The authors have declared that no competing interests exist.
Distant metastases generally indicate disseminated disease and the standard treatment for these patients is palliative chemotherapy. Retrospective series showed that selected patients with metastatic lung cancer and a solitary extrathoracic disease could be effectively treated with curative intention by resection of both primary tumor and the single site of metastatic disease.
According to current data, adrenalectomy might be considered as an alternative option for patients with isolated adrenal metastases. Significant morbidity and mortality may be happened by these procedures, and a cautious analysis of pros and cons should be discussed with the patient.
We present a review of the literature and updated recommendations focusing lung cancer with solitary adrenal metastasis.
Isolated adrenal metastasis are reported in 1,6 -3,5% of patients with primary non-small cell lung cancer (NSCLC), presenting with resectable tumors, and it increases up to 40% as the disease progresses
The setting of distant metastasis generally indicates disseminated disease and the standard treatment for these patients is palliative chemotherapy. Retrospective series suggest that some stage IV non-small-cell-lung cancer (NSCLC) patients with a solitary synchronous/metachronous extrathoracic metastatic disease (“micrometastatic disease”) might be cured by resection of both primary tumor and isolated metastases
We adopted a comprehensive assessment of the literature where studies published in English were included.
Studies on adrenal metastases and NSCLC were identified using Pubmed, (until December 2017) and the Cochrane Library (until December 2017).
The search words were: adrenal metastases, adrenal metastasectomy, adrenal metastases resection, surgery for adrenal metastases, non-small cell lung cancer adrenal metastases
To be considered to enter in this review, studies consisted of reviews and case series. Entry criteria for studies included: operative morbidity and mortality, type of resection, systemic therapy, primary tumor characteristics, disease free-interval, and adrenal nodules/ masses aspects. The surgical approach included unilateral or bilateral adrenalectomy.
The authors attempted to view adrenal metastasectomy as a surgical option for patients with adrenal nodules/masses resected – in patients with previous NSCLC diagnosed- also offering a critical review of this technique.
The results of adrenal metastasectomy should be analyzed from the point of view according to the critical factors that can affect survival. Such analysis results should also be grounded in reviews of studies in primary tumor characteristics, or in patients with bilateral or unilateral metastases, and synchronous or metachronous metastases in a sufficient number of patients.
Prognostic factors were reviewed in several series in order to show its influence alone or in combination for survival analysis and the description that best fits the selection criteria. The results from the collected data confirm that adrenal metastasectomy is a form of potential therapy for healing that can be safe with low mortality
According to the principles of oncological surgery, complete removal of all pulmonary foci is associated with increased survival. The data also suggest that the preoperative radiological work-up evaluation however, has higher accuracy with PET-CT
Laparoscopic resection can not always provide efficiency for the complete nodule/ mass removal
A limitation of this study lies in the fact that no evaluation of variables related to the biological behavior of different histological types (adenocarcinoma vs epidermoid carcinoma), which may explain the evolution of clinical metastases. Currently, adrenalectomy may be indicated for the or resection of metastases in patients specially with single nodules and metachronous metastases, after PET-CT evaluation
The role of adrenalectomy is less evident in patients with bilateral and synchronous lesions, and in primary tumors with lymph node metastases
Isolated adrenal gland metastases found during staging work-up in patients with resectable lung cancer are rare in the pre- PET-CT era. Although, adrenal metastases might be higher due to the low accuracy of image to detect small tumors
Direct lymphatic spread, via retroperitoneal channels, might be the main reason of adrenal metastasis
Usually, the imaging screening used for diagnosis of adrenal metastasis are: CT scans (
Nevertheless, in another study, only 28 out of 39 (71.8%) patients who underwent adrenalectomy for suspect adrenal tumor by FDG-PET/CT confirmed metastasis. Ten of those were benign adenoma and one was a non-functional pheochromocytoma
PET-CT results for adrenal glands increases the likelihood of malignancy, but may only be considered indicative, not certainty of malignancy.
Adrenal biopsies (
There is limited understanding of the efficacy of surgical resection because of low incidence of isolated adrenal metastasis in patients with stage IV NSCLC. Some series showed that the time from diagnosis of primary lung cancer diagnosis of adrenal metastasis - disease-free interval (DFI) – is a prognostic factor
It is not known why patients with metachronous metastases performedbetter. Certainly, patients in the synchronous group experience early morbidity/mortality due to lung tumor resection, and those with a metachronous metastases had already recovered from thoracic surgery. Also, theoretically, the biology of the tumors is different in those presenting as synchronous lesions tend to be more aggressive.
In one study, none of the 10 patients with synchronous metastasis survived beyond two years
The results associated with surgical treatment between metachronous and synchronous metastasis is clinically relevant. For patients with a synchronous metastasis, the decision for an adrenalectomy depends on the definitive management of the primary lung cancer. As opposed to palliative chemotherapy alone, these procedures may result in a significant morbidity and mortality, and the decision should be discussed with the patient in a multidisciplinary setting. Node involvement decreased significantly the prognosis when identified (p < 0.05) and any further invasiveness must be discouraged.
Unfortunately, to date, there have been few reviews on this subject. Most studies analyze and report data combining synchronous and metachronous metastases. Others include patients with only synchronous or metachronous metastases alone (
Author | Year | No. patients | Survival (mo)Synchronous | Survival (mo)Metachronous |
Higashiyama | 1994 | 9 | 9 | 17-40 |
Wade | 1998 | 47 | - | 0.7-61 |
Bretcha-Boix | 2000 | 14 | - | 8-16 |
Lucchi | 2005 | 15 | 9-12 | 14-80 |
Mercier | 2005 | 23 | 0.3-16 | 2-110 |
Pfannschmidt | 2005 | 11 | 9-72 | 6-40 |
Porte | 2001 | 43 | - | - |
Sebag | 2006 | 16 | 1-68 | 24 |
Strong | 2007 | 89 | 2-127 | 3-97 |
Moreno | 2013 | 148 | 23 | 30 |
Romero | 2014 | 29 | - | - |
Kawai | 2014 | 10 | 9 | 25 |
In one of this series, there was no difference in median disease- free survival (DFS amongst 72 patients who underwent synchronous adrenalectomy (9 months) versus metachronous (11 months) diseases (p=0.79)
Tamura e cols reported recently the rare, but potentially fatal, occurrence of bilateral adrenal hemorrhage due to adrenal metastasis of lung cancer. This is an additional argument reinforcing the appeal for surgical approaches for oligometastatic diseases
The retrospective review of the Memorial Sloan-Kettering Cancer Center
Aranda e cols advocate that adrenalectomy not only is feasible in the synchronous setting, but also is safe and must be done first, followed further by lung resection. This approach resulted in a disease-free survival at 2 years of 60%, 5-year overall survival of 30% and a median survival of 41.5 months in 108 laparoscopic adrenalectomies performed by this group
Luketich and Burt
Laparoscopic adrenalectomy was not inferior to open adrenalectomy regarding safety and the anticancer effect, and it has proven itself as a minimally invasive treatment in another study
Adrenal metastases in both sides do not appear to be a contraindication for a more intensive treatment
Conversely to the data showing benefit in outcomes of patients submitted to adrenalectomy, there are reports opposing that approach. A study performed between 2001 and 2015 in 22 out 1,302 patients with NSCLC and solitary adrenal metastasis who underwent adrenalectomy did not show any gain of survival compared to those undergoing nonsurgical treatment. With a median overall survival of 11 months and 1-year survival rate of 51.4% (p=0.209), these data do not support metastasectomy and primary radical resection since this approach did not improved the outcomes in this population
A multicenter study reported by Porte et al.
We need to point out that none of the studies included were prospectivelyrandomized between adrenalectomy or no adrenalectomy; maybe, the poor outcomes associated to palliative chemotherapy is difficult to conduct, since no long-term survival is expected in patients with advanced NSCLC.
The following criteria were proposed for the indication of adrenalectomy for the treatment NSCLC with isolated adrenal metastases: (1) primary lung cancer could be resected or cured by radical treatment, (2) metastasis restricted to the adrenal gland, (3) adrenal metastases had not invaded the surrounding organs, and (4) the size of the adrenal tumor did not exceed 10 cm
Finally, a safe and feasible alternative for adrenalectomy are noninvasive methods for disease control. In a study, 31 patients were submitted to computed tomography (CT)-guided percutaneous microwave ablation (MWA) of unilateral adrenal metastasis from lung cancer (1.5 - 5.4 cm in diameter)
The indication of resection or non-surgical local therapy (SBRT or microwave) is feasible, but the biggest question imposed is the real validity of adrenal local control in the metastatic setting, while the most frequent cause of death is systemic progression. However, it is important to emphasize that there is a compelling new evidence from a randomized, multicenter phase 2 trial
Comparing this analysis along with molecular data, until now is not known if the prognosis of patients particularly with adrenal metastasis has any correlation with molecular alteration or any difference from those without involvement of this specific site as happens in case of bone metastasis and Kras mutation. In a study with 500 caucasian metastatic lung cancer patients (28.6% were Kras-mutated), a significantly higher tendency for intrapulmonary metastasis was identified in the Kras mutated group (35% versus 26.5%, p = 0.0125) compared to those with extrapulmonary ones
Adrenal metastasis control does not differ from the others, being necessary a cautious analysis case-by-case in order to improve quality of life and delay symptoms and the necessity to change therapy. The NCCN recommendation for localized treatment of isolated adrenal metastasis is grade 2B – that is, based on “lower-level” evidence; there is consensus that the intervention is appropriate
Adrenalectomy should be considered as a therapeutic option for patients with isolated adrenal metastases, especially with metachoronous presentation.
Although the median survival in the adrenal metastases synchronous group is comparable to palliative chemotherapy in patients with advanced disease, there was an expected five-year overall survival of 25%.
Review of the literature suggests different outcomes in patients with ipsilateral vs. contralateral adrenal metastasis. Adrenalectomy should be considered as a therapeutic option for patients with isolated adrenal metastases, especially with metacoronary presentation. Although the median survival in the synchronous group of adrenal metastases is comparable to palliative chemotherapy in patients with advanced disease, there was an overall expected five-year survival of 25%. The review of the literature suggests a difference in the results of patients with ipsilateral adrenal metastasis vs. contralateral. However, the current guidelines of the National Comprehensive Cancer Network do not make a distinction in the treatment of adrenal metastasis based on laterality.