Squamous Cell Carcinoma Of Unknown Primary Research Articles

Human papillomavirus circulating tumor DNA: a diagnostic tool in squamous cell carcinoma of unknown primary-a pilot study.

Neck mass is the most common presentation of human papillomavirus-related (HPV-related) oropharyngeal squamous cell carcinoma (OPSCC). Recently, circulating tumor HPV-DNA (ctHPVDNA) assays have been developed to detect active OPSCC. This pilot study investigates the diagnostic accuracy of ctHPVDNA in establishing HPV status for known vs. unknown OPSCC presenting as a neck mass. A single-institution pilot study was conducted on all patients with OPSCC presenting as a neck mass between 2021 and 2022. The diagnostic accuracy of ctHPVDNA was compared to that of standard diagnostic procedures used to obtain HPV status according to the American Society of Clinical Oncology (ASCO) guideline for squamous cell carcinoma of unknown primary (SCCUP). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of ctHPVDNA were calculated. A total of 27 patients were included; 70.4% were current or former smokers, 48.1% (N = 13) had identifiable primaries, and 51.9% (N = 14) had SCCUP. Four patients with known primaries required operative direct laryngoscopy with biopsy (DLB) to establish HPV status. Two patients with SCCUP underwent diagnostic transoral robotic surgery (TORS) to establish HPV status and localize the primary. Twelve patients underwent therapeutic TORS and neck dissection. The gold standard for HPV status was based on final histopathologic p16 or HPV in situ hybridization (ISH) staining during workup/treatment. ctHPVDNA had 95.8% sensitivity, 100% specificity, 100% PPV, and 75% NPV in predicting HPV-positive OPSCC in the whole sample. Binary logistic regression model using ctHPVDNA results to predict HPV-positive OPSCC was significant (-2 log likelihood = 5.55, χ2=8.70, p <.01, Nagelkerke's R squared = .67). Among patients with identifiable primaries, all patients had HPV-positive tumors on final pathology, and ctHPVDNA was positive in 100%. In the unknown primary patients, ctHPVDNA had 90.9% sensitivity, 100% specificity, 100% PPV, and 75% NPV. ctHPVDNA demonstrated good diagnostic accuracy for both known and unknown primaries. Incorporation of ctHPVDNA into the diagnostic algorithm for SCCUP may reduce the need for multiple procedures to establish HPV status.

Influence of the radiotherapy target volume and prognostic factors on the results of treatment of patients with cervical lymph nodes metastases of squamous cell carcinoma of unknown primary

Introduction: The issues of the radiotherapy target volumes in cases of cervical lymph nodes metastases of squamous cell carcinoma of unknown primary (SCCUP) remain unresolved due to the lack of clinical studies. Escalation or de-escalation of treatment may be directly related to prognostic factors. Purpose of this study was to evaluate the results of treatment using ipsilateral (only involved side of the neck) or total (bilaterally neck and pharyngeal mucosa) radiation therapy (RT) and to analyze the influence of clinical factors on overall survival (OS) and progression-free survival (PFS).Methods: A retrospective non-randomized clinical trial was conducted. Two-year OS and PFS were assessed in 26 SCCUP patients, who underwent combined treatment, including radiation therapy. Inoperable patients received either definitive RT (3.85 %) or sequential chemoradiation therapy (CRT, 11.5 %), or concurrent CRT (3.85 %). Operable patients underwent neoadjuvant RT with lymph node dissection (34.6 %) or lymph node dissection with adjuvant RT (11.5 %) or adjuvant sequential CRT (7.7 %) or adjuvant concurrent CRT (27 %); 50 % of patients received RT in a dose of more than 60 Gy, in 50 % it was less than 60 Gy. In 54 % of patients, only the ipsilateral cervical lymph nodes were included in the irradiation volume while 46 % of patients received RT to the pharyngeal mucosa and lymph nodes of the neck bilaterally (total radiation therapy group).Results: The median follow-up was 17 months. The 2‑year OS was 71.5 % (95 % CI 49.3–85.3 %), the 2‑year PFS was 72.1 % (95 % CI 44.5–87.6 %). There were no significant differences in 2‑year OS between the ipsilateral and total radiotherapy groups (HR = 1.08 [0.29–4.06], p = 0.904). Only a factor of extranodal extension (ENE) had a statistically significant impact on OS (HR = 6.05 [1.45–25.19], p = 0.0134).Conclusion: There was no statistically significant difference in 2‑year OS and PFS between the ipsilateral and total radiation therapy groups. A negative prognostic factor is the extranodal extension (ENE) of a metastatic tumor. Prospective randomized trials are needed.

Association of circulating tumor HPV16DNA levels and quantitative PET parameters in patients with HPV-positive head and neck squamous cell carcinoma

Circulating tumor DNA (ctDNA), which circulates in the blood after being shed from cancer cells in the body, has recently gained attention as an excellent tumor marker. The purpose of this study was to evaluate whether ct human papillomavirus (HPV) 16 DNA (ctHPV16DNA) levels were associated with quantitative PET parameters in patients with HPV-positive head and neck (HN) squamous cell carcinoma (SCC). Fifty patients with oropharyngeal SCC (OPSCC) and 5 with SCC of unknown primary (SCCUP) before treatment were included. They all underwent blood sampling to test ctHPV16DNA levels and FDG PET-CT examinations. Quantitative PET parameters included SUVmax, metabolic tumor volume (MTV), MTV of whole-body lesions (wbMTV), and 56 texture features. ctHPV16DNA levels were compared to texture features of primary tumors in OPSCC patients (Group A) or the largest primary or metastatic lymph node lesions in OPSCC and SCCUP patients (Group B) and to other PET parameters. Spearman rank correlation test and multiple regression analysis were used to confirm the associations between ctHPV16DNA levels and PET parameters. ctHPV16DNA levels moderately correlated with wbMTV, but not with SUVmax or MTV in Groups A and B. ctHPV16DNA levels exhibited a weak negative correlation with low gray-level zone emphasis in Groups A and B. Multiple regression analysis revealed that wbMTV and high gray-level zone emphasis were the significant factors for ctHPV16DNA levels in Group B. These results were not observed in Group A. This study demonstrated that ctHPV16DNA levels correlated with the whole-body tumor burden and tumor heterogeneity visualized on FDG PET-CT in patients with HPV-positive HNSCC.

Comprehensive genomic profiling (CGP) of squamous cell carcinoma of unknown primary (SCCUP) presenting with inguinal, pelvic, and retroperitoneal (I/P/RP) metastases.

7 Background: Nodal metastases from SCC are a clinical challenge in urologic and gynecologic oncology. Strategies employing CGP to identify targeted therapies for CUPs have shown potential; however, the molecular landscape of SCCUP remains poorly defined. We report the results of CGP testing in patients with SCCUPs identified in the Foundation Medicine, Inc. database, with a focus on those with I/P/RP involvement. Methods: SCCUP cases with FoundationOneCDx (F1CDx) assay results were identified based on a reported diagnosis of CUP and the presence of SCC histology. After central pathologist review, cases were excluded if a known primary site could be determined based on histology and disease location. Cases with I/P/RP involvement were selected based on the site of tissue biopsy. Genomic alterations (GAs) were assessed using the FoundationCORE database. Results: Ninety-seven cases of SCCUP presenting with I/P/RP involvement were identified. GAs were observed in 140 of 324 genes evaluated by the F1CDx assay. The most frequently altered genes were PIK3CA (38.1%) , TP53 (37.1%) , KMT2D (23.7%) , PTEN (21.6%) , and CDKN2A (19.6%). The most frequently altered potentially actionable GAs were in PIK3CA, PTEN, FGFR3 (9.1%), MTAP (7.2%), BRCA1 (5.2%) and BRCA2 (5.2%). One patient had microsatellite instability high disease, while 27 (27.8%) had a tumor mutational burden ≥ 10 mut/Mb. Of 54 evaluable patients, 18 (33.3%) had high-positive PD-L1 expression. Two patients (2.1%) had TMPRSS2-ERG fusions supporting occult prostate cancer, while 13 (13.4%) had UV light exposure signatures suggesting unrecognized cutaneous origin. No significant differences in GAs were observed between 64 patients with inguinal disease and 33 patients with pelvic and retroperitoneal disease. An additional 346 cases of SCCUP were identified with involvement outside of the I/P/RP. Compared to these patients, those with I/P/RP involvement were more likely to be female (64% vs 42%,odds ratio [OR] 2.46, p=0.001), and were less likely to have mutations in CDKN2A (19.6% vs 41.9%, OR 0.34, p=0.002), TP53 (37.1% vs 69.7%, OR 0.26, p&lt;0.001), and KRAS (2% vs 12.7%, OR 0.14, p=0.02). Patients with I/P/RP disease were also more likely to have evidence of HPV infection (54.6% vs 14.4%, OR 7.1, p&lt;0.001) and APOBEC mutation signatures (70% vs 18.7%, OR 10.1, p&lt;0.001), which have been associated with viral infection. Conclusions: Fifty-three of 97 (54.6%) patients with SCCUPs presenting with I/P/RP involvement had at least one GA that could potentially guide targeted treatment decisions including entry into biomarker-driven clinical trials. I/P/RP SCCUP patients frequently demonstrated HPV infection and APOBEC mutation signatures. To our knowledge, this is the first report that describes the genomic landscape of SCCUPs presenting with I/P/RP metastases.

Cervical squamous cell carcinoma of unknown primary: Oncological outcomes and prognostic factors.

Cervical squamous cell carcinoma of unknown primary (SCCUP) is a rare entity within head and neck cancer and both treatment regimens as well as identified potential predictors for oncological outcomes vary between published series. In this study, we evaluated oncological outcomes and identified potential prognostic factors for outcome. This retrospective monocentric cohort study includes 82 SCCUP patients diagnosed and treated between January 2000 and June 2021. Overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS) and locoregional recurrence-free survival (LRFS) were evaluated. The Cox proportional hazards model was used to analyze the prognostic effect of patient and tumor characteristics on oncological outcomes. Five year OS, DSS, DFS and LRFS were respectively 53.9%, 72.2%, 68.9% and 67.3%. The p16 status was evaluated in 55 patients with 40% being p16 positive. On univariable analysis, p16 negative SCCUPs had significantly worse survival and recurrence rates in the presence of clinical extranodal extension (cENE) (OS: p=0.0013, DSS: p=0.0099, DFS: p=0.0164, LRFS: p=0.0099) and radiological extranodal extension (rENE) (OS: p=0.0034, DSS: p=0.0137, DFS: p=0.0167, LRFS: p=0.0100). In p16 positive SCCUP patients, rENE had a significantly negative prognostic effect on DFS (p=0.0345) and LRFS (p=0.0367). Total group multivariate analysis identified rENE as an independent negative predictor for all oncological outcomes. The "number of positive lymph nodes" was a second independent predictor for DSS (p=0.0257) and DFS (p=0.0435). We report favorable oncological outcomes, comparable to previously published results. Although the presence of rENE seems associated with poor oncological outcomes, the differential effect of clinical, radiological and pathological ENE in both p16 positive and negative subgroups remain to be elucidated by further prospective research.

Prognostic impact of copy number alterations and tumor mutational burden in carcinoma of unknown primary.

Chromosomal aberrations are known to drive metastatic spread, but their profile is still elusive in carcinoma of unknown primary (CUP). Therefore, the aim of this study was to characterize the chromosomal aberration pattern in CUP depending on histological and clinical features and to assess its prognostic impact together with chromothripsis, tumor mutational burden (TMB), microsatellite instability (MSI), and mutational profiles as potential prognostic biomarkers. Chromosomal aberrations and chromothripsis were detected by methylation-based copy number variation (CNV) analysis, whereas TMB and MSI were calculated based on large next-generation sequencing (NGS) panels. Putative primaries were assigned by consensus between two independent oncologists. CNV losses varied depending on putative primaries and were more abundant in patients harboring TP53 mutations and/or deletions 17p. CNV loss was prognostically adverse in localized CUP treated with surgery and/or radiotherapy, but not in disseminated poor-risk CUP treated with palliative chemotherapy. CNV loss also worsened the prognosis in squamous cell CUP. Chromothripsis was detected in 18/59 (30.5%) patients without prognostic effect. TMB was highest in cases with MSI, squamous cell histology, and with lung, anal or cervical putative primaries. Overall, CNV, chromothripsis, TMB, and MSI profiles in CUP are reminiscent of biological characteristics known from other cancer entities without a unifying CUP-specific signature. Markedly, high-level CNV loss is an adverse predictive biomarker in localized but not disseminated chemotherapy-treated CUP. This implies that chromosomal losses drive CUP progression, but also increase susceptibility to chemotherapy, with both effects apparently leveling out in disseminated CUP.

Diagnostic value of tonsillectomy in positron emission tomography and computerised tomography negative carcinoma of unknown primary

&lt;p class="abstract"&gt;Carcinoma of unknown primary (CUP) represents a heterogeneous group of malignancy metastasis unique biology of which remains poorly understood. Even after a complete diagnostic workup including positron emission tomography and computerised tomography (PET-CT) scans the primary site of origin may remain unclear. This case series analysed the diagnostic value of bilateral palatine tonsillectomy in evaluating PET-CT negative head and neck squamous cell CUP. From retrospective analysis of cluster of 68 cases with metastatic cervical nodes with no obvious primary referred for ENT evaluation during a period of 20 months, we identified 5 cases where pan endoscopy and radiological evaluation including PET-CT were negative in detecting the primary. All 5 patients underwent bilateral palatine tonsillectomy along with biopsies from base of tongue and nasopharynx as a part of completion of diagnostic work-up. Tonsillar squamous cell carcinoma was revealed by subsequent histopathology examination in 4 out of 5 patients despite negative PET-CT evaluation. Blind biopsies from other sites like nasopharynx and base of tongue were unfruitful. Our experience strongly emphasises the fact that bilateral palatine tonsillectomy has a high yield in detecting primary even in PET negative CUP, though it needs a larger evidence base.&lt;/p&gt;

Human Papillomavirus and Squamous Cell Carcinoma of Unknown Primary in the Head and Neck Region: A Comprehensive Review on Clinical Implications.

Squamous cell carcinoma of unknown primary (SCCUP) is a challenging diagnostic subgroup of oropharyngeal squamous cell carcinoma (OPSCC). The incidence of SCCUP is increasing in parallel with the well-documented increase in OPSCC and is likewise driven by the increase in human papillomavirus (HPV). The SCCUP patient often presents with a cystic lymph node metastasis and undergoes an aggressive diagnostic and treatment program. Detection of HPV in cytologic specimens indicates an oropharyngeal primary tumor origin and can guide the further diagnostic strategy. Advances in diagnostic modalities, e.g., transoral robotic surgery and transoral laser microsurgery, have increased the successful identification of the primary tumor site in HPV-induced SCCUP, and this harbors a potential for de-escalation treatment and increased survival. This review provides an overview of HPV-induced SCCUP, diagnostic modalities, and treatment options.

Diagnostic performance of 18F-FDG PET/CT for the detection of occult primary tumors in squamous cell carcinoma of unknown primary in the head and neck: a single-center retrospective study.

To investigate the diagnostic performance of 18F-FDG PET/computed tomography (CT) for the detection of occult primary tumors in patients with squamous cell carcinoma of unknown primary (SCCUP) in the head and neck. From March 2016 to January 2020, 37 patients diagnosed as SCCUP before PET/CT were retrospectively reviewed. The diagnosis of SCCUP was made when an overt primary tumor location could not be found for histologically proven squamous cell cervical lymphadenopathy after a complete diagnostic workup which includes full medical history, physical examinations, flexible rhinolaryngoscopy and CT or MRI. The PET/CT images were visually assessed by two nuclear medicine radiologists. Histopathological investigations after the PET scan served as the reference standard. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of PET/CT for SCCUP were 71.4, 43.8, 62.5, 53.9 and 59.5%, respectively. PET/CT allowed identification of previously undetected lesions in 40.5% of the SCCUP patients. A total of 24 PET/CT scans indicated a positive result. Among them, nine were categorized into false-positive because of negative results from subsequent targeted and random biopsies. There were 13 PET/CT scans with a negative result, six of which, however, were revealed to have a primary site by subsequent random biopsies. 18F-FDG PET/CT was shown to be useful in detecting a primary tumor for SCCUP, but had limitations in terms of both false-positive cases and false-negative cases. Therefore, histopathological investigations such as targeted and random biopsy should be viewed as necessary practice irrespective of PET/CT results.

Detection and Oncologic Outcomes of Head and Neck Squamous Cell Carcinoma of Unknown Primary Origin.

To assess factors that predict detection of tumors and oncologic outcomes in head and neck squamous cell carcinoma of unknown primary (SCCUP). This was a retrospective cohort study at a single tertiary care institution. The primary site was detected at examination under anesthesia (EUA) in 92 (51.1%) patients. The primary site was detected by directed biopsies in 60 (65%), palatine tonsillectomy in 28 (30.4%), and lingual tonsillectomy in 4 patients (4.3%). Four of eight lingual tonsillectomies were positive (50%). Primary locations included: palatine tonsils (51, 28.3%), base of tongue (37, 20.6%), larynx (4, 2.2%), oral cavity (3, 1.67%) and nasopharynx (1, 0.6%). Human papillomavirus (HPV) positive status (HR=0.26, p=0.004) and treatment with chemoradiation (CRT) (HR=0.38, p=0.004) were associated with better disease free survival (DFS). A primary site was located after aggressive investigation in approximately half of the patients. More research is warranted towards the use of lingual tonsillectomy. Predictors of favorable prognosis included HPV positive status and treatment with CRT.

Significance of the Neutrophil-to-Lymphocyte Ratio in p16-Negative Squamous Cell Carcinoma of Unknown Primary in Head and Neck.

Objective: The neutrophil-to-lymphocyte ratio (NLR) has been reported to be associated with survival in solid malignancies. The main goal was to evaluate the prognostic significance of the NLR in patients with p16-negative squamous cell carcinoma of unknown primary (SCCUP) in head and neck.Methods: The association between the NLR and clinical pathologic variables was evaluated by the chi-square test. The primary endpoint of interest was disease-specific survival (DSS). Univariate and Coxmodel analyses were used to evaluate prognostic factors.Results: A total of 153 patients were included in the analysis. Cancer cachexia was noted in 10 patients. The mean NLR value was 3.9 (range: 1.4–8.3). A high NLR was significantly associated with cancer cachexia development. The 5-year DSS rate was 58%. In patients with NLRs varying from 1.4 to 3.7, the 5-year DSS rate was 71%; in patients with NLRs varying from 3.7 to 6.0, the 5-year DSS rate was 57%; in patients with NLRs varying from 6.0 to 8.3, the 5-year DSS rate was 39%, and the difference was significant (p = 0.001). Further Cox model analysis confirmed the independence of the NLR in predicting survival.Conclusions: In patients with p16-negative SCCUP, an NLR ≥ 6.0 is significantly associated with worse prognosis.

Narrow band imaging in head and neck unknown primary carcinoma: A systematic review and meta-analysis.

To estimate the diagnostic performance of Narrow Band Imaging (NBI) in patients with cervical metastasis from head and neck squamous cell carcinoma of unknown primary (SCCUP) origin. PubMed, Embase, and Scopus databases were systematically scrutinized up to July 1, 2019, looking for studies that encompassed the NBI in the SCCUP diagnostic work up. The main inclusion criteria for eligible articles for the meta-analysis were non-evidence of primary tumor after physical examination and conventional cross-section imaging before NBI assessment and the availability of complete data on the diagnostic accuracy of NBI. A set of random-effects model meta-analyses was then performed following the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines. Five studies, conducted between January 2003 and September 2016, comprising 169 patients imaged with NBI, were included in the meta-analysis. The pooled sensitivity and specificity of NBI in patients with head and neck SCCUP was 0.83 (99% CI, 0.54-0.95) and 0.88 (99% CI, 0.55-0.97), respectively. The positive and negative likelihood ratios were 6.38 (99% CI, 1.6-25.44) and 0.06 (99% CI, 0.005-0.86). The pooled diagnostic odds ratio (DOR) was 82.15 (99% CI, 7.06-955). The overall detection rate of NBI was 0.35 (99% CI, 0.18-0.53), which allowed localization the primary tumor in 61 out of 169 patients, otherwise not detected by the usual diagnostic work-up. Current available evidence suggests that NBI has a considerable diagnostic accuracy in patients affected by head and neck SCCUP. Laryngoscope, 130:1692-1700, 2020.

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

Human papillomavirus (HPV)-related squamous cell carcinoma of unknown primary (SCCUP) is currently rising in incidence but lacks a validated management approach. This paper reviews the clinical presentation, diagnosis, and treatment of HPV-related SCCUP. 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. 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. 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 18 F-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. 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.

FDG PET/CT for metastatic squamous cell carcinoma of unknown primary of the head and neck

ObjectiveThe role of FDG PET/CT is uncertain in squamous cell carcinoma of unknown primary (SCCUP). Published data are limited by heterogeneity of pathology, varied diagnostic criteria, and small sample size. Materials/methodsThis retrospective study was conducted in 40 patients who had FDG PET/CT for SCCUP. Prior to PET/CT, patients had underwent standard clinical evaluations including flexible rhinolaryngoscopy. The majority of the patients had anatomic imaging. All subjects had histopathological investigations, and follow-up data after PET/CT. ResultsFDG PET/CT detected the primary in 16 of 40 patients (40%), and the most common locations of the primary were in the base of the tongue, palatine tonsil, and hypopharynx. There were 10 false positive and 6 false negative PET/CT scans. There was no difference in the mean SUVs of the suspected primary lesions between true and false positive groups. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall accuracy of FDG PET/CT for SCCUP in this patient cohort were 72.7% (16/22), 44.4% (8/18), 61.5% (16/26), 57.1% (8/14), and 60% (24/40), respectively. The tonsil was the site with the most false positive and false negative findings. ConclusionsFDG PET/CT might be an effective single shot of whole-body imaging for detection of the primary in SCCUP. Low specificity remained the most notable weakness of FDG-PET in work-up for SCCUP. In addition to varied physiologic uptake or inflammatory related uptake in the common locations of the primary, the image indication bias might be another significant contributor of high false positive rate.

Role of palatine tonsillectomy in the diagnostic workup of head and neck squamous cell carcinoma of unknown primary origin: A systematic review and meta-analysis.

This systematic review and meta-analysis aims to evaluate the effectiveness of palatine tonsillectomy in patients with cervical metastasis from squamous cell carcinoma of unknown primary (SCCUP) origin. A systematic review including studies that encompassed palatine tonsillectomy in the SSCUP diagnostic evaluation was conducted. A single arm meta-analysis was then made to obtain the overall identification rate of tonsillectomy. Fourteen studies were included, comprising 673 patients who underwent 416 palatine tonsillectomies, 338 preformed during examination under anesthesia (EUA) and 78 managed with transoral robotic surgery (TORS). A total of 140 occult tonsillar malignancies were identified; of these, 124 (89%) were ipsilateral, 2 (1%) contralateral, and 14 (10%) synchronous bilateral. Meta-analysis of 11 studies showed an overall detection rate of tonsillectomy of 0.34 (99% confidence interval 0.23-0.46). Palatine tonsillectomy is a valuable diagnostic tool in the management of patients with head and neck SCCUP. Bilaterality of tonsillectomy should be taken into consideration.

Cervical lymph node metastases of squamous cell carcinoma of unknown origin: the diagnostic value of FDG PET/CT and clinical outcome

FDG PET/CT is perceived as a valuable diagnostic tool in addition to the standard diagnostic workup for patients with isolated neck lymph nodes of squamous cell carcinoma of unknown primary (SCCUP). For patients with SCCUP intended for primary radiotherapy, we hypothesize that the previously reported FDG PET/CT detection rates are too high. From 2008 to 2015, 30 SCCUP patients were examined with FDG PET/CT. The objective of the FDG PET/CT examination was twofold: (1) improve the radiotherapy target definition, and (2) identify the primary cancer. Before the FDG PET/CT, the patients had been through a standard workup consisting of CT of the neck and chest, examination with flexible endoscopy with patient awake, panendoscopy and examination under general anesthesia, tonsillectomy and sometimes blind sampling biopsies, and MRI (floor of the mouth). All FDG PET/CTs were performed applying a flat table, head support and fixation mask as part of the radiotherapy treatment planning. Diagnostic CT with contrast was an integrated part of the PET/CT examination. Only 1/30 patients (cancer of the vallecula) had their primary cancer detected by FDG PET/CT. In addition, a non-biopsied patient with high uptake in the ipsilateral palatine tonsil was included, giving a detection rate of ≤7% (95% CI 2-21%). In this retrospective study, we found that the FDG PET/CT detection rate of the primary for SCCUP patients is lower than previously reported. It is questionable whether FDG PET/CT is necessary for these patients when improved, advanced workup is available.

The prevalence of human papillomavirus in squamous cell carcinoma of unknown primary site metastatic to neck lymph nodes: a systematic review.

A subset of head and neck squamous cell carcinoma, which mainly arise from the crypt epithelium of the palatine and lingual tonsils, may be caused by high-risk human papillomavirus (HPV) infections. This topographical restriction together with other overlapping clinical features have led investigators to suspect that HPV plays a role in squamous cell carcinoma of unknown primary (SCCUP) site metastatic to neck lymph nodes. We performed a systematic review of articles listed in PubMed to identify studies testing HPV and/or p16(INK4a) status (p16) in tissue samples from initial and definitive SCCUP. The prevalence of HPV-related (HPV DNA-positive and/or p16 positive) SCCUP was calculated for all the SCCUP, initial SCCUP, suspected definitive SCCUP, and true definitive SCCUP whenever a minimum of 10 cases of each category was identified. In addition, data concerning patients' diagnostic work-up, the HPV detection methods, and the correlations between HPV-status, the localization of the occult primary tumor, and the clinical outcome were also extracted. Eighteen retrospective cohort studies, assessing a total of 659 patients, met the inclusion criteria. The overall median prevalences of HPV-DNA(pos), of p16(pos), and of positivity for both HPV markers were, respectively, 37.0, 48.5, and 36.0 %. Patients with diagnosis of initial SCCUP had overall median prevalences of HPV-DNA(pos), of p16(pos), and of positivity for both HPV markers, respectively, of 81.8, 86.2, and 80.8 %. The data uncovered by this systematic review confirm that SCCUP is frequently causally associated to HPV-driven oropharyngeal squamous cell carcinomas. This finding supports the view that HPV-status could be routinely assessed in SCCUP patients as it may lead to identifying the primary tumor and the decision to de-escalate treatment.

Transoral robotic surgery for the management of head and neck squamous cell carcinoma of unknown primary

Conclusion: The addition of transoral robotic surgery (TORS) in the diagnostic management of patients classified with head and neck squamous cell carcinoma of unknown primary (SCCUP) is promising and appears to improve detection rates of the primary tumour. The approach presented in this first Scandinavian study could potentially minimize the radiation field to the pharyngeal axis in patients with identified primary tumours. Objectives: The aim of the study was to investigate whether bilateral lingual tonsillectomy performed with TORS is feasible, and whether it could improve the detection rates of primary tumours in patients diagnosed and classified as having SCCUP. Methods: The study was retrospective and included 13 patients with SCCUP who were referred to TORS between October 2013 and January 2015. All 13 patients had previously undergone a full investigation programme following the national guidelines including whole-body PET/CT, examination in general anaesthesia, including random biopsies of the base of the tongue and bilateral palatine tonsillectomy without identification of the primary tumour. Results: The primary tumour was identified by TORS in seven of the 13 patients (54%) at the lingual tonsils. Human papillomavirus DNA and p16 were positive in all identified primary tumour specimens and in the corresponding lymph node metastases.

Head and Neck Squamous Cell Carcinoma of Unknown Primary (SCCUP): Neck Dissection (ND) and Radiotherapy (RT) versus Definitive RT

Head and Neck Squamous Cell Carcinoma of Unknown Primary (SCCUP): Neck Dissection (ND) and Radiotherapy (RT) versus Definitive RT

O46 Potential use of gene expression micro-array in identifying primary site in patients with squamous cell carcinoma of unknown primary (SCCUP)

O46 Potential use of gene expression micro-array in identifying primary site in patients with squamous cell carcinoma of unknown primary (SCCUP)