Skip to main content

Advertisement

SpringerLink
Log in

Predictors of survival and recurrence after primary surgery for cervical metastasis of unknown primary

  • Original Article – Clinical Oncology
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Cervical metastasis from unknown primary (CUP) is commonly classified as an advanced overall stage. P16 or human papillomavirus (HPV) positivity in metastatic lymph nodes (LN) might be associated with a favorable survival outcome of CUP. Therefore, we evaluated the prognostic values of p16 immuno-positivity in LN and other clinicopathological factors in patients with squamous cell carcinoma CUP (SCCUP).

Methods

This study involved 83 patients who underwent therapeutic neck dissection and panendoscopic examination and biopsy for suspected CUP. P16 immunostaining and HPV typing in LN were performed in 56 patients. Cox proportional hazard regression analyses were used to identify factors associated with overall survival (OS) and disease-free survival (DFS).

Results

Postoperatively, primary tumors (PT) were found in 32 (38.6%) patients, mainly (90.6%) in the oropharynx, and not found in 51 (61.4%) patients. The clinicopathological data (except for histological grade) and 5-year OS and DFS rates did not significantly differ between patients with and without PT identification (all P > 0.05). P16 positivity was associated with favorable OS and DFS outcomes in the patients with PT (P < 0.05) but not in those without PT (P > 0.1). Multivariate analyses showed that age (> 60 years) and LN ratio (≥ 0.1) were the independent predictors of OS and DFS outcomes (all P < 0.05). P16 positivity or other factors were not independent factors.

Conclusion

Age and LN ratio are significant risk factors of survival and recurrence after primary surgery for SCCUP. Prognostic significance of LN p16 positivity should be further studied.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig 1
Fig. 2

Similar content being viewed by others

References

  • Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tan PF, Westra WH, Chung CH, Jordan RC, Lu C, Kim H, Axelrod R, Silverman CC, Redmond KP, Gillison ML (2010) Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 363(1):24–35

    Article  CAS  Google Scholar 

  • Begum S, Gillison ML, Ansari-Lari MA, Shah K, Westra WH (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 

  • Boscolo-Rizzo P, Schroeder L, Romeo S, Pawlita M (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

    Article  CAS  Google Scholar 

  • Denaro N, Merlano MC, Russi EG (2016) Follow-up in head and neck cancer: do more does it mean do better? A systematic review and our proposal based on our experience. Clin Exp Otorhinolaryngol 9(4):287–297

    Article  Google Scholar 

  • Divi V, Chen MM, Nussenbaum B, Rhoads KF, Sirjani DB, Holsinger FC, Shah JL, Hara W (2016) Lymph node count From neck dissection predicts mortality in head and neck cancer. J Clin Oncol 34(32):3892–3897

    Article  Google Scholar 

  • Dixon PR, Au M, Hosni A, Perez-Ordonez B, Weinreb I, Xu W, Song Y, Huang SH, O'Sullivan B, Goldstein DP, de Almeida JR (2016) Impact of p16 expression, nodal status, and smoking on oncologic outcomes of patients with head and neck unknown primary squamous cell carcinoma. Head Neck 38(9):1347–1353

    Article  Google Scholar 

  • D'Souza G, Kreimer AR, Viscidi R, Pawlita M, Fakhry C, Koch WM, Westra WH, Gillison ML (2007) Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 356(19):1944–1956

    Article  CAS  Google Scholar 

  • Dunne AA, Muller HH, Eisele DW, Kessel K, Moll R, Werner JA (2006) Meta-analysis of the prognostic significance of perinodal spread in head and neck squamous cell carcinomas (HNSCC) patients. Eur J Cancer 42(12):1863–1868

    Article  CAS  Google Scholar 

  • Galloway TJ, Ridge JA (2015) Management of squamous cancer metastatic to cervical nodes with an unknown primary site. J Clin Oncol 33(29):3328–3337

    Article  CAS  Google Scholar 

  • Heagerty PJ, Lumley T, Pepe MS (2000) Time-dependent ROC curves for censored survival data and a diagnostic marker. Biometrics 56(2):337–344

    Article  CAS  Google Scholar 

  • Ho AS, Kim S, Tighiouart M, Gudino C, Mita A, Scher KS, Laury A, Prasad R, Shiao SL, Van Eyk JE, Zumsteg ZS (2017) Metastatic lymph node burden and survival in oral cavity cancer. J Clin Oncol 35(31):3601–3609

    Article  Google Scholar 

  • Ho AS, Kim S, Tighiouart M, Gudino C, Mita A, Scher KS, Laury A, Prasad R, Shiao SL, Ali N, Patio C, Mallen-St Clair J, Van Eyk JE, Zumsteg ZS (2018) Association of quantitative metastatic lymph node burden with survival in hypopharyngeal and laryngeal cancer. JAMA Oncol 4(7):985–989

    Article  Google Scholar 

  • Johansen J, Eigtved A, Buchwald C, Theilgaard SA, Hansen HS (2002) Implication of 18F-fluoro-2-deoxy-D-glucose positron emission tomography on management of carcinoma of unknown primary in the head and neck: a Danish cohort study. Laryngoscope 112(11):2009–2014

    Article  Google Scholar 

  • Joo YH, Cho JK, Koo BS, Kwon M, Kwon SK, Kwon SY, Kim MS, Kim JK, Kim H, Nam I, Roh JL, Park YM, Park IS, Park JJ, Shin SC, Ahn SH, Won S, Ryu CH, Yoon TM, Lee G, Lee DY, Lee MC, Lee JK, Lee JC, Lim JY, Chang JW, Jang JY, Chung MK, Jung YS, Cho JG, Choi YS, Choi JS, Lee GH, Chung PS (2019) Guidelines for the surgical management of oral cancer: Korean society of thyroid-head and neck surgery. Clin Exp Otorhinolaryngol 12(2):107–144

    Article  Google Scholar 

  • Keller LM, Galloway TJ, Holdbrook T, Ruth K, Yang D, Dubyk C, Flieder D, Lango MN, Mehra R, Burtness B, Ridge JA (2014) p16 status, pathologic and clinical characteristics, biomolecular signature, and long-term outcomes in head and neck squamous cell carcinomas of unknown primary. Head Neck 36(12):1677–1684

    Article  Google Scholar 

  • Kim SY, Nam SY, Choi SH, Cho KJ, Roh JL (2011) Prognostic value of lymph node density in node-positive patients with oral squamous cell carcinoma. Ann Surg Oncol 18(8):2310–2317

    Article  Google Scholar 

  • Kim BH, Park SJ, Jeong WJ, Ahn SH (2018) Comparison of treatment outcomes for T3 glottic squamous cell carcinoma: a meta-analysis. Clin Exp Otorhinolaryngol 11(1):1–8

    Article  Google Scholar 

  • Koch WM, Bhatti N, Williams MF, Eisele DW (2001) Oncologic rationale for bilateral tonsillectomy in head and neck squamous cell carcinoma of unknown primary source. Otolaryngol Head Neck Surg 124(3):331–333

    Article  CAS  Google Scholar 

  • Kwon M, Roh JL, Lee J, Cho KJ, Choi SH, Nam SY, Kim SY (2015) Extranodal extension and thickness of metastatic lymph node as a significant prognostic marker of recurrence and survival in head and neck squamous cell carcinoma. J Craniomaxillofac Surg 43(6):769–778

    Article  Google Scholar 

  • Lydiatt WM, Patel SG, O'Sullivan B, Brandwein MS, Ridge JA, Migliacci JC, Loomis AM, Shah JP (2017) Head and neck cancers-major changes in the American Joint Committee on cancer eighth edition cancer staging manual. CA Cancer J Clin 67(2):122–137

    Article  Google Scholar 

  • Mermod M, Tolstonog G, Simon C, Monnier Y (2016) Extracapsular spread in head and neck squamous cell carcinoma: a systematic review and meta-analysis. Oral Oncol 62:60–71

    Article  Google Scholar 

  • Miller FR, Karnad AB, Eng T, Hussey DH, Stan McGuff H, Otto RA (2008) Management of the unknown primary carcinoma: long-term follow-up on a negative PET scan and negative panendoscopy. Head Neck 30(1):28–34

    Article  Google Scholar 

  • Mintzer DM, Warhol M, Martin AM, Greene G (2004) Cancer of unknown primary: changing approaches. A multidisciplinary case presentation from the Joan Karnell cancer center of pennsylvania hospital. Oncologist 9(3):330–338

    Article  Google Scholar 

  • Mork J, Lie AK, Glattre E, Hallmans G, Jellum E, Koskela P, Moller B, Pukkala E, Schiller JT, Youngman L, Lehtinen M, Dillner J (2001) Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck. N Engl J Med 344(15):1125–1131

    Article  CAS  Google Scholar 

  • O'Rorke MA, Ellison MV, Murray LJ, Moran M, James J, Anderson LA (2012) Human papillomavirus related head and neck cancer survival: a systematic review and meta-analysis. Oral Oncol 48(12):1191–1201

    Article  CAS  Google Scholar 

  • Park GC, Lee M, Roh JL, Yu MS, Choi SH, Nam SY, Kim SY, Cho KJ (2012) Human papillomavirus and p16 detection in cervical lymph node metastases from an unknown primary tumor. Oral Oncol 48(12):1250–1256

    Article  CAS  Google Scholar 

  • Park GC, Jung JH, Roh JL, Lee JH, Cho KJ, Choi SH, Nam SY, Kim SY (2014) Prognostic value of metastatic nodal volume and lymph node ratio in patients with cervical lymph node metastases from an unknown primary tumor. Oncology 86(3):170–176

    Article  CAS  Google Scholar 

  • Patel SG, L WM, Ridge CM, Mukherji SK, Ghossein RA, Brandwein-Gensler M (2017) In: Amin MB, Greene FL, Byrd DR, Brookland RK, Washington MK (eds) AJCC cancer staging manual, 8th edn. Springer, New York, pp 67–78

    Chapter  Google Scholar 

  • Roh JL, Kim JS, Lee JH, Cho KJ, Choi SH, Nam SY, Kim SY (2009) Utility of combined (18)F-fluorodeoxyglucose-positron emission tomography and computed tomography in patients with cervical metastases from unknown primary tumors. Oral Oncol 45(3):218–224

    Article  Google Scholar 

  • Ross RB, Koyfman SA, Reddy CA, Houston N, Geiger JL, Woody NM, Joshi NP, Greskovich JF Jr, Burkey BB, Scharpf J, Lamarre ED, Prendes B, Lorenz RR, Adelstein DJ, Ward MC (2018) A matched comparison of human papillomavirus-induced squamous cancer of unknown primary with early oropharynx cancer. Laryngoscope 128(6):1379–1385

    Article  Google Scholar 

  • Schroeder L, Boscolo-Rizzo P, Dal Cin E, Romeo S, Baboci L, Dyckhoff G, Hess J, Lucena-Porcel C, Byl A, Becker N, Alemany L, Castellsague X, Quer M, Leon X, Wiesenfarth M, Pawlita M, Holzinger D (2017) Human papillomavirus as prognostic marker with rising prevalence in neck squamous cell carcinoma of unknown primary: a retrospective multicentre study. Eur J Cancer 74:73–81

    Article  Google Scholar 

  • Schroeder L, Wichmann G, Willner M, Michel A, Wiesenfarth M, Flechtenmacher C, Gradistanac T, Pawlita M, Dietz A, Waterboer T, Holzinger D (2018) Antibodies against human papillomaviruses as diagnostic and prognostic biomarker in patients with neck squamous cell carcinoma from unknown primary tumor. Int J Cancer 142(7):1361–1368

    Article  CAS  Google Scholar 

  • Sedghizadeh PP, Billington WD, Paxton D, Ebeed R, Mahabady S, Clark GT, Enciso R (2016) Is p16-positive oropharyngeal squamous cell carcinoma associated with favorable prognosis? A systematic review and meta-analysis. Oral Oncol 54:15–27

    Article  Google Scholar 

  • Talmi YP, Takes RP, Alon EE, Nixon IJ, Lopez F, de Bree R, Rodrigo JP, Shaha AR, Halmos GB, Rinaldo A, Ferlito A (2018) Prognostic value of lymph node ratio in head and neck squamous cell carcinoma. Head Neck 40(5):1082–1090

    Article  Google Scholar 

  • Tribius S, Hoffmann AS, Bastrop S, Gorogh T, Haag J, Rocken C, Clauditz T, Grob T, Wilczak W, Tennstedt P, Borcherding A, Petersen C, Hoffmann M (2012) HPV status in patients with head and neck of carcinoma of unknown primary site: HPV, tobacco smoking, and outcome. Oral Oncol 48(11):1178–1184

    Article  Google Scholar 

  • Vatcheva KP, Lee M, McCormick JB, Rahbar MH (2016) Multicollinearity in regression analyses conducted in epidemiologic studies. Epidemiology (Sunnyvale) 6(2):227

    Article  Google Scholar 

  • Yoo SH, Roh JL, Kim SO, Cho KJ, Choi SH, Nam SY, Kim SY (2015) Patterns and treatment of neck metastases in patients with salivary gland cancers. J Surg Oncol 111(8):1000–1006

    Article  Google Scholar 

  • Zhang MQ, El-Mofty SK, Davila RM (2008) Detection of human papillomavirus-related squamous cell carcinoma cytologically and by in situ hybridization in fine-needle aspiration biopsies of cervical metastasis: a tool for identifying the site of an occult head and neck primary. Cancer 114(2):118–123

    Article  Google Scholar 

  • Zheng CM, Ji YB, Song CM, Ge MH, Tae K (2018) Number of metastatic lymph nodes and ratio of metastatic lymph nodes to total number of retrieved lymph nodes are risk factors for recurrence in patients with clinically node negative papillary thyroid carcinoma. Clin Exp Otorhinolaryngol 11(1):58–64

    Article  Google Scholar 

Download references

Funding

This study was supported by the National Research Foundation of Korea (NRF) grant, funded by the Ministry of Science and ICT (MSIT), the Government of Korea (No. 2019R1A2C2002259) (J.-L.R.).

Author information

Authors and Affiliations

  1. Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Won Ki Cho, Seung-Ho Choi, Soon Yuhl Nam & Sang Yoon Kim

  2. Department of Otorhinolaryngology-Head and Neck Surgery, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea

    Jong-Lyel Roh

  3. Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Kyung-Ja Cho

Authors
  1. Won Ki Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jong-Lyel Roh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kyung-Ja Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Seung-Ho Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Soon Yuhl Nam
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sang Yoon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jong-Lyel Roh.

Ethics declarations

Conflict of interest

The authors have no conflicts of interest to declare.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research board and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors. Informed consent from all individual participants was waved because of the retrospective nature of this study.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cho, W.K., Roh, JL., Cho, KJ. et al. Predictors of survival and recurrence after primary surgery for cervical metastasis of unknown primary. J Cancer Res Clin Oncol 146, 925–933 (2020). https://doi.org/10.1007/s00432-019-03111-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-019-03111-x

Keywords

Search

Navigation