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European Archives of Oto-Rhino-Laryngology

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01-01-2015 | Head and Neck

Management of neck metastases of unknown primary origin united in two European centers

Authors: Jos Straetmans, Julia Vent, Martin Lacko, Ernst-Jan Speel, Christian Huebbers, Robert Semrau, Frank Hoebers, Zlatan Mujagic, Jens-Peter Klussmann, Simon F Preuss, Bernd Kremer

Published in: European Archives of Oto-Rhino-Laryngology | Issue 1/2015

Abstract

Combined analysis of diagnostic and therapeutic management of neck metastases of carcinoma of unknown primary origin (‘true CUP’) in two European tertiary referral centers (University Medical Centers of Maastricht, NL and Cologne, D) to contribute to the ongoing discussion on management in CUP. Retrospective analysis of 29 (Maastricht) and 22 (Cologne) true cervical CUP syndrome patients (squamous cell carcinoma). The diagnostic and therapeutic approaches were correlated with clinical follow-up data and HPV status. In total, 48 out of 51 true CUP patients received postsurgical adjuvant radiotherapy. In eight patients from Cologne, this was combined with concomitant platin-based chemotherapy. Neither in Cologne nor in Maastricht, radiotherapy of the pharyngeal mucosa was commonly performed (n = 6, 12.5 %) The percentage of patients who were irradiated ipsilaterally or bilaterally did not differ between both institutes (N = 21/27 in Maastricht vs. 11/21 in Cologne), nor did the 5-year overall survival differ significantly. Oncogenic HPV was only found in 4 out of 51 CUPs (7, 8 %). Therefore, no relation with overall and recurrence-free survival could be detected. No occult primary tumors were revealed during follow-up despite de-escalation of therapy by abandoning irradiation of the pharyngeal mucosa in both institutes. There were no significant differences between ipsilateral and bilaterally irradiated patients regarding overall and recurrence-free survival. The occurrence of distant metastases was more often noticed in ipsilaterally treated patients as compared to bilaterally radiated patients (8 vs. 2, p = 0.099). Those patients all had been classified N2b or higher. International guidelines still are not unified and there is an urgent need for a consented therapeutic regimen. Comparison of two international strategies on the management of CUP patients is presented and further research is recommended regarding the role of radiotherapy of the pharyngeal axis, the value of unilateral and bilateral radiotherapy and the role of concomitant or induction chemotherapy in CUP patients, particularly in N2b or higher-staged neck disease. The prevalence and role of HPV in true CUP after thorough diagnostic work-up seem limited in our case series, particularly when compared to the role in oropharyngeal carcinomas.

Weber A, Schmoz S, Bootz F (2001) CUP (carcinoma of unknown primary) syndrome in head and neck: clinic, diagnostic, and therapy. Onkologie 24(1):38–43PubMedCrossRef

Lee NK, Byers RM, Abbruzzese JL, Wolf P (1991) Metastatic adenocarcinoma to the neck from an unknown primary source. Am J Surg 162(4):306–309PubMedCrossRef

Löffler H, Neben K, Krämer A (2014) CUP-Syndrom. Der Radiologe 54(2):107–111

Hüebner G, Bokemeyer C (2005) CUP-Syndrome. German Society of Hemato-Oncology. http://www.dghoonkopedia.de/de/onkopedia/archiv/cup-syndrom/cup-syndrom-stand-dez

St Pigortsch, Zimmermann F (2009) Halslymphknotenmetastasen bei unbekanntem Primärtumor. In: Mast G (ed) Manual Kopf-Hals-Malignome, 4th edn. W. Zuckerschwerdt, Munich, pp 308–311

Calabrese L, Jereczek-Fossa BA, Jassem J et al (2005) Diagnosis and management of neck metastases from an unknown primary. Acta Otorhinolaryngol Ital 25(1):2–12PubMedCentralPubMed

Hossfeld DK, Wittekind Ch (2005) Metastasen bei unbekanntem Primärtumor—Das CUP-Syndrom. Deutsches Ärzteblatt 102(13):904–907

Haas I, Hoffmann TK, Engers R, Ganzer U (2002) Diagnostic strategies in cervical carcinoma of an unknown primary (CUP). Eur Arch Otorhinolaryngol 259(6):325–333PubMed

Balm AJ, van Velthuysen ML, Hoebers FJ, Vogel WV, van den Brekel MW (2010) Diagnosis and treatment of a neck node swelling suspicious for a malignancy: an algorithmic approach. Int J Surg Oncol 2010:581540PubMedCentralPubMed

10.

Rodel RM, Matthias C, Blomeyer BD, Wolff HA, Jung K, Christiansen H (2009) Impact of distant metastasis in patients with cervical lymph node metastases from cancer of an unknown primary site. Ann Otol Rhinol Laryngol 118(9):662–669PubMedCrossRef

11.

Park JJ, Emmerling O, Westhofen M (2012) Role of neck ultrasound during follow-up care of head and neck squamous cell carcinomas. Acta Otolaryngol 132(2):218–224PubMedCrossRef

12.

Menzel C, Berner U, Grünwald F (2012) Positronen-Emissions-Tomographie in der Onkologie (PET in Oncology). Hessisch Ärzteblatt 2002(07):405–411

13.

Rades D, Kuhnel G, Wildfang I, Borner AR, Knapp W, Karstens JH (2001) The value of positron emission tomography (PET) in the treatment of patients with cancer of unknown primary (CUP). Strahlenther Onkol 177(10):525–529PubMedCrossRef

14.

Koivunen P, Laranne J, Virtaniemi J et al (2002) Cervical metastasis of unknown origin: a series of 72 patients. Acta Otolaryngol 122(5):569–574PubMedCrossRef

15.

Cianchetti M, Mancuso AA, Amdur RJ et al (2009) Diagnostic evaluation of squamous cell carcinoma metastatic to cervical lymph nodes from an unknown head and neck primary site. Laryngoscope 119(12):2348–2354PubMedCrossRef

16.

Boscolo-Rizzo P, Da Mosto MC, Gava A, Marchiori C (2006) Cervical lymph node metastases from occult squamous cell carcinoma: analysis of 82 cases. ORL J Otorhinolaryngol Relat Spec 68(4):189–194PubMedCrossRef

17.

Donta TS, Smoker WR (2007) Head and neck cancer: carcinoma of unknown primary. Top Magn Reson Imaging 18(4):281–292PubMedCrossRef

18.

Jereczek-Fossa BA, Jassem J, Orecchia R (2004) Cervical lymph node metastases of squamous cell carcinoma from an unknown primary. Cancer Treat Rev 30(2):153–164PubMedCrossRef

19.

Boscolo-Rizzo P, Gava A, Da Mosto MC (2007) Carcinoma metastatic to cervical lymph nodes from an occult primary tumor: the outcome after combined-modality therapy. Ann Surg Oncol 14(5):1575–1582PubMedCrossRef

20.

Hauswald H, Lindel K, Rochet N, Debus J, Harms W (2008) Surgery with complete resection improves survival in radiooncologically treated patients with cervical lymph node metastases from cancer of unknown primary. Strahlenther Onkol 184(3):150–156PubMedCrossRef

21.

Kothari P, Randhawa PS, Farrell R (2008) Role of tonsillectomy in the search for a squamous cell carcinoma from an unknown primary in the head and neck. Br J Oral Maxillofac Surg 46(4):283–287PubMedCrossRef

22.

Randall DA, Johnstone PA, Foss RD, Martin PJ (2000) Tonsillectomy in diagnosis of the unknown primary tumor of the head and neck. Otolaryngol Head Neck Surg 122(1):52–55PubMedCrossRef

23.

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):6469–6475PubMed

24.

Begum S, Gillison ML, Nicol TL, Westra WH (2007) 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 13(4):1186–1191PubMedCrossRef

25.

Desai PC, Jaglal MV, Gopal P et al (2009) Human papillomavirus in metastatic squamous carcinoma from unknown primaries in the head and neck: a retrospective 7 year study. Exp Mol Pathol 87(2):94–98PubMedCrossRef

26.

Hoffmann M, Gottschlich S, Gorogh T et al (2005) Human papillomaviruses in lymph node neck metastases of head and neck cancers. Acta Otolaryngol 125(4):415–421PubMed

27.

El-Mofty SK, Zhang MQ, Davila RM (2008) Histologic identification of human papillomavirus (HPV)-related squamous cell carcinoma in cervical lymph nodes: a reliable predictor of the site of an occult head and neck primary carcinoma. Head Neck Pathol 2(3):163–168PubMedCentralPubMedCrossRef

28.

Weiss D, Koopmann M, Rudack C (2011) Prevalence and impact on clinicopathological characteristics of human papillomavirus-16 DNA in cervical lymph node metastases of head and neck squamous cell carcinoma. Head Neck 33(6):856–862PubMedCrossRef

29.

Barwad A, Sood S, Gupta N, Rajwanshi A, Panda N, Srinivasan R (2012) Human papilloma virus associated head and neck cancer: a PCR based study. Diagn Cytopathol 40(10):893–897. doi:10.1002/dc.21667

30.

Armas GL, Su CY, Huang CC, Fang FM, Chen CM, Chien CY (2008) The impact of virus in N3 node dissection for head and neck cancer. Eur Arch Otorhinolaryngol 265(11):1379–1384PubMedCrossRef

31.

Compton AM, Moore-Medlin T, Herman-Ferdinandez L et al (2011) Human papillomavirus in metastatic lymph nodes from unknown primary head and neck squamous cell carcinoma. Otolaryngol Head Neck Surg 145(1):51–57PubMedCrossRef

32.

Goldenberg D, Begum S, Westra WH et al (2008) Cystic lymph node metastasis in patients with head and neck cancer: an HPV-associated phenomenon. Head Neck 30(7):898–903PubMedCrossRef

33.

Klop WM, Balm AJ, Keus RB, Hilgers FJ, Tan IB (2000) Diagnosis and treatment of 39 patients with cervical lymph node metastases of squamous cell carcinoma of unknown primary origin, referred to Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, 1979-98. Ned Tijdschr Geneeskd 144(28):1355–1360PubMed

34.

Erkal HS, Mendenhall WM, Amdur RJ, Villaret DB, Stringer SP (2001) Squamous cell carcinomas metastatic to cervical lymph nodes from an unknown head-and-neck mucosal site treated with radiation therapy alone or in combination with neck dissection. Int J Radiat Oncol Biol Phys 50(1):55–63PubMedCrossRef

35.

Christiansen H, Hermann RM, Martin A, Nitsche M, Schmidberger H, Pradier O (2005) Neck lymph node metastases from an unknown primary tumor retrospective study and review of literature. Strahlenther Onkol 181(6):355–362PubMedCrossRef

36.

Patel RS, Clark J, Wyten R, Gao K, O’Brien CJ (2007) Squamous cell carcinoma from an unknown head and neck primary site: a “selective treatment” approach. Arch Otolaryngol Head Neck Surg 133(12):1282–1287PubMedCrossRef

37.

Ligey A, Gentil J, Crehange G et al (2009) Impact of target volumes and radiation technique on loco-regional control and survival for patients with unilateral cervical lymph node metastases from an unknown primary. Radiother Oncol 93(3):483–487PubMedCrossRef

38.

Grau C, Johansen LV, Jakobsen J, Geertsen P, Andersen E, Jensen BB (2000) Cervical lymph node metastases from unknown primary tumours. Results from a national survey by the Danish society for head and neck oncology. Radiother Oncol 55(2):121–129PubMedCrossRef

39.

Grau C, Johansen LV, Jakobsen J, Geertsen PF, Andersen EV, Jensen BB (2001) Cervical lymphatic metastases from occult primary tumor. A nation-wide 20-year study from the Danish society of head and neck oncology. Ugeskr Laeger 163(10):1432–1436PubMed

40.

Erkal HS, Mendenhall WM, Amdur RJ, Villaret DB, Stringer SP (2001) Squamous cell carcinomas metastatic to cervical lymph nodes from an unknown head and neck mucosal site treated with radiation therapy with palliative intent. Radiother Oncol 59(3):319–321PubMedCrossRef

41.

Vent J, Haidle B, Wedemeyer I et al (2013) p16 expression in carcinoma of unknown primary: diagnostic indicator and prognostic marker. Head Neck 35(11):1521–1526PubMedCrossRef

42.

Hafkamp HC, Speel EJ, Haesevoets A et al (2003) A subset of head and neck squamous cell carcinomas exhibits integration of HPV 16/18 DNA and overexpression of p16INK4A and p53 in the absence of mutations in p53 exons 5-8. Int J Cancer 107(3):394–400PubMedCrossRef

43.

Hafkamp HC, Manni JJ, Speel EJ (2004) Role of human papillomavirus in the development of head and neck squamous cell carcinomas. Acta Otolaryngol 124(4):520–526PubMedCrossRef

44.

Robbins KT (1998) Classification of neck dissection: current concepts and future considerations. Otolaryngol Clin N Am 31(4):639–655CrossRef

45.

Robbins KT, Shaha AR, Medina JE et al (2008) Consensus statement on the classification and terminology of neck dissection. Arch Otolaryngol Head Neck Surg 134(5):536–538PubMedCrossRef

46.

Schroeder U, Dietlein M, Wittekindt C et al (2008) Is there a need for positron emission tomography imaging to stage the N0 neck in T1-T2 squamous cell carcinoma of the oral cavity or oropharynx? Ann Otol Rhinol Laryngol 117(11):854–863PubMedCrossRef

47.

Balm AJ, Brown DH, De Vries WA, Snow GB (1990) Blindness: a potential complication of bilateral neck dissection. J Laryngol Otol 104(2):154–156PubMedCrossRef

48.

Marur S, D’Souza G, Westra WH, Forastiere AA (2010) HPV-associated head and neck cancer: a virus-related cancer epidemic. Lancet Oncol 11(8):781–789PubMedCrossRef

49.

Straetmans JM, Olthof N, Mooren JJ, de JJ, Speel EJ, Kremer B (2009) Human papillomavirus reduces the prognostic value of nodal involvement in tonsillar squamous cell carcinomas. Laryngoscope 119(10):1951–1957PubMedCrossRef

50.

Forastiere A, Koch W, Trotti A, Sidransky D (2001) Head and neck cancer. N Engl J Med 345(26):1890–1900PubMedCrossRef

51.

Forastiere A, Weber R, Ang K (2008) Treatment of head and neck cancer. N Engl J Med 358(10):1076–1078PubMedCrossRef

52.

Hoffmann M, Gottschlich S, Gorogh T et al (2005) Human papillomaviruses in lymph node neck metastases of head and neck cancers. Acta Otolaryngol 125(4):415–421PubMed

53.

Varadhachary GR (2007) Carcinoma of unknown primary origin. Gastrointest Cancer Res 1(6):229–235PubMedCentralPubMed

54.

Fakhrian K, Thamm R, Knapp S et al (2012) Radio (chemo) therapy in the management of squamous cell carcinoma of cervical lymph nodes from an unknown primary site. a retrospective analysis. Strahlenther Onkol 188(1):56–61PubMedCrossRef

Title: Management of neck metastases of unknown primary origin united in two European centers
Authors: Jos Straetmans
Julia Vent
Martin Lacko
Ernst-Jan Speel
Christian Huebbers
Robert Semrau
Frank Hoebers
Zlatan Mujagic
Jens-Peter Klussmann
Simon F Preuss
Bernd Kremer
Publication date: 01-01-2015
Publisher: Springer Berlin Heidelberg
Published in: European Archives of Oto-Rhino-Laryngology / Issue 1/2015
Print ISSN: 0937-4477
Electronic ISSN: 1434-4726
DOI: https://doi.org/10.1007/s00405-014-2934-5

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Management of neck metastases of unknown primary origin united in two European centers

Abstract

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Abstract

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