Jason T. Lewis

An Analysis of Breast Cancer Risk in Women With Single, Multiple, and Atypical Papilloma

Breast papillomas may be single or multiple and associated with atypical ductal or lobular hyperplasias (ADH/ALH). The risk of breast carcinoma development in patients with papillomas, particularly those with multiple or atypical lesions, is incompletely defined. Fibrocystic lesions were histopathologically classified in a benign breast disease cohort of 9155 who underwent biopsy from 1967 to 1991, with papilloma assessment in 9108. Individuals with papillomas (N=480) were classified into 4 groups: single papilloma (SP, N=372), single papilloma with ADH or ALH (SP+A, N=54), multiple (>5) papillomas (MP, N=41), and multiple papillomas with ADH or ALH (MP+A, N=13). Those without papillomas were classified as nonproliferative (NP, N=6053), proliferative without atypia (PDWA, N=2308), and ADH/ALH [atypical hyperplasia (AH), N=267]. The relative risk of cancer development within our cohort was compared to that expected in the general population using standardized incidence ratios. The relative risk of breast cancer development associated with SP [2.04, 95% confidence interval (CI) 1.43-2.81] was greater than NP (1.28, 95% CI 1.16-1.42) but similar to PDWA (1.90, 95% CI 1.66-2.16). The risk associated with SP+A (5.11, 95% CI 2.64-8.92) was highly elevated but not substantively different than atypical hyperplasia (4.17, 95% CI 3.10-5.50). Patients with MP are at increased risk compared with PDWA or SP (3.01, 95% CI 1.10-6.55), particularly those with MP+A (7.01, 95% CI 1.91-17.97). There was a marginal increase in breast cancer risk (16%) among patients with proliferative disease if a papilloma was present, but this did not reach statistical significance (P=0.29). The observed frequency of ipsilateral (vs. contralateral) breast cancer development in papilloma subsets was not significantly different than other patient groups. We conclude that SP imparts a cancer risk similar to conventional proliferative fibrocystic change. The presence of papilloma in, or associated with, atypia does not modify the risk connotation of ADH/ALH overall. MP constitutes a proliferative breast disease subset having unique clinical and biologic behavior.

Prevalence and risk factors for gallbladder neoplasia in patients with primary sclerosing cholangitis: Evidence for a metaplasia-dysplasia-carcinoma sequence

Primary sclerosing cholangitis (PSC) carries an increased risk (10% to 20%) of hepatobiliary malignancy, especially cholangiocarcinoma (CC). Dysplasia, adenomas, and carcinomas of the gallbladder have been described in PSC but are less common than bile duct carcinomas. However, the prevalence and risk factors for gallbladder neoplasia among patients with PSC undergoing orthotopic liver transplantation (OLT) have not been well studied. We evaluated 72 gallbladders from 100 consecutive liver explants for PSC, including 66 cholecystectomies performed at the time of OLT and 6 performed before OLT. All specimens were totally embedded for histologic examination. We evaluated the following histologic features: presence of diffuse lymphoplasmacytic chronic cholecystitis, pyloric metaplasia, intestinal metaplasia, dysplasia (low-grade or high-grade), and adenocarcinoma. Gallbladder dysplasia and adenocarcinoma were correlated with several clinicopathologic parameters using Fisher exact test and t test, including: (1) sex, (2) age, (3) PSC duration, (4) inflammatory bowel disease (IBD) at time of OLT, and (5) concomitant bile duct dysplasia or carcinoma. Lymphoplasmacytic chronic cholecystitis was present in 35 (49%), pyloric metaplasia in 69 (96%), intestinal metaplasia in 36 (50%), dysplasia in 27 (37%; low-grade in 12 and high-grade in 15), and adenocarcinoma in 10 (14%; 2 with lamina propria invasion and 8 with invasion into muscularis or adventitia). Gallbladder carcinoma was associated with intrahepatic bile duct dysplasia (P=0.001), CC (P=0.023), and IBD (P=0.03). Gallbladder dysplasia was associated with hilar/intrahepatic bile duct dysplasia (P=0.0006), CC (P=0.028), IBD (P=0.0014), and older age at OLT (P=0.007). Neither gallbladder carcinoma nor dysplasia had a significant association with sex or PSC duration. These results indicate that complete histologic evaluation of gallbladders in patients undergoing transplantation for PSC yields high frequencies of inflammatory, metaplastic, and neoplastic changes. The strong correlation between gallbladder dysplasia/adenocarcinoma and bile duct dysplasia/CC supports the concept of a neoplastic “field effect” along the intrahepatic and extrahepatic biliary tract in PSC.

Assessment of Liver Viscoelasticity by Using Shear Waves Induced by Ultrasound Radiation Force

PURPOSE To investigate the value of viscosity measured with ultrasonographic (US) elastography in liver fibrosis staging and to determine whether the use of a viscoelastic model to estimate liver elasticity can improve its accuracy in fibrosis staging. MATERIALS AND METHODS The study, which was performed from February 2010 to March 2011, was compliant with HIPAA and approved by the institutional review board. Written informed consent was obtained from each subject. Ten healthy volunteers (eight women and two men aged 27-55 years) and 35 patients with liver disease (17 women and 18 men aged 19-74 years) were studied by using US elasticity measurements of the liver (within 6 months of liver biopsy). US data were analyzed with the shear wave dispersion ultrasound vibrometry (SDUV) method, in which elasticity and viscosity are measured by evaluating dispersion of shear wave propagation speed, as well as with the time-to-peak (TTP) method, where tissue viscosity was neglected and only elasticity was estimated from the effective shear wave speed. The hepatic fibrosis stage was assessed histologically by using the METAVIR scoring system. The correlation of elasticity and viscosity was assessed with the Pearson correlation coefficient. The performances of SDUV and TTP were evaluated with receiver operating characteristic (ROC) curve analysis. RESULTS The authors found significant correlations between elasticity and viscosity measured with SDUV (r = 0.80) and elasticity measured with SDUV and TTP (r = 0.94). The area under the ROC curve for differentiating between grade F0-F1 fibrosis and grade F2-F4 fibrosis was 0.98 for elasticity measured with SDUV, 0.86 for viscosity measured with SDUV, and 0.95 for elasticity measured with TTP. CONCLUSION The results suggest that elasticity and viscosity measured between 95 Hz and 380 Hz by using SDUV are correlated and that elasticity measurements from SDUV and TTP showed substantially similar performance in liver fibrosis staging, although elasticity calculated from SDUV provided a better area under the ROC curve.

IgG4+ plasma cell infiltrates in liver explants with primary sclerosing cholangitis.

Sclerosing cholangitis can be primary (PSC) or secondary. One unusual cause of secondary sclerosing cholangitis is the newly recognized entity of IgG4-associated cholangitis. The prevalence and significance of IgG4+ plasma cells in patients, who are clinically and radiologically classified as PSC, however, are unknown. Clinical information and histology of liver explants of 98 consecutive liver transplants performed for PSC were reviewed. IgG4 immunohistochemical stain was performed on sections from hilar areas that contained large bile ducts and corresponding cholecystectomy specimens (available in 74 cases). Serum IgG4 levels were measured in stored serum from 81 cases. Tissue IgG4 positivity (≥10 IgG4+ plasma cells/high power field) was correlated with clinical features (age, sex, presence of inflammatory bowel disease and cholangiocarcinoma, pancreatogram, PSC duration, PSC recurrence after transplant, and number of acute rejection episodes) and histologic findings (periductal lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis) in the liver explants. Twenty-three (23%) liver explants showed periductal infiltration with IgG4+ plasma cells. Eighteen cases (22%) had elevated serum IgG4 levels, including 8 without tissue IgG4 positivity. All cases showed dense periductal fibrosis; none had storiform fibrosis or obliterative phlebitis. IgG4 positivity in the liver strongly correlated with moderate-to-marked periductal lymphoplasmacytic inflammation (P=0.002). Clinically, IgG4 positivity in tissue, but not in serum, was correlated with shorter PSC duration before transplant and higher risk of recurrence after transplant. Nearly one quarter of explanted livers that carry a clinical diagnosis of PSC contain increased IgG4+ periductal plasma cell infiltrates and positive serum IgG4 levels. However, none of the explants show histologic features diagnostic of IgG4-associated cholangitis. PSC with tissue IgG4 positivity has a more aggressive clinical course manifested by shorter time to transplant and a higher likelihood of recurrence than IgG4 negative PSC.

Significance of Neoplastic Involvement of Margins Obtained by Endoscopic Mucosal Resection in Barrett's Esophagus

OBJECTIVES:Although EMR has been used for elimination of neoplasia in BE, the significance of positive carcinoma margins and depth of invasion on endoscopic resection pathology has not been assessed using a valid standard. The aim of this study was to assess the accuracy of tumor staging by EMR using esophagectomy as the standard.METHODS:Medical records of patients, who underwent endoscopic resection for esophageal carcinoma or high-grade dysplasia in BE followed by esophagectomy, were reviewed. Data were abstracted from a prospectively maintained EMR database. Endosonography and endoscopic resection were performed by a single experienced endoscopist. Two experienced GI pathologists interpreted all histological results. Standard statistical tests were used to compare continuous and categorical variables.RESULTS:Twenty-five patients were included in the study. Three patients had mucosal carcinoma and 16 had submucosal carcinoma following endoscopic resection. Surgical pathology staging was consistent with preoperative EMR staging in all patients. No patient with negative mucosal resection margins had residual tumor at the resection site at esophagectomy. In patients with submucosal carcinoma, 8 had residual carcinoma at the EMR site at surgery and 5 patients had metastatic lymphadenopathy.CONCLUSIONS:Tumor staging using EMR pathology is accurate when compared with surgical pathology following esophagectomy. Negative margins on EMR pathology correlate with absence of residual disease at the EMR site at esophagectomy. Submucosal carcinoma on EMR specimens was associated with a high prevalence of residual disease at surgery (50%) and metastatic lymphadenopathy (31%).

Prevalence and significance of human papillomavirus in oral tongue cancer: the Mayo Clinic experience.

PURPOSE Cigarette smoking and alcohol use have markedly decreased in the past 40 years. However, there has been an increasing trend in the incidence of tongue cancer, particularly in young patients without traditional risk factors. This study sought to examine the prevalence and significance of human papillomavirus (HPV) infection and its clinical significance in patients with oral tongue cancer. PATIENTS AND METHODS Fresh-frozen tissues from 51 patients with oral tongue cancer, treated with primary surgery from January 2004 to December 2006, were included in the study. The presence of HPV infection in tumor specimens was analyzed by polymerase chain reaction with HPV L1 consensus primers (GP 5+/GP 6+) and HPV-16-specific E6 primer pairs. Demographic and clinical data were collected to analyze patient outcomes. RESULTS The overall frequency of HPV in oral tongue cancer in our study was 1.96% (1/51). Young patients below the age of 45 years accounted for 15.7% (8/51) of the total number of patients. Eighty-seven percent of the younger age group, including a single patient with an HPV-16-positive tumor, were alive and free from disease during the follow-up period. The overall survival of the study group was 81.4%. CONCLUSIONS Our data suggest that the incidence of HPV in oral tongue cancer is low and is unlikely to play a significant role in the etiology, pathogenesis, and clinical outcomes of oral tongue cancer. In addition, HPV is unlikely to constitute a significant factor in the rising trend of oral tongue cancer in the young population.

Inflammatory pseudotumor of the spleen associated with a clonal Epstein-Barr virus genome: Case report and review of the literature

We report a case of an inflammatory pseudotumor (IPT) of the spleen occurring in an 81-year-old woman with a history of a monoclonal gammopathy of undetermined significance. Eighteen-month follow-up after splenectomy demonstrated no tumor recurrence or progression of underlying plasma cell disease. Histologic examination of the tumor demonstrated a polymorphic population of inflammatory and epithelioid and spindle cells. Immunophenotyping showed large numbers of T cells, B cells, and polyclonal plasma cells. The epithelioid and spindle cells were positive for vimentin and CD68 but lacked expression of follicular dendritic cell markers and actin. Epstein-Barr virus (EBV) genome was identified in the epithelioid and spindle cell population by in situ hybridization using probes specific for EBV-encoded RNAs (EBER1 and EBER2). Southern blot analysis of digested DNA extracted from the tumor using an EBV-specific probe (XhoI) demonstrated the presence of a single high-intensity band, indicative of EBV monoclonality. While there have been 2 previous reports of hepatic IPTs containing a monoclonal population of EBV-infected tumor cells, this is the first report of such an association occurring in the spleen. The presence of clonal EBV DNA suggests some splenic IPTs may be true neoplasms.

Precancerous bile duct pathology in end-stage primary sclerosing cholangitis, with and without cholangiocarcinoma

Patients with primary sclerosing cholangitis (PSC) are at increased risk for developing cholangiocarcinoma (CCA). However, the morphology of precursor lesions and the prevalence of biliary dysplasia among patients undergoing liver transplantation for PSC are incompletely defined, and the earlier studies using relatively small number of cases have yielded conflicting results. We retrospectively evaluated 100 consecutive formalin-fixed PSC liver explants (including 30 with CCA) by randomly sampling the hilar and large intrahepatic bile ducts (10 additional tissue cassettes submitted per case). The following histologic features were evaluated and quantitated according to the number of ducts involved: mucinous metaplasia, pyloric metaplasia, intestinal metaplasia, pancreatic acinar metaplasia, and biliary dysplasia [low-grade vs. high-grade (biliary intraepithelial neoplasia-2 or neoplasia-3), papillary vs. flat]. Using Fisher exact test and t test, these features were correlated with the presence or absence of CCA and with the following clinical parameters: sex, age, PSC duration, cirrhotic-stage liver disease, and inflammatory bowel disease at the time of transplant. We found high frequencies of mucinous metaplasia (77%), pyloric metaplasia (73%), and pancreatic acinar metaplasia (10%), which did not differ between CCA and non-CCA livers. However, livers with CCA were more likely to harbor intestinal metaplasia (43% vs. 19%, P=0.013), dysplasia (of any grade) (83% vs. 36%, P<0.0001), and high-grade dysplasia (60% vs. 11%, P<0.0001), and also contained greater numbers of dysplastic ducts than non-CCA cases (P<0.0001). The relative frequency of papillary (44%) versus flat (56%) dysplasia did not differ between CCA and non-CCA cases. Overall, intestinal metaplasia was a significant predictor of bile duct dysplasia (P=0.0005) and CCA (P=0.013), low-grade dysplasia predicted high-grade dysplasia (P<0.0001) and CCA (P=0.0004), and high-grade dysplasia predicted CCA (P<0.0001). Among the clinical parameters, there were no significant differences in age, sex, history of inflammatory bowel disease, or PSC duration, but patients transplanted for CCA were less likely to have cirrhosis (60% vs. 86%, P=0.008). These data strongly support a metaplasia–low-grade dysplasia–high-grade dysplasia–carcinoma sequence in PSC-associated CCA, and underscore the known lack of relationship between patient age and PSC duration in the development of CCA. Even in the absence of CCA, bile duct dysplasia is still a relatively frequent finding, seen at least focally in 36% of benign end-stage PSC explants. Dysplasia, however, is generally confined to large and septal-size bile ducts and its presence may not be recognized unless multiple sections specifically targeted to the biliary tree are examined.

Depth of Submucosal Invasion Does Not Predict Lymph Node Metastasis and Survival of Patients With Esophageal Carcinoma

BACKGROUND & AIMS There is controversy over the outcomes of esophageal adenocarcinoma with superficial submucosal invasion. We evaluated the impact of depth of submucosal invasion on the presence of metastatic lymphadenopathy and survival in patients with esophageal adenocarcinoma. METHODS Pathology reports of esophagectomy samples collected from 1997 to 2007 were reviewed. Specimens from patients with esophageal adenocarcinoma and submucosal invasion were reviewed and classified as superficial (upper 1 third, sm1) or deep (middle third, sm2 or deepest third, sm3) invasion. Outcomes studied were presence of metastatic lymphadenopathy and overall survival. Variables of interest were analyzed as factors that affect overall and cancer-free survival using Cox proportional hazards modeling. A multivariate model was constructed to establish independent associations with survival. RESULTS The study included 80 patients; 31 (39%) had sm1 carcinoma, 23 (29%) had sm2 carcinoma, and 26 (33%) had sm3 carcinoma. Superficial and deep submucosal invasion were associated with substantial rates of metastatic lymphadenopathy (12.9% and 20.4%, respectively). The mean follow-up time was 40.5 +/- 4 months and the mean overall unadjusted survival time was 53.8 +/- 4.1 months. Factors significantly associated with reduced survival time included the presence of metastatic lymph nodes (hazard ratio [HR], 2.89; confidence interval [CI], 1.13-6.88) and esophageal cancer recurrence (HR 6.39, CI 2.40-16.14), but not depth of submucosal invasion. CONCLUSIONS Patients with sm1 esophageal carcinoma have substantial rates of metastatic lymphadenopathy. Endoscopic treatment of superficial submucosal adenocarcinoma is not advised for patients that are candidates for surgery.

Muscularis mucosae duplication and the musculo-fibrous anomaly in endoscopic mucosal resections for Barrett esophagus: Implications for staging of adenocarcinoma

Endoscopic mucosal resection (EMR) is increasingly used for management of Barrett esophagus (BE)-related neoplasia. Duplication of the muscularis mucosae (MM) has been described in BE esophagectomy specimens, where it can pose difficulties with accurate staging of carcinoma. The frequency, morphologic characteristics, and effect of MM duplication in adenocarcinoma staging in EMRs have not yet been evaluated. We studied 122 EMR specimens from 100 patients from 1999 to 2006. The following histologic features were scored: depth of EMR, presence of MM duplication and its extent, prolapse changes (extension of smooth muscle into lamina propria), gland entrapment, and diagnosis (original and study/final). Carcinomas reaching the level of submucosa were classified as invasive adenocarcinoma (INV); those confined to lamina propria or MM were classified as intramucosal adenocarcinoma (IMAC). Of 122 EMRs, 11 (9%) reached mucosa only, 109 (89%) extended to submucosa, and 2 (2%) extended into muscularis propria. MM duplication was present in 67% (75 of 111 specimens that reached at least submucosa). Prolapse changes were noted in 65 (54%) cases and gland entrapment in 67 (56%). Final pathologic diagnoses were 9 (7%) no specialized Barrett mucosa, 4 (3%) BE without dysplasia, 13 (11%) low-grade dysplasia, 51 (42%) high-grade dysplasia, 33 (27%) IMAC, and 12 (10%) INV. EMRs without BE were less likely to show MM duplication (P=0.01) and there was a trend toward less frequent prolapse change (P=0.08) and less gland entrapment (P=0.08) as compared with EMRs with BE. However, there were no significant differences with respect to MM duplication, prolapse change, or gland entrapment between BE with or without dysplasia, IMAC, or INV. Among 33 cases of IMAC, tumor invaded lamina propria in 10 (30%), inner or single MM in 14 (42%), space between duplicated MM in 5 (15%), and outer MM layer in 4 (12%). Lymphatic invasion was seen in 2 (10%) cases in which tumor reached the space between MM layers. Overstaging of carcinomas occurred in the original reports in 8 (7%) cases due to misinterpretation of the muscular anatomy, including one case in which the deep MM was interpreted as muscularis propria. These results show that MM duplication is commonly seen in EMR specimens. It is closely associated with the presence of BE but is not affected by neoplastic progression in the Barrett epithelium. Pathologists need to be aware of this distinctive anatomy of BE for accurate staging of adenocarcinomas, particularly to avoid mistaking a thickened outer MM as muscularis propria. Level of IMAC may be a critical feature because of potential access to lymphatic spaces between duplicated MM layers, and we therefore recommend including an explicit statement about the depth of adenocarcinoma invasion rather than using only broad terms such as IMAC or INV in the diagnostic report.