Search Results (84)

Background and Objectives: Cervical adenocarcinoma (CAC) is a histologically distinct subtype of cervical cancer with a rising incidence in many regions. While the roles of key driver mutations are known, a comprehensive understanding of its genomic landscape, particularly variations across different populations and tumor stages, remains incomplete. This study aims to characterize the somatic genomic landscape of CAC by identifying recurrent mutations, copy number alterations (CNAs), and patterns of co-occurrence, with a focus on variations across racial groups and between primary and metastatic tumors. Materials and Methods: We conducted a comprehensive genomic analysis of 102 tumor samples from 99 patients diagnosed with cervical adenocarcinoma using data from the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database. Results: The most frequently mutated genes were PIK3CA (25.5%), TP53 (21.6%), ARID1A (20.6%), and KRAS (16.7%). Significant amplification of ERBB2 was also observed (n = 3; 4.83%). Our analysis revealed notable genomic disparities across racial groups, with TP53 mutations being significantly more frequent in White patients compared to Asian and Black patients (p = 0.0236). Furthermore, we identified significant co-occurrence between mutations in KRAS and MSH2 (p = 0.011) as well as ATM and STK11 (p = 0.037). In comparing tumor types, mutations in BCL6 were found to be significantly enriched in metastatic samples. Conclusions: This study validates the primary drivers of cervical adenocarcinoma and reveals novel findings, including notable racial disparities in TP53 mutation frequency and unique patterns of co-occurring mutations. These findings highlight the genomic heterogeneity of the disease and suggest that ancestry and tumor evolution may influence its molecular pathogenesis, offering potential avenues for the development of targeted therapies and personalized biomarkers. Full article

Head and neck cancer surgery has evolved from radical organ-sacrificing procedures to function-preserving approaches integrated within multidisciplinary frameworks. This comprehensive literature review, concentrating on studies from the past five years while incorporating relevant publications from the last three decades and landmark historical papers, examines the evolving role of surgery emphasizing diagnostic methodologies including comprehensive genomic profiling, validated imaging biomarkers, and their clinical integration for treatment selection and response prediction. Modern surgical practice demonstrates a paradigm shift toward precision medicine through validated diagnostic technologies. Comprehensive genomic profiling identifies clinically actionable alterations in over 90% of head and neck squamous cell carcinomas, with tumor mutational burden serving as a validated predictive biomarker for immunotherapy response. Programmed death-ligand 1 (PD-L1) combined positive score functions as a validated diagnostic biomarker for immunotherapy efficacy, demonstrating significant clinical benefit in biomarker-selected populations. Radiomics-based predictive models utilizing machine learning algorithms achieve diagnostic accuracies exceeding 85% for treatment response prediction when validated across independent cohorts. Quantitative ultrasound spectroscopy combined with magnetic resonance imaging radiomics demonstrates high sensitivity and specificity for radiation response prediction. Habitat imaging techniques characterizing tumor microenvironmental heterogeneity predict pathologic complete response to neoadjuvant chemoimmunotherapy with area under the curve values approaching 0.90 in validation studies. Integration of these diagnostic methodologies enables response-adaptive treatment strategies, with neoadjuvant chemotherapy facilitating mandibular preservation and adjuvant therapy omission in over half of human papillomavirus (HPV)-associated cases following surgical downstaging. Clinical validation of these diagnostic platforms enables accurate treatment response prediction and informed surgical decision-making, though standardization across institutions and demonstration of survival benefits through prospective trials remain essential for broader implementation. Full article

Cervical cancer progression, particularly in the context of HPV infection, is driven by complex transcriptional alterations within the tumor microenvironment. Understanding the molecular mechanisms underlying HPV-induced immune evasion is crucial for developing effective therapeutic strategies. Transcriptomic analyses were performed using three independent datasets (GSE127265, GSE166466, and GSE218460) to identify differentially expressed genes (DEGs) between HPV-positive and HPV-negative cervical cancer samples. Protein–protein interaction networks were constructed using Cytoscape and STRING, and immune infiltration was assessed via the TIMER database. A total of 572 DEGs were commonly identified between tumor and normal tissues, with HPV-positive samples showing distinct transcriptional profiles. Several downregulated hub genes were associated with immune regulation and receptor tyrosine kinase signaling. Immune infiltration analysis revealed altered dendritic cell and T cell patterns, indicating HPV-mediated immune modulation. Pathway enrichment identified the leukocyte transendothelial migration pathway as a key mechanism impaired by HPV infection. These findings highlight the critical role of immune-related hub genes in HPV-driven cervical cancer progression and suggest potential therapeutic targets to counteract HPV-induced immune suppression. Full article

Bartholin gland carcinoma (BGC) is a rare malignancy, comprising 3–7% of vulvar cancers and <1% of gynecologic tumors. Due to its low incidence, high-level evidence is lacking, and management is largely extrapolated from vulvar cancer guidelines. This comprehensive narrative review synthesizes current evidence on BGC, emphasizing histotype-specific features, diagnostic criteria, molecular profiling, and treatment strategies. The three most common subtypes are squamous cell carcinoma, adenoid cystic carcinoma (AdCC), and adenocarcinoma. HPV-associated tumors tend to occur in younger women and carry favorable prognoses. Accurate diagnosis requires exclusion of metastases and integration of clinical, imaging, and immunohistochemical data, including p16/HPV for squamous tumors, MYB/MYBL1 fusions for AdCC, and CK20/CDX2/SATB2 for intestinal-type adenocarcinoma. Approximately 50% of cases are diagnosed at an advanced stage due to misclassification as benign cysts or abscesses. Nodal metastasis occurs in >40% of cases, with histotype influencing prognosis. Adenocarcinoma and node-positive disease independently predict worse survival. Treatment hinges on complete surgical excision with 2–3 mm margins, bilateral groin evaluation, and histology-tailored adjuvant therapy. Emerging data support the use of immune checkpoint inhibitors in squamous BGC and targeted agents (e.g., mTOR/CDK4/6 inhibitors) in adenocarcinoma. We propose a practical molecular testing algorithm and highlight the urgent need for prospective, multinational collaboration to establish BGC-specific guidelines. Full article

Background/Objectives: In a series of 33 patients with advanced penile squamous cell carcinoma (PSCC), we evaluated tissue factor (TF), TROP2, and nectin-4 protein expression as potential therapeutic targets. Expression levels of these proteins were also correlated to clinicopathological characteristics, including high-risk human papillomavirus (HPV), CDKN2A (p16) status, and aberrant p53 expression. Methods: A tissue microarray (TMA) was constructed with three cores per patient tumor (99 total cores). Anti-TF antibody staining was performed by immunohistochemistry, and H-scores for membrane and cytoplasm staining were assessed (range 0–300). The percentage of cores and patient tumors staining positive for TF (≥10% of tumor cells with at least 1+ intensity in cytoplasm and/or membrane) and H-scores were described and compared with HPV and p16 status. The association of TF expression with tumor grade, presence of metastatic disease, lymphovascular invasion (LVI), perineural invasion (PNI), aberrant p53 expression, recurrence-free survival (RFS), and cancer-specific survival (CSS) was assessed. Nectin-4 and TROP2 staining and their association with clinical/pathological data were determined in a similar manner. Results: TF staining was evident in 26 (81.3%) of the cohort and was more prominent in HPV-negative tumors in both the membrane (H-score 69.6 vs. 18.8; p = 0.003) and cytoplasm (H-score 59.2 vs. 17.7, p = 0.007). Cytoplasmic (H-score 61.7 vs. 11.7, p < 0.001) and membrane TF staining (H-score 71.7 vs. 15.0, p < 0.001) favored p16-negative tumors. The p53 status was more likely to be aberrant in the higher TF staining samples (cytoplasm H-score 61.7 vs. 18.3, p = 0.012; membrane H-score 67.5 vs. 20.3, p = 0.006). We observed an association with TROP2 staining and positive p16 status (membrane H-score 120.3 vs. 85, p = 0.052; cytoplasmic H-score 135 vs. 107.5, p = 0.041). We observed an association of TROP2 staining with positive LVI (membrane H-score 136.7 vs. 66.7, p = 0.014; cytoplasmic H-score 110 vs. 93.3, p = 0.04). We found no association between TF, TROP2, or nectin-4 staining with CSS or RFS; however, we suspect that this was due to our small sample size. Conclusions: Our results indicate that TF was expressed in the majority of advanced PSCC with enhanced expression among HPV-independent, p53-aberrant tumors and may represent a novel therapy target in advanced PSCC. Full article

Cervical cancer is a major global health concern with serious implications for women’s health. It is most often caused by persistent infection with high-risk human papillomavirus (HPV) types. However, about 5–11% of cervical carcinoma cases are HPV-independent, entities with their own unique set of histopathological, molecular, and clinical features. The histopathological forms of HPV-independent cervical cancer include gastric-type adenocarcinoma, clear-cell, mesonephric, and endometrioid carcinoma. Unlike HPV-associated cervical cancers, which require E6 and E7 oncogenes for their expression, HPV-independent tumors exhibit specific mutations such as TP53, PIK3CA, KRAS, STK11, and PTEN. These mutations lead to alternative oncogenic pathways. Diagnosis of HPV-independent cervical adenocarcinoma is often delayed because of possible misclassification as endometrial adenocarcinomas, which frequently results from inadequate HPV testing. This often leads to advanced presentation stages, higher rates of lymphovascular invasion, and, in many cases, a reduced response to chemotherapy and immunotherapy—though outcomes can vary across histotypes and selected patient subgroups—due to the immune-cold tumor microenvironment. Although these morphologic and molecular characteristics describe tumors that are very difficult to manage, PI3K/mTOR and KRAS inhibitors may offer potential therapeutic options for selected patients. This review focuses on the pathogenic and molecular mechanisms, histopathological features, prognosis, and therapeutic difficulties of HPV-independent cervical cancers. Moreover, it provides a comprehension of contemporary issues in diagnostic methods and some new therapeutic approaches, suggesting the need for precision medicine in this aggressive type of cervical cancer. Further studies are necessary to enhance early detection, improve treatment results, and increase survival rates for patients with HPV-independent cervical cancer. Full article

Head and neck squamous cell carcinoma (HNSCC) is often diagnosed at advanced stages. Due to pronounced intratumoral heterogeneity (ITH), reliable risk stratification and prediction of treatment response remain challenging. This study aimed to identify peptide signatures in HNSCC tissue that are associated with treatment outcomes in HPV-negative, advanced-stage HNSCC patients undergoing 5-fluorouracil/platinum-based chemoradiotherapy (CDDP-CRT). We integrated matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) of tryptic peptides with univariate statistics and machine learning approaches to uncover potential prognostic patterns. Formalin-fixed, paraffin-embedded whole tumor sections from 31 treatment-naive, HPV-negative HNSCC patients were digested in situ with trypsin, and the generated peptides were analyzed using MALDI-MSI. Clinical follow-up revealed recurrence or progression (RecPro) in 20 patients, while 11 patients showed no evidence of disease (NED). Classification models were developed based on the recorded peptide profiles using both unrestricted and feature-restricted approaches, employing either the full set of m/z features or a subset of the most discriminatory m/z features, respectively. The unrestricted model achieved a balanced accuracy of 71% at the patient level (75% sensitivity, 66% specificity), whereas the feature-restricted model reached a balanced accuracy of 72%, showing increased specificity (92%) but reduced sensitivity (52%) in the CDDP-CRT cohort. In order to assess treatment specificity, models trained on the CDDP-CRT cohort were tested on an independent patient cohort treated with mitomycin C-based CRT (MMC-CRT). Neither model demonstrated prognostic performance in the MMC-CRT patient cohort, suggesting specificity for platinum-based therapy. Presented findings highlight the potential of MALDI-MSI–based proteomic profiling to identify patients at elevated risk of recurrence following CDDP-CRT. This approach may support more personalized risk assessment and treatment planning, ultimately contributing to improved therapeutic outcomes in HPV-negative HNSCC. Full article

Background/Objectives: Tumor mutational burden (TMB) has emerged as a potential biomarker of response to immunotherapy across multiple solid tumors. However, its role in cervical cancer remains insufficiently defined. This study aimed to evaluate the genomic landscape and TMB profile in a cohort of patients with cervical cancer treated at a tertiary gynecologic oncology center, with a focus on TMB’s associations with clinical features, HPV infection, and treatment modalities. Methods: A total of 61 patients diagnosed with cervical cancer (82.0% ca. planoepitheliale, 18.0% adenocarcinoma) were retrospectively analyzed. Tumor samples were collected during primary surgery, biopsy, or conization and subjected to targeted next-generation sequencing using the ONCOaccuPanel™ and BRCAaccuTest PLUS™ (NGeneBio). TMB was calculated as non-synonymous mutations per megabase and analyzed using NGeneAnalySys^® software. Variant classification followed ACMG guidelines. Comparative analyses were conducted between TMB-high (≥10 mut/Mb) and TMB-low subgroups, and correlations with clinical and molecular variables were assessed using univariable statistics. Results: High TMB was identified in 36 patients (59.0%), while microsatellite instability was found in only 2 cases (3.3%). No significant associations were observed between TMB status and FIGO stage, histologic subtype, or HPV 16/18 infection. However, higher TMB values were observed in patients with nodal involvement, diabetes, and HPV52 infection. A diverse spectrum of mutations was detected, with PIK3CA and ARID1A being most frequently altered. Several variants of uncertain significance were identified in genes not classically associated with cervical cancer. Conclusions: TMB-high status is relatively frequent in cervical cancer and appears to be independent of FIGO stage or histological subtype. While not predictive of clinical stage, TMB correlates with specific molecular and comorbidity profiles, suggesting its potential relevance for future patient stratification in immunotherapy trials. Full article

Background: p16 immunohistochemistry (IHC) serves as a surrogate marker for high-risk human papillomavirus (hrHPV) and is widely used in gynecologic pathology. However, few studies have directly compared the staining performance and reproducibility of different p16 antibody clones in this context. Methods: We retrospectively evaluated 176 gynecologic tumor specimens including 42 whole slide sections and 134 tissue microarray cores from the cervix, endometrium, vulva, and ovary using three fully automated p16 IHC assays: E6H4 (Ventana/Roche), JC8 (Agilent/Dako), and 6H12 (Leica). Two pathologists independently reviewed each case, and concordance and interobserver agreement were analyzed. Sensitivity, specificity, and Cohen’s κ statistics were calculated, with E6H4 serving as the reference. Results: All three antibody clones demonstrated excellent staining performance with preserved tissue morphology and minimal background artifacts. Concordance for p16 positivity/negativity was 100% across all clone pairings (95% CI: 97.9–100%). Interobserver reproducibility was also perfect, with a κ coefficient of 1.00 (95% CI: 0.94–1.00). Minor non-block staining patterns did not impair interpretability. Conclusions: Our findings indicate that E6H4, JC8, and 6H12 clones yield comparable staining results when used in conjunction with standardized automated protocols. These results support the practical interchangeability of these clones in clinical and research settings, particularly when cost, availability, or risk management require substitution. Laboratories should continue to perform internal validation and utilize external quality assurance programs when implementing p16 IHC. Full article

HPV-independent cervical cancers represent a small proportion of these types of cancers, predominantly glandular lesions. It should be noted that some cases may depend on diagnostic problems that lead to false negative cases. However, the most recent classifications distinguish cervical tumors into HPV-associated and HPV-independent cancers. HPV-negative cervical carcinomas (5–11% of all cases) mainly include rare adenocarcinomas (gastric, mesonephric, clear, serous, and endometrioid) and present distinct clinical and molecular features. These tumors usually affect older women and are diagnosed at more advanced stages than HPV-positive tumors, with an overall worse prognosis. This concerning and notably worse prognosis highlights the need for further research and understanding. Unlike HPV-positive carcinomas (which depend on the viral oncogenes E6/E7), HPV-independent tumors accumulate genomic mutations that activate oncogenes and inactivate suppressor genes. Therefore, a comprehensive overview of these aspects can be the key to a better understanding and developing personalized treatments. In the present review, the main mutated genes, the signaling pathways involved, the differences from HPV-positive tumors, the distinctive immunohistochemical markers, and the diagnostic and therapeutic implications are explored in depth. Full article

Head and Neck Squamous Cell Carcinoma (HNSCC) ranks sixth in incidence and seventh in cancer mortality worldwide. Approximately 30% of HNSCC cases are related to human papillomavirus (HPV) infection, the oropharynx being the anatomical subsite most associated with HPV infection. Traditionally, HPV-positive HNSCC has been considered to have better treatment response and clinical outcome. However, HPV-positive HNSCC is a heterogeneous group since 30% of the cases present early relapse, which implies that there are differences in molecular profiles within HPV-positive patients. In this study, we used bioinformatic data analysis from open-access repositories to compare molecular profiles differentially expressed between HPV-positive and -negative HNSCC patients. Using the TCGA HNSCC transcriptomic data, we identified a group of genes, whose expression is related to clinical outcome in patients. Our findings were validated in an independent cohort confirming that the expression levels of FABP4, HMGA2, S100A10, GDNF, SLC7A,2 and GPR18 genes were associated with overall survival (OS) exclusively in HPV-positive HNSCC patients, while ST6GALNAC1 expression was associated with OS in HPV-negative HNSCC. The expression of OS-related genes was independent of tumor stage and history of alcoholism. Our findings suggest that transcriptional profiles in HPV-positive HNSCC are an excellent source of information for the search for potential prognostic biomarkers. Full article

Background and Objectives: Despite developments in cervical cancer (CC) treatment, an advanced stage is a poor prognostic factor. Cervical cancer is an immunogenic tumor in which viruses, like HPV, play a role in carcinogenesis. Therefore, systemic inflammatory markers (SIMs) may have prognostic value. Most studies on SIMs focus on the early stage by evaluating pretreatment levels. This study aims to evaluate the prognostic and predictive values of both pretreatment and post-treatment parameters at the advanced stage, as well as treatment efficacy after progression with first-line treatment. Materials and Methods: A total of 133 advanced-stage CC patients with progression on first-line platin–paclitaxel and bevacizumab were evaluated retrospectively. Demographic and histopathological characteristics were recorded along with treatment details. Pre-treatment baseline blood parameters and post-treatment follow-up values were recorded to calculate SIMs as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and systemic inflammatory response index (SIRI). Results: Median values for SIMs were accepted as cut-off values. Post-treatment values demonstrated stronger predictive power, with pre-treatment SIRI and NLR being significant only in univariate analysis, but not in multivariate analysis. High post-treatment SIRI (>2.1) was correlated with shorter overall survival (OS) and considered a poor prognostic factor. High post-treatment SIRI (>2.1), -SII (>746), and -PLR (>197) emerged as independent prognostic factors for progression-free survival (PFS). Their prognostic values were clearer in the whole population and the metachronous metastatic subgroup. Rechallenge of platinum-based chemotherapy was an option for those who had at least 6 months of PFS with first-line platinum-based chemotherapy. Bevacizumab addition to single-agent or combination regimens led to improved ORR as well. Conclusions: Post-treatment SIRI is a promising prognostic factor for OS, while post-treatment SIRI, SII, and PLR may serve as convenient SIMs for PFS. Platinum-based combination chemotherapy reinduction is a feasible second-line treatment strategy, especially with the addition of bevacizumab. Full article

Background/Objectives: Cervical cancer (CC) is a significant global health challenge, particularly in low- and middle-income countries (LMICs), where limited access to human papillomavirus (HPV) vaccination and effective CC screening results in a majority of cases and fatalities among women. Moreover, existing vaccines do not target HPV-independent cancers. Current screening methods are expensive and time-consuming, with a limited emphasis on CC protein biomarkers. Therefore, we aimed to validate critical markers that allow the development of affordable point-of-care screening tests for resource-limited settings. Methods: This study first optimized a cell lysis and protein extraction protocol for CC cell lines and clinical cervical swabs. Subsequently, four proteins—topoisomerase II alpha (TOP2A), minichromosome maintenance complex component 2 (MCM2), valosin-containing protein (VCP), and cyclin-dependent kinase inhibitor 2A (p16INK4a)—were quantified in the resulting lysates using enzyme-linked immunosorbent assays, as well as in cervical tumors and squamous intraepithelial lesions (SILs) using immunohistochemistry for further validation. Results: Acetone precipitation allowed for efficient cell isolation, and radioimmunoprecipitation assay buffer yielded the highest protein recovery. VCP and p16INK4a were overexpressed across all cancer cell lines compared to primary cells. All four biomarkers were overexpressed in high-grade SIL (HSIL) swab specimens and tumor samples, including CC subtypes, G1–G3 tumor grades, and HSILs. Lastly, we showed that the proteins could accurately classify swabs and tissue specimens into clinically relevant groups. Conclusions: The quantitative analysis of these biomarkers, along with the subsequent sensitive and specific clinical classification, highlights their potential application in SIL early detection and CC prevention, particularly in LMICs. Full article

Background: Squamous cell carcinoma (SCC) of the penis accounts for approximately 95% of penile cancers and is associated with substantial morbidity and mortality. SCC typically develops in uncircumcised men, most commonly affecting the foreskin or glans. While slow-growing, early detection is crucial to improve survival outcomes. Risk factors include advanced age, lack of circumcision, poor hygiene, HPV infection (types 16 and 18), chronic inflammation, and smoking. Methods: We conducted a retrospective, single-center study at IRCCS Hospital “G. Pascale” of Naples, Italy, involving 59 patients treated between January 2015 and January 2023. The inclusion criteria were surgically treated primary tumors, confirmed SCC pathology, and pathologically verified inguinal lymph node metastasis (ILNM). We analyzed clinical variables including lymph node involvement, lymphovascular invasion (LVI), spongiosum corpus involvement (SCI), HPV infection, and tumor differentiation. Univariate and multivariate logistic regression analyses were performed to determine independent predictors of ILNM. Results: The mean age of patients was 66.67 ± 13.97 years. ILNM was confirmed in 24 patients (40.6%), while 35 (59.3%) had no lymph node involvement. Univariate analysis identified lymph node involvement at diagnosis (p = 0.005), LVI (p = 0.003), and SCI (p = 0.003) as significant predictors of ILNM. These factors were confirmed in the multivariate analysis, with lymph node involvement (p = 0.004), LVI (p = 0.025), and SCI (p = 0.028) as independent predictors. Conclusions: Lymph node status, LVI, and SCI are significant predictors of ILNM in penile SCC. Identifying these factors can aid in risk stratification, optimizing surgical decisions, and potentially reducing unnecessary morbidity. Further large-scale studies are recommended to validate these findings and refine prognostic models. Full article

Inflammation appears to play a crucial role in the development and progression of penile cancer (PeCa). Two molecular pathways of PeCa are currently described: HPV-dependent and HPV-independent. The tumor immune microenvironment (TIME) of PeCa is characterized by the presence of tumor-associated macrophages, cancer-associated fibroblasts, and tumor-infiltrating lymphocytes. The components of the TIME produce pro-inflammatory cytokines and chemokines, which have been found to be overexpressed in PeCa tissues and are associated with tumor progression and unfavorable prognoses. Additionally, the nuclear factor kappa B (NF-κB) pathway and secreted phosphoprotein 1 (SPP1) have been implicated in PeCa pathogenesis. Elevated C-reactive protein (CRP) levels and the neutrophil-to-lymphocyte ratio (NLR) have been identified as potential prognostic biomarkers in PeCa. This overview presents the complex contribution of the inflammatory process and collates projects aimed at modulating TIME in PeCa. Full article