Human papillomavirus as prognostic marker with rising prevalence in neck squamous cell carcinoma of unknown primary: A retrospective multicentre study.
Patients with neck squamous cell carcinomas of unknown primary tumour (NSCCUP) present with lymph node metastasis without evidence for a primary tumour. Most patients undergo an aggressive multimodal treatment, which induces severe, potentially unnecessary toxicity. Primary tumours of NSCCUP can be hidden in the oropharynx. Human papillomavirus (HPV) is causally involved in a subgroup of oropharyngeal squamous cell carcinomas (OPSCC) associated with early lymph node metastasis and good prognosis. Detection of markers for HPV transformation in NSCCUP could allow focussing on the oropharynx in primary tumour search and could be of value for choice and extent of treatment. In a retrospective multicentre study (Germany, Italy and Spain), we analysed metastatic lymph nodes from 180 NSCCUP patients for the presence of HPV DNA, HPV E6*I mRNA and cellular p16INK4aoverexpression, a surrogate marker for HPV-induced transformation. HPV status, defined as positivity for viral mRNA with at least one additional marker, was correlated with clinical parameters and survival outcome. A substantial proportion (16%) of NSCCUP were HPV-driven, mainly by HPV16 (89%). HPV prevalence increased with year of diagnosis from 9% during 1998-2004 to 23% during 2005-2014 (p = 0.007). HPV-driven NSCCUP had significantly better overall and progression-free survival rates (p ≤ 0.008). Based on this survival benefit, it is contended that HPV RNA status should be included in NSCCUP diagnosis and in therapeutic decision-making. Deintensification of radiation in patients with HPV-driven NSCCUP, while concurrently concentrating on the oropharynx appears to be a promising therapeutic strategy, the efficacy of which should be assessed in prospective trials. To our knowledge, this is the largest study on HPV in NSCCUP.
Division of Molecular Diagnostics of Oncogenic Infections, Infection, Inflammation and Cancer Program, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany.
Lea
L
Schroeder
Department of Neurosciences, ENT Clinic and Regional Center for Head and Neck Cancer, University of Padua, School of Medicine, Treviso Regional Hospital, Piazza Ospedale 1, 31100 Treviso, Italy.
Paolo
P
Boscolo-Rizzo
Department of Neurosciences, ENT Clinic and Regional Center for Head and Neck Cancer, University of Padua, School of Medicine, Treviso Regional Hospital, Piazza Ospedale 1, 31100 Treviso, Italy.
Elisa
E
Dal Cin
Department of Pathology, San Donà di Piave Hospital, Via Nazario Sauro 23, 30027 San Donà di Piave, Italy.
Salvatore
S
Romeo
Division of Molecular Diagnostics of Oncogenic Infections, Infection, Inflammation and Cancer Program, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany.
Lorena
L
Baboci
Molecular Cell Biology Group, Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.
Gerhard
G
Dyckhoff
Section Experimental and Translational Head and Neck Oncology, Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Heidelberg and Molecular Mechanism of Head and Neck Tumors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.
Jochen
J
Hess
NCT Tissue Bank of the National Center of Tumor Diseases (NCT) Heidelberg and Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany.
Carlota
C
Lucena-Porcel
NCT Cancer Registry, University Hospital Heidelberg and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Anne
A
Byl
NCT Cancer Registry, University Hospital Heidelberg and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Nikolaus
N
Becker
Unit of Infections and Cancer, Institut Català d'Oncologia (ICO), IDIBELL, L'Hospitalet de Llobregat, Avinguda Granvia 199-203, 08908 Barcelona, Catalonia, Spain; Centro de Investigación Biomédica en Red: Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
Laia
L
Alemany
Unit of Infections and Cancer, Institut Català d'Oncologia (ICO), IDIBELL, L'Hospitalet de Llobregat, Avinguda Granvia 199-203, 08908 Barcelona, Catalonia, Spain; Centro de Investigación Biomédica en Red: Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
Xavier
X
Castellsagué
Servicio de Otorrinolaringología, Hospital de la Santa Creu i Sant Pau, Carrer de Sant Quintí, 89, 08026 Barcelona, Spain.
Miquel
M
Quer
Servicio de Otorrinolaringología, Hospital de la Santa Creu i Sant Pau, Carrer de Sant Quintí, 89, 08026 Barcelona, Spain.
Xavier
X
León
Division of Biostatistics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Manuel
M
Wiesenfarth
Division of Molecular Diagnostics of Oncogenic Infections, Infection, Inflammation and Cancer Program, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany.
Michael
M
Pawlita
Division of Molecular Diagnostics of Oncogenic Infections, Infection, Inflammation and Cancer Program, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany. Electronic address: d.holzinger@dkfz.de.
Dana
D
Holzinger
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D002294:Carcinoma, Squamous Cell / Q000401:mortality* / Q000821:virology; D002471:Cell Transformation, Neoplastic; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D005260:Female; D005858:Germany / Q000453:epidemiology; D006258:Head and Neck Neoplasms / Q000401:mortality* / Q000821:virology; D006801:Humans; D007558:Italy / Q000453:epidemiology; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009382:Neoplasms, Unknown Primary / Q000401:mortality* / Q000821:virology; D027383:Papillomaviridae / Q000235:genetics / Q000302:isolation & purification*; D015995:Prevalence; D011379:Prognosis; D012333:RNA, Messenger / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012189:Retrospective Studies; D013030:Spain / Q000453:epidemiology
D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D012333:RNA, Messenger; D012367:RNA, Viral
Biomarker; CUP; DNA; HPV; Head and neck; Metastasis; Prevalence; Survival; mRNA; p16