The Clinical Relevance of p16 and p53 Status in Patients with Squamous Cell Carcinoma of the Vulva

Objective. To investigate the prognostic significance of HPV status in vulvar squamous cell carcinomas (VSCC) and to determine whether preoperative determination of p16 or p53 status would have clinical relevance. Methods. Patients treated for VSCC at a tertiary hospital in Sydney, Australia, from 2002 to 2014, were retrospectively evaluated (n = 119). Histological specimens were stained for p53 and p16 expression, and HPV status was determined by PCR detection of HPV DNA. Results. HPV DNA was detected in 19%, p16 expression in 53%, and p53 expression in 37% of patients. Kaplan–Meier survival estimates indicated that p16/HPV-positive patients had superior five-year disease-free survival (76% versus 42%, resp., p=0.004) and disease-specific survival (DSS) (89% versus 75% resp., p=0.05) than p53-positive patients. In univariate analysis, nodal metastases (p<0.001), tumor size >4 cm (p=0.03), and perineural invasion (p=0.05) were associated with an increased risk of disease progression and p16 expression with a decreased risk (p=0.03). In multivariable analysis, only nodal metastases remained independent for risk of disease progression (p=0.01). For DSS, lymph node metastases (p<0.001) and tumor size (p=0.008) remained independently prognostic. Conclusion. The p16/HPV and p53 status of VSCC allows separation of patients into two distinct clinicopathological groups, although 10% of patients fall into a third group which is HPV, p16, and p53 negative. p16 status was not independently prognostic in multivariable analysis. Treatment decisions should continue to be based on clinical indicators rather than p16 or p53 status.

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The Genetics of Myelodysplastic Syndromes: Clinical Relevance

Genes ◽

10.3390/genes12081144 ◽

2021 ◽

Vol 12 (8) ◽

pp. 1144

Author(s):

Chiara Chiereghin ◽

Erica Travaglino ◽

Matteo Zampini ◽

Elena Saba ◽

Claudia Saitta ◽

...

Keyword(s):

Disease Progression ◽

Myelodysplastic Syndromes ◽

Clinical Relevance ◽

Driver Mutations ◽

Significant Information ◽

Hematopoietic Stem ◽

Probability Of Survival ◽

Mutational Status ◽

Increased Risk ◽

Risk Of Disease

Myelodysplastic syndromes (MDS) are a clonal disease arising from hematopoietic stem cells, that are characterized by ineffective hematopoiesis (leading to peripheral blood cytopenia) and by an increased risk of evolution into acute myeloid leukemia. MDS are driven by a complex combination of genetic mutations that results in heterogeneous clinical phenotype and outcome. Genetic studies have enabled the identification of a set of recurrently mutated genes which are central to the pathogenesis of MDS and can be organized into a limited number of cellular pathways, including RNA splicing (SF3B1, SRSF2, ZRSR2, U2AF1 genes), DNA methylation (TET2, DNMT3A, IDH1/2), transcription regulation (RUNX1), signal transduction (CBL, RAS), DNA repair (TP53), chromatin modification (ASXL1, EZH2), and cohesin complex (STAG2). Few genes are consistently mutated in >10% of patients, whereas a long tail of 40–50 genes are mutated in <5% of cases. At diagnosis, the majority of MDS patients have 2–4 driver mutations and hundreds of background mutations. Reliable genotype/phenotype relationships were described in MDS: SF3B1 mutations are associated with the presence of ring sideroblasts and more recent studies indicate that other splicing mutations (SRSF2, U2AF1) may identify distinct disease categories with specific hematological features. Moreover, gene mutations have been shown to influence the probability of survival and risk of disease progression and mutational status may add significant information to currently available prognostic tools. For instance, SF3B1 mutations are predictors of favourable prognosis, while driver mutations of other genes (such as ASXL1, SRSF2, RUNX1, TP53) are associated with a reduced probability of survival and increased risk of disease progression. In this article, we review the most recent advances in our understanding of the genetic basis of myelodysplastic syndromes and discuss its clinical relevance.

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Evaluation of local control in patients with non-metastatic Ewing sarcoma of the bone: A report from the Children's Oncology Group

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.10013 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 10013-10013

Author(s):

S. G. DuBois ◽

M. D. Krailo ◽

E. F. Cook ◽

N. J. Tarbell ◽

C. J. Fryer ◽

...

Keyword(s):

Disease Progression ◽

Local Control ◽

Ewing Sarcoma ◽

Tumor Size ◽

Cumulative Incidence ◽

Hazard Ratio ◽

Local Failure ◽

Control Mode ◽

Distant Failure ◽

Risk Of Disease

10013 Background: Options for local control in patients (pts) with Ewing sarcoma (EWS) include surgery (S), radiation (R), or surgery plus radiation (S+R). The choice of local control depends on factors that also impact outcome in EWS, including tumor site, tumor size, and age. Our objective was to determine if risk of disease progression differs between local control methods, after controlling for potential confounders. Methods: We analyzed the cohort of pts with non-metastatic EWS of the bone treated on Intergroup Study-0091 (Grier et al, NEJM, 2003). Local control decisions were made on an individual basis. We excluded pts with tumors of the skull/face, progression prior to end of local control, or incomplete local control data. Disease progression was recorded from end of local control. Cumulative incidence of disease progression was determined using a competing risks approach. We constructed a Cox proportional hazards model of progression free survival incorporating local control mode and potential confounders into the model. Secondary analyses evaluated overall survival, local failure, and distant failure. Results: 329 pts met eligibility criteria for analysis. 122 pts received S, 142 received R, and 65 received S+R. The cumulative incidence of disease progression at 5 years was 22.1% (95% CI 15.1–29.9%) for S, 36.9% (29.0–44.9%) for R, and 48.1% (35.5- 59.7%) for S+R. Using R as the reference group and controlling for age, tumor size, tumor location, and chemotherapy regimen, the hazard ratio for progression was 0.66 (95% CI 0.38–1.13) for S and 1.55 (0.96–2.49) for S+R. The hazard ratio for death was 0.77 (95% CI 0.44–1.34) for S and 1.46 (0.88–2.42) for S+R. The hazard ratio for local failure was 0.38 (95% CI 0.15–0.98; p=0.04) for S and 0.77 (0.34–1.75) for S+R. The hazard ratio for distant failure was 0.78 (0.42–1.46) for S and 1.60 (0.91–2.82) for S+R. Conclusions: Observed differences in outcome between local control groups are largely due to confounding factors that affect outcome and local control choice. Risk of disease progression, distant failure, or death does not differ between pts who receive S or R. Pts who receive S have a decreased risk of local failure compared to pts who receive R. No significant financial relationships to disclose.

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Annexin A1 and HPV in oropharyngeal squamous cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e22150 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e22150-e22150

Author(s):

Cleberson Jean dos Santos Queiroz ◽

Cintia Mara de Amorim Gomes Nakata ◽

Amilcar Sabino Damazo

Keyword(s):

Hpv Infection ◽

Oropharyngeal Carcinoma ◽

Annexin A1 ◽

Hpv Dna ◽

Hpv Status ◽

Formalin Fixed Paraffin Embedded ◽

P53 Status ◽

Bonferroni Test ◽

The Difference ◽

Student’S T

e22150 Background: Annexin-A1 (ANXA1) is a protein involved in signal transduction and inflammation. Its expression is increased in some tumors (i.e. hepatocellular carcinomas, gliomas, pancreatic adenocarcinomas), but in head and neck tumors, its expression is usually reduced. Tumor suppressor p53 is frequently expressed in cancers due to mutation. HPV infection is strongly linked to oropharyngeal tumors. Methods: We analyzed 21 formalin-fixed paraffin-embedded samples of oropharyngeal carcinoma. Using immunofluorescence (IF), ANXA1 expression was quantified by measuring mean optical density (MOD). We also evaluated p53 positivity using IF. Presence of HPV DNA (serotypes 16/18 and 31/33) was analyzed through chromogenic in situ hybridization. Interaction between ANXA1, p53 and HPV was performed by Student's t test and ANOVA, with Bonferroni test, using the software Graph Pad Prism. Results: HPV DNA was found in 12 of 21 cases (57%). Serotypes 16/18 were found in all HPV + samples, whereas serotypes 31/33 were found in 2 of the 12. Among HPV+ cases, we noticed a decreased expression of ANXA1 in tumor compared to epithelium, independent of p53 status. With respect to HPV- cases, we have found a reduced expression of ANXA1 in the tumor versus epithelium, but the difference was only statistically significant in p53+ samples. In epithelia, we observed an increased expression of ANXA1 in HPV+ compared with HPV- samples. Conclusions: Our results confirm a decreased expression of ANXA1 in oropharyngeal carcinoma independently of HPV status, suggesting its involvement in the carcinogenesis. There was no difference in the expression of ANXA1 according to p53 status. In normal epithelia, we observed an increased expression of ANXA1 in HPV+ samples, which may suggest the involvement of the protein in the early stages of HPV-driven carcinogenesis. [Table: see text]

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Association of tobacco (T) use with risk of distant metastases (DM), tumor recurrence, and death in patients (pts) with HPV-positive (+) squamous cell cancer of the oropharynx (SCCOP)

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.6001 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 6001-6001

Author(s):

F. P. Worden ◽

J. Hooton ◽

J. Lee ◽

A. Eisbruch ◽

G. T. Wolf ◽

...

Keyword(s):

Disease Progression ◽

Chart Review ◽

Squamous Cell Cancer ◽

Lung Metastases ◽

Cell Cancer ◽

Distant Metastases ◽

Favorable Prognosis ◽

Hpv Status ◽

Risk Of Disease ◽

Second Primaries

6001 Background: Chemoradiation (CRT) for HPV (+) SCCOP is associated with a more favorable prognosis than HPV-negative (-) SCCOP. However, the interaction of HPV and T in terms of etiology and disease progression remains unclear. HPV (+) SCCOP pts were prospectively studied to determine if T use was a key variable in discriminating which pts would develop DM, locoregional recurrences (LR), or second primaries (SP). Methods: From 1999–2007, 124 pts with stage III/IV SCCOP were enrolled in one of two CRT trials. Tumor specimens were analyzed for HPV presence and type. Use of T, determined via self-reporting and chart review, was recorded as both continuous (number of pack-yrs) and categorical (never, former, and current) variables. Former T users were subdivided into an early cessation group (quit ≥ 20 yrs prior to diagnosis) and a late cessation group (quit < 20 yrs prior to diagnosis). T use and HPV status were analyzed with respect to survival & the development of DM, LR, or SP. Results: Of the 124 pts, 100 (81%) were HPV (+), 22 of which developed disease progression (22%). Twenty-four were HPV (-), 12 of which had disease progression (50%). Seventeen of 124 pts (14%) developed DM [12 HPV (+), 5 HPV (-)]. Nine of 124 (7%) developed LR [5 HPV (+), 4 HPV (-)], and 8 of 124 (7%) developed SP [5 HPV (+), 3 HPV (-)]. Thirty-two HPV (+) pts were never-T users, 88% (28/32) of which remain alive with no evidence of disease; 3 died from other causes and 1 died of lung metastases from SCCOP. Sixty-eight were HPV (+) and had T exposure. Of 46 former T users, 37/46 (80%) are living. Twenty were HPV (+) and in the early cessation group, 35% (7/20) of which had disease progression [3 LR, 3 DM, 1 SP]. Twenty-six HPV (+) pts were former T users in the late cessation group, 11% (3/26) of which had disease progression [2 DM, 1 SP]. Of 22 HPV (+) current T users, 68% (15/22) are alive and 36% (8/22) have developed disease progression. Seventeen of the 24 HPV (-) pts were current T users, 47% (8/17) of which developed disease progression. Conclusions: Never-T users with HPV-positive SCCOP have improved survival & reduced risk of disease progression compared to HPV (+) & HPV (-) former & current T users. No significant financial relationships to disclose.

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HPV Status as Prognostic Biomarker in Head and Neck Cancer—Which Method Fits the Best for Outcome Prediction?

Cancers ◽

10.3390/cancers13184730 ◽

2021 ◽

Vol 13 (18) ◽

pp. 4730

Author(s):

Jan Philipp Kühn ◽

Wendelin Schmid ◽

Sandrina Körner ◽

Florian Bochen ◽

Silke Wemmert ◽

...

Keyword(s):

Head And Neck Cancer ◽

Head And Neck ◽

Neck Cancer ◽

Oropharyngeal Cancer ◽

Direct Detection ◽

Multivariable Analysis ◽

Tissue Samples ◽

Hpv Dna ◽

Hpv Status ◽

Dna Pcr

The incidence of human papillomavirus (HPV)-related head and neck cancer (HNSCC) is rising globally, presenting challenges for optimized clinical management. To date, it remains unclear which biomarker best reflects HPV-driven carcinogenesis, a process that is associated with better therapeutic response and outcome compared to tobacco/alcohol-induced cancers. Six potential HPV surrogate biomarkers were analyzed using FFPE tissue samples from 153 HNSCC patients (n = 78 oropharyngeal cancer (OPSCC), n = 35 laryngeal cancer, n = 23 hypopharyngeal cancer, n = 17 oral cavity cancer): p16, CyclinD1, pRb, dual immunohistochemical staining of p16 and Ki67, HPV-DNA-PCR, and HPV-DNA-in situ hybridization (ISH). Biomarkers were analyzed for correlation with one another, tumor subsite, and patient survival. P16-IHC alone showed the best performance for discriminating between good (high expression) vs poor outcome (low expression; p = 0.0030) in OPSCC patients. Additionally, HPV-DNA-ISH (p = 0.0039), HPV-DNA-PCR (p = 0.0113), and p16-Ki67 dual stain (p = 0.0047) were significantly associated with prognosis in uni- and multivariable analysis for oropharyngeal cancer. In the non-OPSCC group, however, none of the aforementioned surrogate markers was prognostic. Taken together, P16-IHC as a single biomarker displays the best diagnostic accuracy for prognosis stratification in OPSCC patients with a direct detection of HPV-DNA by PCR or ISH as well as p16-Ki67 dual stain as potential alternatives.

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Selective Resection of Type 1 Gastric Neuroendocrine Neoplasms and the Risk of Progression in an Endoscopic Surveillance Programme

Digestive Surgery ◽

10.1159/000510962 ◽

2020 ◽

pp. 1-8

Author(s):

Jun Liong Chin ◽

Jim O’Connell ◽

Cian Muldoon ◽

Niall Swan ◽

John Vincent Reynolds ◽

...

Keyword(s):

Disease Progression ◽

Distant Metastases ◽

Endoscopic Surveillance ◽

Neuroendocrine Neoplasms ◽

Nodal Metastases ◽

Risk Of Progression ◽

Risk Of Disease ◽

Current Guidance ◽

Significant Disease

Background: Current guidance for type 1 gastric neuroendocrine neoplasms (gNENs) recommends either resection of all visible lesions or selective resection of gNENs >10 mm. We adopt a selective strategy targeting lesions approaching 10 mm for endoscopic mucosal resection (EMR) and provide surveillance for smaller lesions. Objectives: This study aimed to describe the incidence of type 1 gNENs requiring endoscopic/surgical resection and the risk of disease progression (both considered significant disease) on endoscopic surveillance. The secondary objective was to assess the risk factors for disease progression during surveillance and the incidence of gastric dysplasia/adenoma/adenocarcinoma. Methods: We collected consecutive patients with type 1 gNENs and obtained demographic and clinical data through the electronic patient record. Results: In our cohort of 57 patients, 12 patients had EMR at index gastroscopy; 7 patients had surgery (4: large/multiple gNENs and 3: nodal metastases) (5.2% [3/57] risk of nodal metastases); and a patient with nodal and liver metastases (1.8% [1/57] risk of distant metastases). The prevalence of gastric adenocarcinoma in our study was 3.5% with an incidence rate of 9.59 per 1,000 persons per year. For patients undergoing surveillance, 29.5% (13/44) of patients progressed requiring resection. Serum gastrin was significantly higher in patients who progressed to resection (p value = 0.023). Conclusion: We concluded that up to a third of patients with type 1 gNENs have significant disease requiring resection. Hence, endoscopic surveillance and resect strategy would benefit patients.

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Clinicopathological and Imaging Features Predictive of Clinical Outcome in Metaplastic Breast Cancer

Current Medical Imaging Formerly Current Medical Imaging Reviews ◽

10.2174/1573405615666190219105810 ◽

2020 ◽

Vol 16 (6) ◽

pp. 729-738

Author(s):

Ga Young Yoon ◽

Joo Hee Cha ◽

Hak Hee Kim ◽

Hee Jung Shin ◽

Eun Young Chae ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Outcome ◽

Clinical Outcomes ◽

Tumor Size ◽

Multivariable Analysis ◽

Disease Free Survival ◽

Imaging Features ◽

Peritumoral Edema ◽

Imaging Findings ◽

Metaplastic Breast Cancer

Background: Metaplastic breast cancer (MC) is a rare disease, thus it is difficult to study its clinical outcomes. Objective: To investigate whether any clinicopathological or imaging features were associated with clinical outcome in MC. Methods: We retrospectively evaluated the clinicopathological and imaging findings, and the clinical outcomes of seventy-two pathologically confirmed MCs. We then compared these parameters between triple-negative (TNMC) and non-TNMCs (NTNMC). Results: Oval or round shape, and not-circumscribed margin were the most common findings on mammography, ultrasound (US), and magnetic resonance imaging (MRI). It was mostly a mass without calcification on mammography, and revealed complex or hypoechoic echotexture, and posterior acoustic enhancement on US, and rim enhancement, wash-out kinetics, peritumoral edema, and intratumoral necrosis on MRI. Of all 72, 64 were TNMCs, and eight were NTNMCs. Clinicopathological and imaging findings were similar between the two groups, except that MRI showed peritumoral edema more frequently in TNMCs than NTNMCs (p=0.045). There were 21 recurrences and 13 deaths. Multivariable analysis showed that larger tumor size and co-existing DCIS were significantly predictive of Disease free survival (DFS), and larger tumor size and neoadjuvant chemotherapy were significantly predictive of overall survival (OS). Conclusion: MC showed characteristic imaging findings, and some variables associated with survival outcome may help to predict prognosis.

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A new risk calculator to predict changes in IPSS score and risk of AUR / BPH-related surgery in BPH patients with moderate-severe symptoms at risk of disease progression receiving placebo, dutasteride, tamsulosin, or combination therapy

European Urology ◽

10.1016/s0302-2838(21)00430-9 ◽

2021 ◽

Vol 79 ◽

pp. S52-S53

Author(s):

S. Gravas ◽

J.M. Palacios ◽

D. Thompson ◽

F. Concas ◽

P.J. Kamola ◽

...

Keyword(s):

At Risk ◽

Combination Therapy ◽

Disease Progression ◽

Risk Calculator ◽

Risk Of Disease

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Tumor-Associated Trypsin Inhibitor (TATI) as a Biomarker of Poor Prognosis in Oropharyngeal Squamous Cell Carcinoma Irrespective of HPV Status

Cancers ◽

10.3390/cancers13112811 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2811

Author(s):

Anni Sjöblom ◽

Ulf-Håkan Stenman ◽

Jaana Hagström ◽

Lauri Jouhi ◽

Caj Haglund ◽

...

Keyword(s):

Trypsin Inhibitor ◽

Poor Prognosis ◽

Tissue Expression ◽

University Hospital ◽

Study Cohort ◽

Hpv Dna ◽

P16 Immunohistochemistry ◽

Tumor Tissues ◽

Hpv Status ◽

Survival Endpoints

Background: We studied the role of tumor-associated trypsin inhibitor (TATI) in serum and in tumor tissues among human papillomavirus (HPV)-positive and HPV-negative OPSCC patients. Materials and methods: The study cohort included 90 OPSCC patients treated at the Helsinki University Hospital (HUS), Helsinki, Finland, in 2012–2016. TATI serum concentrations (S-TATIs) were determined by an immunofluorometric assay. Immunostaining was used to assess tissue expression. HPV status was determined with a combination of p16 immunohistochemistry and HPV DNA PCR genotyping. The survival endpoints were overall survival (OS) and disease-specific survival (DSS). Results: A significant correlation was found between S-TATI positivity and poor OS (p < 0.001) and DSS (p = 0.04) in all patients. In HPV-negative cases, S-TATI positivity was linked to poor OS (p = 0.01) and DSS (p = 0.05). In HPV-positive disease, S-TATI positivity correlated with poor DSS (p = 0.01). S-TATI positivity was strongly associated with HPV negativity. TATI serum was negatively linked to a lower cancer stage. TATI expression in peritumoral lymphocytes was associated with favorable OS (p < 0.025) and HPV positivity. TATI expression in tumor and in peritumoral lymphocytes correlated with lower cancer stages. Conclusion: Our results suggest that S-TATI positivity may be a biomarker of poor prognosis in both HPV-positive and HPV-negative OPSCC.

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