Editors: Michael Cibull, MD, professor emeritus, University of Kentucky College of Medicine, Lexington; Rouzan Karabakhtsian, MD, attending pathologist, Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY; Thomas Cibull, MD, dermatopathologist, Evanston Hospital, NorthShore University HealthSystem, Evanston, Ill.; and Rachel Stewart, DO, resident physician, Department of Pathology and Laboratory Medicine, University of Kentucky.
Molecular detection of tuberculosis on fresh and paraffin-embedded tissues
Risk-adjusted margin positivity rate as a quality indicator in rectal cancer surgery
Prognostic value of nuclear HIF1A expression in sporadic and familial male breast cancer
Molecular detection of tuberculosis on fresh and paraffin-embedded tissues
Little has been published about the performance of tuberculosis polymerase chain reaction with respect to the quality of tissue specimens. Laboratories often receive liquid samples from fine-needle aspirates with no visible tissue for testing. The sensitivity of tuberculosis polymerase chain reaction (TB PCR) on these specimens is unknown. The authors conducted a study in which TB PCR was compared to culture or a combination of clinical and histopathological evidence of tuberculosis. A separate analysis excluded patients undergoing treatment or who were previously treated. The results of the study found that 65 patients had 81 positive samples—69 by PCR and 43 by culture. Excluding those on treatment, 51 of 57 were PCR positive versus 43 of 61 by culture. Forty-four samples had no visible tissue noted. Five were PCR positive; only one was culture positive. At least two samples were falsely negative. The authors concluded that sensitivity of TB PCR is superior to culture on tissue. Five of seven TB cases with no visible tissue were PCR positive. The quality of the specimen deserves comment because the two (five percent) known false-negative findings were of concern.
McKew GL, Dubedat SM, Chan RC. Do the eyes have it? Performance of molecular detection of tuberculosis on fresh and paraffin embedded tissues, including those with no visible tissue. J Clin Pathol. 2014;67:1104–1105.
Correspondence: Dr. Genevieve L. McKew at genevieve.mckew@sswahs.nsw.gov.au
ERG expression in intraductal carcinoma of prostate and in adjacent invasive prostatic adenocarcinoma: a comparison
Intraductal carcinoma of the prostate is a growth pattern of prostatic adenocarcinoma that has not been well characterized from a molecular standpoint. Still being debated is whether intraductal carcinoma of the prostate represents colonization of benign glands by pre-existing conventional prostatic adenocarcinoma or progression of high-grade prostatic intraepithelial neoplasia. TMPRSS2-ERG is the most common gene fusion in conventional prostatic adenocarcinoma, identified in about 40 percent to 70 percent of cases. The authors conducted a study in which they compared the expression of ERG in intraductal carcinoma of the prostate and adjacent conventional prostatic adenocarcinoma. Thirty-one confirmed cases of intraductal carcinoma of the prostate, with adjacent conventional prostatic adenocarcinoma and available tissue blocks, were identified in the study. Immunohistochemical stains were performed for ERG using a rabbit anti-ERG monoclonal antibody. The ERG expression in the intraductal carcinoma of the prostate component was compared with that in the adjacent conventional prostatic adenocarcinoma. The mean patient age was 65 years (range, 48–79 years). Positive ERG expression was identified in 11 of 31 (35 percent) cases of intraductal carcinoma of the prostate. In all of those cases with positive ERG expression in the intraductal carcinoma of the prostate component, ERG expression was also positive in the adjacent conventional prostatic adenocarcinoma. In the 20 of 31 (65 percent) cases with negative ERG expression in the intraductal carcinoma of the prostate component, ERG was also negative in the adjacent conventional prostatic adenocarcinoma. The authors concluded that based on identical ERG expression (positive or negative) in intraductal carcinoma of the prostate and the adjacent conventional prostatic adenocarcinoma, intraductal carcinoma of the prostate most likely represents colonization of benign glands by adjacent pre-existing conventional prostatic adenocarcinoma.
Schneider TM, Osunkoya AO. ERG expression in intraductal carcinoma of the prostate: comparison with adjacent invasive prostatic adenocarcinoma. Mod Pathol. 2014;27:1174–1178.
Correspondence: Dr. A. O. Osunkoya at adeboye.osunkoya@emory.edu
Histologic grade as a prognostic factor for breast cancer regardless of number of positive lymph nodes and tumor size
The appropriate staging of breast cancers includes an evaluation of tumor size and nodal status. Histological grade in breast cancer, though important and assessed for all tumors, is not integrated within tumor staging. The authors conducted a study to determine whether histologic grade remains a prognostic factor for breast cancer regardless of tumor size and number of involved axillary lymph nodes. Using a new clustering algorithm, the 10-year survival for every combination of T, N, and histologic grade was determined for cases of breast cancer obtained from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute. There were 36 combinations of TN, defined according to the American Joint Committee on Cancer, and grade. The authors found that for each combination of T and N, a categorical increase in the histologic grade was associated with a progressive decrease in 10-year survival regardless of the number of involved axillary lymph nodes or size of the primary tumor. Absolute survival differences between high and low grade persisted despite larger tumor sizes and greater nodal involvement, though trends were apparent with increasing breast cancer stage. Statistical significance depended on the number of cases for each combination. The authors concluded that histologic grade continues to be of prognostic importance for overall survival despite tumor size and nodal status. Furthermore, these results seem to indicate that assignment of histologic grade has been consistent among pathologists when evaluated in a large data set of patients with breast cancer. The incorporation of histologic grade in tumor-node-metastasis staging for breast cancer provides important prognostic information.
Schwartz AM, Henson DE, Chen D, et al. Histologic grade remains a prognostic factor for breast cancer regardless of the number of positive lymph nodes and tumor size: a study of 161 708 cases of breast cancer from the SEER program. Arch Pathol Lab Med. 2014;138: 1048–1052.
Correspondence: Dr. Arnold M. Schwartz at aschwartz@mfa.gwu.edu
Risk-adjusted margin positivity rate as a quality indicator in rectal cancer surgery
Margin positivity after rectal cancer resection is associated with poorer outcomes. The authors previously developed an instrument for calculating hospital risk-adjusted margin positivity rate (RAMP) that allows identification of performance-based outliers and may represent a rectal cancer surgery quality metric. The authors conducted an observational cohort study of patients with rectal cancer within the National Cancer Data Base (2003–2005). Hospital performance was categorized as low outlier (better than expected), high outlier (worse than expected), or non-RAMP outlier using standard observed-to-expected methodology. The association between outlier status and overall risk of death at five years was evaluated using Cox shared frailty modeling. Among 32,354 patients with cancer (mean age, 63.8 ± 13.2 years; 56.7 percent male; 87.3 percent white) treated at 1,349 hospitals (4.9 percent high outlier, 0.7 percent low outlier), 5.6 percent of patients were treated at high outliers and 3.0 percent were treated at low outliers. Various structural (academic status and volume), process (pathologic nodal evaluation and neoadjuvant radiation therapy use), and outcome (sphincter preservation, readmission, and 30-day postoperative mortality) measures were significantly associated with outlier status. The five-year overall survival rate was better at low outliers (79.9 percent) than high outliers (64.9 percent) and nonoutliers (68.9 percent; log-rank test, P<0.001). Risk of death was lower at low outliers than high outliers (hazard ratio [HR], 0.61; 95 percent confidence interval [CI], 0.50–0.75) and nonoutliers (HR, 0.69; 95 percent CI, 0.57–0.83). And risk of death was higher at high outliers than nonoutliers (HR, 1.12; 95 percent CI, 1.03–1.23). The authors concluded that hospital RAMP outlier status is a rectal cancer surgery composite metric that reliably captures hospital quality across all levels of care and could be integrated into existing quality improvement initiatives for hospital performance.
Massarweh NN, Hu CY, You YN, et al. Risk-adjusted pathologic margin positivity rate as a quality indicator in rectal cancer surgery. J Clin Oncol. 2014;32:2967–2974.
Correspondence: Dr. George J. Chang at gchang@mdanderson.org
Morphologic and molecular characterization of traditional serrated adenomas of distal colon and rectum
Of the serrated polyps, the origin, morphologic features, molecular alterations, and natural history of traditional serrated adenomas are the least understood. Recent studies suggest that these polyps may arise from precursor lesions. The frequencies of KRAS and BRAF mutations vary between these studies, and only one small study has measured CpG island methylation using current markers of methylation. Mutations in GNAS, a gene commonly mutated in colorectal villous adenomas, have not been fully evaluated in traditional serrated adenomas (TSAs). Finally, the expression of annexin A10 (ANXA10), a recently discovered marker of sessile serrated adenomas/polyps, has not been studied in these polyps. To further characterize these polyps, five gastrointestinal pathologists reviewed 55 left-sided polyps diagnosed as TSA at a single institution. The pathologists assessed various histologic features, including cytoplasmic eosinophilia, ectopic crypt foci, presence of conventional dysplasia, and presence of precursor serrated lesions. KRAS, BRAF, and GNAS mutational analysis was performed, as well as CpG island methylation and ANXA10 immunohistochemistry. Ectopic crypt foci were seen in 62 percent of TSAs. Precursor lesions were seen in 24 percent of the study polyps, most of which were hyperplastic. KRAS and BRAF mutations were common and were present in 42 percent and 48 percent of polyps, respectively. GNAS mutations occurred in eight percent of polyps, often in conjunction with a BRAF mutation. Unlike sessile serrated adenomas/polyps, TSAs rarely had diffuse expression of ANXA10. Importantly, BRAF-mutated TSAs had more widespread methylation of a five-marker CpG island panel compared with KRAS-mutated polyps. However, ectopic crypt foci, a proposed defining feature of TSA, were not associated with a specific molecular alteration.
Wiland HO, Shadrach B, Allende D, et al. Morphologic and molecular characterization of traditional serrated adenomas of the distal colon and rectum. Am J Surg Pathol. 2014;38(9):1290–1297.
Correspondence information not provided.
Prognostic value of nuclear HIF1A expression in sporadic and familial male breast cancer
Male breast cancer is poorly understood, with a large proportion arising in the familial context, particularly with the BRCA2 germline mutation. Because phenotypic and genotypic differences between sporadic and familial male breast cancers have been noted, the authors investigated the importance of hypoxic drive in these cancers since this pathway has been shown to be of importance in familial female breast cancer. Expression of two major hypoxia-induced proteins, hypoxia-inducible factor-1a (HIF1A) and carbonic anhydrase IX (CA9), were examined within a large cohort that included 61 familial (three BRCA1, 28 BRCA2, 30 BRCAx) and 225 sporadic male breast cancers. This showed that 31 percent of all male breast cancers expressed HIF1A (25 percent) or CA9 (eight percent), or both, in the combined cohort. Expression of HIF1A correlated with an increased incidence of a second major malignancy (P=0.04), histological tumor type (P=0.005), and basal phenotype (P=0.02). Expression of CA9 correlated with age (P=0.004) in sporadic cases and increased tumor size (P=0.003). Expression of HIF1A was prognostic for disease-specific survival in sporadic male breast cancer (hazard ratio [HR], 3.8; 95 percent confidence interval [CI], 1.5–9.8; P=0.006) but not in familial male breast cancer, whereas CA9 was prognostic in familial male breast cancer (HR, 358; 95 percent CI, 9.3–13781.7; P=0.002) but not in sporadic male breast cancer. The study concluded that hypoxic drive is less prevalent in male breast cancer than female breast cancer, possibly due to differing breast microenvironments. The prognostic impact of HIF1A is greatest in sporadic male breast cancer with an alternate dominant mechanism for the oncogenic drivers suggested in high-risk familial male breast cancer.
Deb S, Johansson I, Byrne D, et al. Nuclear HIF1A expression is strongly prognostic in sporadic but not familial male breast cancer. Mod Pathol. 2014;27:1223–1230.
Correspondence: Dr. S. Deb at siddhartha.deb@petermac.org