Molecular Investigation of the Association Among Common Interleukin-6 Polymorphism and Human Papillomavirus Genotypes with Cervical Cancer Among Iranian Women.

Cervical cancer is the fourth most commonly identified cancer and the third important reason for cancer-related death among women in less developed nations. Aside from the human papillomavirus (HPV), the host genetic factors, especially some polymorphisms in the interleukin 6 (IL-6) gene, might relate to the risk of cervical cancer. This study aims to investigate the molecular investigation of HPV infection and its association with the common polymorphism of IL-6 in cervical carcinoma in Iran. This case-control study collected 62 precancerous and cancerous lesions and 62 healthy samples from cancer-free women, subsequent negative colposcopy, and cervical cytology. The frequency of HPV genotypes and the genotyping of IL-6 rs1800795 and rs1800796 were done by different PCR techniques. Results were analyzed using the Epi Info version 7, 2012, with the χ2 test. Compared with cervical intraepithelial neoplasia grade 1 (CINI), the HPV positivity rate is saliently higher in CINII/III and squamous cell carcinoma (SCC) (56.25%, 66.66%, and 73.63%, respectively, p < 0.001). The HPV positivity rate is also higher in SCC in comparison with CINII/III (p < 0.01). Furthermore, the most detected HPV genotypes were HPV16 and 33 in CINI; HPV16, 31, and 35 in CINII/III; and HPV16 and 18 in SCC groups. HPV16 was the most commonly detected genotype in CINI, CINII/III, and SCC, accounting for 44.44%, 50%, and 71.42%, respectively. In addition, the frequency of GG, CG, and CC genotypes from rs1800795 polymorphism was 0.58, 0.32, and 0.10, respectively (p = 0.033), but in the control group, it was 0.70, 0.27, and 0.03, respectively. The findings suggest that HPV16 plays an important role in the emergence of cervical lesions in Iranian patients. As a result, rs1800795 CC genotype and HPV might increase cervical cancer risk in Iranian women.

p16 status and high-risk human papilloma virus infection in squamous cell carcinoma of the nasal vestibule.

OBJECTIVE: The status of human papilloma virus (HPV) and p16 overexpression for nasal vestibule squamous cell carcinoma (NVSCC) is unclear. The purpose of this retrospective study was to analyze the presence of HPV and the role of p16 overexpression as a surrogate marker in cases of NVSCC. METHODS: Retrospective analysis was performed on patients who were diagnosed and treated for NVSCC at the University of Tokyo Hospital, Japan. p16 immunohistochemistry was considered positive with at least moderate staining intensity and diffuse staining (≥75% of tumor cells), according to the 8th edition of the American Joint Commission on Cancer. HPV-DNA testing was performed using multiplex polymerase chain reaction. RESULTS: Five patients were included in the study. Ages ranged from 55 to 78 years; there were two men and three women; two had T2N0, and three had T4aN0. Surgery was performed in one case, surgery plus radiation therapy (RT) in one case, and chemoradiation therapy (CRT) in three cases. Four of the five tumors showed p16 overexpression. One of five cases had an HPV-16 genotype. The mean follow-up period was 73 months, and all the patients survived. One patient with p16-negative carcinoma had local recurrence and underwent salvage surgery. Of the four patients with p16-positive carcinoma, one with CRT and one with surgery plus RT, each had delayed cervical lymph node metastasis, which was salvaged with neck dissection subsequent RT. CONCLUSIONS: In NVSCC, four of the five cases were p16-positive, and one was high-risk HPV infection.

"From molecular to clinic": The pivotal role of CDC42 in pathophysiology of human papilloma virus related cancers and a correlated sensitivity of afatinib.

Background: Human papilloma virus (HPV)-related cancers are global health challenge. Insufficient comprehension of these cancers has impeded the development of novel therapeutic interventions. Bioinformatics empowered us to investigate these cancers from new entry points. Methods: DNA methylation data of cervical squamous cell carcinoma (CESC) and anal squamous cell carcinoma (ASCC) were analyzed to identify the significantly altered pathways. Through analyses integrated with RNA sequencing data of genes in these pathways, genes with strongest correlation to the TNM staging of CESC was identified and their correlations with overall survival in patients were assessed. To find a potential promising drug, correlation analysis of gene expression levels and compound sensitivity was performed. In vitro experiments were conducted to validate these findings. We further performed molecular docking experiments to explain our findings. Results: Significantly altered pathways included immune, HPV infection, oxidative stress, ferroptosis and necroptosis. 10 hub genes in these pathways (PSMD11, RB1, SAE1, TAF15, TFDP1, CORO1C, JOSD1, CDC42, KPNA2 and NUP62) were identified, in which only CDC42 high expression was statistically significantly correlated with overall survival (Hazard Ratio: 1.6, P = 0.045). Afatinib was then screened out to be tested. In vitro experiments exhibited that the expression level of CDC42 was upregulated in HaCaT/A431 cells transfected with HPV E6 and E7, and the inhibitory effect of afatinib on proliferation was enhanced after transfection. CDC42-GTPase-effector interface-EGFR-afatinib was found to be a stable complex with a highest ZDOCK score of 1264.017. Conclusion: We identified CDC42 as a pivotal gene in the pathophysiology of HPV-related cancers. The upregulation of CDC42 could be a signal for afatinib treatment and the mechanism in which may be an increased affinity of EGFR to afatinib, inferred from a high stability in the quaternary complex of CDC42-GTPase-effector interface-EGFR-afatinib.

Global burden of HPV-attributable squamous cell carcinoma of the anus in 2020, according to sex and HIV status: A worldwide analysis.

Squamous cell carcinoma of the anus (SCCA) is caused by HPV, and is elevated in persons living with HIV (PLWHIV). We aimed to estimate sex- and HIV-stratified SCCA burden at a country, regional and global level. Using anal cancer incidence estimates from 185 countries available through GLOBOCAN 2020, and region/country-specific proportions of SCCA vs non-SCCA from the Cancer Incidence in Five Continents (CI5) Volume XI database, we estimated country- and sex-specific SCCA incidence. Proportions of SCCA diagnosed in PLWHIV, and attributable to HIV, were calculated using estimates of HIV prevalence (UNAIDS 2019) and relative risk applied to SCCA incidence. Of 30 416 SCCA estimated globally in 2020, two-thirds occurred in women (19 792) and one-third among men (10 624). Fifty-three percent of male SCCA and 65% of female SCCA occurred in countries with a very high Human Development Index (HDI). Twenty-one percent of the global male SCCA burden occurred in PLWHIV (n = 2203), largely concentrated in North America, Europe and Africa. While, only 3% of global female SCCA burden (n = 561) occurred in PLWHIV, mainly in Africa. The global age-standardized incidence rate of HIV-negative SCCA was higher in women (0.55 cases per 100 000) than men (0.28), whereas HIV-positive SCCA was higher in men (0.07) than women (0.02). HIV prevalence reached >40% in 22 countries for male SCCA and in 10 countries for female SCCA, mostly in Africa. Understanding global SCCA burden by HIV status can inform SCCA prevention programs (through HPV vaccination, screening and HIV control) and help raise awareness to combat the disease.

HPV-positive cervical squamous cell carcinoma metastasis to the breast, mimicking primary tumor.

INTRODUCTION: Metastatic disease to the breast is a rare condition, with contralateral breast metastasis being the most common primary site. CASE PRESENTATION: We present the case of a patient who underwent treatment for an HPV positive squamous cell carcinoma (SCC) of the cervix who, during follow-up, complained of a nodule in her left breast. Anatomopathological results indicating squamous carcinoma, which was not able to be differentiated from breast metaplastic carcinoma. Resection of the lesion was carried out, confirming carcinoma with squamous cell differentiation with negativity for GCDFP-15, mammaglobin, p63 and SOX10, but with positivity for p16 and for high risk HPV, confirming a single metastatic lesion of cervical carcinoma. DISCUSSION/CONCLUSION: In the presence of SCC in the breast, the differential diagnosis may consider the presence of primary lesion, metaplastic carcinoma with squamous cell differentiation or metastatic disease. The use of markers such as p63, SOX10 and p16, may help for a definitive diagnosis.

Loss of p16 expression is a risk factor for recurrence in sinonasal inverted papilloma.

BACKGROUND: The purpose of this study was to evaluate p16, p53, EGFR, pEGFR protein expression and HPV infection as possible markers of tumor progression in a series of sinonasal inverted papilloma (SNIP) and sinonasal squamous cell carcinoma (SNSCC). METHODS: A series of 49 SNIP, 11 SNSCC associated with SNIP (SNIP-SNSCC) and 52 SNSCC not associated with SNIP were analyzed for p16, p53, EGFR, and phosphorylated EGFR (pEGFR) expression by immunohistochemistry. Human papillomavirus (HPV) infection status was evaluated by DNA-PCR. Results were correlated to clinical and follow-up data. RESULTS: Reduced or loss of p16 expression was observed in 18% SNIP, 64% SNIP-SNSCC and 87% of SNSCC. Reduced or loss p16 staining in SNIP correlated with shorter recurrent SNIP-free follow-up. In contrast, p16 expression was not predictive of recurrent SNSCC in cases with SNIP-SNSCC and SNSCC. P53, EGFR, and pEGFR expression did not differ between the tumor groups, nor were they related to recurrent SNIP-free follow-up or recurrent SNSCC. Oncogenic HPV types 16 and 18 were detected in 5% of SNIP and 18% of SNIP-SNSCC, but not in SNSCC. There was no correlation between HPV infection and >70% p16 immunostaining. CONCLUSIONS: HPV infection appears to play a minor role in SNIP and SNSCC and p16 immunostaining does not appear a valid surrogate marker for HPV. However, reduced or loss p16 expression may have prognostic value as a risk marker for recurrent SNIP.

The value of HPV genotypes combined with clinical indicators in the classification of cervical squamous cell carcinoma and adenocarcinoma.

BACKGROUND: To investigate the differences in HPV genotypes and clinical indicators between cervical squamous cell carcinoma and adenocarcinoma and to identify independent predictors for differentiating cervical squamous cell carcinoma and adenocarcinoma. METHODS: A total of 319 patients with cervical cancer, including 238 patients with squamous cell carcinoma and 81 patients with adenocarcinoma, were retrospectively analysed. The clinical characteristics and laboratory indicators, including HPV genotypes, SCCAg, CA125, CA19-9, CYFRA 21-1 and parity, were analysed by univariate and multivariate analyses, and a classification model for cervical squamous cell carcinoma and adenocarcinoma was established. The model was validated in 96 patients with cervical cancer. RESULTS: There were significant differences in SCCAg, CA125, CA19-9, CYFRA 21-1, HPV genotypes and clinical symptoms between cervical squamous cell carcinoma and adenocarcinoma (P < 0.05). Logistic regression analysis showed that SCCAg and HPV genotypes (high risk) were independent predictors for differentiating cervical squamous cell carcinoma from adenocarcinoma. The AUC value of the established classification model was 0.854 (95% CI: 0.804-0.904). The accuracy, sensitivity and specificity of the model were 0.846, 0.691 and 0.899, respectively. The classification accuracy was 0.823 when the model was verified. CONCLUSION: The histological type of cervical cancer patients with persistent infection of high-risk HPV subtypes and low serum SCCAg levels was more prone to being adenocarcinoma. When the above independent predictors occur, the occurrence and development of cervical adenocarcinoma should be anticipated, and early active intervention treatment should be used to improve the prognosis and survival of patients.

Stage IA1 HPV-associated cervical squamous cell carcinoma metastasizing to ovary by special pathway: a case report and literature review.

BACKGROUND: As the leading cancer of the female reproductive tract, it is not uncommon for human papilloma virus (HPV)-associated cervical squamous cell carcinoma (HPV-CSCC) to metastasize to pelvic organs and lymph nodes in advanced stages. However, herein, we present a rare case in which superficial invasive HPV-CSCC metastasized to the unilateral ovary as a large mass by spreading directly through the endometrium and fallopian tubes and lymph-vascular space invasion. The case is so unexpected that the misdiagnosis most likely could be proceeded as a primary ovarian cancer. CASE PRESENTATION: A 58-year-old postmenopausal woman presented vaginal bleeding for more than 4 months, never received hormonal treatment and had no family history of malignant diseases. Routine ultrasound revealed a 12 × 10 × 10 cm right ovarian mass. Intraoperative frozen section was diagnosed as a borderline Brenner tumour with local highly suspected invasive carcinoma. Accordingly, omentectomy surgery then occurred. Unbelievably, by observation under a microscope, immunohistochemistrial staining, and HPV RNA scope, we found that the carcinoma originated from the uterine cervix. In the uterine cervix, stage IA1 superficial invasive squamous carcinoma was found, and the carcinoma directly spread to the endometrium and bilateral fallopian tube, was planted into the right ovary and eventually grew as a large mass. Moreover, lymph-vascular space invasion (LVSI) was also discovered. To date, the patient has been given 6 cycles of chemotherapy and has experienced no recurrence. CONCLUSIONS: The diagnosis of superficial invasive cervical squamous cell carcinoma metastasizing to the ovary is very challenging for pathological doctors, especially in intraoperative consultations.

Demographic Profile of p16 Immunopositive and HPV DNA PCR Positive Oral Squamous Cell Carcinoma in a Large Cohort of Indian Patients.

BACKGROUND: The Indian subcontinent has the highest incidence of oral cavity squamous cell carcinoma in the world. The high incidence of tobacco chewing habit with or without smoking has been found to be the chief culprit. However in a minor subset of patients Human Papilloma Virus may play a role. MATERIALS AND METHODS: A total of 800 cases of Oral squamous cell carcinoma were included in the study. The patients were given a questionnaire comprising of questions about demographic details and habits. The biopsy samples were routinely processed for immunohistochemistry for p16 (E6H4 clone, CINtec histology, Roche diagnostics). Cases with 2+/3+ positive nuclear staining with more than 75% cells immunopositive were taken as p16 immunopositive as per the AJCC criteria and were further subjected to HPV DNA PCR for which DNA was extracted from the formalin fixed paraffin embedded tissue. RESULTS: Out of 800 OSCC cases 139 (17.37%) showed p16 immunopositivity by AJCC criteria. Out of these, 104 (104/139, 74.8%) cases were positive by HPV DNA PCR for HPV-16/18. Following patient characteristics were associated with a higher proportion of p16 and HPV DNA positivity-urban residence, vegetarian diet, illiteracy, graduate or higher education. No correlation was noted with gender, tobacco smoking or chewing habits, religion, occupation or site of tumor. The p16 immunopositivity was higher in the younger age group with no tobacco habits. CONCLUSION: A significant proportion of OSCC cases in India are associated with HPV infection. A higher percentage of p16 immunopositivity amongst younger patients with no tobacco habits points towards a distinct subset of patients in whom HPV may be the chief culprit and not just playing a supporting role.

Lack of CD44 and Sox-2 Overexpression as Two Independent Favourable Prognostic Factors in HPV Positive Patients with Oropharyngeal Cancers.

INTRODUCTION: In our earlier publications, in the group of 63 patients with oropharyngeal cancer, we have found HPV16 infection (assessed by qPCR) in 25 tumours (39.7%), immunohistochemical overexpression of CD44, CD98, ALDH1/2 and Nanog in, respectively: 43 (68.2%), 30 (47.6%), 33 (52.4%), and 53 (84.1%) cancers. Analysing CD44, CD98, ALDH1/2, we have also shown that lack of CD44 overexpression indicates excellent prognosis in patients with HPV16 positivity. The aim of the present study was to compare prognostic potential of Nanog, Oct3/4, Sox-2 expression in relation to CD44, CD98, ALDH1/2 immunoreactivity (assessed by us earlier) and clinicopathological features in the subgroups of patients: with HPV16 positivity and HPV16 negativity. METHODS: Status of Oct3/4 and Sox-2 expression was assessed for 63 patients with oropharyngeal cancers based on immunohistochemistry. In survival analysis, two endpoints were applied: overall survival (OS) and disease-free survival (DFS). RESULTS: Overexpression of Oct3/4 and Sox-2 was found in 0 (0.0%) and 27 (42.9%) of patients. In the subgroup with HPV16 positivity, the DFS for patients with lack of Sox-2 overexpression was significantly (p = 0.003) higher than for patients with Sox-2 overexpression. In the subgroup with HPV16 negativity, Nanog and Sox-2 immunoexpression did not significantly influence OS and DFS. In multivariate analysis performed for the subgroup with HPV16 positivity, lack of CD44 overexpression (p = 0.012) and lack of Sox-2 overexpression (p = 0.027) were positive independent prognostic factors. CONCLUSION: Based on CD44 and Sox-2 immunoreactivity, it is possible to differentiate the prognosis of HPV16-positive patients with oropharyngeal cancers.

The CT and PET/CT findings in primary pulmonary lymphoepithelioma-like carcinoma with pathological correlation: a study of 215 cases.

AIM: To investigate the computed tomography (CT) and integrated positron-emission tomography (PET)/CT findings of primary pulmonary lymphoepithelioma-like carcinoma (PLELC). MATERIALS AND METHODS: The imaging and histopathological data of 215 patients with PLELC confirmed at histopathology were analysed retrospectively. All patients underwent CT, and 70 underwent PET/CT. None of the cohort had nasopharyngeal lymphoepithelioma-like carcinoma. RESULTS: The PLELC was demonstrated as a solitary nodule/mass in 188 cases (188/215, 87%), multiple nodules/masses in 12 cases (12/215, 6%), lobar or segmental consolidation in 15 cases (15/215, 7%). The tumour showed a well-defined margin in 171 cases (171/215, 80%), lobular sign in 177 cases (177/215, 82%), and spicule sign in 91 cases (91/215, 42%). Most of the cases showed homogeneous density in unenhanced CT (128/215, 60%), and vascular shadows inside the tumour in the arterial stage were found in 105 cases (105/158, 66%). Involvement of the bronchus was found in 154 cases (154/215, 72%). Hilar or mediastinal lymph nodes were enlarged in 160 patients (160/215, 74%). Seventy cases demonstrated avid 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) uptake on PET/CT. The range of maximum standardised uptake values (SUVmax) was 2.1-28.5 (14 ± 5.93). Microscopic pathological classification of 124 resected specimens included 87 cases of the Regaud type and 37 cases of the Schmincke type. Epstein-Barr virus (EBV)-encoded small RNAs (EBERs) was positive in all 215 cases. CONCLUSION: PLELC should be suspected when a large, lobulate, well-defined lung tumour with homogeneous density, vascular encasement, and high 18F-FDG uptake is found. Moreover, EBERs are helpful in patients with suspected PLELC.

The peri- and intratumoral immune cell infiltrate and PD-L1 status in invasive squamous cell carcinomas of the penis.

INTRODUCTION: Penile carcinomas are rare tumors throughout Europe. Therefore, little attention is drawn to this disease. That makes it important to study tumor-associated key metrics and relate these to known data on penile neoplasias. MATERIALS AND METHODS: A cohort of 60 well-defined penile invasive carcinomas with known human papillomavirus (HPV) infection status was investigated. Data on tumor type, grading and staging were recorded. Additionally, data on the peri- and intratumoral immune cell infiltrate in a semiquanititave manner applying an HE stain were assessed. RESULTS: Our study showed a significant correlation of immune cell infiltrate and pT stage with overall survival. Therefore, in a subset of tumors, PD-L1 staining was applied. For tumor proportion score (TPS), 26 of 30 samples (87%) were scored >0%. For the immune cell score (IC), 28 of 30 samples (93%) were defined as >0% and for CPS, 29 of 30 samples (97%) scored >0. PD-L1 expression was not associated with overall survival. CONCLUSION: PD-L1 is expressed in penile carcinomas, providing a rationale for targeted therapy with checkpoint inhibitors. We were able to show that immune reaction appears to be prognostically relevant. These data enhance the need for further studies on the immune cell infiltrate in penile neoplasias and show that PD-L1 expression is existent in our cohort, which may be a potential target for checkpoint inhibitor therapy.

Postoperative Radiation Therapy Refusal in Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma.

OBJECTIVES/HYPOTHESIS: Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is a distinct clinical entity with good prognosis, unique demographics, and a trend toward treatment deintensification. Patients with this disease may opt out of recommended postoperative radiation therapy (PORT) for a variety of reasons. The aim of this paper was to examine factors that predict patient refusal of recommended PORT in HPV-associated OPSCC, and the association of refusal with overall survival. STUDY DESIGN: Retrospective population-based cohort study of patients in the National Cancer Database. METHODS: We conducted a retrospective cohort study of patients in the National Cancer Database diagnosed with OPSCC between January 2010 and December 2015. We primarily assessed overall survival and the odds of refusing PORT based on demographic, socioeconomic, and clinical factors. Analysis was conducted using multivariable logistic regression and multivariable Cox proportional hazards model. RESULTS: A total of 4229 patients were included in the final analysis, with 156 (3.7%) patients opting out of recommended PORT. On multivariable analysis, patient refusal of PORT was independently associated with a variety of socioeconomic factors such as race, insurance status, comorbidity, treatment at a single facility, and margin status. Lastly, PORT refusal was associated with significantly lower overall survival compared to receipt of recommended PORT (hazard ratio 1.69, confidence interval 1.02-2.82). CONCLUSIONS: Patient refusal of recommended PORT in HPV-associated OPSCC is rare and associated with variety of disease and socioeconomic factors. PORT refusal may decrease overall survival in this population. Our findings may help clinicians when counseling patients and identifying those who may be more likely to opt out of recommended adjuvant therapy. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:339-348, 2022.

Oropharyngeal Carcinoma Treated with Surgery Alone: Outcomes and Predictors of Failure.

OBJECTIVE: To analyze the oncologic outcomes and risk factors for recurrence in patients who underwent surgery for oropharyngeal squamous cell carcinoma (OPSCC), and in whom adjuvant therapy was not recommended or was declined. METHODS: Retrospective cohort study of patients with OPSCC who were treated with transoral surgery only at a tertiary care academic medical center from April 2010 to March 2019. RESULTS: Seventy-four patients met inclusion criteria. In 16, adjuvant therapy was recommended but declined. There were 8 recurrences, of which 6 had been given recommendations for adjuvant therapy. Of the 8 recurrences, 2 died, 2 are alive with disease, and 4 were successfully salvaged. Five patients died of unrelated causes. Lymphovascular invasion (LVI, P = .016) had a significant impact on recurrence, while other pathologic features of the primary tumor such as size, location, human papillomavirus (HPV) status, and margin status did not. Margins were classified as "positive" in 4 patients, "close" in 54, and "negative" in 16. There were 3 local recurrences (4.1%), each of whom had declined adjuvant therapy. Lymph node features such as N-stage (P = .0004), number of positive nodes (P = .0005), and presence of extra-nodal extension (ENE, P = .0042) had a statistically significant impact on relapse. Smoking history and surgical approach showed no significant impact on recurrence. CONCLUSION: Patients who undergo surgery for HPV-positive OPSCC with negative margins, no PNI, no LVI, and ≤1 positive lymph node without ENE have low risk for recurrence. These patients can likely be safely treated with surgery alone. Patients with these risk factors who decline adjuvant therapy are at risk for recurrence, and should be monitored.

Human Papillomavirus in Patients With Hypopharyngeal Squamous Cell Carcinoma.

OBJECTIVE: Assess the testing rates and prognostic significance of human papilloma virus (HPV) status in hypopharynx malignancies. STUDY DESIGN: Historical cohort study. SETTING: National Cancer Database. METHODS: Review of the National Cancer Database was conducted between 2010 and 2017 for squamous cell carcinomas (SCCs) of the hypopharynx. We investigated how often the tumors were tested for HPV and whether it was associated with survival outcomes. RESULTS: A total of 13,269 patients with hypopharynx malignancies were identified. Most cases were not tested for HPV status (n = 8702, 65.6%). Of those tested, 872 (19.1%) were positive for HPV and 3695 (80.9%) were negative. The proportion of nonoropharyngeal SCCs tested for HPV increased nearly every year during the study, with roughly one-third of cases (31.9%) being tested in 2017. In the facilities classified as high-testing centers of nonoropharyngeal SCCs of the head and neck, 18.7% of hypopharyngeal tumors were HPV positive. HPV-negative status was associated with worse survival on multivariable analysis. In propensity score-matched analysis controlling for all factors significant in multivariable regression, 2-year survival remained higher in the HPV-positive cohort (77.7% vs 63.1%, P < .001). CONCLUSIONS: HPV-positive tumors constitute a sizable minority of hypopharynx tumors and are associated with improved survival. Expansion of HPV testing to hypopharynx malignancies may be warranted.

Cell-Free Human Papillomavirus-DNA for Monitoring Treatment Response of Head and Neck Squamous Cell Carcinoma: Systematic Review and Meta-Analysis.

OBJECTIVES/HYPOTHESIS: The aim of this study was to assess the value of cell-free human papillomavirus-DNA (cfHPV-DNA) as a diagnostic test for the post-treatment surveillance of patients with HPV-positive head and neck squamous cell carcinoma (HNSCC) through a systematic review and meta-analysis. STUDY DESIGN: Systematic review and meta-analysis. METHODS: A literature search was conducted in three databases (MEDLINE, Embase, and Scopus) in January 2021. The population included patients with HPV-positive HNSCC. The intervention was the use of the repeated liquid biopsy with circulating HPV-DNA detection during follow-up. The outcome was to establish the value of cfHPV-DNA as a diagnostic test for the post-treatment surveillance of patients with HPV-positive HNSCC. RESULTS: Ten studies included in the meta-analysis provided a total of 457 patients with HPV-positive HNSCC. The meta-analytic study estimated the diagnostic performance of cfHPV-DNA as follows: pooled sensitivity and specificity of 0.65 (95% confidence interval [CI]: 0.40-0.84) and 0.99 (99% CI: 0.96-0.99), respectively; positive and negative likelihood ratios of 62.5 (99% CI: 22.9-170.2) and 0.05 (99% CI: 0.013-0.24), respectively; and pooled diagnostic odds ratio of 371.66 (99% CI: 60.4-2286.7). CONCLUSION: Currently, the follow-up protocol for HNSCC patients includes routine clinical evaluation and radiological imaging. Biomarkers to monitor this disease are not established. Considering its high specificity, cfHPV-DNA represents a potential confirmatory test in the case of positive positron emission tomography and computed tomography. In the near future, cfHPV-DNA could be used as a biomarker for monitoring the treatment response during the clinical trials of de-escalation therapy or immunotherapy. Larger sample sizes and the homologation of study protocols and methodology are needed to better establish its utility in the clinical practice. Laryngoscope, 132:560-568, 2022.