorization to perform this retrospective study without individual consent was granted by Centro Hospitalar Universitário de São João ethics committee providing that patients’ pri- vacy was preserved adequately (authorization number 113/19).
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