Adjunctive use of p16 immunohistochemistry for optimizing management of CIN lesions in a high-risk human papillomavirus-positive population.

INTRODUCTION: Immunostaining with p16INK4a (p16), a tumor-suppressor surrogate protein biomarker for high-risk human papillomavirus (hrHPV) oncogenic activity, may complement standard hematoxylin and eosin (H&E) histology review, and provide more objective criteria to support the cervical intraepithelial neoplasia (CIN) diagnosis. With this study we assessed the impact of p16 immunohistochemistry on CIN grading in an hrHPV-based screening setting. MATERIAL AND METHODS: In this post-hoc analysis, 326 histology follow-up samples from a group of hrHPV-positive women were stained with p16 immunohistochemistry. All H&E samples were centrally revised. The pathologists reported their level of confidence in classifying the CIN lesion. RESULTS: Combining H&E and p16 staining resulted in a change of diagnosis in 27.3% (n = 89) of cases compared with the revised H&E samples, with a decrease of 34.5% (n = 18) in CIN1 and 22.7% (n = 15) in CIN2 classifications, and an increase of 18.3% (n = 19) in no CIN and 20.7% (n = 19) in CIN3 diagnoses. The level of confidence in CIN grading by the pathologist increased with adjunctive use of p16 immunohistochemistry to standard H&E. CONCLUSIONS: This study shows that adjunctive use of p16 immunohistochemistry to H&E morphology reduces the number of CIN1 and CIN2 classifications with a proportional increase in no CIN and CIN3 diagnoses, compared with standard H&E-based CIN diagnosis alone. The pathologists felt more confident in classifying the material with H&E and p16 immunohistochemistry than by using H&E alone, particularly during assessment of small biopsies. Adjunctive use of p16 immunohistochemistry to standard H&E assessment of CIN would be valuable for the diagnostic accuracy, thereby optimizing CIN management and possibly decreasing overtreatment.

[A new form of Kaposi sarcoma]. / Een nieuwe vorm van het kaposisarcoom.

BACKGROUND: Kaposi sarcoma is an vascular neoplasm caused by infection with human herpesvirus-8. Known risk groups are Mediterranean, eastern European Jewish and African ancestry men or men with AIDS. Nowadays we distinguish more subgroups. CASE DESCRIPTION: We present a healthy 39 year old man with a lesion on the right foot, having homosexual contacts, without HIV infection. Previous histology revealed signs of hemangioma. Recent clinical signs and histology confirmed multifocal Kaposi sarcoma. He was treated with radiotherapy. We also present a 65 year old MSM with and a lesion on the sole of the foot. Histology revealed for a solitary nodular Kaposi sarcoma. A short term relapse after surgical excision occurred. CONCLUSION: Kaposi sarcoma is subdivided into different categories. Kaposi Sarcoma in HIV-negative MSM is seen more frequently today, yet usually shows an indolent course. An adjusted less aggressive treatment and follow-up is therefore justified.

Measuring the depth of invasion in vulvar squamous cell carcinoma: interobserver agreement and pitfalls.

AIMS: The depth of invasion is an important prognostic factor for patients with vulvar squamous cell carcinoma (SCC). The threshold of 1 mm distinguishes between FIGO stages IA and ≥IB disease and guides the need for groin surgery. Therefore, high interobserver agreement is crucial. The conventional and the alternative method are described to measure the depth of invasion. The aims of this study were to assess interobserver agreement for classifying the depth of invasion using both methods and to identify pitfalls. METHODS AND RESULTS: Fifty slides of vulvar SCC with a depth of invasion approximately 1 mm were selected, digitally scanned and independently assessed by 10 pathologists working in a referral or oncology centre and four pathologists in training. The depth of invasion was measured using both the conventional and alternative method in each slide and categorised into ≤1 and >1 mm. The percentage of agreement and Light's kappa for multi-rater agreement were calculated, and 95% confidence intervals were calculated by bootstrapping (1000 runs). The agreement using the conventional method was moderate (κ = 0.57, 95% confidence interval = 0.45-0.68). The percentage of agreement among the participating pathologists using the conventional method was 85.0% versus 89.4% using the alternative method. Six pitfalls were identified: disagreement concerning which invasive nest is deepest, recognition of invasive growth and where it starts, curved surface, carcinoma situated on the edge of the tissue block, ulceration and different measurement methods. CONCLUSIONS: Pathologists reached only moderate agreement in determining the depth of invasion in vulvar SCC, without a notable difference between the two measurement methods.

Evaluation of p16/Ki-67 dual-stained cytology as triage test for high-risk human papillomavirus-positive women.

The aim of this study was to evaluate the clinical utility of p16/Ki-67 dual staining, for the identification of CIN in high-risk HPV-positive women from a non-responder screening cohort. P16/Ki-67 dual staining, Pap cytology, and HPV16/18 genotyping were performed on physician-taken liquid-based samples from 495 women who tested high-risk HPV positive on self-sampled material (PROHTECT-3B study). Different triage strategies involving p16/Ki-67 dual staining were evaluated for sensitivity, specificity, and predictive value for ≥CIN2 and ≥CIN3, and compared to Pap cytology with a threshold of atypical cells of undetermined significance. Centrally revised histology or an adjusted endpoint with combined high-risk HPV negative and cytology negative follow-up at 6 months was used as gold standard. Pap cytology (threshold atypical cells of undetermined significance) triage of high-risk HPV-positive samples showed a sensitivity of 93% (95% confidence interval: 85-98) with a specificity of 49% (95% confidence interval: 41-56) for ≥CIN3. Three triage strategies with p16/Ki-67 showed a significantly increased specificity with similar sensitivity. P16/Ki-67 triage of all high-risk HPV-positive samples had a sensitivity of 92% (95% confidence interval: 84-97) and a specificity of 61% (95% confidence interval: 54-69) for ≥CIN3. Applying p16/Ki-67 triage to only high-risk HPV-positive women with low-grade Pap cytology showed a similar sensitivity of 92% (95% confidence interval: 84-97), with a specificity for ≥CIN3 of 64% (95% confidence interval: 56-71). For high-risk HPV-positive women with low-grade and normal Pap cytology, triage with p16/Ki-67 showed a sensitivity of 96% (95% confidence interval: 89-99), and a specificity of 58% (95% confidence interval: 50-65). HPV16/18 genotyping combined with Pap cytology showed a sensitivity and specificity for ≥CIN3 similar to Pap cytology with an atypical cells of undetermined significance threshold. Because the quality of Pap cytology worldwide varies, and differences in sensitivity and specificity are limited between the three selected strategies, p16/Ki-67 triage of all high-risk HPV-positive samples would be the most reliable strategy in triage of high-risk HPV-positive women with an increased specificity and similar sensitivity compared with Pap cytology triage.

Increasing incidence of invasive and in situ cervical adenocarcinoma in the Netherlands during 2004-2013.

In the developed world, the incidence of cervical squamous cell carcinoma has decreased, however, the incidence of adenocarcinoma in situ (AIS) and invasive adenocarcinoma increased, predominantly in young females. The goal of this study was to evaluate the most recent incidence rates of AIS, adenocarcinoma, and squamous cell carcinoma of the uterine cervix in the Netherlands in 2004-2013. By using Dutch national pathology and cancer registries, we calculated European standardized incidence rates (ESR) and estimated annual percentage changes (EAPC) for AIS during 2004-2013 and for invasive cervical carcinomas during 1989-2013. For AIS, presence or absence of concomitant cervical intraepithelial neoplasia (CIN) was explored. The estimated annual percentage change (EAPC) of squamous cell carcinoma decreased significantly in 1989-2013, predominantly in 1989-2003. The EAPC of invasive adenocarcinoma decreased in 1989-2003, but remained stable in 2004-2013. The EAPC of AIS increased significantly, predominantly in women of 25-39 years old. Of these AIS cases, 58.9% had concomitant CIN and AIS with concomitant CIN showed a significantly higher EAPC compared to AIS without CIN. Our conclusion is that despite a nationwide screening program for cancer of the uterine cervix, the incidence of adenocarcinoma in the Netherlands remained stable during 2004-2013 and the incidence of adenocarcinoma in situ increased. This was most predominant in cases with concomitant CIN and in younger females. The incidence of squamous cell carcinoma decreased in the same timeframe.