Download PDF
CC BY-NC-ND 4.0 · Int Arch Otorhinolaryngol 2023; 27(04): e687-e693
DOI: 10.1055/s-0042-1759575
Original Research

Survival Outcome in True Carcinoma of Unknown Primary (tCUP) with p16 + Cervical Metastasis

Muhammad Faisal 
1   Department of Surgical Oncology, Shaukat Khanum Memorial Cancer Hospital and Research Center, Lahore, Pakistan
2   Institute of Head and Neck Diseases, Evangelical Hospital, Vienna, Austria
,
Nguyen-Son Le
3   Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
,
Stefan Grasl
3   Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
,
Johannes Pammer
4   Department of Clinical Pathology, Medical University of Vienna, Vienna, Austria
,
Stefan Janik
3   Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
,
Gregor Heiduschka
3   Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
,
Annemarie U. Schratter-Sehn
5   Institute of Radio-Oncology, Kaiser-Franz-Josef Hospital, Vienna, Austria
,
Peter Franz
6   Department of Otorhinolaryngology, Head and Neck Surgery, Rudolfstiftung Hospital, Vienna, Austria
,
Meinhard Königswieser
6   Department of Otorhinolaryngology, Head and Neck Surgery, Rudolfstiftung Hospital, Vienna, Austria
,
Matthaeus Ch. Grasl
3   Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
,
Boban M. Erovic
2   Institute of Head and Neck Diseases, Evangelical Hospital, Vienna, Austria
› Author Affiliations Funding This study was funded by the Medical University of Vienna.
› Further Information
Also available at
   Permissions and Reprints

Abstract

Introduction Age and lymph node ratio have been attributed as independent predictors for survival and recurrence in carcinoma of unknown primary (CUP).

Objective The purpose of this study was to analyze the prognostic value of p16 overexpression for CUP in the absence of true primary (TP).

Methods The study involved 43 patients who underwent therapeutic lymph node dissection (LND) from 2000 to 2015 after all the diagnostic work up for CUP. Immunohistochemistry for p16 overexpression was performed. Cox proportional hazard regression analysis was used to analyze the prognostic impact on 5-year overall survival (OS) and recurrence-free survival (RFS).

Results The male-to-female ratio was 5.1:1, with a median age of 62 years. The clinicopathological data, except for p16 overexpression, did not differ significantly in terms of 5-year OS and RFS. The Cox regression analysis proposed p16 positivity to be an independent prognosticator of regional recurrence-free survival (RRFS) (hazard ratio [HR] 6.180, p = 0.21). The median time to recurrence and death were 10 and 25 months, respectively.

Conclusion Cervical metastasis with p16 overexpression is a significant prognostic factor of improved RFS after surgery in CUP. The prognostic significance of lymph node p16 positivity should be further studied.

Keywords

unknown primary - neoplasm metastasis - head and neck neoplasms

Ethics Approval and Consent to Participate

Ethical exemption was granted by the ethics committee of the Medical University of Vienna.


Availability of Data and Materials

All data generated or analyzed during this study are included in this published article.


Authors' Contributions

B. E. and S.G.: conceptualization; S. J., J. P.: methodology; N. S.: software; A. S., M. G.: validation; N. S.: formal analysis; S. G.: investigation; S. J.: resources; S. G., S.J.: data curation; M. F.: writing and original draft preparation, B. E., M. F., J. P.: writing, review and editing; G. H.: visualization; B. E.: supervision.




Publication History

Received: 18 September 2021

Accepted: 22 August 2022

Article published online:
23 October 2023

© 2023. Fundação Otorrinolaringologia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Thieme Revinter Publicações Ltda.
Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil

 

  • References

  • 1 Miller FR, Karnad AB, Eng T, Hussey DH, Stan McGuff H, Otto RA. Management of the unknown primary carcinoma: long-term follow-up on a negative PET scan and negative panendoscopy. Head Neck 2008; 30 (01) 28-34
    CrossrefPubMedSearch in Google Scholar
  • 2 Galloway TJ, Ridge JA. Management of Squamous Cancer Metastatic to Cervical Nodes With an Unknown Primary Site. J Clin Oncol 2015; 33 (29) 3328-3337
    CrossrefPubMedSearch in Google Scholar
  • 3 Pavlidis N, Khaled H, Gaafar R. A mini review on cancer of unknown primary site: A clinical puzzle for the oncologists. J Adv Res 2015; 6 (03) 375-382
    CrossrefPubMedSearch in Google Scholar
  • 4 Pavlidis N, Pentheroudakis G, Plataniotis G. Cervical lymph node metastases of squamous cell carcinoma from an unknown primary site: a favourable prognosis subset of patients with CUP. Clin Transl Oncol 2009; 11 (06) 340-348
    CrossrefPubMedSearch in Google Scholar
  • 5 Guntinas-Lichius O, Peter Klussmann J, Dinh S. et al. Diagnostic work-up and outcome of cervical metastases from an unknown primary. Acta Otolaryngol 2006; 126 (05) 536-544
    Search in Google Scholar
  • 6 Challis GB, Stam HJ. The spontaneous regression of cancer. A review of cases from 1900 to 1987. Acta Oncol 1990; 29 (05) 545-550
    CrossrefPubMedSearch in Google Scholar
  • 7 van de Wouw AJ, Jansen RL, Speel EJ, Hillen HF. The unknown biology of the unknown primary tumour: a literature review. Ann Oncol 2003; 14 (02) 191-196
    CrossrefPubMedSearch in Google Scholar
  • 8 Boscolo-Rizzo P, Da Mosto MC, Gava A, Marchiori C. Cervical lymph node metastases from occult squamous cell carcinoma: analysis of 82 cases. ORL J Otorhinolaryngol Relat Spec 2006; 68 (04) 189-194
    CrossrefPubMedSearch in Google Scholar
  • 9 Koivunen P, Laranne J, Virtaniemi J. et al. Cervical metastasis of unknown origin: a series of 72 patients. Acta Otolaryngol 2002; 122 (05) 569-574
    CrossrefPubMedSearch in Google Scholar
  • 10 Villeneuve H, Després P, Fortin B. et al. Cervical lymph node metastases from unknown primary cancer: a single-institution experience with intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2012; 82 (05) 1866-1871
    CrossrefPubMedSearch in Google Scholar
  • 11 Haas I, Hoffmann TK, Engers R, Ganzer U. Diagnostic strategies in cervical carcinoma of an unknown primary (CUP). Eur Arch Otorhinolaryngol 2002; 259 (06) 325-333
    CrossrefPubMedSearch in Google Scholar
  • 12 Müller von der Grün J, Bon D, Rödel C, Balermpas P. Patterns of care analysis for head & neck cancer of unknown primary site: a survey inside the German society of radiation oncology (DEGRO). Strahlenther Onkol 2018; 194 (08) 750-758
    CrossrefPubMedSearch in Google Scholar
  • 13 O'Rorke MA, Ellison MV, Murray LJ, Moran M, James J, Anderson LA. Human papillomavirus related head and neck cancer survival: a systematic review and meta-analysis. Oral Oncol 2012; 48 (12) 1191-1201
    CrossrefPubMedSearch in Google Scholar
  • 14 Dixon PR, Au M, Hosni A. et al. Impact of p16 expression, nodal status, and smoking on oncologic outcomes of patients with head and neck unknown primary squamous cell carcinoma. Head Neck 2016; 38 (09) 1347-1353
    CrossrefPubMedSearch in Google Scholar
  • 15 Rassy E, Nicolai P, Pavlidis N. Comprehensive management of HPV-related squamous cell carcinoma of the head and neck of unknown primary. Head Neck 2019; 41 (10) 3700-3711
    Search in Google Scholar
  • 16 Deng Z, Hasegawa M, Aoki K. et al. A comprehensive evaluation of human papillomavirus positive status and p16INK4a overexpression as a prognostic biomarker in head and neck squamous cell carcinoma. Int J Oncol 2014; 45 (01) 67-76
    CrossrefPubMedSearch in Google Scholar
  • 17 Mork J, Lie AK, Glattre E. et al. Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck. N Engl J Med 2001; 344 (15) 1125-1131
    CrossrefPubMedSearch in Google Scholar
  • 18 D'Souza G, Kreimer AR, Viscidi R. et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 2007; 356 (19) 1944-1956
    CrossrefPubMedSearch in Google Scholar
  • 19 Lydiatt WM, Patel SG, O'Sullivan B. et al. Head and Neck cancers-major changes in the American Joint Committee on cancer eighth edition cancer staging manual. CA Cancer J Clin 2017; 67 (02) 122-137
    CrossrefPubMedSearch in Google Scholar
  • 20 Keller LM, Galloway TJ, Holdbrook T. et al. p16 status, pathologic and clinical characteristics, biomolecular signature, and long-term outcomes in head and neck squamous cell carcinomas of unknown primary. Head Neck 2014; 36 (12) 1677-1684
    CrossrefPubMedSearch in Google Scholar
  • 21 Axelsson L, Nyman J, Haugen-Cange H. et al. Prognostic factors for head and neck cancer of unknown primary including the impact of human papilloma virus infection. J Otolaryngol Head Neck Surg 2017; 46 (01) 45
    CrossrefPubMedSearch in Google Scholar
  • 22 Jensen DH, Hedback N, Specht L. et al. Human papillomavirus in head and neck squamous cell carcinoma of unknown primary is a common event and a strong predictor of survival. PLoS One 2014; 9 (11) e110456
    CrossrefPubMedSearch in Google Scholar
  • 23 Schroeder L, Wichmann G, Willner M. et al. Antibodies against human papillomaviruses as diagnostic and prognostic biomarker in patients with neck squamous cell carcinoma from unknown primary tumor. Int J Cancer 2018; 142 (07) 1361-1368
    CrossrefPubMedSearch in Google Scholar
  • 24 Graboyes EM, Sinha P, Thorstad WL, Rich JT, Haughey BH. Management of human papillomavirus-related unknown primaries of the head and neck with a transoral surgical approach. Head Neck 2015; 37 (11) 1603-1611
    CrossrefPubMedSearch in Google Scholar
  • 25 Bersani C, Sivars L, Haeggblom L. et al. Targeted sequencing of tonsillar and base of tongue cancer and human papillomavirus positive unknown primary of the head and neck reveals prognostic effects of mutated FGFR3. Oncotarget 2017; 8 (21) 35339-35350
    CrossrefPubMedSearch in Google Scholar
  • 26 Sivars L, Näsman A, Tertipis N. et al. Human papillomavirus and p53 expression in cancer of unknown primary in the head and neck region in relation to clinical outcome. Cancer Med 2014; 3 (02) 376-384
    CrossrefPubMedSearch in Google Scholar
  • 27 Hung YH, Liu SA, Wang CC, Wang CP, Jiang RS, Wu SH. Treatment outcomes of unknown primary squamous cell carcinoma of the head and neck. PLoS One 2018; 13 (10) e0205365
    CrossrefPubMedSearch in Google Scholar
  • 28 Adams JR, O'Brien CJ. Unknown primary squamous cell carcinoma of the head and neck: a review of diagnosis, treatment and outcomes. Asian J Surg 2002; 25 (02) 188-193
    CrossrefPubMedSearch in Google Scholar
  • 29 Begum S, Gillison ML, Ansari-Lari MA, Shah K, Westra WH. Detection of human papillomavirus in cervical lymph nodes: a highly effective strategy for localizing site of tumor origin. Clin Cancer Res 2003; 9 (17) 6469-6475
    PubMedSearch in Google Scholar
  • 30 Zhang MQ, El-Mofty SK, Dávila RM. 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 2008; 114 (02) 118-123
    CrossrefPubMedSearch in Google Scholar
  • 31 Le NS, Janik S, Simmel H, Erovic BM. Bilateral vs ipsilateral adjuvant radiotherapy in patients with cancer of unknown primary of the head and neck: An analysis of the clinical outcome and radiation-induced side effects. Head Neck 2019; 41 (06) 1785-1794
    CrossrefPubMedSearch in Google Scholar
  • 32 Ang KK, Harris J, Wheeler R. et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010; 363 (01) 24-35
    CrossrefPubMedSearch in Google Scholar
  • 33 Sedghizadeh PP, Billington WD, Paxton D. et al. Is p16-positive oropharyngeal squamous cell carcinoma associated with favorable prognosis? A systematic review and meta-analysis. Oral Oncol 2016; 54: 15-27
    CrossrefPubMedSearch in Google Scholar
  • 34 Cho WK, Roh JL, Cho KJ, Choi SH, Nam SY, Kim SY. Predictors of survival and recurrence after primary surgery for cervical metastasis of unknown primary. J Cancer Res Clin Oncol 2020; 146 (04) 925-933
    Search in Google Scholar
  • 35 Chung CH, Zhang Q, Kong CS. et al. p16 protein expression and human papillomavirus status as prognostic biomarkers of nonoropharyngeal head and neck squamous cell carcinoma. J Clin Oncol 2014; 32 (35) 3930-3938
    CrossrefPubMedSearch in Google Scholar
  • 36 McDowell LJ, Young RJ, Johnston ML. et al. p16-positive lymph node metastases from cutaneous head and neck squamous cell carcinoma: No association with high-risk human papillomavirus or prognosis and implications for the workup of the unknown primary. Cancer 2016; 122 (08) 1201-1208
    CrossrefPubMedSearch in Google Scholar
  • 37 Ebrahimi A, Clark JR, Zhang WJ. et al. Lymph node ratio as an independent prognostic factor in oral squamous cell carcinoma. Head Neck 2011; 33 (09) 1245-1251
    CrossrefPubMedSearch in Google Scholar
  • 38 Patel SG, Amit M, Yen TC. et al; International Consortium for Outcome Research (ICOR) in Head and Neck Cancer. Lymph node density in oral cavity cancer: results of the International Consortium for Outcomes Research. Br J Cancer 2013; 109 (08) 2087-2095
    CrossrefPubMedSearch in Google Scholar
  • 39 Wang YL, Feng SH, Zhu J. et al. Impact of lymph node ratio on the survival of patients with hypopharyngeal squamous cell carcinoma: a population-based analysis. PLoS One 2013; 8 (02) e56613
    CrossrefPubMedSearch in Google Scholar
  • 40 Rudra S, Spiotto MT, Witt ME, Blair EA, Stenson K, Haraf DJ. Lymph node density–prognostic value in head and neck cancer. Head Neck 2014; 36 (02) 266-272
    CrossrefPubMedSearch in Google Scholar
  • 41 Ong W, Zhao R, Lui B. et al. Prognostic significance of lymph node density in squamous cell carcinoma of the tongue. Head Neck 2016; 38 (Suppl 1): E859-E866
    PubMedSearch in Google Scholar
  • 42 Prabhu RS, Hanasoge S, Magliocca KR. et al. Lymph node ratio influence on risk of head and neck cancer locoregional recurrence after initial surgical resection: implications for adjuvant therapy. Head Neck 2015; 37 (06) 777-782
    CrossrefPubMedSearch in Google Scholar
  • 43 Sano D, Yabuki K, Takahashi H. et al. Lymph node ratio as a prognostic factor for survival in patients with head and neck squamous cell carcinoma. Auris Nasus Larynx 2018; 45 (04) 846-853 [published correction appears in Auris Nasus Larynx. 2019 Oct;46(5):818–819]
    CrossrefPubMedSearch in Google Scholar