Bone is one of the most common organs in cancer metastasis, especially in lung, breast, and prostate cancer (1, 2). Once bone metastasis is developed, patients’ survival and quality of life will be significantly declined (3). The prognosis of bone metastases from different tumor types varies greatly. Therefore, to identify the primary pathologic type of bone metastasis is the key to the treatment of such patients. However, up to 30% of patients present with bone metastasis of unknown origin after detailed investigations (4). The spine is reported to be the most common site of bone metastasis of unknown origin, followed by the pelvis and long bones (5). Some studies showed that patients with bone metastasis of unknown origin had a poor outcome with a mean survival ranging from 3 to 12 months from diagnosis (6–9). The characteristics and survival of patients with bone metastasis of a certain known origin have been widely reported. However, few studies have been reported on the characteristics and risk factors affecting the prognosis in patients with bone metastasis of unknown origin. Additionally, effective treatments for such patients remain unknown.

To date, there was no large-sample studies to analyze the prognosis of patients with bone metastasis of unknown origin. The different characteristics and survival of patients with bone metastasis of unknown origin still need to be elucidated. In order to provide an insight into the bone metastasis of unknown origin, we used the Surveillance, Epidemiology, and End Results (SEER) database to reveal the clinicopathologic features and prognostic factors. Our findings may provide timely interventions for those patients to improve their survival.

Bone is the third most common metastatic site following the liver and lung (10). Cancer of unknown origin refers to malignancies, where metastases are histologically confirmed, but where no primary site can be identified on the basis of a comprehensive clinical and imaging evaluation (11–13). To our knowledge, the current study is the largest population-based study to explore the clinical features and survival predictors for patients with bone metastasis of unknown origin. With the progress of diagnosis and treatment technology, the proportion of unknown primary tumors in metastatic tumors has steadily declined (13). However, those patients experienced extremely poor prognosis. In the present study, we first defined the clinicopathological features and prognosis of this special population. Our study found that the 1-year OS and CSS rates for patients with bone metastasis of unknown origin were 14.5% and 15.9%, respectively. Therefore, accurate assessment of patients’ prognostic risk factors is helpful to improve their prognosis and assist clinicians to make reasonable treatment decisions. More importantly, this study provides evidence for future treatment guidelines for such patients.

It is worth mentioning that our analysis found that gender and age were not independent risk factors for survival. However, many previous studies on bone metastasis have found that they indeed correlated with the patient’s prognosis (14, 15). This may be due to the diverse pathologic types of the primary lesion. In terms of race, significant difference was observed in OS but not in CSS, which was not in line with other studies on bone metastasis (16, 17). Further researches are needed to clarify this risk factor. Regarding the tumor histopathology, adenomas and adenocarcinomas type accounted for almost half of all cases, but it was not an independent predictor of survival. It seems that the histopathologic type of the tumor has little effect on prognosis in patients with bone metastasis of unknown origin.

Generally, once a tumor develops distant metastasis in one organ, it may accelerate metastasis in other organs. Interestingly, bone metastasis combined with lung metastasis do not result in a worse prognosis in these patients, whereas bone metastasis combined with brain or liver metastases do. Ya Qin et al. (18) also reported the similar results among esophageal cancer patients with bone metastasis. It seems that there is a homologous relationship between bone metastasis and lung metastasis. Most studies have found that lung, liver and brain metastases are closely related to the prognosis of patients (19–21). Our study revealed that marital status was not associated with survival. However, some researches demonstrated that marital status was an independent prognostic factor for survival among patients with bone metastasis of known origin (19, 22).

A standard treatment for patients with bone metastasis of unknown origin has not yet been developed. Treatments for vertebral lesions include surgical excision and non-surgical management (10, 23). Our multivariable analyses revealed that radiotherapy and chemotherapy were significantly correlated with prognosis, which provides an optimal strategy for treating them. Chemotherapy was also an independent survival predictor for primary bone tumors, such as osteosarcoma (24). Various chemotherapeutic regimens are reported in the treatment of malignant primary bone tumors of the spine. However, rare studies reported the chemotherapeutic regimens for treating bone metastasis. This may be an important research direction for bone metastases in the future. Recently, some novel treatments including molecular targeting, immunotherapy and stem cell therapy provide hope for the treatment of spinal tumors (10). Further studies are warranted to determine the novel treatment methods for those patients.

The current study still has certain limitations. First, this is a retrospective study with inherent bias. Second, detailed data regarding the radiotherapy and chemotherapy were unavailable. Third, the SEER database does not provide any information regarding local recurrence or distant metastasis during follow-up. Therefore, clinical randomized trials are urgently needed to verify our findings and improve the survival.

Survival predictors for patients with bone metastasis of unknown origin included race, brain metastasis, liver metastasis, radiotherapy, and chemotherapy. Therefore, large range screening of the above independent risk factors can effectively improve the prognosis to a certain extent. Additionally, this study provides valuable reference information for clinicians and patients to make treatment decisions.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by Ethics Committee of the Second Affiliated Hospital, Zhejiang University School of Medicine. The studies were conducted in accordance with the local legislation and institutional requirements. The ethics committee/institutional review board waived the requirement of written informed consent for participation from the participants or the participants’ legal guardians/next of kin because clinical data in the present study were extracted from a public database with no patient identification info.

ZW and NZ conceived and designed the study. YR, SQ, and GX collected the data. YR, SQ, GX, and ZC performed the statistical analysis. YR wrote the manuscript. ZW revised it. All authors contributed to the article and approved the submitted version.