p16 Expression in cutaneous squamous carcinomas with neck metastases: A potential pitfall in identifying unknown primaries of the head and neck

Beadle, Beth M.; William, William N.; McLemore, Michael Steven; Sturgis, Erich M.; Williams, Michelle D.

doi:10.1002/hed.23188

Cited by 56 publications

(41 citation statements)

References 25 publications

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“…According to Park et al p16 expression was only observed in OPSCC [25]. On the other hand p16 overexpression but not HPV DNA positivity was also detected in cervical lymph node metastases of squamous cell carcinomas of the skin [34]. Therefore, a positive HPV-status of the lymph node metastases in our study was defined by immunohistochemical p16 possibly allows for the avoidance of adjuvant RT or even chemoradiation to mucosal surfaces depending on the margin status and pathological features of the PT.…”

Section: Discussionsupporting

confidence: 48%

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: 48%

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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“…In the absence of cystic/necrotic adenopathy, our finding of high nodal PET/CT parameters, specifically SUV max of 7.66 or higher in association with HPV+ OP SCC may be a useful tool when evaluating CUP cases as well by directing attention to the oropharynx. Although recent literature regarding CUP is somewhat contradictive 28,29 , Vent 28 reported that p16 positive nodal disease in CUP is most likely to be OP SCC.…”

Section: Discussionmentioning

confidence: 99%

Do 18F-FDG PET/CT Parameters in Oropharyngeal and Oral Cavity Squamous Cell Carcinomas Indicate HPV Status?

Kendi¹,

Magliocca²,

Corey³

et al. 2015

Clinical Nuclear Medicine

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Objective To explore the relationship of PET/CT parameters with HPV status of oropharyngeal (OP) and oral cavity (OC) squamous cell carcinomas (SCC). Material and Methods We retrospectively reviewed 39 patients with OC and OP SCC who underwent staging 18F-FDG PET/CT. PET/CT parameters were measured for the primary tumor and the hottest involved node, including maximum, mean, peak standardized uptake values (SUV max, SUV mean, SUV peak), metabolic tumor volume (MTV), total lesion glycolysis (TLG), standardized added metabolic activity (SAM), normalized standardized added metabolic activity (N SAM). Patient characteristics compared between HPV positive (HPV+) and negative (HPV−) groups. ROC analysis was used to dichotomize PET/CT parameters into high and low. Logistic regression models predicting HPV status were fit for each PET/CT parameter. Results The HPV+ group was comprised of 18 patients all with OP SCC; the HPV− group consisted of 21 patients, 4 OP cancer patients and 17 OC cancer patients. The HPV+ group had a higher proportion of N2 stage (94% vs 43%; p<0.001). Nodal PET/CT parameters were higher in the HPV+ group (p<0.01), this difference was not present for the primary lesion. After adjusting for sex and age, the association of higher nodal SUV max (OR 9.67), SUV mean (OR 10.48), SUV peak (OR 9.67), MTV (OR 14.52), TLG (OR 11.84) and SAM, N SAM (OR 16.21) with HPV+ status remained statistically significant (p<0.05). Conclusion Nodal PET/CT parameters predict HPV status. High nodal FDG uptake should raise suspicion for positive HPV status in the evaluation of the primary lesion.

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“…55 HPV-RNA assessment using the E6/E7 mRNA in situ hybridization identifies transcriptionally active HPV which might be considered the gold standard for high-risk HPV detection. [64][65][66][67] Therefore, the use of p16 expression as a surrogate biomarker to OPSCC has limitations in SCCUP. 57 Immunohistochemical p16 expression as an indicator of HPV infection has gained wide popularity after the development of commercially available and low-cost antibodies.…”

Section: Pathology and Hpv Assessmentmentioning

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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p16 Expression in cutaneous squamous carcinomas with neck metastases: A potential pitfall in identifying unknown primaries of the head and neck

Abstract: p16 expression is relatively common in lymph node-positive cutaneous head and neck SCCs; thus, p16 expression as an independent biomarker and mechanism to determine the oropharyngeal source of an unknown primary is not advised.

Cited by 56 publications

References 25 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

Do 18F-FDG PET/CT Parameters in Oropharyngeal and Oral Cavity Squamous Cell Carcinomas Indicate HPV Status?

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

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