Impact of p16 expression, nodal status, and smoking on oncologic outcomes of patients with head and neck unknown primary squamous cell carcinoma

Dixon, Peter R.; Au, Michael; Hosni, Ali; Perez-Ordonez, Bayardo; Weinreb, Ilan; Xu, Wei; Song, Yuyao; Huang, Shao Hui; Dp, Goldstein; Almeida, de

doi:10.1002/hed.24441

Cited by 34 publications

(62 citation statements)

References 33 publications

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“…Keller et al [58] reported on even more pronounced survival differences in p16 positive compared to p16 negative patients (5y OS 92% vs 30% and 5y DSS 92% vs 60%) [58]. Similar results were demonstrated by Jensen et al [57], Schroeder et al [27] and Axelsson et al [64], whereas Tribius et al [55] and Dixon et al [65] did not find any survival difference. In contrast to some [1,2,27,[66][67][68] but in line with other reports [54,56] nodal stage did not have an impact on survival in our cohort.…”

Section: Discussionsupporting

confidence: 69%

Impact of the 8th edition of the UICC TNM classification on staging and survival in patients with neck metastases of unknown primary tumor

Nussbaumer-Vorburger¹,

Förbs²,

Jochum³

et al. 2017

Otorhinolaryngol Head Neck Sur

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Objectives: The aims of this study were to assess the predictive value of HPV-positivity in cervical lymph node metastases for the detection of a primary tumor (PT), to investigate the influence of HPV-positivity in cervical lymph node metastases on tumor control and survival and to analyse the impact of the 8 th edition of the UICC TNM classification on staging and survival.Methods: Neck dissection specimen of 47 consecutively included patients were analysed by PCR-based HPV DNA-testing and p16-immunostaining and survival analysis by Kaplan-Meier and Cox proportional hazard regression models were performed. Results:After standard work-up algorithm in patients with suspected CUP 27/47 patients (57%) remained a CUP whereas in 20/47 (43%) a PT was detected (tonsils, lung, parotid gland, skin). 14/20 (70%) with detected PT and 9/27 (30%) with CUP had HPV-positive cervical lymph node metastases (LNM). Sensitivity, specificity, positive predictive value and negative predictive value of HPV-positivity in LNM for diagnosis of a PT in the oropharynx achieved 65%, 95%, 94% and 69%, respectively. In the subgroup of patients with CUP the 5-year overall/disease specific survival (OS/DSS) of patients with HPV-positive compared to HPVnegative LNM was higher (5y-OS 73% vs. 41%, p=0.01, 5y-DSS 73% vs. 53%, p=0.02). The use of the new UICC TNM classification leads to down staging of 65% of patients with detected PT and 33% with CUP. Furthermore, advanced N-category becomes an important negative prognosticator for OS (N≥2: HR 3.05, 95% CI 1.21-7.67, p=0.01). Conclusion:HPV-positivity in LNM directs the detection of PT in the oropharynx in patients with CUP. One third of LNM in patients with CUP were HPVpositive associated with improved OS and DSS. When applying the 8 th edition advanced N-category and UICC stages are negative prognosticators for survival supporting the role for integration of biomarkes in staging systems.

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Section: Discussionsupporting

confidence: 69%

Impact of the 8th edition of the UICC TNM classification on staging and survival in patients with neck metastases of unknown primary tumor

Nussbaumer-Vorburger¹,

Förbs²,

Jochum³

et al. 2017

Otorhinolaryngol Head Neck Sur

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“…6,16,17,20 The male predominance correlates with the ease of female-to-male HPV transmission which is precipitated by the high number of sexual partners and oral sex encounters. 16,17,19,20,[22][23][24] However, one retrospective analysis of a small series of patients showed that the HPV status does not correlate with neck stage at presentation. The clinical N classification at diagnosis is usually N2/N3 (11%-95%).…”

Section: Clinical Presentationmentioning

confidence: 99%

“…16,19,24,51,57,68 In these studies, HPV-related SCCUP has a good prognosis which constitutes the backdrop for separating this entity from non-HPV-related SCCUP. 16,19,24,51,57,68 In these studies, HPV-related SCCUP has a good prognosis which constitutes the backdrop for separating this entity from non-HPV-related SCCUP.…”

Section: Treatment Of Hpv-related Sccupmentioning

confidence: 99%

Comprehensive management of HPV‐related squamous cell carcinoma of the head and neck of unknown primary

2019

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Background Human papillomavirus (HPV)‐related squamous cell carcinoma of unknown primary (SCCUP) is currently rising in incidence but lacks a validated management approach. Aims This paper reviews the clinical presentation, diagnosis, and treatment of HPV‐related SCCUP. Materials and Methods The Medline/Pubmed database was searched by using the following keywords “CUP”, “cancer of unknown primary”, “HPV”, “human papilloma virus”, and “head and neck”. The references of the publications of interest were also screened for relevant papers. Results The clinical assessment of HPV‐related SCCUP includes a complete clinical examination, an endoscopic evaluation with white‐light and narrow band imaging, and radiologic assessment using morphologic and metabolic imaging. If the diagnosis remains unconfirmed, endoscopic examination under anesthesia with tonsillectomy ± base of tongue mucosectomy is performed. The therapeutic rationale aims to eradicate the involved lymph nodes and potential primary tumor with a sequence of chemoradiotherapy and neck dissection. Discussion As a general approach, p16‐negative SCCUP are truly HPV negative, whereas p16‐positive specimens require confirmation with HPV in situ hybridization or polymerase chain reaction to confirm HPV infection. If a cervical metastasis is considered HPV positive, the primary lesion is likely in the oropharynx, and further diagnostic interventions such as tonsillectomy seems to be mandatory. Whether the optimal treatment is neck dissection followed by adjuvant radiotherapy or concomitant chemoradiotherapy (CRT) (in case of extranodal extension or advanced lymph node stages) or definitive CRT followed by neck dissection (in case of positive 18F‐FDG‐PET/CT) remains a matter of debate. Solid scientific evidence supporting treatment de‐escalation in HPV‐related SCCUP is lacking, and the results of ongoing trials are at the brink of reporting. Conclusion Currently, the treatment of patients with HPV‐related SCCUP should not differ from the standard treatment of other SCCUP patients and is similarly based on the staging of the disease and general condition of the patient.

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“…As a HPV surrogate marker, immunohistochemical staining of p16, a human tumor-suppressor protein [59–65], is also widely used. Despite showing a significantly improved disease-free survival, some authors like Dixon et al could not find an improved overall survival for p16-positive HNCUP patients in their studies [66]. Other reports showed a significant positive impact of HPV/p16 only when combined with other factors like (non-)smoking [67].…”

Section: Introductionmentioning

confidence: 99%

Diagnostic and treatment modalities for patients with cervical lymph node metastases of unknown primary site – current status and challenges

et al. 2017

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Background and PurposeThis review aims to provide a comprehensive overview of the literature and elucidate open questions for future clinical trials concerning diagnostics and treatment modalities for cervical cancer of unknown primary (CUP).MethodsA literature search for head and neck CUP was performed with focus on diagnostics and therapies as well as molecular markers.ResultsHigh level evidence on CUP is limited. However, it seems that a consensus exists regarding the optimal diagnostic procedures. The correct implementation of biomarkers for patient stratification and treatment remains unclear. An even greater dispute dominates about the ideal treatment with publications ranging from sole surgery to surgery with postoperative bilateral radiotherapy with inclusion of the mucosa and concomitant chemotherapy.ConclusionsCervical CUP represents a very heterogeneous malignant disease. On this account many aspects concerning treatment optimization remain unclear, despite a considerable number of publications in the past. Future research in form of prospective randomized trials is needed in order to better define patient stratification criteria and enable tailored treatment.

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Impact of p16 expression, nodal status, and smoking on oncologic outcomes of patients with head and neck unknown primary squamous cell carcinoma

Abstract: Among patients with CUP, p16-positive status is an independent predictor of DFS but not overall survival (OS). © 2016 Wiley Periodicals, Inc. Head Neck, 2016 © 2016 Wiley Periodicals, Inc. Head Neck 38: 1347-1353, 2016.

Cited by 34 publications

References 33 publications

Impact of the 8th edition of the UICC TNM classification on staging and survival in patients with neck metastases of unknown primary tumor

Impact of the 8th edition of the UICC TNM classification on staging and survival in patients with neck metastases of unknown primary tumor

Comprehensive management of HPV‐related squamous cell carcinoma of the head and neck of unknown primary

Diagnostic and treatment modalities for patients with cervical lymph node metastases of unknown primary site – current status and challenges

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