Surgical resection of adrenal metastasis from colorectal cancers: a systematic review

The decision for resection of adrenal metastasis from colorectal cancers remain controversial and there is no proposed standard treatment. The aim of the article is to review the available literature on outcomes and complications rates following adrenalectomy for adrenal metastasis from colorectal cancer.


Introduction
Colorectal cancer is the third most diagnosed cancer worldwide. 1It was estimated that colorectal cancer accounted for 9.7% of all new cancer cases diagnosed and contributed to 11% of all deaths from cancer in 2022 in Australia. 2About two third of patients diagnosed with colorectal cancer will develop distant recurrence. 3Liver and lung are main metastatic site for colorectal cancers, while adrenal metastases from colorectal cancers occur less commonly. 3,4The incidence of adrenal metastasis from a colorectal malignant lesion ranges between 1.9% and 17.4%. 5ue to advances in diagnostic radiology techniques including computed tomography (CT) and magnetic resonance imaging (MRI), there has been increased detection of colorectal metastasis, including clinically silent adrenal metastases. 6lthough the presence of adrenal metastasis is usually regarded as an indicator of systemic disease, it has been reported that aggressive surgical resection of adrenal metastasis results in improved overall survival in selective patients. 7To date, all published articles on adrenal metastasis from colorectal cancer consist mostly of case reports.The decision for resection of adrenal metastasis remains controversial, currently there is no proposed standard treatment, and little is known about the clinical outcomes following adrenalectomy for patients with adrenal metastases from colorectal cancer.
Hence, the aim of the article is to review the available literature on outcomes and complications rates following adrenalectomy for adrenal metastasis from colorectal cancer.
The search had no restriction on study type, language, or time of publication.Additional articles suitable for inclusion in the study were obtained through Google and GoogleScholar using the keywords listed above.Duplicates were removed and the abstracts of the selected titles were screened for eligibility.

Eligibility criteria
Inclusion criteria included all articles related to surgical intervention for adrenal metastasis from colorectal cancer.A full text review was performed on the eligible articles and relevant information pertaining to patients with adrenal metastasis from colorectal cancer underwent data extraction.For articles that evaluated outcomes following adrenalectomy for adrenal metastasis for cancers other than colorectal cancers, if data was unable to be extracted for adrenal metastasis from colorectal cancer exclusively, the paper was excluded from data extraction.If histopathology results identified an adrenal lesion not consistent with adrenal metastasis from colorectal cancer (e.g., adenoma), the case was excluded from data extraction.

Data extraction
Data was extracted independently by two authors (VN and ZN) on a Microsoft Excel spreadsheet up to June 2023.The data included the name of authors, publication year, country where the study was performed, basic demographics, location, histology and stage of primary cancer, interval to adrenal metastasis (synchronous vs. metachronous), index operation for primary cancer, neoadjuvant or adjuvant following index operation, single vs. bilateral adrenal metastasis, CEA level at time of adrenal metastasis discovery, radiological investigation findings of adrenal lesion (CT, MRI, PET and ultrasound (USS)), surgical management for adrenal metastasis, histology of adrenal metastasis, presence of other metastases, postoperative complications, whether adjuvant chemoradiotherapy was given following surgical removal of adrenal metastasis and follow up findings including length of survival.The selection pathway is described as per the PRISMA flowchart in Figure 1.Adrenal metastasis was defined as a synchronous lesion if detected within 6 months and metachronous if discovered 6 months following treatment of the primary tumour.

Statistical analysis and quality assessment
Meta-analysis was not undertaken due to marked heterogeneity of the data.A formal quality assessment of the articles was not undertaken as a significant proportion of the articles are case reports and case series.

Results
A total of five retrospective cohort studies, two cross-sectional studies, four case series, 28 case reports with accessible full text and 16 articles with accessible abstracts were included in the final analysis, generating a total of 145 cases of adrenal metastasis from colorectal cancer that has undergone surgical intervention currently reported in literature.

Patient demographics
From the 55 articles included in this systematic review, 32 (58.2%) studies originated from Asia,16 (29.1%) from Europe, four (7.2%) from North America, two (3.6%) from South America and one (1.8%)from Africa.The range of age for patients was 22 to 88 years old (Table 1).The mean age of patients from the retrospective studies ranged from 59 to 70 years old.From the reported cases of adrenal metastasis from colorectal cancers, 64.1% (n = 93) of patients were male, 30.3% (n = 44) were females and the ratio of male to female patients was not reported in a single retrospective study which included a total of 8 (5.5%) patients. 53

Clinical presentation
Overall, 41 (28.3%) patients presented with a primary colonic cancer and 36 (24.9%) patients with a primary rectal cancer (Table 1).The site of primary colorectal cancer was not specified in four studies (68 patients, 46.9%).From those patients presenting with a primary colonic cancer, 10 (6.9%) cases were right-sided (ascending or transverse colon), 17 (11.7%)cases were left-sided (descending or sigmoid colon), and two (1.4%) cases involved both the ascending and rectosigmoid junction.One retrospective cohort study included 12 (8.3%)patients with a primary colonic cancer but the location was not specified. 6

Characteristics of adrenal metastasis
The reporting of the size of adrenal metastasis was inconsistent and varied between the studies.The size of the adrenal metastasis was either estimated radiologically or from histological assessment of the resected lesion (Table 1).The maximum diameter of right sided adrenal metastasis ranged from 20 to 105 mm.For left sided adrenal metastasis the maximum diameter ranged from 25 to 98 mm.One retrospective study reported a mean adrenal lesion size of 67.4 mm (n = 6, range 30 mm to 105 mm). 54Characterization of the adrenal lesion was mostly commonly performed by CT, reported to be utilized in at least 63 (43.4%) cases.MRI was less frequently used and was part of the preoperative work up for only 9 (6.2%) cases.However, these numbers are likely to be underestimated because several studies did not report the mode of preoperative imaging used for adrenal metastasis from colorectal cancers.Biopsy of the adrenal lesion was only performed in 4 (2.8%) cases and described to be performed by CT-guided biopsy in 2 out of the 4 cases.

Surgical intervention
An open adrenalectomy was performed in 45 patients (31.0%), laparoscopic approach in 41 patients (28.3%), robotic adrenalectomy in one (0.7%) patient and a laparoscopic converted to open approach in one (0.7%) patient (Table 1).The surgical approach for adrenalectomy was not reported for 57 (39.3%) patients.A large proportion of patients had an uneventful postoperative recovery following surgical adrenalectomy.
The LOS post-adrenalectomy was only reported by 9 (6.2%) studies and ranged from 2 days to 14 days.One patient suffered from a myocardial infarction and died on the second post-operative  day following adrenalectomy. 42Another patient died 2 months following a simultaneous rectal resection and adrenalectomy due to anastomotic leak and sepsis. 55In a study of 14 patients, it was reported that no patients died within 60 days of adrenalectomy and post-operative complications were observed in only three patients. 6rom these three patients, one developed pneumonia which was successfully treated with antibiotics, one patient developed thrombosis of the inferior cava veins managed with heparin and another patient had an infected perihepatic fluid collection which resolved following antibiotic treatment. 6juvant therapy following adrenalectomy A total of 30 patients (20.7%) were reported to have undergone adjuvant therapy following adrenalectomy (Table 2).Chemotherapy agents utilized post adrenalectomy included single agent fluoropyrimidine; combination of oxaliplatin and/or bevacizumab to a fluoropyrimidine; FOLFIRI; XELIRI; cetuximab and irinotecan; doxyfloyuridine; combination adriamycin, mitomycin C and fluorouracil; and combination cyclophosphamide, mitomycin C and fluorouracil.

Length of follow up, recurrence and overall survival
The mean length of follow-up ranged from 2 months to 9.5 years (Table 1).In one study (n = 4), three patients were alive with disease and one patient was dead from disease after a mean length of follow-up of 38.75 months (range 16-52 months).A total of 33 (22.8%) patients were alive with no evidence of recurrence; two (1.4%) patients had recurrence in the bed of adrenalectomy; two (1.4%) patients were alive with recurrence in the contralateral adrenal gland; four (2.8%) patients were alive with extra-adrenal metastasis, and seven (4.8%) patients were alive with no comments regarding local and systemic recurrence.Recurrence in the bed of adrenalectomy was reported to have occurred due to rupture of the tumour during surgery for one patient and incomplete resection (R2) for the second patient. 56The overall mortality following adrenalectomy was reported in 60 (41.3%) patients.1 (0.7%) patient died due to systemic sepsis following anastomotic leak from colorectal anastomosis, 25 (17.2%)patients died due to disease progression and the cause of death was not identified in 34 (23.4%)patients.Follow-up findings were unreported for 37 (25.5%)patients.
Median survival ranged from 23 months to 34.7 months for patients following adrenalectomy for adrenal metastasis from colorectal cancers.Samsel et al. reported a significantly better overall survival was observed for patients with colorectal cancer (median 29.5 months) metastases compared to other primary tumours including non-small cell lung cancer (median 10 months). 54In a retrospective study including 14 patients with adrenal metastasis from colorectal cancers, median survival was 23 months after the diagnosis of adrenal metastasis, and was not influenced by the type of treatment (chemotherapy plus adrenalectomy or chemotherapy alone). 6However, one patient survived more than 7 years following combined surgery and chemotherapy, indicating that long-term remission may be possible in highly selected patients. 6In the 6 patients who underwent metachronous adrenalectomy, median survival after diagnosis of adrenal metastasis was 19 months (range 10-28 months). 6A single study reported one-year disease-free survival of 78% (95% CI 64%-87%). 57

Discussion
Despite the poor prognosis associated with metastatic disease in colorectal cancer, there are well established data supporting a real survival benefit following an aggressive surgical approach for liver and lung metastasis of colorectal carcinoma. 58,59However, no consensus currently exists for the surgical resection of adrenal metastasis from colorectal cancers.Due to advances in high-resolution imaging studies, adrenal metastasis from colorectal cancer is becoming increasingly identified during preoperative tumour workup or postoperative surveillance.
Despite previous evidence suggesting that solitary adrenal metastatic lesions are infrequent, solitary metastasis to the adrenal glands occurred in nearly half of the patients (44.8%) included in this review and more commonly in a metachronous setting.Adrenal metastases can occur via the arterial, portal venous or lymphatic routes. 27Owing to its rich blood supply, the adrenal glands are a favoured site for metastatic spread and hematogenous spread is considered the major route of primary carcinoma metastasis to the adrenal. 27Adrenal metastasis from colorectal cancers was identified to have occurred more commonly in male patients, with an average age of over 59 years.
To date, surgical treatment for adrenal metastasis has not yet been widely adopted due to the probable association with advanced metastatic disease.However, considering poor results reported in literature associated with radiation and chemotherapy for adrenal metastasis, an aggressive surgical approach for adrenal metastasis may be warranted, even for patient with advanced colorectal cancers. 60A large retrospective study of survival, prognostic factors and complications in patients undergoing adrenal metastasectomy included in this review found that colorectal cancer origin was associated with favourable survival outcomes. 57Evidence from the cases identified in this review demonstrated that adrenalectomy for colorectal adrenal metastasis appears to be safe with minimal perioperative morbidity in selected patients regardless of the surgical approach adopted.Although a significant proportion of patients was from individual case reports or small case series, they represent excellent long-term survival outcomes in well-selected group of patients.The small number of bilateral adrenal metastases reported meant no recommendations can be provided and each case should be individualized.The lack of long-term survival outcomes in large series should prompt further multicentre prospective studies to evaluate the long-term survival outcomes.
A large proportion of patients included in this review developed a metachronous adrenal lesion and were mostly asymptomatic, without abdominal pain or adrenal insufficiency.Adrenal metastases were generally suspected from an elevated serum level of CEA or identified through routine surveillance CT scans.Based on these results, CT or FDG-PET scan should be utilized to identify adrenal metastasis from colorectal cancers during surveillance in patients Adrenal metastasis from colorectal cancers with increased CEA level.If an adrenal lesion is identified, surgical resection should be considered over ongoing surveillance or noninvasive treatment (with radiation or chemotherapy) regardless of the size of the adrenal lesion.The results of this review are limited by the heterogeneity of the studies included.Comparisons and analysis of data was difficult due to the highly varied study groups and limited number of patients able to be extracted from literature.Nevertheless, this represents an opportunity to further research into this topic in the era of aggressive metastatectomy and continuous development of chemo-and immuno-therapy for colorectal cancers.

Conclusion
In conclusion, if complete resection can be achieved, surgical adrenalectomy in the surgically fit patient should be strongly considered, especially in patients with solitary adrenal metastasis which may translate into survival benefits and potential surgical cure.However, no recommendations can be made regarding bilateral adrenalectomy for bilateral metastatic lesions due to limited results and lack of evidence surrounding the risks surrounding lifelong exogenous steroid dependency.

Fig. 1 .
Fig. 1.PRISMA flow chart of search pathway for adrenalectomy of adrenal metastatic lesions from colorectal cancers.

Table 1
Clinical characteristics of patients and tumour

Table 2
Adjuvant therapy after adrenalectomy ANZ Journal of Surgery published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Surgeons.