On the issue of adrenalectomy using videoendoscopic approaches in adrenocortical cancer

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Introduction

Currently, surgery remains the only treatment option for patients with adrenocortical carcinoma (ACC), potentially providing a complete cure for the disease. The leading clinical prognostic factor is the radicality of the surgery (R0 resection) [1; 2].

The introduction of endovideosurgical technologies marked a new stage in the development of adrenal surgery. M. Gagner was the first to perform laparoscopic adrenalectomy in 1992 [3]. Subsequently, the author reported 97 cases of laparoscopic adrenalectomy with zero mortality, no recurrence of hormonal disorders, and a conversion rate of 3 % [4]. In 1995, S. Mercan et al. published their experience using retroperitoneal access in 8 patients [5]. The advantages of videoendoscopic approaches have been convincingly proven in the works of many authors [6–11]. However, due to the potentially higher probability of damage to the tumor capsule and the non-radical nature of resection, the possibility of using endoscopic surgical technologies in ACC is still actively debated. In addition, in the absence of signs of local invasion and/or regional metastases, according to many authors, an important factor in choosing a surgical approach is the size of the tumor, while there is no clear understanding in the community of endocrine surgeons and oncologists at what tumor size an operation from an endoscopic approach is not permissible.

 An analysis of the results of surgical treatment of patients with ACC using endovideosurgical operations and patients with benign adrenal tumors was conducted in the work of S.I. Emelyanov et al. [12]. The authors conclude that laparoscopic adrenalectomy for stage I ACC (tumor less than 5 cm) provides a high level of safety of surgical intervention; however, the small number of observations (n = 9) and the lack of long-term treatment results do not allow this work to be considered as an argument in favor of videoendoscopic adrenalectomy for ACC. In a larger study by D. Brix et al., based on an analysis of the surgical treatment results of 152 patients with stage I–III of ACC, the median tumor size removed using videoendoscopic approaches was 6.2 cm, while no statistically significant differences were found between the rate of non-radical resection (R1) and tumor capsule integrity violations in the groups of patients operated on using the open and laparoscopic approaches. The recurrence-free and overall survival rates in these groups also did not differ [13]. On the contrary, in the study by B. Miller et al., when analyzing a similar cohort of patients (156 patients with ACC stages I–III), worse results were shown for the endoscopic approach: the occurrence of positive resection margins (R1) or tumor capsule rupture was 14 % higher than in the “open” adrenalectomy group, the overall survival rates of patients after open adrenalectomy, as well as the recurrence-free period, were higher [14]. The average tumor size in the group of patients who underwent endoscopic adrenalectomy was 7.4 cm. More recent studies also show no consensus on the possibility of using video-endoscopic approaches in ACC surgery and the borderline tumor size at which this is appropriate. Thus, in the work of J.J. Hue et al., when analyzing the results of surgical treatment of 999 patients (patients were divided into groups depending on the size of the primary tumor: less than 5 cm, 5–10 cm, more than 10 cm), it was shown that there is no effect of tumor size on survival, but a larger tumor size correlates with a higher frequency of conversion and non-radical resection (R1) in the group of videoendoscopic approaches and, accordingly, an unfavorable prognosis. The authors presented the conclusion that endoscopic technologies for surgical treatment of ACC can be used for tumors smaller than 5 cm [15]. In the work of L.P. Kotelnikova et al., when analyzing the long-term results of surgical treatment of 15 patients, a statistically significant lack of correlation was shown between the indicators of one-year overall survival and the chosen surgical approach [16]. The results of surgical treatment using videoendoscopic access were statistically significantly worse in the work of K. Wu et al. (44 patients, ACC stages I–II) compared to the “open” one: local tumor recurrence and carcinomatosis developed 20% more often, the period without disease progression was shorter. However, 5-year overall and relapse-free survival rates in both groups did not differ significantly [17]. The study by D. Kastelan et al. also did not reveal statistically significant differences in overall and relapse-free survival when analyzing a group of patients with ACC similar in the number of observations (46 patients with ACC stages I–III) , however, in the group of videoendoscopic operations, the median tumor size was smaller (75 and 120 mm, respectively). In addition, the tumors had more favorable clinical and morphological characteristics: the proportion of localized forms was higher, the median Ki67 index was lower [18].

When comparing endoscopic and “open” approaches, no statistically significant differences were found in the rates of non-radical resection (R1), overall and relapse-free survival in a meta-analysis by E. Mpaili et al. (1171 patients) [19]. Meta-analysis (2207 observations) of X. Hu et al. showed that when performing laparoscopic adrenalectomy, non-radical resection and peritoneal carcinomatosis were observed more often, the relapse-free period was shorter, while the overall and relapse-free survival rates did not differ significantly in presented statistics [20].

Russian and international clinical guidelines regulate the use of videoendoscopic approaches for ACC in the following clinical situations: tumor size less than 6 cm, stage I and II disease according to ENSAT (absence of signs of tumor invasion into surrounding structures), sufficient experience of such interventions by the surgeon and the medical institution.

Thus, due to the small number of studies on this topic, differences in their design, the relatively small number of patients included in the studies, the influence of technical aspects of the operation and the personal experience of a particular surgeon on the outcome, it is difficult to make a definitive conclusion about the applicability of endoscopic approaches in the surgical treatment of ACC, which served as the basis for conducting our own study.

Materials and Methods

A single-center retrospective-controlled cohort study for the period from 1998 to 2024 examined the immediate results of surgical treatment of 58 patients with stage I–III adrenocortical cancer and survival rates of these patients. The main group consisted of 23 patients (18 women and 5 men) in whom adrenalectomy was performed using videoendoscopic approaches (lateral laparoscopic – 21, retroperitoneoscopic – 2). The median age of patients was 46 [39; 58] years. In 56 % (13/23) of cases, the tumor was located on the right side, in 44 % (10/23) it was located on the left. The tumor was non-functioning in most cases (83 %, 19/23). In 3 cases, hypersecretion of cortisol with the development of Cushing's syndrome was detected, and in another, hypersecretion of aldosterone with the development of Cohn's syndrome was found. The comparison group included 35 patients (9 men and 26 women) who underwent surgery through an "open" approach - thoracophrenolaparotomy. The median age of patients was 50 [41; 62] years. In 54 % (19/35) of cases, the tumor was located on the right side, while left-sided localization occurred in 46 % (16/35). The tumor was hormonally inactive in 57 % (20/35) of cases. Almost all tumors were cortisol-producing among the hormonally active ACCs, which accounted for 43% (15/35), with the exception of one case in which virilization syndrome was observed. All cases were examined by histology and IHC test with a discussion of the results and a peer review by pathologist. Surgical complications were assessed using the Clavien-Dindo scale. Statistical analysis of the results was performed using Microsoft Office Excel (Office 365 2020) and IBM SPSS Statistics 20. The distribution of quantitative variables was assessed using histograms. Measures of central tendency of quantitative data were assessed by determining the median and quartiles (25th and 75th percentiles (Q₂₅–Q₇₅)). Absolute and relative frequencies were calculated for qualitative variables; Fisher's exact test was used for 2×2 tables to identify differences in variables in the groups under consideration. Survival analysis was performed using the Kaplan-Meier multiplier estimator. Differences were considered statistically significant if the null hypothesis probability (p) was less than 0.05. Time to event in the overall survival analysis was considered as the period from the date of surgery to the date of death from the disease or last contact. The onset of an event was defined as the patient's death from the disease. The time to event for the relapse-free survival analysis was considered the period from the date of surgery to the date of detection of local tumor recurrence and/or distant metastases or the last contact. The onset of an event was defined as the diagnosed local tumor recurrence and/or distant metastases.

Results and Discussion

The tumor size in patients in the main group ranged from 2 to 13 cm (median was 4.8 cm [3.7; 6.1]). The majority of patients (n = 21, 91 %) underwent a standard surgical procedure – adrenalectomy with removal of periadrenal tissue. In 2 cases (9 %), adrenalectomy was supplemented by lymph node dissection (paracaval, lymph node dissection of the renal hilum), and in another case – by marginal liver resection.

The tumor size in patients in the comparison group ranged from 2.5 to 19 cm (median was 8 cm [6; 12]). The majority (n = 32, 92 %) underwent a standard surgical procedure – adrenalectomy with removal of periadrenal tissue. In 8% of cases, extended adrenalectomy was performed: in 2 cases, adrenalectomy was supplemented by marginal liver resection, and in another case, para-aortic lymph node dissection.

There were no intraoperative complications or cases of tumor capsule rupture in either group. When analyzing postoperative complications, two patients in the study group experienced Class I complications according to the Clavien-Dindo scale. In the comparison group, postoperative complications developed more frequently (17 %) and were more severe: 4 class I complications, one class IIIb complication (postoperative bleeding), in one case, acute coronary syndrome developed in the early postoperative period, which resulted in the patient’s death (class V on the Clavien-Dindo scale). All patients included in the study underwent radical surgical treatment, which was confirmed by morphological examination – resection status R0. The study group consisted predominantly of patients with localized forms of ACC: 65 % (15/23) had stage I–II of the disease, 35 % (8/23) had stage III. No cases of invasion into surrounding organs (T4 according to the ENSAT classification) were recorded at this stage. In the comparison group, the proportion of patients with localized forms of ACC was lower and amounted to 54% (19/35), the proportion of tumors with microscopic extraadrenal invasion was 46%, and no cases of invasion into surrounding organs were recorded.

In the study group, the Weiss index varied within 3–6, with a median of 4 [4; 5] points. The median Ki67 of the expression level was 12 % [7; 19.5], with the maximum value being 47 % and the minimum 3 %. In the comparison group, the median Ki67 of the expression level was higher and was 22 % ([11.5; 26], with a minimum value of 7 % and a maximum of 41 %). The median Weiss index was also higher and was 6 [5; 6] points (Table).

When analyzing the long-term results in the study group, the overall 5-year survival rate was 83 %, relapse-free survival was 77 %, while in the comparison group these figures were significantly lower as per statistical data: 64 % (p = 0.037) and 51 % (p = 0.046), respectively (Figure).

 

Characteristics of the main group of patients and the comparison group

Characteristic	Videoendoscopic access		“Open” access		Level of significance of differences p
Number of patients	n = 23		n = 35
Gender	M = 5	F = 18	M = 9	F = 26	0.492
Median age, years	46 [39; 58]		50 [41; 62]		0.326
Side	R = 13 (56 %)	L = 10 (44 %)	R = 19 (54 %)	L = 10 (44 %)	0.547
Hormonal activity, abs. (%)	HNT = 19 (83) SIC = 3 (13) WGA = 1 (4)		HNT = 20 (57) SIC = 14 (40) VS = 1 (3)		0.481
Median tumor size, cm	4.8 [3.7; 6.1]		8 [6; 12]		0.153
Complications (category according to the Clavien-Dindo scale), abs. (%)	I – 2 (9)		I – 4 (11) IIIb – 1 (3) V – 1 (3)		0.631
ENSAT stage, abs. (%)	I–II = 15 (65)	III = 8 (35)	I–II = 19 (54)	III = 16 (46)	0.510
Median Weis Index (points)	4 [4; 5]		6 [5; 6]		0.243
Median Ki67 of the expression level, %	12 [7; 19, 5]		22 [11, 5; 26]		0.071
Five-year relapse-free survival, %	77		83		0.046
Overall five-year survival rate, %	51		64		0.037

Note: HNT – hormonally inactive tumor, SIC – Itsenko-Cushing syndrome, VS – virilism.

 

Fig. Survival: a – relapse-free; b – overall

 

Thus, all patients in both groups underwent radical surgery (R0 resections). Patients operated on using videoendoscopic approaches had fewer postoperative complications, and their severity was less significant. In the group of patientsoperated using videoendoscopic approaches, the overall and relapse-free survival rates were significantly higher, which is probably due to more favorable morphological prognostic factors (the level of Ki67 expression and the Weiss index), and not the chosen approach. In our opinion, if radical surgery is performed, the decisive factor determining the prognosis of the disease is the biological characteristics of the tumor, which is reflected by morphological factors such as the Weiss index and the Ki67 level. As noted above, Russian and foreign clinical guidelines regulate the use of videoendoscopic approaches for ACC smaller than 6 cm in the absence of signs of tumor invasion into surrounding structures (stages I–II of the disease according to ENSAT). In our work, as in a number of works by other authors, cases of radical operations with a tumor size of more than 6 cm [13; 15; 18] with a favorable outcome of surgical treatment are described. In this regard, in our opinion, the size of the tumor is not decisive in choosing a surgical approach, and the factor limiting the use of videoendoscopic operations in ACC are signs of macroscopic local invasion and regional metastases (T4N0–1M0), which complicates radical removal of the tumor.

Conclusions

Videoendoscopic surgery can be considered as an effective method of treating patients with adrenocortical cancer in the absence of invasion into surrounding organs and metastases in regional lymph nodes (at stages T1–T3N0M0 according to ENSAT). Tumor size in these cases is not a decisive factor in choosing a surgical approach, as evidenced by the absence of cases of non-radical resection, satisfactory immediate results, and survival rates for patients operated on using videoendoscopic technologies, even for tumors with sizes 6 cm or larger.

About the authors

Aleksej V. Krivosheev

Moscow Regional Research and Clinical Institute named after M.F. Vladimirskiy

Author for correspondence.
Email: alexeyk275@gmail.com
ORCID iD: 0000-0003-3643-6810

Junior Researcher of the Department of Surgical Endocrinology

Russian Federation, Moscow

Timur A. Britvin

Moscow Regional Research and Clinical Institute named after M.F. Vladimirskiy

Email: t.britvin@gmail.com
ORCID iD: 0000-0001-6160-1342

DSc (Medicine), Head of the Department of Surgical Endocrinology

Russian Federation, Moscow

Hanum G. Babaeva

Moscow Regional Research and Clinical Institute named after M.F. Vladimirskiy

Email: Khanumbabaeva@gmail.com
ORCID iD: 0009-0008-7360-3335

Junior Researcher of the Department of Surgical Endocrinology

Russian Federation, Moscow

References

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