Skip to main content
SpringerLink
Log in

A Review on Cancer of Unknown Primary Origin: The Role of Molecular Biomarkers in the Identification of Unknown Primary Origin

  • Protocol
  • First Online:
Precision Medicine

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2204))

Abstract

The primary site cannot be found after clinical and pathological evaluation, which are called cancers of unknown primary origin (CUP). CUPs may resemble a specific primary tumor site which shares common clinicopathological characteristics and prognosis. However, it may be present as a distinct disease entity with undifferentiated pathological features. More than 4% of patients are diagnosed as CUP. These patients were diagnosed as malignant tumors by cytology or pathology. And they were usually treated with empirical chemotherapy and associated with a poor prognosis. How to accurately diagnose and treat a cancer of unknown primary origin is a major clinical concern. To address this question, a complex assessment is carried out which includes a complete medical history of the patient, physical examination, complete blood count, urinalysis, serum chemistries, histologic evaluation, chest radiograph, computed tomography, magnetic resonance imaging, and immunohistochemistry (IHC) studies. Molecular diagnostic information reflects that CUP’s molecular characteristics are similar to primary tumors with the development of genomics and the expansion of gene sequencing technology. Gene expression profiling is the most commonly used molecular diagnostic method for CUP. In this chapter, we summarize the current diagnostic methods and challenges of CUP, and the clinical value of the molecular-level tumor diagnostic technique.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Pavlidis N et al (2003) Diagnostic and therapeutic management of cancer of an unknown primary. Eur J Cancer 39(14):1990–2005

    CAS  PubMed  Google Scholar 

  2. Pentheroudakis G, Golfinopoulos V, Pavlidis N (2007) Switching benchmarks in cancer of unknown primary: from autopsy to microarray. Eur J Cancer 43(14):2026–2036

    PubMed  Google Scholar 

  3. Yang M, Nonaka D (2010) A study of immunohistochemical differential expression in pulmonary and mammary carcinomas. Mod Pathol 23(5):654–661

    CAS  PubMed  Google Scholar 

  4. Pentheroudakis G, Greco FA, Pavlidis N (2009) Molecular assignment of tissue of origin in cancer of unknown primary may not predict response to therapy or outcome: a systematic literature review. Cancer Treat Rev 35(3):221–227

    CAS  PubMed  Google Scholar 

  5. Tomuleasa C et al (2017) How to diagnose and treat a cancer of unknown primary site. J Gastrointestin Liver Dis 26(1):69–79

    PubMed  Google Scholar 

  6. Pavlidis N, Pentheroudakis G (2012) Cancer of unknown primary site. Lancet 379(9824):1428–1435

    PubMed  Google Scholar 

  7. Kamposioras K, Pentheroudakis G, Pavlidis N (2013) Exploring the biology of cancer of unknown primary: breakthroughs and drawbacks. Eur J Clin Investig 43(5):491–500

    CAS  Google Scholar 

  8. Hainsworth JD et al (2009) Paclitaxel/carboplatin plus bevacizumab/erlotinib in the first-line treatment of patients with carcinoma of unknown primary site. Oncologist 14(12):1189–1197

    PubMed  Google Scholar 

  9. Frost P (1991) Unknown primary tumors: an example of accelerated (type 2) tumor progression. Basic Life Sci 57:233–237. discussion 237-40

    CAS  PubMed  Google Scholar 

  10. Klein CA (2009) Parallel progression of primary tumours and metastases. Nat Rev Cancer 9(4):302–312

    CAS  PubMed  Google Scholar 

  11. Pavlidis N, Khaled H, Gaafar R (2015) A mini review on cancer of unknown primary site: A clinical puzzle for the oncologists. J Adv Res 6(3):375–382

    PubMed  Google Scholar 

  12. Klein G (1998) Foulds’ dangerous idea revisited: the multistep development of tumors 40 years later. Adv Cancer Res 72:1–23

    CAS  PubMed  Google Scholar 

  13. Bross ID, Viadana E, Pickren J (1975) Do generalized metastases occur directly from the primary? J Chronic Dis 28(3):149–159

    CAS  PubMed  Google Scholar 

  14. Abbruzzese JL et al (1995) Analysis of a diagnostic strategy for patients with suspected tumors of unknown origin. J Clin Oncol 13(8):2094–2103

    CAS  PubMed  Google Scholar 

  15. Roh JL, Kim JM, Park CI (2008) Lateral cervical lymph node metastases from papillary thyroid carcinoma: pattern of nodal metastases and optimal strategy for neck dissection. Ann Surg Oncol 15(4):1177–1182

    PubMed  Google Scholar 

  16. Begum S et al (2003) Detection of human papillomavirus in cervical lymph nodes: a highly effective strategy for localizing site of tumor origin. Clin Cancer Res 9(17):6469–6475

    CAS  PubMed  Google Scholar 

  17. Fu TS et al (2016) The role of transoral robotic surgery, transoral laser microsurgery, and lingual tonsillectomy in the identification of head and neck squamous cell carcinoma of unknown primary origin: a systematic review. J Otolaryngol Head Neck Surg 45(1):28

    PubMed  PubMed Central  Google Scholar 

  18. Pavlidis N, Pentheroudakis G, Plataniotis G (2009) Cervical lymph node metastases of squamous cell carcinoma from an unknown primary site: a favourable prognosis subset of patients with CUP. Clin Transl Oncol 11(6):340–348

    PubMed  Google Scholar 

  19. Lee JR et al (2015) Detection of occult primary tumors in patients with cervical metastases of unknown primary tumors: comparison of (18)F FDG PET/CT with contrast-enhanced CT or CT/MR imaging-prospective study. Radiology 274(3):764–771

    PubMed  Google Scholar 

  20. Ettinger DS et al (2014) Occult primary, version 3.2014. J Natl Compr Cancer Netw 12(7):969–974

    Google Scholar 

  21. Olson JA Jr et al (2000) Magnetic resonance imaging facilitates breast conservation for occult breast cancer. Ann Surg Oncol 7(6):411–415

    PubMed  Google Scholar 

  22. Ambrosini V et al (2006) 18F-FDG PET/CT in the assessment of carcinoma of unknown primary origin. Radiol Med 111(8):1146–1155

    CAS  PubMed  Google Scholar 

  23. Pentheroudakis G, Lazaridis G, Pavlidis N (2010) Axillary nodal metastases from carcinoma of unknown primary (CUPAx): a systematic review of published evidence. Breast Cancer Res Treat 119(1):1–11

    PubMed  Google Scholar 

  24. Lin F, Liu H (2014) Immunohistochemistry in undifferentiated neoplasm/tumor of uncertain origin. Arch Pathol Lab Med 138(12):1583–1610

    PubMed  Google Scholar 

  25. Wittwer CT et al (1997) The LightCycler: a microvolume multisample fluorimeter with rapid temperature control. BioTechniques 22(1):176–181

    CAS  PubMed  Google Scholar 

  26. Erlander MG et al (2011) Performance and clinical evaluation of the 92-gene real-time PCR assay for tumor classification. J Mol Diagn 13(5):493–503

    PubMed  PubMed Central  Google Scholar 

  27. Meiri E et al (2012) A second-generation microRNA-based assay for diagnosing tumor tissue origin. Oncologist 17(6):801–812

    PubMed  PubMed Central  Google Scholar 

  28. Sotiriou C, Piccart MJ (2007) Taking gene-expression profiling to the clinic: when will molecular signatures become relevant to patient care? Nat Rev Cancer 7(7):545–553

    CAS  PubMed  Google Scholar 

  29. Bender RA, Erlander MG (2009) Molecular classification of unknown primary cancer. Semin Oncol 36(1):38–43

    CAS  PubMed  Google Scholar 

  30. Yu J et al (2007) Feature selection and molecular classification of cancer using genetic programming. Neoplasia 9(4):292–303

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Vanneschi L et al (2011) A comparison of machine learning techniques for survival prediction in breast cancer. BioData Min 4:12

    PubMed  PubMed Central  Google Scholar 

  32. Rosenwald S et al (2010) Validation of a microRNA-based qRT-PCR test for accurate identification of tumor tissue origin. Mod Pathol 23(6):814–823

    CAS  PubMed  Google Scholar 

  33. Hainsworth JD, Greco FA (2014) Gene expression profiling in patients with carcinoma of unknown primary site: from translational research to standard of care. Virchows Arch 464(4):393–402

    CAS  PubMed  Google Scholar 

  34. Stancel GA et al (2012) Identification of tissue of origin in body fluid specimens using a gene expression microarray assay. Cancer Cytopathol 120(1):62–70

    CAS  PubMed  Google Scholar 

  35. Kerr SE et al (2012) Multisite validation study to determine performance characteristics of a 92-gene molecular cancer classifier. Clin Cancer Res 18(14):3952–3960

    CAS  PubMed  Google Scholar 

  36. Boscolo-Rizzo P et al (2015) The prevalence of human papillomavirus in squamous cell carcinoma of unknown primary site metastatic to neck lymph nodes: a systematic review. Clin Exp Metastasis 32(8):835–845

    CAS  PubMed  Google Scholar 

  37. Hainsworth JD et al (2013) Molecular gene expression profiling to predict the tissue of origin and direct site-specific therapy in patients with carcinoma of unknown primary site: a prospective trial of the Sarah Cannon research institute. J Clin Oncol 31(2):217–223

    CAS  PubMed  Google Scholar 

  38. Rosenfeld N et al (2008) MicroRNAs accurately identify cancer tissue origin. Nat Biotechnol 26(4):462–469

    CAS  PubMed  Google Scholar 

  39. Bochtler T, Loffler H, Kramer A (2018) Diagnosis and management of metastatic neoplasms with unknown primary. Semin Diagn Pathol 35(3):199–206

    PubMed  Google Scholar 

  40. Ryska A et al (2009) Paraganglioma-like medullary thyroid carcinoma: fine needle aspiration cytology features with histological correlation. Cytopathology 20(3):188–194

    CAS  PubMed  Google Scholar 

  41. Pillai R et al (2011) Validation and reproducibility of a microarray-based gene expression test for tumor identification in formalin-fixed, paraffin-embedded specimens. J Mol Diagn 13(1):48–56

    PubMed  PubMed Central  Google Scholar 

  42. Golfinopoulos V et al (2009) Comparative survival with diverse chemotherapy regimens for cancer of unknown primary site: multiple-treatments meta-analysis. Cancer Treat Rev 35(7):570–573

    CAS  PubMed  Google Scholar 

  43. Oien KA, Dennis JL (2012) Diagnostic work-up of carcinoma of unknown primary: from immunohistochemistry to molecular profiling. Ann Oncol 23(Suppl 10):x271–x277

    PubMed  Google Scholar 

  44. Greco FA, Pavlidis N (2009) Treatment for patients with unknown primary carcinoma and unfavorable prognostic factors. Semin Oncol 36(1):65–74

    CAS  PubMed  Google Scholar 

  45. Greco FA (2013) Molecular diagnosis of the tissue of origin in cancer of unknown primary site: useful in patient management. Curr Treat Options in Oncol 14(4):634–642

    Google Scholar 

  46. Pentheroudakis G, Stoyianni A, Pavlidis N (2011) Cancer of unknown primary patients with midline nodal distribution: midway between poor and favourable prognosis? Cancer Treat Rev 37(2):120–126

    PubMed  Google Scholar 

  47. Stoyianni A, Pentheroudakis G, Pavlidis N (2011) Neuroendocrine carcinoma of unknown primary: a systematic review of the literature and a comparative study with other neuroendocrine tumors. Cancer Treat Rev 37(5):358–365

    PubMed  Google Scholar 

  48. Piccioli A et al (2015) Bone metastases of unknown origin: epidemiology and principles of management. J Orthop Traumatol 16(2):81–86

    PubMed  PubMed Central  Google Scholar 

  49. Conner JR, Hornick JL (2015) Metastatic carcinoma of unknown primary: diagnostic approach using immunohistochemistry. Adv Anat Pathol 22(3):149–167

    CAS  Google Scholar 

  50. Casali PG et al (2018) Gastrointestinal stromal tumours: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 29(Suppl 4):iv267

    CAS  PubMed  Google Scholar 

  51. Pavlidis N, Pentheroudakis G (2010) Cancer of unknown primary site: 20 questions to be answered. Ann Oncol 21(Suppl 7):vii303–vii307

    PubMed  Google Scholar 

  52. Hainsworth JD et al (2012) A retrospective study of treatment outcomes in patients with carcinoma of unknown primary site and a colorectal cancer molecular profile. Clin Colorectal Cancer 11(2):112–118

    PubMed  Google Scholar 

  53. Sorin T et al (2015) Occult cancer in specimens of reduction mammaplasty aimed at symmetrization. A multicentric study of 2718 patients. Breast 24(3):272–277

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Geneis (Beijing) Co., Ltd., Chaoyang District Beijing, People’s Republic of China

    Na Yan, Yanxiang Zhang, Xuejie Guo, Dawei Yuan, Geng Tian & Jialiang Yang

Authors
  1. Na Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yanxiang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xuejie Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dawei Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Geng Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jialiang Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jialiang Yang .

Editor information

Editors and Affiliations

  1. Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China

    Tao Huang

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Yan, N., Zhang, Y., Guo, X., Yuan, D., Tian, G., Yang, J. (2020). A Review on Cancer of Unknown Primary Origin: The Role of Molecular Biomarkers in the Identification of Unknown Primary Origin. In: Huang, T. (eds) Precision Medicine. Methods in Molecular Biology, vol 2204. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-0904-0_10

Download citation

  • DOI: https://doi.org/10.1007/978-1-0716-0904-0_10

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-0903-3

  • Online ISBN: 978-1-0716-0904-0

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation