Head and neck cancers of unknown primary: A diagnostic and therapeutic challenge

Enache, Raluca; Sarafoleanu, Dorin; Sarafoleanu, Codrut

doi:10.2478/rjr-2023-0003

Abstract

Head and neck cancers of unknown primary (CUP) represent up to 10% of all cancers located in the head and neck. True cancers of unknown primary, which remain of undetected primary origin after a correct clinical, imaging, surgical evaluation, have a reported frequency of between 1% and 2%. Cancers of unknown primary of the head and neck are a diagnostic challenge, considering that their main clinical manifestation is represented by the appearance of lymph node metastases in the cervical region.

In general, the detection of cancers with an unknown starting point is late, difficult, with significant therapeutic failure. The diagnostic-therapeutic approach starts from the histopathological structure of the lymph node metastasis and continues with a correct and complete imaging evaluation.

In this review are presented the diagnosis and therapeutic challenges and importance of head and neck cancers with unknown primary.

References

1. Martin H. Untimely lymph node biopsy. Am J Surg. 1961;102(1):17-18. DOI: 10.1016/0002-9610(61)90679-1.
Open DOI Search in Google Scholar Back to article
2. Civantos FJ, Vermorken JB, Shah JP, Rinaldo A, Suarez C, Kowalski LP, et al. Metastatic squamous cell carcinoma to the cervical lymph nodes from an unknown primary cancer: management in the HPV era. Front Oncol. 2020;10:593164. DOI: 10.3389/fonc.2020.593164.
Open DOI Search in Google Scholar Back to article
3. Pavlidis N, Briasoulis E, Hainsworth J, Greco F. Diagnostic and therapeutic management of cancer of an unknown primary. Eur J Cancer. 2003;39(14):1990-2005.
Search in Google Scholar Back to article
4. Guntinas-Lichius O, Klussman J, Dinh S, Dinh M, Schmidt M, Semrau R, et al. Diagnostic work-up and outcome of cervical metastases from an unknown primary. Acta Otolaryngol. 2006;126(5):536-44.
Search in Google Scholar Back to article
5. Jereczek-Fossa BA, Jassem J, Orecchia R. Cervical lymph node metastases of squamous cell carcinoma from an unknown primary. Cancer Treat Rev. 2004;30(2):153-64. DOI: 10.1016/j.ctrv.2003.10.001.
Open DOI Search in Google Scholar Back to article
6. Chernock RD, Lewis JS. Approach to metastatic carcinoma of unknown primary in the head and neck: squamous cell carcinoma and beyond. Head Neck Pathol. 2015;9(1):6-15. DOI: 10.1007/s12105-015-0616-2.
Open DOI Search in Google Scholar Back to article
7. Cianchetti M, Mancuso AA, Amdur RJ, Werning JW, Kirwan J, Morris CG, et al. Diagnostic evaluation of squamous cell carcinoma metastatic to cervical lymph nodes from an unknown head and neck primary site. Laryngoscope. 2009;119(12):2348-54. DOI: 10.1002/lary.20638.
Open DOI Search in Google Scholar Back to article
8. Schroeder L, Boscolo-Rizzo P, Cin ED, Romeo S, Baboci L, Dyckhoff G, et al. Human papillomavirus as prognostic marker with rising prevalence in neck squamous cell carcinoma of unknown primary: A retrospective multicentre study. Eur J Cancer. 2017;74:73-81. DOI: 10.1016/j.ejca.2016.12.020.
Open DOI Search in Google Scholar Back to article
9. Balk M, Rupp R, Mantsopoulos K, Sievert M, Gostian M, Allner M, et al. Factors influencing the outcome of head and neck cancer of unknown primary (HNCUP). J Clin Med. 2022;11(10):2689. DOI: 10.3390/jcm11102689.
Open DOI Search in Google Scholar Back to article
10. Kennel T, Garrel R, Costes V, Boisselier P, Crampette L, Favier V. Head and neck carcinoma of unknown primary. Eur Ann Otorhinolaryngol Head Neck Dis. 2019;136(3):185-92. DOI: 10.1016/j.anorl.2019.04.002.
Open DOI Search in Google Scholar Back to article
11. Issing WJ, Taleban B, Tauber S. Diagnosis and management of carcinoma of unknown primary in the head and neck. Eur Arch Otorhinolaryngol. 2003;260(8):436-43. DOI: 10.1007/s00405-003-0585-z.
Open DOI Search in Google Scholar Back to article
12. Robbins KT, Clayman G, Levine PA, Medina J, Sessions R, Shaha A, et al. Neck dissection classification update: revisions proposed by the American Head and Neck Society and the American Academy of Otolaryngology- Head and Neck Surgery. Arch Otolaryngol Head Neck Surg. 2002;128(7):751-8. DOI: 10.1001/archotol.128.7.751.
Open DOI Search in Google Scholar Back to article
13. Neagu A. Diagnosticul si tratamentul tumefactiilor cervicale. In: Popescu I, Ciuce C (red.), Sarafoleanu C (coord.). Tratat de chirurgie. Vol. 1: Otorinolaringologie si chirurgie cervico-faciala. Editura Academiei Romana, Bucuresti; 2012, p. 383-425.
Search in Google Scholar Back to article
14. Weiss D, Koopman M, Rudack C. Prevalence and impact on clinicopatho-logical characteristics of human papillomavirus-16 DNA in cervical lymph node metastases of head and neck squamous cell carcinoma. Head Neck. 2011;33(6):856-62.
Search in Google Scholar Back to article
15. Oren N, Vaysberg A, Ginat DT. Updated WHO nomenclature of head and neck lesions and associated imaging findings. Insights Imaging. 2019;10(1):72. DOI: 10.1186/s13244-019-0760-4.
Open DOI Search in Google Scholar Back to article
16. Deschler DG, Richmon JD, Khariwala SS, Ferris RL, Wand MB. The “new” head and neck cancer patient – young, nonsmoker, nondrinker, and HPV positive: Evaluation. Otolaryngol Head Neck Surg. 2014;151(3):375-80. DOI: 10.1177/0194599814538605.
Open DOI Search in Google Scholar Back to article
17. Kalavacherla S, Sanghvi P, Lin GY, Guo T. Updates in the management of unknown primary of the head and neck. Front Oncol. 2022;12:991838. DOI: 10.3389/fonc.2022.991838.
Open DOI Search in Google Scholar Back to article
18. Grani G, Fumarola A. Thyroglobulin in lymph node fine-needle aspiration washout: a systematic review and meta-analysis of diagnostic accuracy. J Clin Endocrinol Metab. 2014;99(6):1970-82. DOI: 10.1210/jc.2014-1098.
Open DOI Search in Google Scholar Back to article
19. Karanikas G, Moameni A, Poetzi C, Zettinig G, Kaserer K, Bieglmayer C, et al. Frequency and relevance of elevated calcitonin levels in patients with neoplas-tic and nonneoplastic thyroid disease and in healthy subjects. J Clin Endocrinol Metab. 2004;89(2):515-9. DOI: 10.1210/jc.2003-030709.
Open DOI Search in Google Scholar Back to article
20. Wong HH, Wang J. Merkel cell carcinoma. Arch Pathol Lab Med. 2010;134(11):1711-6. DOI: 10.5858/2009-0165-RSR2.1.
Open DOI Search in Google Scholar Back to article
21. Trosman S, Chute D, Wood B, Lamarre E. Unknown primary mucoepidermoid carcinoma: diagnosis and treatment. Head Neck. 2015;37(2):E22-5. DOI: 10.1002/hed.23766.
Open DOI Search in Google Scholar Back to article
22. López F, Rodrigo JP, Silver CE, Haigentz M, Bishop JA, Strojan P, et al. Cervical lymph node metastases from remote primary tumor sites. Head Neck. 2016;38(Suppl 1):E2374-85. DOI: 10.1002/hed.24344.
Open DOI Search in Google Scholar Back to article
23. Grau C, Johansen LV, Jakobsen J, Geertsen P, Andersen E, Jensen BB. Cervical lymph node metastases from unknown primary tumours. Results from a national survey by the Danish Society for Head and Neck Oncology. Radio-ther Oncol. 2000;55(2):121-9. DOI: 10.1016/s0167-8140(00)00172-9.
Open DOI Search in Google Scholar Back to article
24. Maghami E, Ismaila N, Alvarez A, Chernock R, Duwuri U, Geiger J, et al. Diagnosis and management of squamous cell carcinoma of unknown primary in the head and neck: ASCO Guideline. J Clin Oncol. 2020;38:2570-96.
Search in Google Scholar Back to article
25. Di Maio P, Iocca O, De Virgilio A, Giudice M, Pellini R, D’Ascanio L, et al. Narrow band imaging in head and neck unknown primary carcinoma: A systematic review and meta-analysis. Laryngoscope. 2020;130(7):1692-1700. DOI: 10.1002/lary.28350.
Open DOI Search in Google Scholar Back to article
26. Shinozaki T, Hayashi R, Ebihara M, Miyazaki M, Daiko H, Saikawa M, et al. Narrow band imaging endoscopy for unknown primary tumor sites of the neck. Head Neck. 2012;34(6):826-9. DOI: 10.1002/hed.21825.
Open DOI Search in Google Scholar Back to article
27. Monnet O, Cohen F, Lecorroller T, Vidal V, Jacquier A, Gaubert JY, et al. Cervical lymph nodes. J Radiol. 2008;89(7-8 Pt 2):1020-36. DOI: 10.1016/s0221-0363(08)73905-2.
Open DOI Search in Google Scholar Back to article
28. Ye W, Arnaud EH, Langerman A, Mannion K, Topf MC. Diagnostic approaches to carcinoma of unknown primary of the head and neck. Eur J Cancer Care (Engl). 2021;30(6):e13459. DOI: 10.1111/ecc.13459.
Open DOI Search in Google Scholar Back to article
29. Sokoya M, Chowdhury F, Kadakia S, Ducic Y. Combination of panendoscopy and positron emission tomography/computed tomography increases detection of unknown primary head and neck carcinoma. Laryngoscope. 2018;128(11):2573-5. DOI: 10.1002/lary.27268.
Open DOI Search in Google Scholar Back to article
30. Han A, Xue J, Hu M, Zheng J, Wang X. Clinical value of 18F-FDG PET-CT in detecting primary tumor for patients with carcinoma of unknown primary. Cancer Epidemiol. 2012;36(5):470-5. DOI: 10.1016/j.canep.2012.03.002.
Open DOI Search in Google Scholar Back to article
31. Deonarine P, Han S, Poon FW, de Wet C. The role of 18F-fluoro-2-deoxyglucose positron emission tomography/computed tomography in the management of patients with carcinoma of unknown primary. Scott Med J. 2013;58(3):154-62. DOI: 10.1177/0036933013496958.
Open DOI Search in Google Scholar Back to article
32. Tandon S, Shahab R, Benton JI, Ghosh SK, Sheard J, Jones TM. Fine-needle aspiration cytology in a regional head and neck cancer center: comparison with a systematic review and meta-analysis. Head Neck. 2008;30(9):1246-52. DOI: 10.1002/hed.20849.
Open DOI Search in Google Scholar Back to article
33. Ferreira VHC, Sassi LM, Zanicotti RTS, Ramos GHA, Jung JE, Schussel JL. Core needle biopsy in the diagnosis of head and neck lesions: a retrospective study of 3 years. Eur Arch Otorhinolaryngol. 2016;273(12):4469-72. DOI: 10.1007/s00405-016-4139-6.
Open DOI Search in Google Scholar Back to article
34. Lydiatt WM, Patel SG, O’Sullivan B, Brandwein MS, Ridge JA, Migliacci JC, 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(2):122-37. DOI: 10.3322/caac.21389.
Open DOI Search in Google Scholar Back to article
35. American Joint Committee on Cancer. AJCC Cancer Staging Form Suppliment. AJCC Cancer Staging Manual, Eighth Edition. [Internet]. [updated Jun 5, 2018]. Available from: file:///C:/Users/enach/OneDrive/Desktop/Head%20neck%20cancer%20unknown%20primary/AJCC%20Cancer%20 Staging%20Form%20Supplement%20to%20the%20AJCC%20Cancer%20 Staging%20Manual,%20Eighth%20Edition%20(%20PDFDrive%20).pdf.
Search in Google Scholar Back to article
36. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Head and neck cancers. NCCN evidence blocksᵀᴹ. Version 2.2022. Available from: file:///C:/Users/enach/OneDrive/Desktop/Head%20neck%20cancer%20unknown%20primary/head-and-neck_blocks.pdf. Accessed November 28, 2022.
Search in Google Scholar Back to article
37. Begum S, Gillison ML, Nicol TL, Westra WH. Detection of human papillomavirus-16 in fine-needle aspirates to determine tumor origin in patients with metastatic squamous cell carcinoma of the head and neck. Clin Cancer Res. 2007;13(4):1186-91. DOI: 10.1158/1078-0432.CCR-06-1690.
Open DOI Search in Google Scholar Back to article
38. Svajdler M Jr., Kaspirkova J, Hadravsky L, Laco J, Dubinsky P, Straka L, et al. Origin of cystic squamous cell carcinoma metastases in head and neck lymph nodes: Addition of EBV testing improves diagnostic accuracy. Pathol Res Pract. 2016;212(6):524-31. DOI: 10.1016/j.prp.2016.03.002.
Open DOI Search in Google Scholar Back to article
39. Frank SJ, Rosenthal DI, Petsuksiri J, Ang KK, Morrison WH, Weber RS, et al. Intensity-modulated radiotherapy for cervical node squamous cell carcinoma metastases from unknown head-and-neck primary site: M. D. Anderson Cancer Center outcomes and patterns of failure. Int J Radiat Oncol Biol Phys. 2010;78(4):1005-10. DOI: 10.1016/j.ijrobp.2009.09.006.
Open DOI Search in Google Scholar Back to article
40. Cooper JS, Zhang Q, Pajak TF, Forastiere AA, Jacobs J, Saxman SB, et al. Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 2012;84(5):1198-205. DOI: 10.1016/j.ijrobp.2012.05.008.
Open DOI Search in Google Scholar Back to article
41. Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tan PF, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363(1):24-35. DOI: 10.1056/NEJMoa0912217.
Open DOI Search in Google Scholar Back to article
42. Bourhis J, Sire C, Graff P, Gregoire V, Maingon P, Calais G, et al. Concomitant chemoradiotherapy versus acceleration of radiotherapy with or without concomitant chemotherapy in locally advanced head and neck carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial. Lancet Oncol. 2012;13(2):145-53. DOI: 10.1016/S1470-2045(11)70346-1.
Open DOI Search in Google Scholar Back to article
43. Denis F, Garaud P, Bardet E, Alfonsi M, Sire C, Germain T, et al. Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemo-therapy in advanced-stage oropharynx carcinoma. J Clin Oncol. 2004;22(1):69-76. DOI: 10.1200/JCO.2004.08.021.
Open DOI Search in Google Scholar Back to article
44. Adelstein DJ, Moon J, Hanna E, Giri PGS, Mills GM, Wolf GT, et al. Docetaxel, cisplatin, and fluorouracil induction chemotherapy followed by accelerated fractionation/concomitant boost radiation and concurrent cisplatin in patients with advanced squamous cell head and neck cancer: A Southwest Oncology Group phase II trial (S0216). Head Neck. 2010;32(2):221-8. DOI: 10.1002/hed.21179.
Open DOI Search in Google Scholar Back to article
45. Zhang Y, Chen L, Hu GQ, Zhang N, Zhu XD, Yang KY, et al. Gemcitabine and cisplatin induction chemotherapy in nasopharyngeal carcinoma. N Engl J Med. 2019;381:1124-35. DOI: 10.1056/NEJMoa1905287.
Open DOI Search in Google Scholar Back to article
46. Axelsson L, Nyman J, Haugen-Cange H, Bove M, Johansson L, De Lara S, 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(1):45. DOI: 10.1186/s40463-017-0223-1.
Open DOI Search in Google Scholar Back to article
47. Sivars L, Tani E, Nasman A, Ramqvist T, Munck-Wikland E, Dalianis T. Human Papillomavirus as a diagnostic and prognostic tool in cancer of unknown primary in the head and neck region. Anticancer Res. 2016;36(2):487-93.
Search in Google Scholar Back to article
48. Cheraghlou S, Torabi SJ, Husain ZA, Otremba MD, Osborn HA, Mehra S, et al. HPV status in unknown primary head and neck cancer: prognosis and treatment outcomes. Laryngoscope. 2019;129(3):684-91. DOI: 10.1002/lary.27475.
Open DOI Search in Google Scholar Back to article

Head and neck cancers of unknown primary: A diagnostic and therapeutic challenge

Abstract

Paradigm

My account