Snapshot of Clinical Implications of p16 Overexpression in Carcinogenesis

Molecular markers are needed to decide the treatment plans of certain cancer types when the histological and other clinical diagnoses are not sufficient to decide the tumor nodular metastasis (TNM) stage. The ubiquitous p16 gene is one of them gained popularity by fulfilling criteria to be a useful biomarker. Over expression of p16, to compensate the inactivity of another two tumor suppressor genes (TSG)s, pRb and p53 due to the integration of E7 and E6 high risk Human Papilloma viral oncoprotein respectively into the host keratinocytes is useful to consider the clinical impact of p16 biomarker in carcinogenesis. The p16 immunohistochemistry helps the diagnosis as well as prognosis of cervical and oropharyngeal squamous cell carcinoma, though there are ambiguities in the cutoff values of p16 positivity. There is also a re-emerging interest on clinical impact of p16 positivity in lung, breast, and colorectal cancer types. High risk HPV genotypes have been already established as the aetiological agents of cervical, other rare ano-genital and oropharyngeal (especially tonsils and base of the tongue) cancers. The HPV associated subset of head and neck cancers demonstrate a unique tumor biology, when compared with HPV non associated ones thus, most effective treatment planning including counselling is much needed to maximize the overall survival of HPV associated cancer patients, in the era of personalized precision medicine. In the shed of light, this communication glimpses on clinical implications of p16 overexpression in carcinogenesis not limiting to cervical and a subset of head and neck carcinomas (HNSCC).

Histological background of dedifferentiated solitary fibrous tumour

AimsDedifferentiation is a histological phenomenon characterised by abrupt transition of histology to a sarcomatous component with high-grade malignant potential in solitary fibrous tumour (SFT). The authors histologically reviewed SFT cases to reveal the histological background of dedifferentiated SFTs.MethodsClinicopathological and histopathological findings of 145 SFT cases were reviewed. Immunohistochemical staining and genetic analysis were also performed.ResultsThe non-dedifferentiated components showed a cellular component in 45 of 145 (31%), high mitotic rate (≥4/10 high-powered field) in 12 of 145 (8.2%) tumours, necrosis in 7 of 145 (4.8%) tumours, multinodular growth pattern in 39 of 132 (29.5%) available tumours and intratumoural fibrous septa in 37 of 131 (28.2%). Immunohistochemically, the non-dedifferentiated components were positive for CD34 in 128 of 141 (90.7%), bcl-2 in 101 of 133 (75.9%), nuclear pattern of β-catenin in 64 of 127 (50.3%) and p16 in 22 of 140 (15.7%). Loss of Rb protein expression was detected in 17 of 110 (15.4%) cases. Statistically, cellular component, multinodular structure, p16 overexpression and Rb protein loss were significantly associated with dedifferentiation. Moreover, cellular component and multinodular structure were significantly associated with p16 overexpression and Rb protein loss. All the non-deddifferentiated components showed wild type of p53 expression. The dedifferentiated components of all 10 dedifferentiated tumours presented positivity for p16 in 9 of 10 (90%) and mutational type of p53 in 5 of 10 (50%). Loss of Rb protein expression was detected in 6 of 10 (60%).ConclusionsThe authors propose that cellular or multinodular transformation may be associated with dedifferentiation. They also suggest that cellular and multinodular transformation may be associated with p16 overexpression and Rb downregulation.

High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer

Cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i), combined with endocrine therapy (ET), have demonstrated higher antitumor activity than ET alone for the treatment of advanced estrogen receptor-positive (ER+) breast cancer (BC). Some ER+ BC are de novo resistant to CDK4/6i and others develop acquired resistance. Therapies for tumors after progression are needed. Here, we demonstrate that p16 overexpression is associated with reduced antitumor activity of CDK4/6i in patient-derived xenografts (PDX; n=37) and ER+ BC cell lines, and reduced response of early/advanced ER+HER2- BC patients (n=49) to CDK4/6i. We also identified heterozygous RB1 loss as biomarker of acquired resistance and poor clinical outcome in ER+, CDK4/6i-treated BC PDX and patients. Combination of CDK4/6i ribociclib with PI3K inhibitor (PI3Ki) alpelisib showed antitumor activity in ER+ non-basal-like BC PDX, independently of PIK3CA or RB1 mutation (n=25). Our results offer new insights into predicting primary and acquired resistance to CDK4/6i and post-progression therapeutic strategies.

P16 and HPV Genotype Significance in HPV-Associated Cervical Cancer—A Large Cohort of Two Tertiary Referral Centers

The expression of p16 is a good surrogate of human papillomavirus (HPV) infection in HPV-associated cancers. The significance of p16 expression, HPV genotype and genera in the outcome of patients with HPV-associated cervical cancer (CC) is unclear. Our aim is to ascertain the prognostic significance of these factors. Data from 348 patients (median age: 47.5 years old) with CC, diagnosed in two referral centers, were retrospectively collected. Advanced disease (FIGO2018 IB2-IV) was present in 68% of patients. A single HPV genotype was identified in 82.8% of patients. The most common HPVs were HPV16 (69%) and HPV18 (14%). HPV genera reflected this distribution. HPV16 tumors presented at an earlier stage. P16 was negative in 18 cases (5.2%), 83.3% of which were squamous cell carcinomas. These cases occurred in older patients who tended to have advanced disease. In the univariate analysis, HPV16 (HR: 0.58; p = 0.0198), α-9 genera (HR: 0.37; p = 0.0106) and p16 overexpression (HR: 0.54; p = 0.032) were associated with better survival. HPV16 (HR: 0.63; p = 0.0174) and α-9 genera (HR: 0.57; p = 0.0286) were associated with less relapse. In the multivariate analysis, only the International Federation of Gynecology and Obstetrics (FIGO) stage retained an independent prognostic value. HPV16, α-9 genera and p16 overexpression were associated with better survival, although not as independent prognostic factors. Patients with p16-negative HPV-associated CC were older, presented with advanced disease and had worse prognosis.

Prevalence of p-16 Positive Laryngeal and Pharyngeal Tumors in Nepalese Population: A Hospital based Cross-sectional Study

Introduction: P16 overexpression is considered as a good prognostic marker for oropharyngeal squamous cell carcinoma. However, there are very few literatures on the prevalence and outcomes of p16 overexpression in non-oropharyngeal squamous cell carcinoma and benign head and neck tumors. The aim of our study was to estimate the hospital based prevalence of p16 positive laryngeal and pharyngeal tumors and to compare it with the prevalence of p16 expression in the non tumor tissue (tonsils). Methods: This was a descriptive cross-sectional study. Cases of all genders >15 years presenting with malignant or benign tumors of larynx and all the subsites of pharynx were included in the study for evaluation of p16 expression by immunohistochemistry. Tonsillar tissue of cases undergoing tonsillectomy for recurrent acute tonsillitis were taken as non-tumorous tissue to evaluate for p16 expression. Results: A total of 48 cases were included in our study with 24 cases having different tumors of head and neck region and 24 cases having recurrent acute tonsillitis who were kept under non-tumor group. Eight cases (33.3%) in the tumor group showed positive stain for p16 in IHC. In non tumor group, 7 cases (29.1%) showed positive IHC staining for p16. Conclusions: P16 expression can be present in both benign and malignant tumors of various subsites of head and neck region and also in tonsillar tissue affected by inflammation.

First case of Ethmoid Metastasis From an Induced Oropharyngeal Squamous Cell Carcinoma HPV, Interest of the P16 as a Diagnosis Aid

We describe the first case of ethmoid metastasis from an oropharyngeal human papillomavirus–induced squamous cell carcinoma using the anti-P16 immunohistochemistry. The p16 overexpression can be a valuable aid in the differential diagnosis.

Prognostic impact of additional HPV diagnostics in 102 patients with p16-stratified advanced oropharyngeal squamous cell carcinoma

Purpose p16 overexpression was considered as surrogate marker to identify human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCCs). Methods 102 patients with advanced stage OPSCCs treated primarily by transoral lasermicrosurgery were included. Prognostic associations of p16- and HPV-status were analyzed separately and combined. Results In contrast to p16, the HPV-status resulted in no significant survival discrepancies (5-year overall survival (OS) HPV-positive 64.9%, HPV-negative 78.7%). Combining both markers, p16-positive (p16-positive/HPV-positive, p16-positive/HPV-negative) and p16-negative/HPV-negative groups demonstrated comparable high survival (OS 78.1% vs. 85.6% vs. 73.6%). Lowest survival was observed for patients with p16-negative/HPV-positive OPSCCs (OS 40.8%). Never smoking patients with p16-positive OPSCCs demonstrated the highest survival, whereas within former/current smokers with p16-positive and p16-negative disease it was comparable low (OS 90.0% vs. 63.0% vs. 57.4%). Conclusions p16- and HPV-status should not be considered as equivalent markers for a better prognosis. Furthermore, they should not generally predominate patient associated factors like smoking.