The impact of tissue block sampling on the detection of p53 signatures in fallopian tubes from women with BRCA 1 or 2 mutations (BRCA+) and controls.

The tubal p53 signature is a putative precursor to pelvic serous carcinoma, but its frequencies in women with inherited mutations in the BRCA1 or BRCA2 genes (BRCA+) and controls has been controversial. An initial section and two levels (100-200 µm) from every block in BRCA+ (24) and control tubes (40) were stained for p53. The frequency of p53 signatures was computed between the populations and across the three levels from each block, and analyzed by Fisher exact test. A total of 17 (71%) BRCA+ and 20 (50%) control tubes were p53 signature positive (P=0.12); 21 and 16% of all tissue blocks sectioned harbored signatures (P=0.29), and 76 and 67% were found in the fimbria. In 49 and 32% of p53 signature positive cases in the two groups, the p53 signatures were not discovered until the second or third round of sectioning. In all, 38 and 40% of BRCA+ and control subjects harbored p53 signatures in more than one focus in a single block. In one case (BRCA+), a highly atypical proliferation was identified in one serial section. The p53 signatures are more common than previously reported and the frequency of detection increases as a function of sectioning through the tissue block, both in absolute frequency and in numbers of p53 signatures detected in a given block. There is a trend for a higher absolute frequency of p53 signatures (71 vs 50%; P=0.12) in BRCA+ subjects, but this is not reflected in a greater average number of p53 signatures or positive blocks per case. This study underscores the importance of systematic immunohistochemical examination of fallopian tubes when conducting epidemiological studies that compare the frequency of p53 signatures in different populations. Attention to this detail is critical when exploring risk factors germane to early serous carcinogenesis.

Histological 'progression' from low (LSIL) to high (HSIL) squamous intraepithelial lesion is an uncommon event and an indication for quality assurance review.

An accurate assessment of 'progression' from a low (LSIL) to high (HSIL) grade squamous intraepithelial lesion (cervical intraepithelial neoplasia (CIN)2 or CIN3) of the cervix is critical to ascertaining HSIL outcome risk, the value of predictive biomarkers, and the need for excisional therapy. We obtained biopsy outcome data on a series of initially diagnosed LSIL to assess this risk. Consecutive biopsy diagnoses of LSIL were obtained from the archives, and the frequency of HSIL biopsy outcomes were ascertained by record and histological review. Then, a 'numerical severity score' was recorded for each diagnosis: LSIL (1-2), CIN2 (3-4) and CIN3 (5-6) with lower and higher values corresponding to the degree (low vs high) of histological severity within each category, respectively. Of 264 initial LSILs, 29 (11%) were reported with an HSIL outcome. However, histological review of 21 of these HSILs confirmed only 8 (38%) HSIL diagnoses by review with the numerical severity score: three cases scored as 5, three cases scored as 4, and two cases scored as 3; the remaining 13 cases were assigned a numerical severity score of 1 or 2. P16 immunostains of corresponding previous and subsequent biopsies were discordant in 4 of 12 cases (33%). In a blind review of a randomly selected series of HSILs from the same practice, HSIL was significantly more likely to be confirmed on re-review (10 of 13 (77%), P=0.024). These findings show that confirmed HSIL outcomes (on review) following an LSIL biopsy are infrequent ( approximately 3%). A diagnosis of HSIL following an LSIL should always be reviewed, as this diagnostic pairing may more likely be associated with a diagnostic error.