The squamocolumnar junction (SCJ) cell population of the uterine cervix is a discrete epithelial area and the putative source of the majority of high-grade squamous intraepithelial lesions (HSIL). The SCJ cells can be identified by immunohistochemical (IHC) stains including cytokeratin 7 (CK7). Others have theorized that an SCJ marker-positive low-grade squamous intraepithelial lesion (LSIL) has a higher risk for future HSIL compared with an SCJ marker-negative LSIL. This study has 2 aims: first, to refine the definition of a positive CK7 immunostaining pattern in cervical lesions, and, second, to test the hypothesis that CK7 positivity in LSIL indicates higher risk for future HSIL, with both questions addressed using a data set with consensus diagnoses. One hundred cases each of LSIL, moderate HSIL (CIN2), and severe HSIL (CIN3) were stained for CK7, with positivity defined as a diffuse cytoplasmic staining pattern (>5 to 6 contiguous cells); all others were considered negative. Using this model, 34% of CIN1, 45% of CIN2, and 60% of CIN3 were CK7 positive. With follow-up, CK7-positive LSILs were more likely to progress to HSIL compared with CK7-negative LSIL (32% vs. 11%, P=0.05), in concordance with the results of other researchers. This study simplifies cervical CK7 IHC grading into a reproducible system and supports the thesis that CK7 positivity in LSIL is associated with increased risk for future HSIL. Larger cohorts using consensus-diagnosed LSIL are needed to confirm these results before CK7 may be considered for clinical validation.
The data suggest that entry barriers have fallen over time for new drug introductions. The increased competitiveness of the pharmaceutical marketplace was likely fueled by changes over time on both the supply and demand sides. The development histories of entrants to new drug classes suggest that development races better characterise new drug development than does a model of post hoc imitation. Thus, the usual distinctions drawn between breakthrough and 'me-too' drugs may not be very meaningful.
A histologic pattern-based system of risk stratification for endocervical adenocarcinoma has been recently proposed on the basis of tumor-stroma interface and lymph-vascular invasion. The key utility of the system lies in separating cases with very low risk for nodal metastases (pattern A) from those with higher risk (patterns B and C), which may alter the treatment approach. In this study, we determine the reproducibility of applying this system among gynecologic pathologists from 2 institutions using blinded review of 49 adenocarcinomas from 2003 to 2013. κ values and pairwise differences are calculated for the proposed 3-tier system (patterns A, B, and C) as well as a modified version comparing pattern A versus patterns B and C combined (2-tier system). Consensus diagnosis for the 3-tier system is reached in 50% of cases, with majority of κ values indicating fair to almost perfect agreement (range, 0.24 to 0.84). When condensed to 2 tiers, consensus is reached in 81.3% of cases with κ values showing modest improvement (range, 0.33 to 0.92). Pairwise difference analysis reveals diagnosis trends for specific pathologists on the 3-tier system that decrease with 2 tiers. Interpretive variability may be of practical significance in application of the proposed 3-tier pattern-based approach to endocervical adenocarcinoma. Additional studies with larger patient cohorts are needed to confirm the negligible risk for lymph node involvement seen in pattern A patients and to further evaluate the applicability of this new classification system.
Human papillomavirus (HPV) infection, most commonly genotype 16 of the alpha-9 family, is implicated in the etiology of a subset of oropharyngeal squamous cell carcinomas (OPSC) worldwide. Data are scarce regarding OPSC in South Africans, and three prior studies suggest no significant etiologic role for HPV. We aimed to investigate for evidence of HPV etiology in OPSCs from black South Africans by polymerase chain reaction (PCR) methodologies with determination of HPV subtype by sequencing, in situ hybridization (ISH), and p16INK4a immunohistochemistry (IHC), as a surrogate marker for an HPV-driven tumor. It was hypothesized that HPV-driven tumors would be positive by PCR plus IHC and/or ISH whereas OPSCs with HPV background infections (HPV-passenger) would be positive by PCR alone. Formalin-fixed, paraffin embedded tissues from 51 OPSCs collected between 2005 and 2010 from 41 patients were analyzed for HPV by GP5?6? PCR (targeting the HPV L1 region), pU-1M/pU- 2R PCR (targeting the HPV E6/E7 region) and HPV-31 specific PCR (targeting the E5 region), chromogenic ISH, and p16INK4a IHC. All cases positive by PCR were subject to sequencing to determine HPV genotype. The patient mean age was 58.0 years and 88 % were male. Of the 51 evaluable tumors, 48 (94.1 %) were positive for HPV DNA by PCR: 25 (49.1 %) met criteria for an HPV-driven tumor, 23 (45.1 %) for HPV-passenger, and 3 (5.9 %) were HPV unrelated. Sequencing of the PCR-positive cases revealed the following genotypes: combined HPV-16 and 31 (41.7 %), HPV-31 (25.0 %), HPV-16 (22.9 %), combined HPV-16 and 18 (6.3 %), and a single case each of HPV 18 and HPV 33. Studies via ISH were negative in all cases. In accordance with worldwide trends but contrary to prior South African data, HPV likely plays an etiologic role in a significant subset (at least 49.1 %) of OPSC in black South Africans. We found that the alpha-9 HPV family, particularly HPV-16 and 31 either in combination or separately, to predominate in our sample tumors. The use of multiple PCR primers increased sensitivity of viral detection, and a HPV-31 specific primer confirmed the presence of this genotype in many samples. Further studies including HPV E6/E7 mRNA assays are needed to better elucidate the pathogenic role of HPV in black South African OPSCs.
Previous studies of p16 immunohistochemistry (IHC) on CIN1 have suggested the likely utility of p16 in stratification of women at risk for subsequent CIN2/3. But those studies had limitations in statistical power, histologic diagnosis, and disease ascertainment. We conducted a retrospective study of p16 IHC on adjudicated CIN1 tissue diagnosed in young women participating in the placebo arm of the quadrivalent human papillomavirus (HPV) vaccine trials. Tissue sections were stained with p16 IHC and hematoxylin and eosin. p16 IHC was scored using LAST criteria, and hematoxylin and eosin-stained sections were reviewed for concordance with the adjudicated diagnosis. p16 IHC, antecedent high-grade cytology, review diagnosis, and HPV16 detection were assessed as independent risk factors for subsequent CIN2/3. Five hundred twenty-four patients with CIN1 biopsies and complete data were identified, 63 (12.0%) of whom developed CIN2/3 in follow-up. p16 positivity (P=0.06), review diagnosis of CIN2/3 (P=0.04), HPV16 positivity (P=0.01), and antecedent high-grade cytology (P=0.02) were (marginally) associated with CIN2/3. In a logistic regression model, the associations with CIN2/3 (vs. other), expressed as odds ratios (95% confidence intervals), were 1.6 (0.91-2.8) for p16, 2.0 (1.0-3.7) for HPV16, and 2.2 (1.1-2.4) for antecedent high-grade cytology. The mean risks for CIN2/3 estimated from the model ranged from 7.6% for negative for all markers to 36.3% for positive for all 3 markers. p16 IHC does not risk stratify CIN1 patients in a manner that would alter recommended management for CIN1. This reinforces the LAST recommendations that p16 should only be used selectively for problematic scenarios, such as CIN2 because of its inherent lack of reproducibility, cases in which one is struggling between CIN1 and CIN2, and benign mimics of CIN3.
Ovary is one of the extrapancreatic sites of origin of solid pseudopapillary neoplasm (SPN). Only 9 cases of primary ovarian SPN, 1 with CTNNB1 mutation similar to pancreatic SPN, have been reported in the English literature. We describe the second case of ovarian SPN with confirmed CTNNB1 mutation. A 49-year-old postmenopausal woman presented with a 4.5 cm right ovarian mass. Ovarian mass showed histologic and immunohistochemical features of pancreatic SPN. The ovarian surface was intact and uninvolved. Ki-67 index was low (1%-5%). DNA sequencing of CTNNB1 exon 3 revealed c.98C>G (p.S33C), a well-characterized activating mutation. Our case adds to the growing body of evidence that primary ovarian SPN are phenotypically and genotypically similar to pancreatic SPN.
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