Distribution and prognosis of uncommon metastases from non-small cell lung cancer

Approximately 50 % of lung cancer cases are metastatic at diagnosis [1]. The major sites of non-small cell lung cancer (NSCLC) metastases include the brain (47 %), bone (36 %), liver (22 %), adrenal glands (15 %), thoracic cavity (11 %) and distant lymph nodes (10 %) [2, 3]. All other organs metastases are very rare and general less than 5 %. So we could define them as uncommon metastases. To our knowledge only some case reports were presented and there were limit information available on uncommon metastases of NSCLC in the literatures [4‐12]. Thus, no systematic body of knowledge on the epidemiology, diagnosis, or treatment of such metastases is available. Misdiagnosis is common because it is difficult to distinguish uncommon metastases from primary malignancies. The treatment is often controversy when uncommon metastasis is solitary. Local therapy is always considered in such settings, although uncommon metastases are grouped as M1b, stage IV based on lung cancer staging system [13]. Herein, we review all cases with uncommon metastases identified at the Guangdong Lung Cancer Institute (GLCI) between 2006 and 2012, and we report the epidemiological characteristics, diagnosis, treatment and prognosis of the patients. Our purpose was to evaluate survival outcomes, to define predictors of survival, and to provide information to clinicians on how to treat uncommon metastases derived from NSCLC.

Overall, 193 cases (6.7 %) were identified as having uncommon metastases among 2,872 consecutive NSCLC cases from 2006 to 2012. Sixteen cases had more than one uncommon metastatic organ.

Numerous case reports and a few studies (with small sample sizes) that have evaluated uncommon metastases from lung carcinomas. Unfortunately, these reports have only marginally improved our understanding of the clinical features and outcomes of patients with the disease. Therefore, we reviewed the medical records of patients with NSCLC treated at the GLCI from 2006 to 2012 and reported the cases with uncommon metastases herein. To our knowledge, this is the largest case series of uncommon metastases from NSCLC.

As shown in Table 1, there were no significant differences in clinical characteristics at baseline between the common and uncommon groups except gender and diagnosis time. The predominant gender was male in cases with uncommon metastasis (P = 0.02), as has been noted in other reports [14]. Uncommon metastases were more likely to be diagnosed later in the disease course (P < 0.01). The reason why uncommon metastases most often occurs at disease course may be that the uncommon metastatic organs couldn’t provide suitable microenvironment to support tumor cells’ survival. It will take time for tumor cells to evolve to adapt the hostile microenvironment. The organs to which lung cancer uncommonly metastasizes are also usually unaffected in patients with other cancers. The reasons why these organs are rarely involved in cancers including NSCLC are as follows. K. A. Kovács, et al. [15] proposed that the skin only shared 5 % of the cardiac output of blood at resting condition, and was a very active part of immune system. The rarity of skeletal muscle metastases has been attributed to changes in pH, metabolite accumulation, variable blood flow, and variation in tissue pressure [16‐18]. The spleen has always been considered “poor soil” for tumor growth, probably because of the high population of immune cells therein and the role played by that organ in “immune surveillance” [19]. Further, anti-angiogenesis factors produced by the spleen may explain the rarity of splenic metastases.

Uncommon metastases from lung tumors are included rarely in prognostic analyses. We speculated that patients with uncommon metastases would be more likely to have a poor outcome, according to previous case reports. A few articles have suggested that certain uncommon metastases, such as subcutaneous metastases [20], are associated with a shorter survival time. According to our multivariate analysis data, uncommon metastases independently predict a poorer survival on multivariate analysis (HR 1.29, P < 0.01). The fact that tumor cells could survive in hostile microenvironment provided by the uncommon organ (s) is evidence that such cells are particularly aggressive and invasive, which may contribute to the poor prognosis of these patients.

Uncommon metastases often develop late in the course of disease but also may present at initial diagnosis. We explored whether synchronous and metachronous metastases are different diseases or simply reflect different courses of the same disease [20]. We compared the baseline clinical characteristics and prognoses of the two groups, and found no significant difference in clinical characteristics or survival time after the diagnosis of an uncommon metastasis between the groups. It is possible that the patients in different groups represent different courses of the disease. Nonetheless, we couldn’t have a definitive explanation for this phenomenon without complete data for further analysis.

Uncommon metastases usually occur in patients with other disseminated metastases. Traditionally, systemic therapy is recommended as the standard therapy for metastatic disease. We administered local treatment in addition to systemic treatment to selected patients with oligometastases. More cases in the disease course group received local treatment. The patients who received systemic treatment plus local treatment had a better outcome than those who did not. Similar results have been observed in other studies [21, 22]. Therefore, we advise systemic treatment plus local treatment for selected patients with oligometastases.

A limitation of our study is its retrospective design, which spanned a long period of time. Regardless, it is the largest case series of uncommon metastases derived from NSCLC to date, and may aid clinicians in their treatment efforts.

In conclusion, uncommon metastases are infrequently and associated with a worse outcome. Systemic treatment plus local treatment is a favorable option for selected patients with oligometastases.