HPV-related Carcinoma Research Articles

Clinicopathologic Analysis of HPV-Related Primary Squamous Cell Carcinoma of the Thyroid.

This study aims to explore the clinical and pathologic characteristics of HPV-related primary thyroid squamous cell carcinoma (PSCCT), a rare tumor classified by WHO-5 as a subtype of anaplastic thyroid carcinoma (ATC). Clinical data, histomorphology, immunohistochemistry, HPV detection, and B-raf gene point mutations of 3 PSCCT cases were analyzed. Subsequent follow-up was conducted post-treatment. All 3 cases involved female patients aged between 60 and 76. Microscopic examination revealed squamous cell carcinoma in cases 1 and 3, whereas case 2 exhibited both squamous cell carcinoma and papillary thyroid carcinoma components. Immunohistochemistry demonstrated CK19, PAX8, and TTF1 expression in the papillary thyroid carcinoma component, and CK5/6, p63, p40, and PAX8 expression in the squamous cell carcinoma component. P16 exhibited diffuse positivity in both squamous cell carcinoma and classic papillary carcinoma. HPV analysis identified low-risk type 6 positivity in cases 1 and 3, while both squamous cell carcinoma and papillary carcinoma areas in case 2 were positive for HPV-33. B-raf gene mutation was exclusive to case 2. Diagnosis of PSCCT necessitates multidisciplinary assessment, incorporating clinical symptoms, imaging, histomorphology, and immunohistochemistry. This study, for the first time, reveals the presence of HPV DNA in both PTC and PSCCT, occurring concurrently but separately. Given the limited scope of 3 case reports, definitive conclusions cannot be drawn, warranting further investigation.

Morphologic Spectrum of HPV-associated Sinonasal Carcinomas.

High-risk human papillomavirus (HR-HPV) infection has been increasingly recognized as a risk factor for sinonasal tract carcinomas. However the prevalence and prognostic significance of HPV-associated sinonasal carcinomas is not well known due to limited studies and inconsistency in HPV testing modalities in literatures. Morphologically, HPV-associated sinonasal carcinomas encompass a diverse group of tumors. HPV-associated sinonasal adenocarcinoma has not been reported. The purpose of this study was to determine the prevalence, morphologic spectrum and prognostic implication of HPV-associated sinonasal carcinomas. This cohort included 153 sinonasal carcinomas. Tissue microarrays were constructed. P16 immunohistochemistry and HR-HPV E6/7 in-situ Hybridization (ISH) were performed. Carcinomas were deemed HPV-associated based on a positive ISH testing. Clinicopathologic data was collected. 28/153 (18%) sinonasal carcinomas were HPV-associated. HPV-associated carcinomas consisted of 26 (93%) squamous cell carcinomas and variants, 1 (3.5%) HPV-related multiphenotypic sinonasal carcinoma and 1 (3.5%) adenocarcinoma. The HPV-associated adenocarcinoma closely resembled HPV-associated endocervical adenocarcinoma morphologically. HPV-associated carcinomas occurred in 8 (29%) women and 20 (71%) men with a median age of 66 years old. HPV-associated carcinomas were predominantly located at nasal cavity. A trend toward improved overall survival and progression free survival in HPV-associated carcinomas patients was observed, yet without statistical significance. Our study identifies a novel HPV-associated sinonasal adenocarcinoma subtype, highlights the broad morphologic spectrum of HPV-associated sinonasal carcinomas, and supports routine p16 testing during pathology practice regardless of tumor subtype followed by a confirmatory HR-HPV testing. This practice is critical for studying the clinical behavior of HPV-associated sinonasal carcinomas.

HPV-related multiphenotypic sinonasal carcinoma: report of a case

HPV-related multiphenotypic sinonasal carcinoma: report of a case

N6-methyladenosine methylation on FSCN1 mediated by METTL14/IGF2BP3 contributes to human papillomavirus type 16-infected cervical squamous cell carcinoma.

Human papillomavirus (HPV) infection has been reported to be associated with N6-methyladenosine (m6A) modification in cancers. However, the underlying mechanism by which m6A methylation participates in HPV-related cervical squamous cell carcinoma (CSCC) remains largely unclear. In this study, we observed that m6A regulators methyltransferase like protein (METTL14) and insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3) were upregulated in HPV-positive CSCC tissues and cell lines, and their high expression predicted poor prognosis for HPV-infected CSCC patients. Cellular functional experiments verified that HPV16 oncogenes E6/E7 upregulated the expression of METTL14 and IGF2BP3 to promote cell proliferation and epithelial mesenchymal transition of CSCC cells. Next, we found that E6/E7 stabilized fascin actin-bundling protein 1 (FSCN1) mRNA and elevated FSCN1 expression in CSCC cells through upregulating METTL14/IGF2BP3-mediated m6A modification, and FSCN1 expression was also validated to be positively associated with worse outcomes of HPV-positive CSCC patients. Finally, HPV16-positive CSCC cell lines SiHa and CaSki were transfected with knockdown vector for E6/E7 or METTL14/IGF2BP3 and overexpressing vector for FSCN1, and functional verification experiments were performed through using MTT assay, flow cytometry, wound healing assay and tumour formation assay. Results indicated that knockdown of E6/E7 or METTL14/IGF2BP3 suppressed cell proliferation, migration and tumorigenesis, and accelerated cell apoptosis of HPV-positive CSCC cells. Their tumour-suppressive effects were abolished through overexpressing FSCN1. Overall, HPV E6/E7 advanced CSCC development through upregulating METTL14/IGF2BP3-mediated FSCN1 m6A modification.

HPV-Related Multiphenotypic Sinonasal Carcinoma: A Clinicoradiological Series of 3 Cases With Full Endoscopic Surgical Outcome.

Context: Human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma (HMSC), formerly known as HPV-related carcinoma with adenoid cystic like features, is a rare tumor subtype with unusual correlation between radiological, histopathological, and surgical findings. The shared histological characteristics with other sinonasal tumors make the diagnosis challenging. Optimal surgical and oncological treatments for this rare condition remains to be clearly defined. Methods: The objective of the study was to describe the unique characteristics and endoscopic surgical treatment of this rare tumor. In this retrospective case series, all patients with an HMSC diagnosis treated in our tertiary center were selected. Results: Three HMSC cases were identified, including 2 male and 1 female patients. All cases originated from the posterior nasal cavity. One case presented with a tumor of 8.9 cm × 6.4 cm × 8.7 cm, which is the largest tumor volume described to date. All patients received exclusively endoscopic surgical treatment, followed by adjuvant radiation therapy. No patient showed clinical or radiological sign of disease recurrence, or regional or distant metastasis, with a follow-up ranging from 9 months to 4 years. In 2 cases, initial diagnoses incorrectly suggested adenoid cystic or basaloid squamous cell carcinoma. HPV-DNA testing confirmed the presence of HPV in all cases, with identification of strains 16 and 18. Conclusion and Relevance: HMSC represents a newly identified diagnosis that constitutes a significant challenge for both clinicians and pathologists. It is crucial to acknowledge its indolent clinical course and the apparent contradiction between aggressive radiological features and the noninvasive nature of surgical findings. Skull base surgeons should be aware that, despite these complexities, endoscopic treatment is achievable in the majority of cases. This understanding is essential for the effective management of HMSC.

Is p16 Testing Sufficient as a Surrogate for HPV-Related Squamous Cell Carcinoma?

Is p16 Testing Sufficient as a Surrogate for HPV-Related Squamous Cell Carcinoma?

Three-dimensional chromatin analysis reveals Sp1 as a mediator to program and reprogram HPV-host epigenetic architecture in cervical cancer

Human papillomavirus (HPV) is predominantly associated with HPV-related cancers, however, the precise mechanisms underlying the HPV-host epigenetic architectures in HPV carcinogenesis remain elusive. Here, we employed high-throughput chromosome conformation capture (Hi-C) to comprehensively map HPV16/18-host chromatin interactions. Our study identified the transcription factor Sp1 as a pivotal mediator in programming HPV-host interactions. By targeting Sp1, the active histone modifications (H3K27ac, H3K4me1, and H3K4me3) and the HPV-host chromatin interactions are reprogrammed, which leads to the downregulation of oncogenes located near the integration sites in both HPV (E6/E7) and the host genome (KLF5/MYC). Additionally, Sp1 inhibition led to the upregulation of immune checkpoint genes by reprogramming histone modifications in host cells. Notably, humanized patient-derived xenograft (PDX-HuHSC-NSG) models demonstrated that Sp1 inhibition promoted anti-PD-1 immunotherapy via remodeling the tumor immune microenvironment in cervical cancer. Moreover, single-cell transcriptomic analysis validated the enrichment of transcription factor Sp1 in epithelial cells of cervical cancer. In summary, our findings elucidate Sp1 as a key mediator involved in the programming and reprogramming of HPV-host epigenetic architecture. Inhibiting Sp1 with plicamycin may represent a promising therapeutic option for HPV-related carcinoma.

Hypothesis of a CD137/Eomes activating axis for effector T cells in HPV oropharyngeal cancers

Chronic Human Papilloma Virus (HPV) infection is supplanting alcohol and tobacco intoxications as the leading cause of oropharyngeal cancer in developed countries. HPV-related squamous cell carcinomas of the oropharynx (HPV + OSC) present better survival and respond better to radiotherapy and chemotherapy. Regulatory T cells (TREG) are mainly described as immunosuppressive and protumoral in most solid cancers. However, TREG are paradoxically associated with a better prognosis in HPV + OSCs. The transcription factor FoxP3 is the basis for the identification of TREG. Among CD4 + FoxP3 + T cells, some have effector functions. A medical hypothesis is formulated here: the existence of a CD137 (4.1BB)-Eomesodermin (Eomes) activated pathway downstream of TCR-specific activation in a subpopulation of CD4 + FoxP3 + T cells may explain this effector function. Evidence suggest that this axis may exist either in CD4 + FoxP3 + T cells or CD8 + T cells. This pathway could lead T cells to strong antitumor cytotoxic activity in a tumor-specific manner. Furthermore, CD137 is one of the most expected targets for the development of agonist immunotherapies. The identification of CD137 + Eomes + FoxP3+/- T cells could be a key element in the selective activation of the most anti-tumor cells in the HPV + OSC microenvironment.

HPV related multiphenotypic sinonasal carcinoma: two case reports

HPV related multiphenotypic sinonasal carcinoma: two case reports

Exploring HPV as an Etiologic Factor for Breast Cancer

Abstract Introduction/Objective Breast ducts communicate with skin, which can expose one to infectious agents. Recent studies demonstrate differences between breast microbiome in normal tissues versus tumor, suggesting a potential role in carcinogenesis. Human Papilloma Virus (HPV) is the etiologic factor in numerous cancers, and studies suggest it may play a role in breast carcinoma. A recent case report identified an analogue to HPV-related multiphenotypic sinonasal carcinoma in the breast. This sinonasal tumor, closely associated with HPV type 33, consists of adenoid cystic-like morphology, basaloid and/or squamous cytology and multi-lineage differentiation (ductal and myoepithelial). Our aim was to determine if HPV is a driver of breast carcinomas with the outlined phenotype by testing with immunohistochemistry (IHC) for p16 and in-situ hybridization (ISH) for High Risk HPV (HR-HPV) E6/E7 mRNA. Methods/Case Report Breast cases from 2010- June 2022 were searched with the terms “adenoid cystic,” “myoepithelial differentiation,” or “basaloid.” Cases of adenoid cystic carcinoma with a diagnostic fusion were excluded. Those with basaloid and/or squamous morphologic features containing ductal and myoepithelial differentiation proven by IHC were included. Nine identified cases were submitted for p16 IHC and HR-HPV ISH. Results (if a Case Study enter NA) Patients ranged in age from 50 to 85. No cases resulted with positive HR-HPV, however all cases displayed staining for p16. All cases with benign breast tissue (6/9) exhibited some p16 positivity within luminal and myoepithelial cells. Conclusion HR-HPV ISH is a sensitive test; however, no cases were positive. Most tumors and benign breast expressed p16 in some form. p16 in basal-like breast cancer has been described, but only 3/7 cases with biomarkers were triple negative. Accordingly, p16 is not a reliable screening tool if detection of HPV becomes clinically relevant in the future. In this series, the phenotypic features assessed do not appear to be consistent harbingers of HPV infection. More studies are needed to assess the breast microbiome and oncogenic organisms to identify potential new therapeutic targets.

P16 Overexpression in Sinonasal Squamous Cell Carcinoma: Association with Human Papillomavirus and Prediction of Survival Outcomes

p16 overexpression is often used as a surrogate marker for human papillomavirus (HPV) infection in oropharyngeal squamous cell carcinoma but remains an uncertain diagnostic tool for HPV-related sinonasal squamous cell carcinoma (SNSCC). Our study involved 79 consecutive SNSCC patients who were treated at a tertiary referral university hospital during 2006–2021. We retrospectively examined their clinical characteristics and conducted p16 immunohistochemistry and HPV detection. We found that 12.7% of the patients exhibited p16 overexpression, which was significantly more common in the nasal cavity and increased from 2015 onward. The HPV was a high-risk type and viral loads ranged from 4.2 to 1.6 × 106 copies/ng DNA with genome integration. Five-year overall survival (OS) and five-year relapse-free survival (RFS) rates were 74.6% and 69.9%, respectively. Our multivariate analysis showed that T category (T1–4a) and hemoglobin levels (≥13.7) were significant favorable prognostic factors for OS, while T category, performance status, and p16 overexpression were significantly associated with RFS. In patients with p16 overexpression, OS was 100% and RFS was 90%. Our findings suggest that p16 overexpression is a reliable surrogate marker for transcriptionally active HPV infection and predicts a favorable prognosis.

784P HPV integration promotes HPV carcinogenesis via remodeling chromatin interactions between universal stripe factors and super-enhancer in HPV-related carcinoma

784P HPV integration promotes HPV carcinogenesis via remodeling chromatin interactions between universal stripe factors and super-enhancer in HPV-related carcinoma

Abstract PO-098: Development of radioimmunotherapy using IL7 and FLT3 in a murine HPV related head and neck squamous cell carcinoma model

Abstract PO-098: Development of radioimmunotherapy using IL7 and FLT3 in a murine HPV related head and neck squamous cell carcinoma model

Challenging differential diagnoses in small biopsies from the sinonasal tract.

Sinonasal biopsy specimens are a challenging area in anatomic pathology. The small, often fragmented or crushed nature of these biopsies can hinder morphologic assessment. Additionally, many of the tumors in this area are rare and share morphologic, and sometime immunophenotypic similarities. In many cases, immunohistochemistry is helpful if not necessary to reach a specific diagnosis. In other cases, a specific diagnosis is not possible and a differential diagnosis must be given on a biopsy specimen despite access to a well-equipped immunohistochemistry laboratory. This review article groups some of the more challenging entities in the sinonasal region based on morphologic patterns. These include low grade squamoid lesions such as sinonasal (Schneiderian) papilloma and DEK::AFF2 rearranged carcinoma, glandular neoplasms such as intestinal and non-intestinal type sinonasal adenocarcinoma, high-grade carcinomas such as HPV-related multiphenotypic sinonasal carcinoma, NUT carcinoma and SWI/SNF deficient carcinomas, small round blue cell tumors such as teratocarcinosarcoma, neuroendocrine carcinoma and olfactory neuroblastoma, and finally, low grade spindle cell neoplasms such as glomangiopericytoma, biphenotypic sinonasal sarcoma and solitary fibrous tumor.

Diagnostic algorithm for challenging blue cell sinonasal carcinoma

The newly emerging sinonasal carcinomas have demonstrated diverse morphologies and specific molecular rearrangements along with deviant clinical behavior from conventional counterparts. We aim to propose a diagnostic algorithm that is based on molecular findings of each sinonasal cancer and is considering the new entities has been called upon. Such a diagnostic algorithm should help diagnostic pathologists establish a diagnosis of a challenging sinonasal blue cell carcinomas and researchers performing retrospective analysis of archival cases. Along with consulting our archival cases, literature mining was conducted to retrieve the immunohistochemical and molecular findings regarding the newly emerging entities. Our proposed algorithm distinguishes poorly differentiated (non) keratinizing SNSCC, from anaplastic myoepithelial carcinoma, NUT midline carcinoma, SMARCB1/SMARCA4-deficient teratocarcinosarcoma, SMARCB1/SMARCA4-deficient carcinosarcoma, olfactory neuroblastoma, sinonasal undifferentiated carcinoma, HPV-related multiphenotypic sinonasal carcinoma and other adenocarcinomas. By incorporating morphologic features, immunohistochemical markers, and molecular investigations, the algorithm enhances the accuracy of diagnosis, particularly in cases where comprehensive molecular testing is not readily available. This algorithm serves as a valuable resource for pathologists, facilitating the proper diagnosis of sinonasal malignancies and guiding appropriate patient management.

Circulating tumour HPV16 DNA quantification – A prognostic tool for progression-free survival in patients with HPV-related oropharyngeal carcinoma receiving curative chemoradiotherapy

Background and PurposeCirculating tumour (ct) human papillomavirus (HPV) DNA is detectable in HPV-related oropharyngeal carcinoma (OPSCC) patients and has the potential to become an important clinical tool. This study aimed to evaluate the prognostic significance of ctHPV16-DNA kinetics during treatment with chemoradiotherapy in HPV-related OPSCC. Patients with p16-positive OPSCC recruited to the ARTSCAN III trial, comparing radiotherapy plus cisplatin with radiotherapy plus cetuximab, constituted the study cohort. Materials and methodsBlood samples before start and at the end of treatment of 136 patients were analysed. ctHPV16-DNA was quantified by real-time (q)PCR. The correlation between ctHPV16-DNA levels and tumour burden was investigated with Pearson regression analysis. The prognostic value of ctHPV16-DNA levels at baseline and decline during treatment was evaluated by area-under-the-curve (AUC) calculations and analysed with univariable and multivariable Cox proportional hazards models. ResultsctHPV16-DNA was detectable with qPCR in 108/136 patients before start of treatment and cleared in 74% of these patients at the end of treatment. Disease burden was significantly correlated with baseline ctHPV16-DNA levels (R = 0.39, p=<0.001). Both lower baseline levels and AUC-ctHPV16DNA were associated with improved progression-free survival (p = 0.01 and p < 0.001), overall survival (p = 0.013 and p = 0.002), but not local tumour control (p = 0.12 and p = 0.2, respectively), with a stronger association for AUC-ctHPV16DNA (likelihood ratio test 10.5 vs 6.5 in Cox regression analyses of progression-free survival). In multivariable analysis including tumour volume (GTV-T) and treatment allocation (cisplatin vs cetuximab), AUC-ctHPV16DNA remained a significant prognostic marker of progression-free survival. ConclusionctHPV16-DNA is an independent prognostic factor in HPV-related OPSCC.

HPV-RELATED MULTIPHENOTYPIC SINONASAL CARCINOMA: AN AGGRESSIVE AND CHALLENGING CASE REPORT

A 54-year-old male patient complained of self-limited epistaxis for two years, the symptoms worsening one year ago. Systemic arterial hypertension for 14 years was reported in the anamnesis. Physical examination revealed an irregular nodule in the left nasal fossa with yellowish secretion, friable to aspiration. MRI revealed an expansile image in the left nasal cavity, measuring 8.3 × 4.3 × 2.8 cm, extending into the nasopharynx, ethmoid, right nasal cavity, and cortical bone of the hard palate. An incisional biopsy was performed. Morphologically, a malignant cellular proliferation with solid basaloid appearance admixed with adenoid cystic-like areas. IHC were positive for AE1/AE3, CK7, p63, and calponin, with focal labeling for CD117 and α-SMA. p16 had diffuse cytoplasmic and nuclear positivity. Ki-67 index was 80%. The morphological and immunohistochemical aspects were conclusive for HPV-related multiphenotypic sinonasal carcinoma. Already in stage IV, the tumor was considered unresectable, and the patient is under oncological treatment and follow-up with chemoradiotherapy. A 54-year-old male patient complained of self-limited epistaxis for two years, the symptoms worsening one year ago. Systemic arterial hypertension for 14 years was reported in the anamnesis. Physical examination revealed an irregular nodule in the left nasal fossa with yellowish secretion, friable to aspiration. MRI revealed an expansile image in the left nasal cavity, measuring 8.3 × 4.3 × 2.8 cm, extending into the nasopharynx, ethmoid, right nasal cavity, and cortical bone of the hard palate. An incisional biopsy was performed. Morphologically, a malignant cellular proliferation with solid basaloid appearance admixed with adenoid cystic-like areas. IHC were positive for AE1/AE3, CK7, p63, and calponin, with focal labeling for CD117 and α-SMA. p16 had diffuse cytoplasmic and nuclear positivity. Ki-67 index was 80%. The morphological and immunohistochemical aspects were conclusive for HPV-related multiphenotypic sinonasal carcinoma. Already in stage IV, the tumor was considered unresectable, and the patient is under oncological treatment and follow-up with chemoradiotherapy.

Cellular states are coupled to genomic and viral heterogeneity in HPV-related oropharyngeal carcinoma.

Head and neck squamous cell carcinoma (HNSCC) includes a subset of cancers driven by human papillomavirus (HPV). Here we use single-cell RNA-seq to profile both HPV-positive and HPV-negative oropharyngeal tumors, uncovering a high level of cellular diversity within and between tumors. First, we detect diverse chromosomal aberrations within individual tumors, suggesting genomic instability and enabling the identification of malignant cells even at pathologically negative margins. Second, we uncover diversity with respect to HNSCC subtypes and other cellular states such as the cell cycle, senescence and epithelial-mesenchymal transitions. Third, we find heterogeneity in viral gene expression within HPV-positive tumors. HPV expression is lost or repressed in a subset of cells, which are associated with a decrease in HPV-associated cell cycle phenotypes, decreased response to treatment, increased invasion and poor prognosis. These findings suggest that HPV expression diversity must be considered during diagnosis and treatment of HPV-positive tumors, with important prognostic ramifications.

HPV-related multiphenotypic sinonasal carcinoma, HPV type 35-related: a case report

Most HPV-related head and neck carcinomas arise in the oropharynx, but can also arise in the sinonasal tract. The entity now referred to as HPV-related multiphenotypic sinonasal carcinoma (HMSC) was previously known as HPV-related carcinoma with adenoid cystic carcinoma-like features. This tumour is characterised by an association with high-risk HPV subtypes (commonly type 33), a sinonasal location and histologic phenotype resembling both adenoid cystic carcinoma and surface derived squamous cell carcinoma.

High-risk HPV-related squamous cell carcinoma in the temporal bone: a rare but noteworthy subtype.

High-risk human papillomavirus (HPV) is a risk factor for the development of several head and neck squamous cell carcinomas (SCCs). However, there have been few reports of high-risk HPV infection in temporal bone squamous cell carcinomas (TBSCCs), and thus the prevalence and clinicopathologic significance of high-risk HPV in TBSCCs are still unclear. We retrospectively collected 131 TBSCCs and analyzed them for transcriptionally active high-risk HPV infection using messenger RNA in situ hybridization; we also assessed the utility of p16-immunohistochemistry (IHC) and Rb-IHC to predict HPV infection. Eighteen (13.7%) of the 131 TBSCCs were positive for p16-IHC, and five of them were positive for high-risk HPV infection (the estimated high-risk HPV positivity rate was 3.8% [5/131]). Interestingly, all five HPV-positive patients were male and had TBSCC on the right side. In the p16-IHC+/HPV+ cases (n = 5), the Rb-IHC showed a partial loss pattern (n = 4) or complete loss pattern (n = 1). In contrast, all p16-IHC-negative cases (n = 113) showed an Rb-IHC preserved pattern. The positive predictive value (PPV) of p16-IHC positivity for high-risk HPV infection was low at 27.8%, while the combination of p16-IHC+/Rb-IHC partial loss pattern showed excellent reliability with a PPV of 100%. The prognostic significance of high-risk HPV infection remained unclear. High-risk HPV-related TBSCC is an extremely rare but noteworthy subtype.