Taylor & Francis Taylor & Francis Group
Endocrine
Research
informa
Sarcopenia is Associated with Reduced Survival following Surgery for Adrenocortical Carcinoma
Mechteld C de Jong, Neel Patel, Zaki Hassan-Smith, Radu Mihai & Shahab Khan
To cite this article: Mechteld C de Jong, Neel Patel, Zaki Hassan-Smith, Radu Mihai & Shahab Khan (2021): Sarcopenia is Associated with Reduced Survival following Surgery for Adrenocortical Carcinoma, Endocrine Research, DOI: 10.1080/07435800.2021.1954942
To link to this article: https://doi.org/10.1080/07435800.2021.1954942
Published online: 03 Aug 2021.
Submit your article to this journal ☒
Article views: 15
Q
View related articles
☒
View Crossmark data ☒ CrossMark
Taylor & Francis Taylor & Francis Group
W Check for updates
Sarcopenia is Associated with Reduced Survival following Surgery for Adrenocortical Carcinoma
Mechteld C de Jong Da, Neel Patelb, Zaki Hassan-Smith (De, Radu Mihai Da, and Shahab Khan iDa
ªDepartment of Endocrine Surgery - Churchill Cancer Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; bDepartment of Radiology - Churchill Cancer Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; “Centre for Endocrinology, Diabetes & Metabolism, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
ABSTRACT
Aim: Adrenocortical cancer (ACC) is an aggressive malignancy and robust prognostic factors remain unclear. The presence of sarcopenia has been shown to negatively impact survival for other malignancies, but has not been extensively analyzed in ACC.
Methods: Patients who underwent resection of their ACC between 2010 and 2020 were identified; therapeutic, operative, and outcome data were analyzed. Sarcopenia was assessed by calculation of the skeletal muscle index (SMI) and was defined as an SMI <52.4cm2/m2 for males and <38.5cm2/m2 for females.
Results: Data on 35 patients (18 F: 17 M; median age 54 [range: 18-86]) who had primary surgical treatment were analyzed. Median tumor size was 10 cm [range:3-15]. In eleven patients (31%), the tumor was hormonally active (cortisol = 8;23%). Seventeen patients (49%) were classified as having sarcopenia on their pre-operative CT scan. The Intraclass Correlation Coefficient (ICC) for intra- and inter-observer variability showed very good agreement (0.99 and 0.98). There was no difference in incidence of sarcopenia stratifying for sex, BMI, or tumor-size, but incidence was higher with increasing age (p < . 05). Overall median survival was 36 months, with 1- and 3-year survival rates of 77% and 52%. The presence of sarcopenia was strongly associated with a shorter overall survival (HR = 3.21; [95%CI: 1.06-9.69];p = . 03) on unadjusted analyses. Moreover, age, higher T-stage, and presence of capsular invasion were also associated with poorer survival on univariable analyses.
Conclusion: The presence of sarcopenia in patients undergoing surgery for ACC could be a predictor of reduced overall survival, although replications of these analyses should be performed in similar, larger cohorts. Specifically, the influence of a patient’s hormonal status on the manifesta- tion of sarcopenia should be further defined.
ARTICLE HISTORY
Received February 22, 2021 Revised May 04, 2021 Accepted July 07, 2021
KEYWORDS
Adrenocortical cancer; survival; sarcopenia
Introduction
Adrenocortical cancer (ACC) is an uncommon and deadly malignancy, with a reported incidence of 1-2/ million population/year.1 Complete surgical resection is the only potential option for cure for localized disease, with reported 5-year survival rates after curative intent resection ranging from about 40-51%.2-4 Long-term survival may be estimated using clinical (i.e. hormonal functionality of the tumor5,6 and a patient’s age7) or pathological parameters (i.e. tumor stage,8 proliferation index of the tumor (e.g. the Weiss score)9 and Ki67 immunostaining10). These were incorporated into sev- eral nomograms; however, their performance was poor when tested in a large patient cohort.11 While molecular and genetic biomarkers might provide better a risk stra- tification, so far these have not yet proven to be feasible in routine clinical practice. 12-14
Sarcopenia, defined as the progressive and general- ized loss of muscle mass and function, is generally asso- ciated with aging (i.e. primary sarcopenia), but cachexia in malignancy can also contribute to its development (i.e. secondary sarcopenia).15 Moreover, while sarcope- nia can be viewed as a surrogate for overall frailty of the patient, defined as a syndrome consisting of the loss of physiological reserve, homeostatic mechanisms, and susceptibility to adverse outcomes, its presence has unsurprisingly been associated with an increased inci- dence of post-operative morbidity among patients undergoing surgery for numerous malignancies,16 such as perihilar cholangiocarcinoma,17 colorectal liver metastasis,18 and urologic oncologic diseases.19 Furthermore, the presence of sarcopenia on pre- operative imaging was found to be associated with a decreased overall survival for patients with various types of malignancies, including esophageal cancer,2
distal cholangiocarcinoma22 and gastric cancer.23,24 It is therefore considered that the presence of sarcopenia might indirectly provide information about the biologi- cal behavior of the tumor.
Limited previous data on sarcopenia among patients with ACC has been published thus far.25,26 As ACC is a very rare disease, large (prospective) multicenter stu- dies to further assess this question will be virtually impossible to set up. The aim of the current study was therefore to assess the prognostic impact of preoperative sarcopenia in patients who underwent surgery for adre- nocortical carcinoma at a tertiary referral center.
Methods
Patient Group
A departmental database was used to identify patients who underwent a resection for ACC between 2010 and 2020 in a tertiary referral center (Oxford University Hospitals Trust, Oxford, United Kingdom). Clinical data were prospectively collected and retrospectively analyzed as part of an ongoing audit of outcomes after surgery for endocrine tumors.
Standard demographic (age, sex), clinical (site and functionality of the tumor), and operative data (type and extent of surgery) were collected. Moreover, histo- logical variables (size of the tumor, ki-67 index,1º resec- tion-margin, and TNM-status27) were noted. The receipt of adjuvant mitotane treatment was also recorded. Short-term outcomes (length of stay and development of post-operative morbidity (classified according to minor (Dindo-Clavien grade <3) versus major (Dindo-Clavien grade ≥3)))28 as well as oncolo- gical outcomes (recurrence of disease and overall survi- val) were recorded.
Pre- and Post-Operative Work-Up
All patients underwent standardized formal work-up as per European Guidelines,29 consisting of a full hormonal work-up, including a urine-steroid profile and fractio- nated metanephrines in 24 hour urine or free plasma- metanephrines; and imaging studies with a CT scan or MRI scan of the abdomen and pelvis and a chest CT scan. In selected cases, an FDG-PET/CT scan was also performed. All patients were discussed in a multidisciplinary adrenal meeting, in the presence of at least one dedicated endocrine surgeon, endocrinolo- gist, oncologist, radiologist, and pathologist both before and after their surgical procedure. The decision for adjuvant treatment with mitotane was also formalized during this meeting.
Follow-up was also carried out in accordance with international guidelines,29 with regular cross-sectional imaging of the abdomen, pelvis, and chest for disease recurrence or progression. Radiological imaging there- fore was obtained approximately every 3 months for a duration of 2 years, and then every 3-6 months for at least a further 3 years. Regular screening for hormone secretion was concomitantly undertaken.
Measurement of Body Composition
CT scans obtained within 30-days before surgery were analyzed by two authors (MdJ and SK). A cross-sec- tional slice at the level of L3 was extracted (Figure 1a. and Figure 1b) and analyzed using CoreSlicer (https:// coreslicer.com), a validated web-based tool to assess body composition semi-automatically.30-32 The CoreSlicer tool (Figure 1c.) uses Hounsfield unit ranges of -29 to 150 for skeletal muscle.3º The muscle area was divided by the height squared to calculate the skeletal muscle index (SMI; cm’2m)-33 The SMI-limit for sarco- penia was set at <52.4 cm2/m2 for male patients and <38.5 cm2/m2 for female patients, as based on estab- lished methods.34
Statistical Analyses
Summary statistics were obtained and presented as percentages or median values. Upon comparing cate- gorical data, the x2-test, or if deemed appropriate Fisher’s exact test, was used, while the Mann- Whitney U-test was used to compare continuous data. The inter- and intra-observer variabilities were calculated using the Intraclass Correlation Coefficient (ICC). A value has a maximum of 1.0 when agreement was considered perfect, while a value of 0 indicated no agreement better than chance agreement. Values between 0 and 1 were interpreted according to estab- lished methods.35
Factors associated with overall and recurrence-free survival were examined using cross-tabs and the non- parametric product limit method. Recurrence of dis- ease was defined as the occurrence of either a local recurrence if disease recurred at the resection site or as a distant recurrence. Recurrence-free survival was defined as the time between the day of surgery and the day of diagnosis of recurrent disease. Overall survival was similarly calculated from the day of surgery until the day of death (i.e. any cause). Cox proportional hazards models were developed using relevant clinicopathologic variables to determine the association of each with survival. Relative risks were expressed as hazard ratios (HRs) with 95% CIs.
A.
B.
C.
Overall, a p-value of less than 0.05 was considered significant. All statistical analyses were performed using IBM SPSS Statistics for Macintosh, Version 23.0 (IBM Corp. IMB SPSS statistics, Armonk, NY).
Results
Patient Characteristics
Table 1 details the demographic, clinical, and perio- perative data of the 35 patients who were included in the current analysis. The male to female ratio was almost 1:1, with 49% of patients being male (n = 17). The median age at the time of diagnosis was 54 years [range: 18-86]. In almost one-third of patients, the tumor was hormonally active (n = 11; 31%). In the majority of these patients, there was
over-production of cortisol (n = 8; 23%); while the tumor was producing androgens (with or without concomitant cortisol-production) in five patients (14%).
Sarcopenia
Overall, 17 patients (49%) had signs of sarcopenia on their pre-operative CT scan. To evaluate the degree of agreement shown by the same rater (MdJ) at a distance of time, the intra-rater reliability was calcu- lated, showing an ICC of 0.99 on repetitive measure- ments, with a 95% CI: 0.99-0.99. Moreover, our estimated reliability between measurers (MdJ and SK) showed an ICC of 0.98, with a 95% CI: 0.92- 0.99, therefore presenting evidence to support the
| Variable; n (%) | Number (%); total n = 35 |
|---|---|
| Patient and disease characteristics | |
| Sex (male) | 17 (49) |
| Age (median [range]), years | 54 [18-86] |
| Side of the tumor | |
| Right | 13 (37) |
| Left | 20 (57) |
| Bilateral | 2 (6) |
| Hormonally functional tumor | 11 (31) |
| Perioperative variables | |
| Type of surgery | |
| Open resection | 30 (86) |
| Laparoscopic resection | 5 (14) |
| Extent of surgery | |
| Adrenalectomy only | 13 (37) |
| Multivisceral resection | 22 (63) |
| Histopathological variables | |
| Size of tumor in largest diameter (median [range]), cm | 10 [3-15] |
| T-stage | |
| 1/2 | 19 (54) |
| 3/4 | 16 (46) |
| N-stage | |
| N0 | 9 (26) |
| N1 | 7 (20) |
| Nx | 19 (54) |
| Metastatic disease present | 6 (17) |
| Capsular invasion present | 19 (54) |
| Ki-67 index* | |
| <10% | 10 (29) |
| ≥10% | 8 (23) |
| Resection margin | |
| R0 | 24 (69) |
| R1/2 | 11 (31) |
| Post-operative variables | |
| Length of stay (median [range]), days | 7 [1-36] |
| Post-operative morbidity | |
| None | 19 (54) |
| Minor (Dindo-Clavien grade <3) | 10 (29) |
| Major (Dindo-Clavien grade ≥3) | 6 (17) |
| Adjuvant mitotane treatment | 23 (66) |
| *Excluding missing values |
reliability of this measurement between the two mea- surers (i.e. inter-rater reliability).
There was no difference in incidence between male and female patients, but the incidence of sarcopenia was higher with increasing age (p = . 01). For patients with an age of 55 years or older, the risk of having sarcopenia was increased (OR = 6.24 [95% CI: 1.44-27.06]; p = . 01) There was no increase in the presence of sarcopenia among those with a higher BMI (p = . 69); nor among those with a tumor measuring at least 10 cm (p = . 11). Additional data comparing those with and without sar- copenia are detailed in Table 2.
In the subgroup of 11 patients with hormone-secreting tumors, sarcopenia was present in 2/6 patients (33%) among those with a solely cortisol-producing tumor, while for those with a mixed-hormones producing tumor including cortisol, the incidence was 1/2 patients (50%). None of the three patients whose tumor was androgen- producing had signs of sarcopenia (0/3). Due to the small
number of hormone-producing tumors, no reliable risk- analyses could be performed.
Details of Surgery and Histopathology
The majority of patients underwent an open resection of their ACC (n = 30; 86%). In almost two-thirds of patients (n = 22; 63%) the surgery consisted of more than an adrenalectomy. More details on the surgical procedure are summarized in Table 1. On final histol- ogy, the median tumor size was 10 cm [range: 3-15]. Capsular invasion was present in 19 patients (54%).
Short-term Outcomes
The median length of stay was 7 days [range: 1-36]. Overall, 16 patients (46%) developed post-operative complications. Further details on post-operative mor- bidity are detailed in Table 1. There was no association found between a lower SMI and the development of
| Variable; n (%) | Number (%); n = 35 | p-Value | |
|---|---|---|---|
| Sarcopenia present(n = 17) | No Sarcopenia present (n = 18) | ||
| Sex (male) | 11 (65) | 6 (33) | 0.06 |
| Age (median [range]), years | 64 [29-78] | 50 [18-86] | 0.01 |
| BMI ≥30 | 3 (18) | 5 (28) | 0.69 |
| Hormonally functional tumor | 3 (18) | 8 (44) | 0.09 |
| Side of the tumor, left | 10 (59) | 10 (56) | 0.36 |
| Size of tumor in largest diameter ≥10 cm | 13 (76) | 9 (50) | 0.11 |
| Type of surgery | 0.34 | ||
| Open resection | 16 (94) | 14 (78) | |
| Laparoscopic resection | 1 (6) | 4 (22) | |
| Extent of surgery | 0.11 | ||
| Adrenalectomy only | 4 (24) | 9 (50) | |
| Multivisceral resection | 13 (76) | 9 (50) | |
| Length of stay (median [range]), days | 7 [4-12] | 7 [1-36] | 0.48 |
| Post-operative morbidity | 0.31 | ||
| None | 7 (41) | 12 (67) | |
| Minor (Dindo-Clavien grade <3) | 6 (35) | 4 (22) | |
| Major (Dindo-Clavien grade ≥3) | 4 (24) | 2 (11) | |
| T-stage | 0.60 | ||
| 1/2 | 10 (59) | 9 (50) | |
| 3/4 | 7 (41) | 9 (50) | |
| N-stage | 0.49 | ||
| N0 | 5 (29) | 4 (22) | |
| N1 | 2 (12) | 5 (28) | |
| Nx | 10 (59) | 9 (50) | |
| Capsular invasion present on histology | 9 (53) | 10 (56) | 0.88 |
| Metastatic disease present | 2 (12) | 4 (22) | 0.66 |
| Ki-67 index* | 0.15 | ||
| <10% | 2 (12) | 8 (44) | |
| ≥10% | 5 (29) | 3 (17) | |
| Resection margin | 0.80 | ||
| R0 | 6 (35) | 12 (67) | |
| R1/2 | 5 (29) | 12 (67) | |
| Adjuvant mitotane treatment | 14 (82) | 9 (50) | 0.02 |
| *Excluding missing values | |||
post-operative morbidity (p = . 31). Moreover, the length of in-hospital stay was similar for those with and with- out sarcopenia on their pre-operative imaging (both: median 7 days; p = . 48).
Long-term Outcomes and Predictors of Survival
At time of last follow-up, 17 (49%) patients had devel- oped recurrent disease after a median recurrence-free survival (RFS) of 23 months, with a 1-year RFS of 76% and a 3-year RFS of 43%. Six patients (17%) developed only local recurrence of their disease, 10 patients (29%) developed recurrent disease at one or more distant loca- tions (e.g. lung or liver) and two patients (6%) developed both local and distant recurrence of disease.
Upon exploring factors associated with an increased risk of recurrence of disease (Table 3), the presence of sarcopenia did not seem to impact the risk of recurrent disease (HR = 1.41 [95% CI: 0.53-3.76]; p = . 49). While age and sex of the patient were also not found to be associated with recurrence, the presence of a hormone- producing tumor (p = . 06) bordered on being associated with an increased risk of disease recurrence. A more
advanced T-status was the only factor found to increase the risk of recurrent disease (T3/T4: HR = 3.67 [95% CI: 1.35-9.93]; p = . 01). Due to the small number of included patients, controlling for competing factors by performance of a multivariate analysis was not deemed feasible.
The median overall survival (OS) for all patients was 36 months, with a 1-year OS of 77% and a 3-year OS of 52%. Table 3 displays the factors associated with OS for the whole cohort of patients. Specifically, patients with signs of sarcopenia on their pre-operative imaging had a more than threefold increased risk of an early death (HR = 3.21 [95% CI: 1.06-9.69]; p = . 03; Figure 2). Other factors deemed to be associated with a shortened overall survival on univariate analyses were age of ≥55 years at the time of diagnosis (HR = 7.35 (95% CI: 2.00-26.95), p = . 003), the presence of local invasion or invasion into adjacent organs (i.e. T-stage of 3 or 4) (HR = 5.09 [95% CI: 1.61-16.12]; p = . 006), signs of capsular invasion on histological examination (HR = 3.71 [95% CI: 1.12- 12.26]; p = . 03). There was no statistically significant difference in overall survival between patients with a functional tumor (median overall survival of
| Prognostic factor | Univariate analyses | |||
|---|---|---|---|---|
| Recurrence-free survival Overall survival | ||||
| HR [95%-CI] | p-Value | HR [95%-CI] | p-Value | |
| Age at time of diagnosis ≥55 years | 1.79 [0.68-4.74] | 0.24 | 7.35 [2.00-26.95] | 0.003 |
| Male sex | 0.89 [0.34-2.38] | 0.83 | 0.78 [0.28-2.17] | 0.64 |
| Sarcopenia present | 1.41 [0.53-3.76] | 0.49 | 3.21 [1.06-9.69] | 0.03 |
| Hormonally functional tumor | 2.67 [0.93-7.64] | 0.06 | 1.53 [0.52-4.53] | 0.44 |
| Left-sided tumor | 1.00 [0.38-2.67] | 0.99 | 1.67 [0.55-5.05] | 0.37 |
| Size in largest diameter ≥10 cm | 0.71 [0.27-1.85] | 0.49 | 0.80 [0.28-2.26] | 0.67 |
| Multivisceral resection performed | 1.59 [0.58-4.37] | 0.37 | 2.71 [0.76-9.62] | 0.12 |
| Post-operative morbidity | 0.93 [0.35-2.47] | 0.89 | 1.10 [0.40-3.04] | 0.87 |
| T-status of tumor | ||||
| T1/2 | Reference | Reference | ||
| T3/4 | 3.67 [1.35-9.93] | 0.01 | 5.09 [1.61-16.12] | 0.006 |
| N-status of tumor | ||||
| N0 | Reference | Reference | ||
| N1 | 3.06 [0.55-16.97] | 0.20 | 2.19 [0.48-10.03] | 0.31 |
| Nx | 1.49 [0.33-6.81] | 0.61 | 0.77 [0.20-2.91] | 0.70 |
| Metastatic disease at time of surgery | 2.24 [0.70-7.18] | 0.17 | 1.94 [0.61-6.23] | 0.26 |
| Capsular invasion present | 2.37 [0.89-6.72] | 0.11 | 3.71 [1.12-12.26] | 0.03 |
| Positive resection margin | 1.32 [0.46-3.76] | 0.61 | 2.29 [0.81-6.49] | 0.12 |
1.0
No sarcopenia present
O.A
Proportion surviving
0.6
Sarcopenia present
0.4
0,2
0.0
p=0.03
·
12
24
36
Time after surgery (months)
33 months) with those with a non-producing tumor (64 months) (p = . 44). While the overall survival for patients whose tumor produced cortisol (9 months) was shorter, this difference only bordered on being sta- tistically significant (p = . 07). Multivariate analysis to exclude confounding was not deemed possible due to the limited sample size.
Discussion
Adrenocortical carcinoma (ACC) is one of the most aggressive malignant tumors and robust clinical risk factors to reliably predict long-term outcomes have not
yet been identified.36 Moreover, as molecular testing is presently not readily available to be used in clinical settings, we explored the impact of sarcopenia on the oncological outcomes for patients who undergo curative intent surgery for ACC as a possible marker of aggres- sive tumor biology. Only limited studies have addressed this question of the feasibility of analytical morphomics and the evaluation for sarcopenia in ACC,25,26 as the concept of diminished survival among those with sarco- penia who underwent treatment for ACC was first pro- posed by Miller et al.26 This group initially explored the possibility to assess sarcopenia objectively in patients with hypercortisolism, by assessing the psoas muscle
density for these patients.25 In their follow-up study, specifically aimed at using analytical morphomics for predicting survival in ACC patients, 125 patients with ACC (stage I-IV) were included. Several morphometric measures, including psoas muscle density (PMD), lean psoas muscle area (LPMA), and intra-abdominal fat (IA), were recorded from CT scans. As for other types of malignancies, these authors describe a diminished length of survival for ACC patients with a decreased muscle mass, although about a quarter of patients included in this study were stage IV at inclusion, and it is therefore likely that not all patients underwent surgery with curative intent, but were receiving palliative med- ical therapies instead.
There are potential advantages of sarcopenia over other frailty scoring methods, as it is objective, quan- titative, and non-cumbersome. Furthermore, the CT scan needed to assess this morphometric parameter is already an integral step in patients’ oncological and surgical work-up, thus there is no need for any addi- tional testing or imaging to be conducted. Moreover, with the current study, we also showed it being fea- sible to obtain morphometric measures using a freely available, validated web-based tool to assess body composition semi-automatically (i.e. CoreSlicer (https://coreslicer.com),30-32 thereby virtually bring- ing these measurements to the surgeon’s desktop. Our analyses of the inter- and intra-observer variabil- ities showed a very strong agreement, thus underlin- ing both a good intra-rater and a good inter-rater reliability. Additionally, sarcopenia is theoretically modifiable, as it could be targeted with exercise strategies.
The current study is based on a fairly typical cohort of patients undergoing curative intent surgery for their ACC,36 reporting on 35 patients from a single institution, with a median age of 54 years and a male-to-female ratio of 1:1. The median size of the tumor was 10 cm, for which the large majority of patients underwent an open resection and in almost two-thirds of patients the operation was more exten- sive than an adrenalectomy only. A relatively small subgroup of 11 patients was found to have a hormone-producing tumor; with most patients hav- ing a cortisol-producing ACC.
Complications following surgery for ACC are thought to be fairly common, probably in a large part owing to the extent of the surgery undertaken. 37,3 Among our cohort, no difference in the occurrence of complications and the presence of sarcopenia could be identified. While there are some groups who corroborate this finding,32,39 several others have described an asso- ciation between sarcopenia and the occurrence of post-
operative morbidity.40-42 The lack of an association between a decreased SMI and the occurrence of post- operative morbidity among the current cohort of patients could partly be due to the already relatively high incidence of complications known to be associated with this type of cancer-surgery or to the presence of unavailable data, such as more clinical data on malnu- trition, fitness, and frailty.
The overall median RFS for our cohort was 23 months and the median OS for all patients was 36 months, comparable to survival-data reported by other groups.8,43,44 The presence of a diminished SMI did not seem to influence the risk of recurrent disease. However, patients with signs of sarcopenia on their imaging prior to surgery had a significantly shorter OS (p = . 03). Moreover, on risk-stratification analysis, patients with an SMI below the sarcopenia threshold, had a more than threefold increased risk of an early death (HR = 3.21). Additional factors deemed to be associated with a shortened OS were an increased age at the time of diagnosis, as patients over the age of 55 had a significantly worse OS compared with patients under 55 years of age, similar to previous data,45 and a more advanced T-stage of the tumor as corroborated by others8 as well as signs of capsular invasion on his- tological examination.9
Due to the limited number of patients included, no further analyses could be undertaken to assess the con- founding or correlation between one or more of these variables. And while sarcopenia, unlike other variables included in the current staging systems, could be viewed as a potentially more individual factor predicting a patient’s prognosis, the strength of this variable prob- ably lies more in the cumulative effect of combining it with other known risk factors. This is also emphasized by the higher incidence of sarcopenia among those patients in whom factors traditionally deemed to impact survival are present (e.g. increased age) and therefore further analyses are needed to address the question of sarcopenia as a risk factor or as a surrogate for other (known) adverse variables.
Unlike in most other malignancies, reduced muscle mass among patients with ACC is most likely not merely due to a combination of cancer cachexia and a patient’s other comorbidity. While sarcopenia in other types of malignancy can probably, at least partly, be explained as a result of cancer cachexia, its presence among patients with ACC is presumably a product of not only cachexia but also of the added hormones’ influences on muscle metabolism as muscle atrophy is thought to be a key feature of endocrine dysregulation.46 The SMI has, for instance, been shown to be significantly impacted by hypercortisolism.25 Moreover, the importance of the
relationship between glucocorticoid secretion/metabolism and muscle phenotype has been demonstrated in various models (e.g. cell culture, animal models, and human observational studies)47-49 Additionally, in a cohort of patients with pheochromocytoma, it was shown that these had a reduced SMI and therefore, catecholamine excess likely also has an adverse effect on skeletal muscle metabolism.50 Conversely, testosterone has been shown to improve sarcopenia. And while in our cohort we could not identify differences in long-term outcomes between those with functioning tumors and those whose tumors did not produce hormones, this could simply be a result of our small sample size or under-reporting of hormonal status. Moreover, we were unfortunately also unable to analyze the differences in sarcopenia among those with functional tumors or the specific subgroups of hormones tumors were producing. Other groups have indeed shown that hormonally active tumors tend to have worse long- term outcomes.5,6 Therefore, additionally to an overall index of patients’ frailty, sarcopenia in patients with ACC could be a true surrogate of their tumor biology.
The present study has several limitations associated with its retrospective nature. Specifically, we did not have details on other parameters related to sarcopenia, such as muscle strength and gait speed. Moreover, the included number of patients appears relatively low, but this is unavoidable when analyzing patients with an exceedingly rare condition treated in a single institution. While this, on one hand, only stresses the highly selected nature of the cohort of patients with ACC who are considered for resection, the small sample size has sta- tistical disadvantages. Specifically, we were unable to properly control for competing factors and exclude con- founding, as multivariate analyses were not deemed appropriate due to the relatively small number of patients in each group or unavailability of necessary data. Another limitation is the relatively low proportion of patients with a hormonally active tumor (31%). With the current study set-up, we were relying on the blood- and urine tests performed during the workup of our patients, causing a possible bias. More recently, evalua- tion of a full urine steroid profile was introduced in the assessment of patients with an ACC, as a more accurate method to assess production of excess/abnormal ster- oids. However, at the time of treatment of the vast majority of the current cohort, such tests were not yet commercially available and were therefore not per- formed. It could thus be that we were unware of abnor- mal hormone levels ofsome of the patients included. We specifically did not perform any risk-analyses based on the presence of hormonal over-activity or the type of hormones that was produced.
In summary, the presence of sarcopenia in patients undergoing surgery for ACC correlates with a shorter overall survival, in this single center study. This finding has a potential to further refine the prognostic models currently used in clinical care. However, as ACC is a rare disease, we advocate for multi-center-based studies, to clarify these findings further and specifically to examine the underlying mechanisms of this association, and thus to define the influence of different subtypes of hormon- ally active tumors on patients’ muscle metabolism.
Conflicts Of Interest/Competing Interests
The authors report no conflict of interest
Data Availability Statement
Due to the nature of this research, participants of this study did not agree for their data to be shared publicly, so supporting data is not available.
Ethical Approval
All procedures performed in this study were in accordance with the ethical standards of our institution and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This retrospective study was registered as an audit of our current practice with our IRB and was exempt from review.
Informed Consent
Not applicable; anonymized retrospective data analysis, con- sent requirement waived.
Funding
The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article
ORCID
Mechteld C de Jong (D http://orcid.org/0000-0003-0279-867X Zaki Hassan-Smith (D http://orcid.org/0000-0002-8387-3039 Radu Mihai (D http://orcid.org/0000-0001-6153-1970 Shahab Khan (D http://orcid.org/0000-0001-8698-8299
References
1. Fassnacht M, Allolio B. Clinical management of adre- nocortical carcinoma. Best Pract Res Clin Endocrinol Metab. 2009 Apr;23(2):273-289. doi:10.1016/j. beem.2008.10.008.
2. Fassnacht M, Libe R, Kroiss M, Allolio B. Adrenocortical carcinoma: a clinician’s update. Nat
Rev Endocrinol. 2011 Jun;7(6):323-335. doi:10.1038/ nrendo.2010.235.
3. Ayala-Ramirez M, Jasim S, Feng L, et al. Adrenocortical carcinoma: clinical outcomes and prognosis of 330 patients at a tertiary care center. Eur J Endocrinol. 2013 Dec;169(6):891-899. doi:10.1530/EJE-13-0519.
4. Puglisi S, Calabrese A, Basile V. et al., New perspectives for mitotane treatment of adrenocortical carcinoma. Best Pract Res Clin Endocrinol Metab. 2020 Mar 5: 101415. doi:10.1016/j.beem.2020.101415.
5. Abiven G, Coste J, Groussin L, et al. Clinical and biolo- gical features in the prognosis of adrenocortical cancer: poor outcome of cortisol-secreting tumors in a series of 202 consecutive patients. J Clin Endocrinol Metab. 2006 Jul;91(7):2650-2655. doi:10.1210/jc.2005-2730.
6. Berruti A, Fassnacht M, Haak H, et al. Prognostic role of overt hypercortisolism in completely operated patients with adrenocortical cancer. Eur Urol. 2014 Apr;65 (4):832-838. doi:10.1016/j.eururo.2013.11.006.
7. Libe R, Borget I, Ronchi CL, et al. Prognostic factors in stage III-IV adrenocortical carcinomas (ACC): an European Network for the Study of Adrenal Tumor (ENSAT) study. Ann Oncol. 2015 Oct;26 (10):2119-2125. doi:10.1093/annonc/mdv329.
8. Fassnacht M, Johanssen S, Quinkler M, et al. Limited prognostic value of the 2004 international union against cancer staging classification for adrenocortical carci- noma: proposal for a revised TNM classification. Cancer. 2009 Jan 15;115(2):243-250. doi:10.1002/ cncr.24030.
9. Weiss LM, Medeiros LJ, Vickery AL Jr. Pathologic fea- tures of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol. 1989 Mar;13(3):202-206. doi:10.1097/00000478-198903000-00004.
10. Beuschlein F, Weigel J, Saeger W, et al. Major prognos- tic role of Ki67 in localized adrenocortical carcinoma after complete resection. J Clin Endocrinol Metab. 2015 Mar; 100(3):841-849. doi:10.1210/jc.2014-3182.
11. de Jong MC, Khan S, Christakis I, Weaver A, Mihai R. Survival after Surgical Resection of Adrenocortical Cancer: Comparative Performances of Nomograms and Conditional Survival. in print BJS Open; 2021 Jan 8;5(1): zraa036.
12. Li X, Gao Y, Xu Z, Zhang Z, Zheng Y, Qi F. Identification of prognostic genes in adrenocortical car- cinoma microenvironment based on bioinformatic methods. Cancer Med. 2020 Feb;9(3):1161-1172. doi:10.1002/cam4.2774.
13. Assie G, Jouinot A, Fassnacht M, et al. Value of mole- cular classification for prognostic assessment of adre- nocortical carcinoma. JAMA Oncol. 2019 Jul 11. 10.1001/jamaoncol.2019.1558.
14. Crona J, Beuschlein F. Adrenocortical carcinoma - towards genomics guided clinical care. Nat Rev Endocrinol. 2019 Sep;15(9):548-560. doi:10.1038/ s41574-019-0221-7.
15. Cruz-Jentoft AJ, Sayer AA. Sarcopenia. Lancet. 2019 Jun;393(10191):2636-2646. doi:10.1016/S0140- 6736(19)31138-9.
16. Weerink LBM, van der Hoorn A, van Leeuwen BL, de Bock GH. Low skeletal muscle mass and postoperative morbidity in surgical oncology: a systematic review and
meta-analysis. J Cachexia Sarcopenia Muscle. 06 2020;11 (3):636-649. doi:10.1002/jcsm.12529.
17. Otsuji H, Yokoyama Y, Ebata T, et al. Preoperative sarcopenia negatively impacts postoperative outcomes following major hepatectomy with extrahepatic bile duct resection. World J Surg. 2015 Jun;39 (6):1494-1500. doi:10.1007/s00268-015-2988-6.
18. Peng PD, van Vledder MG, Tsai S, et al. Sarcopenia negatively impacts short-term outcomes in patients undergoing hepatic resection for colorectal liver metastasis. HPB (Oxford). 2011 Jul;13(7):439-446. doi:10.1111/j.1477-2574.2011.00301.x.
19. Guo Z, Gu C, Gan S, et al. Sarcopenia as a predictor of postoperative outcomes after urologic oncology sur- gery: a systematic review and meta-analysis. Urol Oncol. 06 2020;38(6):560-573.doi:10.1016/j. urolonc.2020.02.014.
20. Boshier PR, Heneghan R, Markar SR, Baracos VE, Low DE. Assessment of body composition and sarcope- nia in patients with esophageal cancer: a systematic review and meta-analysis. Dis Esophagus. 2018;31(8): Aug. doi:10.1093/dote/doy047.
21. Elliott JA, Doyle SL, Murphy CF, et al. Sarcopenia: prevalence, and impact on operative and oncologic out- comes in the multimodal management of locally advanced esophageal cancer. Ann Surg. 11 2017;266 (5):822-830.doi:10.1097/SLA.0000000000002398.
22. Umetsu S, Wakiya T, Ishido K, et al. Effect of sarcopenia on the outcomes after pancreaticoduodenectomy for distal cholangiocarcinoma. ANZ J Surg. 2018;88(9): E654-E658. 09. doi:10.1111/ans.14304.
23. Kamarajah SK, Bundred J, Tan BHL. Body composition assessment and sarcopenia in patients with gastric can- cer: a systematic review and meta-analysis. Gastric Cancer. 2019;22(1):10-22. doi:10.1007/s10120-018- 0882-2. 01.
24. Su H, Ruan J, Chen T, Lin E, Shi L. CT-assessed sarcopenia is a predictive factor for both long-term and short-term outcomes in gastrointestinal oncology patients: a systematic review and meta-analysis. Cancer Imaging. 2019 Dec;19(1):82. doi:10.1186/s40644-019-0270-0.
25. Miller BS, Ignatoski KM, Daignault S, et al. A quantitative tool to assess degree of sarcopenia objec- tively in patients with hypercortisolism. Surgery. 2011 Dec;150(6):1178-1185. doi:10.1016/j.surg.2011.09.020.
26. Miller BS, Ignatoski KM, Daignault S, et al. Worsening central sarcopenia and increasing intra-abdominal fat correlate with decreased survival in patients with adre- nocortical carcinoma. World J Surg. 2012 Jul;36 (7):1509-1516. doi:10.1007/s00268-012-1581-5.
27. AJCC Cancer Staging Manual. Eighth edition staging. [cited 12 Oct 2020]. https://cancerstaging.org/refer ences-tools/deskreferences/Documents/AJCC% 20Cancer%20Staging%20Form%20Supplement.pdf
28. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004 Aug;240(2):205-213. doi:10.1097/01. sla.0000133083.54934.ae.
29. Fassnacht M, Dekkers OM, Else T, et al. European Society of Endocrinology clinical practice guidelines on the management of adrenocortical carcinoma in
adults, in collaboration with the European network for the study of adrenal tumors. Eur J Endocrinol. 2018;179 (4):G1-G46.doi:10.1530/EJE-18-0608.
30. Mullie L, Afilalo J. CoreSlicer: a web for analytic morphomics. BMC Med Imaging. 2019 Febtoolkit 11;19(1):15. doi:10.1186/s12880-019-0316-6.
31. Drudi LM, Phung K, Ades M, et al. Psoas muscle area predicts all-cause mortality after endovascular and open aortic aneurysm repair. Eur J Vasc Endovasc Surg. 2016 Dec;52(6):764-769. doi:10.1016/j. ejvs.2016.09.011.
32. den Boer RB, Jones KI, Ash S, et al. Impact on post- operative complications of changes in skeletal muscle mass during neoadjuvant chemotherapy for gastro-oesophageal cancer. BJS Open. 2020 Oct;4 (5):847-854. doi:10.1002/bjs5.50331.
33. Portal D, Hofstetter L, Eshed I. et al. L3 skeletal muscle index (L3SMI) is a surrogate marker of sarcopenia and frailty in non-small cell lung cancer patients. Cancer Manag Res. 2019;11:2579-2588. doi:10.2147/CMAR. S195869.
34. Prado CM, Lieffers JR, McCargar LJ, et al. Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gas- trointestinal tracts: a population-based study. Lancet Oncol. 2008 Jul;9(7):629-635. doi:10.1016/S1470- 2045(08)70153-0.
35. Rankin G, Stokes M. Reliability of assessment tools in rehabilitation: an illustration of appropriate statistical analyses. Clin Rehabil. 1998 Jun;12(3):187-199. doi:10.1191/026921598672178340.
36. Mihai R. Diagnosis, treatment and outcome of adreno- cortical cancer. Br J Surg. 2015 Mar;102(4):291-306. doi:10.1002/bjs.9743.
37. Eichhorn-Wharry LI, Talpos GB, Rubinfeld I. Laparoscopic versus open adrenalectomy: another look at outcome using the Clavien classification system. Surgery. 2012 Dec;152(6):1090-1095. doi:10.1016/j. surg.2012.08.020.
38. Margonis GA, Amini N, Kim Y, et al. Incidence of perioperative complications following resection of adre- nocortical carcinoma and its association with long-term survival. World J Surg. 2016 Mar;40(3):706-714. doi:10.1007/s00268-015-3307-y.
39. Lodewick TM, van Nijnatten TJ, van Dam RM, et al. Are sarcopenia, obesity and sarcopenic obesity predictive of outcome in patients with colorectal liver metastases? HPB (Oxford). 2015 May;17(5):438-446. doi:10.1111/ hpb.12373.
40. Joglekar S, Nau PN, Mezhir JJ. The impact of sarcopenia on survival and complications in surgical oncology: a review of the current literature. J Surg Oncol. 2015 Oct;112(5):503-509. doi:10.1002/jso.24025.
41. O’Brien S, Twomey M, Moloney F, et al. Sarcopenia and post-operative morbidity and mortality in patients with gastric cancer. J Gastric Cancer. 2018 Sep;18 (3):242-252. doi:10.5230/jgc.2018.18.e25.
42. Ratnayake CBB, Wells C, Olsson M, Windsor JA, Pandanaboyana S. Sarcopenic obesity and post-operative morbidity after pancreatic surgery: a cohort study. ANZ J Surg. 2019;89(12):1587-1592. doi:10.1111/ans.15431. 12.
43. Saade N, Sadler C, Goldfarb M. Impact of regional lymph node dissection on disease specific survival in adrenal cortical carcinoma. Horm Metab Res. 2015 Oct;47(11):820-825. doi:10.1055/s-0035-1549877.
44. Vanbrabant T, Fassnacht M, Assie G, Dekkers OM. Influence of hormonal functional status on survival in adrenocortical carcinoma: systematic review and meta-analysis. Eur J Endocrinol. 2018 Dec 1;179 (6):429-436. doi:10.1530/EJE-18-0450.
45. Asare EA, Wang TS, Winchester DP, Mallin K, Kebebew E, Sturgeon C. A novel staging system for adrenocortical carcinoma better predicts survival in patients with stage I/II disease. Surgery. 2014 Dec;156 (6):1378-1385. doi:10.1016/j.surg.2014.08.018. discus- sion 1385-6.
46. Clegg A, Hassan-Smith Z. Frailty and the endocrine system. Lancet Diabetes Endocrinol. 09 2018;6 (9):743-752. doi:10.1016/S2213-8587(18)30110-4.
47. Hassan-Smith ZK, Morgan SA, Sherlock M, et al. Gender-specific differences in skeletal muscle 11ß- HSD1 expression across healthy aging. J Clin Endocrinol Metab. 2015 Jul;100(7):2673-2681. doi:10.1210/jc.2015-1516.
48. Morgan SA, McCabe EL, Gathercole LL, et al. 11ß- HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess. Proc Natl Acad Sci U S A. 2014 Jun;111(24):E2482-91. doi:10.1073/ pnas.1323681111.
49. Morgan SA, Hassan-Smith ZK, Doig CL, Sherlock M, Stewart PM, Lavery GG. Glucocorticoids and 11ß- HSD1 are major regulators of intramyocellular protein metabolism. J Endocrinol. 2016;229(3):277-286. doi:10.1530/JOE-16-0011. 06.
50. Lee SH, Kwak MK, Ahn SH, et al. Change of skeletal muscle mass in patients with pheochromocytoma. J Bone Miner Metab. 2019 Jul;37(4):694-702. doi:10.1007/s00774-018-0959-3.