p16 staining has limited value in predicting the outcome of histological low-grade squamous intraepithelial lesions of the cervix.

In order to evaluate the usefulness of p16 staining in predicting the outcome of histological low-grade squamous intraepithelial lesion/cervical intraepithelial neoplasia grade 1 (LSIL/CIN1) we prospectively recruited all the patients referred to colposcopy from 2003 to 2011 due to abnormal screening test results and diagnosed with LSIL/CIN1 at biopsy (n=507). All biopsies were stained for p16 and re-evaluated after three years by the same gynecological pathologist using the LAST criteria. Follow-up was conducted every 6 months and included a Pap test (liquid-based cytology), high-risk human papillomavirus testing (Hybrid Capture 2 test), and colposcopy. The mean follow-up was 28 months. An outcome diagnosis of HSIL was defined as a histological diagnosis of high-grade SIL/CIN (HSIL/CIN2-3). The diagnosis of LSIL/CIN1 was confirmed in 416 out of 507 biopsies (82%), whereas 58 (11%) were reclassified as negative and 33 (6%) as HSIL/CIN2-3. During follow-up, 86/507 women initially diagnosed with LSIL/CIN1 (17%) showed an outcome diagnosis of HSIL/CIN2-3, with the rate of HSIL final diagnosis of 3% (2/58) in the women with biopsies reclassified as negative, 17% (70/416) in the group with confirmed LSIL and 42% (14/33) in the women with biopsies reclassified as HSIL (P<0.001). p16 was positive in 245/507 patients (48%) and in 210/416 patients (50%) with confirmed LSIL/CIN1 at re-evaluation. Although positive p16 immunostaining was associated with risk of HSIL/CIN2-3 outcome in the multivariate analysis (Hazard ratio (HR) 1.9; 95% confidence interval (CI): 1.2-3.1; P=0.009) in the overall group of patients with LSIL/CIN1, this association was not verified in the subset of patients with confirmed LSIL/CIN1 after re-evaluation (HR: 1.6; 95% CI: 0.9-2.6; P=0.095). In conclusion, in LSIL/CIN1 lesions p16 should be limited to equivocal cases in which HSIL/CIN2 is included in the differential diagnosis since it has low value in clinical practice as a marker of progression of LSIL/CIN1.

Atypical cytological changes mimicking SIL of the uterine cervix in allogenic hematopoietic stem cell transplantation recipients treated with busulfan.

BACKGROUND: Allogenic hematopoietic stem cell transplantation (allo-HSCT) is a common procedure in hematological disorders and is preceded by a conditioning regimen that usually includes busulfan. The immunosuppression caused by the conditioning regimen and graft-versus-host disease prophylaxis is associated with human papillomavirus (HPV) persistence and, consequently, with an increased risk of cervical cancer (CC) and squamous intraepithelial lesions (SILs)-the precursors of CC. A gynecological check-up that includes CC screening is recommended in these patients. METHODS: All female recipients of allo-HSCT undergo routine gynecological check-up that includes CC screening. Cervical samples were obtained for liquid-based cytology and HPV testing. Cytology smears were stained with the Papanicolaou (Pap) technique. A colposcopy evaluation was performed if any abnormal result in the screening tests was obtained. RESULTS: Among 15 women undergoing gynecological examination at 1 year after allo-HSCT who had received a conditioning regimen that included busulfan, 4 (26.7%) showed atypical squamous cells in the Pap smear, suggesting high-grade SIL. The abnormalities were identified from 136 to 271 days after allo-HSCT. In all cases, HPV testing was negative, and colposcopy examination was normal. The cytological abnormalities regressed in 3 of the women after 1 year but persisted in 1 woman at day 382 after allo-HSCT. CONCLUSIONS: Treatment-related atypia mimicking SIL is a common finding in allo-HSCT recipients who have received busulfan, particularly in the first year after the procedure. However, atypical changes may persist for more than 1 year. Clinical information, HPV testing, and colposcopy examination are critical to prevent misdiagnosis and overtreatment in these patients.

Value of HPV 16/18 Genotyping and p16/Ki-67 Dual Staining to Predict Progression to HSIL/CIN2+ in Negative Cytologies From a Colposcopy Referral Population.

OBJECTIVES: To assess the prognostic value of human papillomavirus (HPV) 16/18 genotyping and p16/Ki-67 dual staining cytology in high-risk HPV (hrHPV)-positive women with no lesion or minor abnormalities. METHODS: We evaluated progression to high-grade squamous intraepithelial lesion/cervical intraepithelial neoplasia grades 2 to 3 or cervical cancer (HSIL/CIN2+), persistence/regression of hrHPV infection in women referred to colposcopy showing hrHPV infection, histology diagnosis different from HSIL/CIN2+, and negative cytology. HPV 16/18 genotyping and dual staining were performed in liquid-based cytologic specimens obtained on the first visit. RESULTS: Progression was observed in 16 (8.0%) of 200 women. Those with HPV 16/18 infection had an increased risk of progression compared with women infected by other hrHPV types, and they also showed more persistence. However, no association was observed between progression or persistence and the result of the dual staining. CONCLUSIONS: HPV 16/18-positive women with no lesions or minor abnormalities are at high risk of progression to HSIL/CIN2+ and hrHPV persistence.

High-risk cervical epithelial neoplasia grade 1 treated by loop electrosurgical excision: follow-up and value of HPV testing.

OBJECTIVE: This study was undertaken to evaluate the value of high-risk human papillomavirus (HPV) testing in the follow-up of cervical intraepithelial neoplasia grade 1/low-grade squamous intraepithelial lesion treated by loop electrosurgical excision procedure because of the risk criteria established by the American Society for Colposcopy and Cervical Pathology (ie, unsatisfactory colposcopy or positive endocervical curettage, persistence of cervical intraepithelial neoplasia grade 1/low-grade squamous intraepithelial lesion, or high-risk HPV infection for longer than 2 years and older than 40 years). STUDY DESIGN: Seventy-seven women with cervical intraepithelial neoplasia grade 1/low-grade squamous intraepithelial lesion treated by loop electrosurgical excision procedure and followed-up with colposcopy, cytology, and high-risk HPV detection using Hybrid Capture II. RESULTS: More than 67% (67.6%) of women had cervical intraepithelial neoplasia grade 1 in the specimen; 22% a cervical intraepithelial neoplasia grade 2-3; and 10.4% had no lesion. Pretreatment HPV testing was positive in 100% of cervical intraepithelial neoplasia grade 2-3, in 93.5% of cervical intraepithelial neoplasia 1, and in 14.3% of cases with no lesion (P < .01). Pretreatment high-risk HPV testing was positive in all cases eventually developing residual/recurrent disease. Fifty percent of women with pretreatment viral load more than 100 relative light units had residual/recurrent disease develop. Posttreatment high-risk HPV testing during the follow-up reached a sensitivity and negative predictive value of 100% for detecting residual/recurrent disease. CONCLUSION: Patients with low-grade squamous intraepithelial lesion/cervical intraepithelial neoplasia grade 1 and risk factors have a significant risk of harboring a cervical intraepithelial neoplasia grade 2-3 lesion. A conservative approach should be considered when basal high-risk HPV test is negative. High pretreatment high-risk HPV loads should be considered a risk factor for developing residual/recurrent disease. Posttreatment Hybrid Capture II has an extremely high sensitivity for detecting recurrences.

Intranuclear inclusions in fine needle aspirates of bronchial low grade mucoepidermoid carcinoma with clear cell change: a report of two cases.

BACKGROUND: Mucoepidermoid carcinoma of the bronchus is a rare neoplasm that can be recognized on histology as well as cytology by the presence of three characteristic cell types: mucus secreting, epidermoid and intermediate. We encountered two cases displaying unusual cytologic features, including clear intranuclear inclusions. CASES: Two females, aged 33 and 39, presented with an intrabronchial tumor and pulmonary parenchymatous mass, respectively. Fine needle aspiration of both tumors showed similar cytologic features, with a dominant population of cells with bland nuclei and wide cytoplasm, and frequent intranuclear inclusions. A minor component of mucus-secreting cells was also recognized. Histologically, both tumors corresponded to the clear cell variant of mucoepidermoid carcinoma. CONCLUSION: The cytologic picture in our cases has not been described previously in fine needle aspirates of mucoepidermoid carcinoma, in neither the bronchus nor salivary gland. The differential diagnosis of a monotonous population of epithelial cells with intranuclear inclusions involves bronchioloalveolar carcinoma, but the absence of the characteristic sheet pattern, as well as the clinical and image findings, excludes this possibility. The lack of atypia and intrabronchial location limits the scope to carcinoid and salivary gland-type tumors of the bronchus. Since we were aware of the possibility of unusual cytologic presentations of mucoepidermoid carcinomas, search for different cellular populations suggested the precise diagnosis.

[Contribution of high risk human papillomavirus testing to the management of premalignant and malignant lesions of the uterine cervix]. / Contribución de la detección del virus del papiloma humano de alto riesgo al estudio de las lesiones premalignas y malignas del cérvix uterino.

BACKGROUND AND OBJECTIVE: High risk human papillomaviruses (HR-HPV) are consistently associated with premalignant and malignant lesions of the uterine cervix. Thus, the use of molecular techniques to detect HPV has been proposed to improve the results of conventional diagnostic strategies. In the present study, we evaluated the usefulness of the detection of HR-HPV in a cervical pathology unit. PATIENTS AND METHOD: 1005 women (mean age [SD], 38.4 [12.3]; range, 16-83) were referred for a cytology of atypical cells of unknown origin (ASCUS), squamous intraepithelial lesion (SIL) or carcinoma in the six months previous to the admission. All patients underwent a colposcopy, Pap test and/or histological study as well as HR-HPV detection using the Hybrid Capture II test. RESULTS: HR-HPV was detected in 96% high grade-SIL, 86% carcinomas of the uterine cervix and 86% low grade-SIL, but only in 25% women with no cervical lesions and 0% women with metastatic carcinomas to the cervix (p<0.001). The sensitivity of this test for high grade-SIL or higher was 90.2% and the negative predictive value was 96.5% (odds ratio=18.9; 95% confidence interval, 10.9-33.1). In patients with ASCUS, a negative result for HR-HPV nearly excluded the presence of a cervical lesion (negative predictive value, 98.52%). CONCLUSIONS: HR-HPV detection using Hybrid Capture II is useful in the study of lesions of the uterine cervix. It displays a high sensitivity for the diagnosis of squamous intraepithelial lesions and invasive carcinomas and a high usefulness in the management of ASCUS cases.

Pre- and post-conization high-risk HPV testing predicts residual/recurrent disease in patients treated for CIN 2-3.

OBJECTIVE: To evaluate whether high-risk human papillomavirus (HR-HPV) detection and viral load prior to treatment and status of cone margins can predict residual/recurrent disease as well as the ability of current diagnostic tools to identify residual/recurrent disease during follow-up of high-grade cervical intraepithelial neoplasia (CIN) treated by conization using loop electrosurgical procedure (LEEP). METHODS: Two hundred and three women (mean age 38.6 +/- 9.7; range 22-83) with CIN2-3 treated by LEEP conization and confirmed in the surgical specimen, attending follow-up visits were included. Age, HR-HPV detection and viral load determined by HybridCapture 2, and cone margins were evaluated as possible predictors of residual/recurrent disease. Value of single and repeated cytology as well as HR-HPV detection and viral load during follow-up were analyzed as screening tools of recurrence. RESULTS: Residual/recurrent disease was demonstrated by colposcopy guided biopsy in 36 patients (17.7%). High HR-HPV load (>1000 RLU) prior to LEEP and positive cone margins were significantly associated with higher risk of recurrence (31.8% vs. 9.4%, P = 0.005; and 36.4% vs. 11.9%, P < 0.001 respectively). HR-HPV detection at 6-12 m after LEEP showed higher sensitivity than a single or repeated cytology (97.2% vs. 83.3% and 94.4% respectively) although it showed less specificity (81.4% vs. 92.2% and 82.6%). The combination of HR-HPV detection and the first cytology during follow-up detected all patients with residual/recurrent disease (sensitivity 100%, negative predictive value 100%) with an acceptable specificity (76.6%). CONCLUSION: The inclusion of HR-HPV testing with cytology in follow-up of patients treated for CIN2-3 would allow for fewer post-treatment visits and avoid unnecessary cytologies. High HR-HPV load prior to LEEP or positive margins should be considered as risk factors for developing residual/recurrent disease.

Human papillomavirus load in Hybrid Capture II assay: does increasing the cutoff improve the test?

OBJECTIVE: The aim of the study was to evaluate whether the results of the Hybrid Capture II (HCII) assay for detecting high-grade squamous intraepithelial lesions (H-SIL) or cervical carcinoma can be improved by increasing the relative light units (RLU) level. STUDY DESIGN: We included 2271 women (mean age 38.7 +/- 12.3, range 15-92) referred to a colposcopic clinic due to cytology of atypical cells of unknown significance, SIL or carcinoma. All women underwent a new Pap test, HR-HPV detection using HCII and colposcopy with biopsy of suspicious areas when present. RESULTS: HR-HPV was detected in 91.7% of carcinomas, 96.6% of H-SIL, 85.1% of low-grade SIL and 21.6% of cases with no lesion. The probability of harboring an H-SIL or a carcinoma significantly increased as RLU increased (P = 0.01). The sensitivity and specificity for H-SIL or carcinoma at different cutoffs were 95.7 and 54.6 at 1 RLU, 93.9 and 59.6 at 2 RLU, 90.1 and 65.1 at 5 RLU and 85.7 and 68.7 at 10 RLU. The percentage of cases not detected with HCII increased from 2.4% for cases with <1 RLU to 9.5% for cases between 1 and 2 RLU, 14.8% between 2 and 3 RLU, 21.7% between 3 and 5 RLU and 28.4% between 5 and 10 RLU. CONCLUSION: The use of a higher cutoff (higher viral load) in the HCII should not be recommended because it significantly increases the number of cases with H-SIL or carcinoma not detected, reducing the sensitivity and negative predictive value of the test.