Metastatic dissemination patterns of different primary tumors to the spine and other bones

Abstract

Metastatic spine disease (MSD) is a severe event in cancer patients. Experimental data indicate that bone metastasis is mostly mediated by blood flow-dependent, passive arrest of circulating tumor cells to the bone metastatic niche (BMN). Here, we have set out to test these experimental observations in a clinical, human setting to improve our understanding of MSD. 507 patients, treated on spinal metastases in our institution from 2005 to  2015 were retrospectively evaluated. We identified 259 patients with accessible staging reports of the skeleton before and at initial diagnosis of MSD. Data analysis comprised localizations of bone metastases, underlying malignancy and time to development of MSD. Dissemination pattern of bone metastasis was correlated with red bone marrow (RBM) content of the respective bone as a measure of blood flow. Spinal metastases occurred most frequently in lung cancer (21%), prostate cancer (19%), and breast cancer (12%). At the diagnosis of MSD, majority of patients have multiple extra-spinal bone metastases (2/3). The distribution of metastases to extra-spinal bones and to the spine is mostly proportional to the RBM content of the involved bone. Corresponding to the high RBM content, thoracic spine, pelvic bones and ribs represent a predilection site for bone metastasis. We confirm a distinct preference of cancer types to metastasize to bones. When it comes to bone metastases all primaries show uniform distribution pattern, which supports the hypothesis of a predominantly blood flow-dependent distribution of tumor cells and passive arrest to the BMN rather than a spine-specific homing mechanism.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. 1.

    Coleman RE (2001) Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev 27(3):165–176

    CAS  Article  Google Scholar 

  2. 2.

    Saad F et al (2007) Pathologic fractures correlate with reduced survival in patients with malignant bone disease. Cancer 110(8):1860–1867

    Article  Google Scholar 

  3. 3.

    Sathiakumar N et al (2011) Mortality following bone metastasis and skeletal-related events among men with prostate cancer: a population-based analysis of US Medicare beneficiaries, 1999–2006. Prostate Cancer Prostatic Dis 14(2):177–183

    CAS  Article  Google Scholar 

  4. 4.

    D'Oronzo S et al (2019) Metastatic bone disease: Pathogenesis and therapeutic options: Up-date on bone metastasis management. J Bone Oncol 15:004–004

    Article  Google Scholar 

  5. 5.

    Mundy GR (2002) Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2(8):584 –593

    CAS  Article  Google Scholar 

  6. 6.

    Azevedo AS et al (2015) Metastasis of circulating tumor cells: favorable soil or suitable biomechanics, or both? Cell Adhes Migr 9(5):345–356

    CAS  Article  Google Scholar 

  7. 7.

    Nguyen DX, Bos PD, Massague J (2009) Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 9(4):274–284

    CAS  Article  Google Scholar 

  8. 8.

    Alix-Panabieres C, Riethdorf S, Pantel K (2008) Circulating tumor cells and bone marrow micrometastasis. Clin Cancer Res 14(16):5013–5021

    CAS  Article  Google Scholar 

  9. 9.

    Byrne NM, Summers MA, McDonald MM (2019) Tumor cell dormancy and reactivation in bone: skeletal biology and therapeutic opportunities. JBMR Plus 3(3):e10125

    Article  Google Scholar 

  10. 10.

    Chambers AF, Groom AC, MacDonald IC (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2(8):563–572

    CAS  Article  Google Scholar 

  11. 11.

    Sowder ME, Johnson RW (2019) Bone as a preferential site for metastasis. JBMR Plus 3(3):e10126

    Article  Google Scholar 

  12. 12.

    Suva LJ et al (2011) Bone metastasis: mechanisms and therapeutic opportunities. Nat Rev Endocrinol 7(4):208–218

    CAS  Article  Google Scholar 

  13. 13.

    Croucher PI, McDonald MM, Martin TJ (2016) Bone metastasis: the importance of the neighbourhood. Nat Rev Cancer 16(6):373–386

    CAS  Article  Google Scholar 

  14. 14.

    Wang CY et al (2013) Comparison of distribution characteristics of metastatic bone lesions between breast and prostate carcinomas. Oncol Lett 5(1):391–397

    Article  Google Scholar 

  15. 15.

    Wang N et al (2014) Prostate cancer cells preferentially home to osteoblast-rich areas in the early stages of bone metastasis: evidence from in vivo models. J Bone Miner Res 29(12):2688–2696

    CAS  Article  Google Scholar 

  16. 16.

    Zhang Y, He W, Zhang S (2019) Seeking for correlative genes and signaling pathways with bone metastasis from breast cancer by integrated analysis. Front Oncol 9:138

    Article  Google Scholar 

  17. 17.

    Balic M et al (2006) Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin Cancer Res 12(19):5615–5621

    CAS  Article  Google Scholar 

  18. 18.

    Burnett RM et al (2015) Organ-specific adaptive signaling pathway activation in metastatic breast cancer cells. Oncotarget 6(14):12682–12696

    Article  Google Scholar 

  19. 19.

    Cetin K et al (2015) Survival in patients with breast cancer with bone metastasis: a Danish population-based cohort study on the prognostic impact of initial stage of disease at breast cancer diagnosis and length of the bone metastasis-free interval. BMJ Open 5(4):e007702

    Article  Google Scholar 

  20. 20.

    Lin H et al (2011) Disseminated and circulating tumor cells: role in effective cancer management. Crit Rev Oncol/Hematol 77(1):1–11

    Article  Google Scholar 

  21. 21.

    Yuh WT et al (1996) Anatomic distribution of metastases in the vertebral body and modes of hematogenous spread. Spine 21(19):2243–2250

    CAS  Article  Google Scholar 

  22. 22.

    Broggini T et al (2016) Passive entrapment of tumor cells determines metastatic dissemination to spinal bone and other osseous tissues. PLoS ONE 11(9):e0162540

    Article  Google Scholar 

  23. 23.

    Gallizia E et al (2017) The spine instability neoplastic score (SINS) in the assessment of response to radiotherapy for bone metastases. Clin Transl Oncol 19(11):1382–1387

    CAS  Article  Google Scholar 

  24. 24.

    Hussain I et al (2018) Patient-reported outcomes after surgical stabilization of spinal tumors: symptom-based validation of the Spinal Instability Neoplastic Score (SINS) and surgery. Spine J 18(2):261–267

    Article  Google Scholar 

  25. 25.

    Caracappa PF, Chao TC, Xu XG (2009) A study of predicted bone marrow distribution on calculated marrow dose from external radiation exposures using two sets of image data for the same individual. Health Phys 96(6):661–674

    CAS  Article  Google Scholar 

  26. 26.

    Cristy M (1981) Active bone marrow distribution as a function of age in humans. Phys Med Biol 26(3):389–400

    CAS  Article  Google Scholar 

  27. 27.

    Maccauro G et al (2011) Physiopathology of spine metastasis. Int J Surg Oncol 2011:107969

    PubMed  PubMed Central  Google Scholar 

  28. 28.

    Batson OV (1995) The function of the vertebral veins and their role in the spread of metastases. 1940. Clin Orthop Relat Res 312:4–9

    Google Scholar 

  29. 29.

    Onuigbo WI (1975) Batson's theory of vertebral venous metastasis: a review. Oncology 32(3–4):145 – 50

    CAS  Article  Google Scholar 

  30. 30.

    Zhu M et al (2019) Bone metastasis pattern of cancer patients with bone metastasis but no visceral metastasis. J Bone Oncol 15:100219

    Article  Google Scholar 

  31. 31.

    Bauernhofer T et al (2005) Association of disease progression and poor overall survival with detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer. Oncol Rep 13(2):179–184

    PubMed  Google Scholar 

  32. 32.

    Ulmar B et al (2007) Prognosis scores of Tokuhashi and Tomita for patients with spinal metastases of renal cancer. Ann Surg Oncol 14(2):998–1004

    Article  Google Scholar 

  33. 33.

    Naumov GN et al (2002) Persistence of solitary mammary carcinoma cells in a secondary site: a possible contributor to dormancy. Cancer Res 62(7):2162–2168

    CAS  PubMed  Google Scholar 

  34. 34.

    Naumov GN et al (2003) Ineffectiveness of doxorubicin treatment on solitary dormant mammary carcinoma cells or late-developing metastases. Breast Cancer Res Treat 82(3):199–206

    CAS  Article  Google Scholar 

  35. 35.

    Haider M-T et al (2014) Modifying the osteoblastic niche with zoledronic acid in vivo-potential implications for breast cancer bone metastasis. Bone 66(100):240–250

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Peter Vajkoczy.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (JPEG 260 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Onken, J.S., Fekonja, L.S., Wehowsky, R. et al. Metastatic dissemination patterns of different primary tumors to the spine and other bones. Clin Exp Metastasis 36, 493–498 (2019). https://doi.org/10.1007/s10585-019-09987-w

Download citation

Keywords

  • Spinal metastasis
  • Dissemination
  • Red bone marrow
  • Blood-flow dependent dissemination