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Nodular regenerative hyperplasia (NRH) of the liver may lead to noncirrhotic portal hypertension with subsequent development of portosystemic shunts. While extrahepatic and macrovascular shunts are readily visualized with imaging or endoscopy, there is no standard technique to detect intrahepatic microvascular portosystemic shunting and quantitatively assess shunt burden. We present a case of a 53-year-old female with suspected NRH and hepatopulmonary syndrome with inconclusive liver biopsies and absent portosystemic shunts per abdominal imaging. A percutaneous transportal infusion of Technetium-99m labeled macroaggregated albumin (99mTc-MAA) successfully identified intrahepatic microvascular portosystemic shunting and quantified a lung shunt fraction of more than 30%. NRH was subsequently confirmed with a surgical wedge biopsy and the patient was successfuly treated with a liver transplant. Transportal 99mTc-MAA could be used to both identify and quantify otherwise occult microvascular portosystemic shunts in patients with clinical sequelae of portal hypertension.

Background Although gastrointestinal involvement is the most common site for extra-genital endometriosis, deep infiltrative endometriosis, which affects the mucosal layer, is very rare. Case presentation We present a case of a 41-year-old white woman with cyclic rectal bleeding. Magnetic resonance imaging was done, together with colonoscopy and histologic staining of biopsied samples, which led to the final diagnosis of intestinal invasive endometriosis with recto-sigmoid stricture. Our patient was treated symptomatically with stool softeners. Conclusion This case provides a rare example of catamenial bleeding. It is important to keep invasive endometriosis on the differential diagnosis whenever a premenopausal woman has cyclical rectal bleeding.

Insulinomas are the most common type of functional pancreatic neuroendocrine tumor. Although insulinomas usually are noninvasive or benign, 10% are deemed invasive or malignant. The pathologic mechanisms that lead to the malignant phenotype are not well elucidated. In this case report, we present a patient with stage 4 malignant insulinoma with metastasis to the liver, bone, and brain. Genetic analysis of the tumor showed that the tumor was mismatch-repair deficient and had a high rate of microsatellite instability. There was loss of MLH1- and PMS2-encoded protein expression, and MLH1 and MEN1 variants were identified. Notably, the liver metastasis showed considerable tumor heterogeneity (well differentiated) compared with the brain metastasis (poorly differentiated).

Energy drinks (ED) are becoming increasingly popular, but little has been reported about their stomach effects. To our knowledge, there is no literature suggesting an association with the development of atrophic gastritis (AG) or gastric intestinal metaplasia (GIM). AG and GIM have been associated with an increased risk of gastric cancer. Reversal of these lesions has shown to reduce the incidence of gastric cancer but has only been studied to eradicate Helicobacter pylori. This case describes a female who consumed high amounts of ED and was subsequently diagnosed with AG and GIM. Interestingly, the pathologies resolved upon cessation of ED.

PURPOSE To evaluate the pathologic outcomes of hepatocellular carcinoma (HCC) treated with Yttrium-90 radiation segmentectomy using glass microspheres prior to liver transplantation and explore parameters associated with pathologic necrosis. MATERIALS AND METHODS A single-institution retrospective analysis of HCC patients who received radiation segmentectomy prior to liver transplantation from November 2016 to May 2020 was performed. Patients were included if the treatment angiosome encompassed the entire tumor and could be correlated with available gross pathology. Archived histology slides were reviewed for percentage of pathologic necrosis. Thirty-three patients with 37 tumors were evaluated. The median tumor size was 2.3 cm (range, 1-6.7 cm). RESULTS All tumors received a single treatment. The median time from radiation segmentectomy to transplantation was 206 days (range, 58-550 days). Objective response per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) was 92% (complete response, 76%; partial response, 16%). A total of 68% (n = 25) of tumors demonstrated ≥99% pathologic necrosis. Complete pathologic necrosis was present in 53% and 75% of tumors treated with >190 Gy (n = 18) and >500 Gy (n = 8) single-compartment Medical Internal Radiation Dose, respectively. Complete response per mRECIST, posttreatment angiosome T1 hypointensity, dose >190 Gy, microsphere specific activity >297 Bq, and a longer time between treatment and transplant were associated with ≥99% tumor necrosis (P < .05). No posttransplant tumor recurrences occurred within a median follow-up of 604 days (range, 138-1,223 days). CONCLUSIONS Radiation segmentectomy can serve as an ablative modality for the treatment of HCC prior to liver transplant.

Purpose To evaluate whether historic risk categories and indications for adjuvant therapy in the pre–human papillomavirus (HPV) and pre–transoral surgery (TOS) era were associated with clinically significant relapse rates in HPV+ oropharyngeal squamous cell cancer patients undergoing TOS. Methods and Materials A multi-institutional retrospective review of intermediate- and high-risk HPV+ oropharyngeal squamous cell cancer patients not receiving adjuvant therapy after TOS was performed. Perineural invasion, lymphovascular invasion, T3-T4, or ≥N2 disease were considered to be intermediate-risk factors, and extracapsular extension or positive margins were considered to be high-risk features, according to established risk categories. Results Median follow-up was 42.9 months. Among all 53 patients, the 3-year cumulative incidence of relapse was 26.0%. The 3-year cumulative incidence was 11.8% in the 37 intermediate-risk patients and 52.4% in the 16 high-risk patients. On univariate analysis only high-risk status was significantly associated with an increased risk of relapse (hazard ratio 3.9; P=.018). The salvage rate for relapse was 77%, with 10 of 13 patients undergoing salvage therapy. Conclusions Risk category was associated with clinically significant relapse rates after TOS alone in HPV+ oropharyngeal cancer, comparable to historical data and traditional indications for adjuvant therapy for all oropharyngeal cancer.

Low-grade dysplasia (LGD) is a risk factor for progression in Barrett's esophagus (BE). Progression estimates however vary and predictors of progression are not well established. We aimed to assess predictors of progression in a multicenter BE-LGD cohort.All subjects with LGD (diagnosed by a GI pathologist) in a prospective BE registry were identified. Progression was defined development of HGD/EAC more than 12 months after index date of LGD diagnosis. Clinical, endoscopic factors and impact of histologic review by an independent panel of two GI pathologists were assessed as predictors of progression. Cox proportional hazard models were used to assess their association with risk of progression.244 BE-LGD subjects met inclusion criteria. Their mean age was 63.2 years. 205 (84%) were males. The median follow up was 4.8 years. Fifty six patients were diagnosed with HGD/EAC in less than 12 months, while 14 progressed to HGD/EAC after 12 months, with an overall annual risk of progression of 1.2%. 29% of LGD subjects were downgraded to non-dysplastic and the remaining re-confirmed as LGD or indefinite dysplasia. The risk of progression in the reconfirmed LGD group was eight fold higher (hazards ratio: 7.6, 95% CI: 1.5-139.4) in a propensity score stratified model.In this large BE-LGD cohort, progression risk increased substantially when an additional panel of two expert GI pathologists re-confirmed a LGD diagnosis. These BE subjects may be candidates for endoscopic therapy. LGD was a marker of prevalent HGD/EAC in 18% of patients.

Crystal-storing histiocytosis (CSH) is an uncommon condition in which histiocytes accumulate a crystalline matter within their cytoplasm. Generally, those crystals are composed of either monoclonal or polyclonal immunoglobulin chains, which have a strong association with an underlying lymphoproliferative or plasma cell disorder (LP-PCD). Rarely, CSH has been reported as local or generalized manifestation of a variety of benign disorders. These cases are associated with crystals composed of nonimmunoglobulin substances. We are reporting an exceptional case of a local colonic CSH with Charcot–Leyden crystals. This patient underwent a screening colonoscopy that detected some polyps. The biopsy reported tubular adenomas, with a markedly dense, transmural inflammatory infiltrates, which were predominantly composed of eosinophils and crystal-storing histiocytes containing Charcot–Leyden crystals. The patient had a negative workup for LP-PCD and autoimmune conditions, including a normal skeletal survey and bone marrow aspirate/biopsy. The only positive laboratory workup was an elevated absolute eosinophil count and a positive IgG anti-Strongyloides antibody. Giving those findings, this parasitic infection is the most likely etiology of the CSH in our patient. Although there was an initial negative evaluation for LP-PCD, close monitoring of patients with either immunoglobulin or nonimmunoglobulin CSH is recommended.

Background and Aims The treatment of submucosal (T1b) esophageal adenocarcinoma (EAC) remains in evolution, with some evidence supporting endoscopic management of low-risk lesions. Using a multicenter cohort, we evaluated outcomes of patients with T1b EAC and predictors of survival. Methods Patients diagnosed between 2001 and 2016 with T1b EAC were identified from 3 academic medical centers in the United States. Demographic, clinical, and outcome data were collected. Outcomes studied were overall and cancer-free survival. Cox proportional hazards models were constructed to assess independent predictors of survival. Results One hundred forty-one patients were included, of whom 68 (48%) underwent esophagectomy and 73 (52%) were treated endoscopically. Most patients (85.8%) had high-risk histologic features. Thirty-day operative mortality was 2.9%. Median follow-up in the esophagectomy and endoscopic cohorts was 49.4 and 43.4 months, respectively. Patients treated endoscopically were older with higher comorbidity scores, with 46 (63%) achieving histologic remission. Nineteen patients (26.0%) also received chemoradiation. Five-year overall survival rates in the surgical and endoscopic cohorts were 89% and 59%, respectively, whereas 5-year cancer-free survival rates were 92% and 69%. Presence of high-risk histologic features was associated with reduced overall survival. Conclusions In this large multicenter study of patients with T1b EAC, esophagectomy was associated with improved overall but not cancer-free survival. High-risk histologic features were associated with poorer survival.

Gastroesophageal reflux disease may elicit a histologic reaction in the squamous mucosa of the esophagus. From a clinical perspective, it is divided into erosive and nonerosive forms. While no histologic feature is specific, reflux esophagitis is associated primarily with eosinophils. These are typically scattered within the epithelium and do not reach the intensity seen in eosinophilic esophagitis. Other features include basal cell hyperplasia, papillary elongation, spongiosis, and increased epithelial thickness. Prolonged reflux esophagitis may result in metaplastic transformation of the squamous mucosa to a columnar mucosa containing goblet cells, referred to as Barrett esophagus. This metaplastic mucosa is a preneoplastic condition, which may ultimately transform into adenocarcinoma through a dysplasia-carcinoma sequence. There are three morphologies of dysplastic Barrett mucosa: intestinal, foveolar, and serrated types. Grading dysplasia is a subjective endeavor and suffers from poor inter- and intra-observer agreement.

Early detection improves hepatocellular carcinoma (HCC) outcomes, but better noninvasive surveillance tools are needed. We aimed to identify and validate methylated DNA markers (MDMs) for HCC detection. Reduced representation bisulfite sequencing was performed on DNA extracted from 18 HCC and 35 control tissues. Candidate MDMs were confirmed by quantitative methylation-specific PCR in DNA from independent tissues (74 HCC, 29 controls). A phase I plasma pilot incorporated quantitative allele-specific real-time target and signal amplification assays on independent plasma-extracted DNA from 21 HCC cases and 30 controls with cirrhosis. A phase II plasma study was then performed in 95 HCC cases, 51 controls with cirrhosis, and 98 healthy controls using target enrichment long-probe quantitative amplified signal (TELQAS) assays. Recursive partitioning identified best MDM combinations. The entire MDM panel was statistically cross-validated by randomly splitting the data 2:1 for training and testing. Random forest (rForest) regression models performed on the training set predicted disease status in the testing set; median areas under the receiver operating characteristics curve (AUCs; and 95% confidence interval [CI]) were reported after 500 iterations. In phase II, a six-marker MDM panel (homeobox A1 [HOXA1], empty spiracles homeobox 1 [EMX1], AK055957, endothelin-converting enzyme 1 [ECE1], phosphofructokinase [PFKP], and C-type lectin domain containing 11A [CLEC11A]) normalized by beta-1,3-galactosyltransferase 6 (B3GALT6) level yielded a best-fit AUC of 0.96 (95% CI, 0.93-0.99) with HCC sensitivity of 95% (88%-98%) at specificity of 92% (86%-96%). The panel detected 3 of 4 (75%) stage 0, 39 of 42 (93%) stage A, 13 of 14 (93%) stage B, 28 of 28 (100%) stage C, and 7 of 7 (100%) stage D HCCs. The AUC value for alpha-fetoprotein (AFP) was 0.80 (0.74-0.87) compared to 0.94 (0.9-0.97) for the cross-validated MDM panel (P < 0.0001). Conclusion: MDMs identified in this study proved to accurately detect HCC by plasma testing. Further optimization and clinical testing of this promising approach are indicated.

We present a rare case of gastrointestinal (GI) bleeding associated with metastatic prostate adenocarcinoma to the stomach. Prostate cancer, which is the most common noncutaneous malignancy among men, rarely spreads to the stomach, with only 7 cases reported in the English literature. Symptoms may include abdominal pain, nausea, vomiting, and GI bleeding. Our patient was treated with epinephrine injection and bipolar cautery, but GI bleeding recurred 7 months later when he had worsening of his thrombocytopenia while using ibuprofen.

Grading criteria for biliary dysplasia associated with primary sclerosing cholangitis (PSC) have been recently described. Although a dysplasia to cholangiocarcinoma (CCA) sequence is implied, supportive data are lacking. Seventeen liver explants with biliary dysplasia from patients with PSC were selected. Formalin-fixed, paraffin-embedded blocks from each patient were evaluated to identify areas of normal/reactive biliary epithelium, intestinal metaplasia, low-grade dysplasia, high-grade dysplasia, and CCA. Areas of interest were assessed for chromosomal alteration with fluorescence in situ hybridization using probes directed to locus 9p21 and centromeres 3, 7, and 17. The cutoffs for calling probe copy number abnormalities for polysomy, single locus gain, and homozygous 9p21 loss were established by receiver operating characteristic curve analysis. Of 4 areas of intestinal metaplasia, 19 low-grade dysplasias, 19 high-grade dysplasias, and 5 CCAs, 0%, 11%, 58%, and 40% displayed polysomy and 0%, 0%, 16%, and 40% exhibited homozygous 9p21 loss as the most severe abnormality, respectively. Patients with prior or current CCA were more likely to display polysomy in dysplasia than patients without CCA (70% versus 14%; P = .05); however, high-grade dysplasia was proportionally more common in the CCA-associated dysplasia group. Polysomy and homozygous 9p21 loss are detected in biliary dysplasia and CCA. These findings support a dysplasia-carcinoma sequence in PSC patients and suggest that fluorescence in situ hybridization analysis could help refine the grading of biliary dysplasia in these patients.

Background & Aims Increased waist circumference and visceral fat are associated with increased risk of Barrett's esophagus (BE) and esophageal adenocarcinoma. This association might be mediated by mechanical and endocrine mechanisms. We investigated the distribution of fat in subjects with BE and its association with esophageal inflammation and dysplasia. Methods We collected data from 50 BE cases and 50 controls (matched for age and sex, identified from a radiology trauma database) seen at the Mayo Clinic in 2009. Abdominal (subcutaneous and visceral) and gastroesophageal junction (GEJ) fat area was measured using computed tomography with standard techniques. Esophageal inflammation (based on a histologic score) and dysplasia grade were assessed from esophageal biopsies of BE cases by a gastrointestinal pathologist. Conditional logistic regression was used to assess the association of body fat depot area with BE status, esophageal inflammation, and dysplasia. Results All BE subjects had controlled reflux symptoms without esophagitis, based on endoscopy. The GEJ fat area (odds ratio [OR], 6.0; 95% confidence interval [CI], 1.3–27.7; P = .02), visceral fat area (OR, 4.9; 95% CI, 1.0–22.8; P = .04), and abdominal circumference (OR, 9.1; 95% CI, 1.4–57.2; P = 0.02) were associated with BE, independent of body mass index (BMI). The subcutaneous fat area was not associated with BE. Visceral and GEJ fat were significantly greater in BE subjects with esophageal inflammation (compared with those without, P = .02) and high-grade dysplasia (compared with those without, P = .01), independent of BMI. Conclusions GEJ and visceral fat are associated with BE, and with increased esophageal inflammation and high-grade dysplasia in BE subjects, independent of BMI. Visceral fat therefore might promote esophageal metaplasia and dysplasia.

Sarcomas of the sinonasal region are rare. We describe a distinct spindle cell sarcoma of the sinonasal region characterized by concomitant neural and myogenic differentiation. Consultation files and surgical cases from Mayo Clinic were reviewed. Twenty-eight cases were identified that met the inclusion criteria. Clinical data were collected from medical records, consultation letters, and referring pathologists. Reverse transcriptase-polymerase chain reaction for synovial sarcoma fusion transcripts was performed on 18 cases. Cytogenetic studies were performed on 2 cases. The 21 female and 7 male patients ranged in age from 24 to 85 years (mean, 52 y). All cases showed a characteristic histology, which included a cellular spindle cell neoplasm with uniform, elongate nuclei and an infiltrative growth pattern. All tumors demonstrated expression of S-100 with actin positivity in 96% of cases tested. Reverse transcriptase-polymerase chain reaction for synovial sarcoma fusion transcripts was negative in all cases tested. Cytogenetic studies conducted on 2 cases demonstrated the chromosomal translocation t(2;4). The nasal cavity (54%) and ethmoid sinus (57%) were the most commonly involved areas, singly or in combination. Follow-up information was available for 57% (16/28) of cases, with a mean of 8.3 years. Of these, 44% (7/16) experienced at least 1 recurrence. No patient has developed metastases or died of disease. We describe a unique tumor with a characteristic morphologic, immunophenotypic, and cytogenetic profile. On the basis of the locally aggressive nature of this lesion we believe it is best considered a low-grade sarcoma and suggest the term low-grade sinonasal sarcoma with neural and myogenic features.

Esophagectomy is usually recommended for patients with submucosal esophageal adenocarcinoma (T1b EAC) because of the potential for lymph node metastasis (LNM). Endoscopic management often differs based on the risk of metastasis. There is limited information on the difference in outcomes for T1b-EAC with and without esophagectomy.To investigate (1) the outcomes of T1b EAC treatments with and without esophagectomy and (2) the percentage of LNM at esophagectomy for T1b-EAC.Retrospective cohort.A tertiary Barrett's esophagus unit.Sixty-eight T1b EAC patients based on EMR histology.Esophagectomy and endoscopic therapies.Survival duration and mortality rate.A total of 68 patients had T1b EAC; cumulative mortality rate was 30.9% and median survival duration was 39.5 months. Thirty-nine underwent esophagectomy and 29 did not. Among patients who underwent esophagectomy, 13 (33.3%) had LNM, and the mortality rate was 50.0% and 11.1% for those with and without LNM, respectively (P.01). For those with and without esophagectomy, the cumulative mortality rates were 25.6% and 37.9%, and median survival duration was 48.9 and 34.8 months, respectively. There was no statistical difference in Charlson comorbidity index, number of EMRs, mortality rate, or survival duration. In Cox proportional hazard model analysis, the hazard ratio for esophagectomy was 0.5 (P = .21).Retrospective, nonrandomized small sample size cohort.Among the patients with T1b EAC found in EMR specimens who underwent esophagectomy, one third had regional LNM. In our small series, patients who underwent esophagectomy did not have a significantly different survival duration from that of those who did not, indicating that these patients may have similar outcomes [corrected].

Biphenotypic sinonasal sarcoma (SNS) is a newly described tumor of the nasal and paranasal areas. Herein, we report the novel recurring chromosomal translocation t(2;4)(q35;q31.1) in SNS. The translocation results in the formation of the fusion protein PAX3-MAML3, which is a potent transcriptional activator of PAX3 response elements. The SNS phenotype is characterized by aberrant expression of genes involved in neuroectodermal and myogenic differentiation, which closely simulates the developmental roles of PAX3.

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.

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

Objective To report 3 cases of primary neuroendocrine tumors (PNT) of the extrahepatic biliary tree (EHBT) in patients with Zollinger-Ellison syndrome (ZES), 2 of whom had multiple endocrine neoplasia type 1 (MEN 1). Methods Three new cases of gastrin-producing tumors of the EHBT are presented, and the pertinent literature relating to PNT of the EHBT is reviewed. Results Eighty-one previous cases of PNT of the EHBT have been reported in the world literature, 7 of which were hormonally active and associated with peptic ulcer disease, diarrhea, or ZES. Three additional patients presented to us with ZES due to PNT of the EHBT. One patient with MEN 1 was treated with a Whipple procedure for a common bile duct gastrinoma. A second patient underwent left hepatectomy with resection of the confluence of the right and left hepatic ducts for a primary left hepatic duct gastrinoma. The second patient with MEN 1 underwent resection of a gastrinoma at the junction of the cystic duct and the common bile duct. Conclusion Although PNT of the EHBT are uncommon, the association with ZES is even more so. Often, nonfunctioning tumors are diagnosed late in the course of the disease from symptoms related to biliary obstruction. Patients with ZES may be diagnosed earlier because of symptoms resulting from gastrin excess. Surgical resection is the only chance for cure and is often helpful in the palliation of symptoms. (Endocr Pract. 2009;15:737-749)

Background: Microscopic colitis is diagnosed based on histologic criteria. There has been no investigation of the reproducibility of the histologic diagnosis of microscopic colitis. Our aim was to evaluate interobserver and intraobserver variation in this diagnosis. Methods: Colonic biopsies from 90 subjects (20 lymphocytic colitis, 20 collagenous colitis, 20 inflammatory bowel disease, and 30 normal) were blindly and independently reviewed by 4 gastrointestinal pathologists. The biopsies were classified by each pathologist into 1 of 6 diagnostic categories: lymphocytic colitis, collagenous colitis, active chronic colitis, focal active colitis, normal, or other. The slides were then relabeled and blindly reinterpreted 3 months later. The degree of agreement was determined using kappa statistics (λ). Results: Interobserver agreement with the 6 diagnostic categories was 69% (κ = 0.76, 95% CI 0.69, 0.83) and 70% (κ = 0.71, 95% CI 0.61, 0.79) for the first and second observations, respectively. Interobserver agreement with final diagnostic categories of microscopic colitis versus nonmicroscopic colitis was 91% (κ = 0.90, 95% CI 0.82, 0.96) and 88% (κ = 0.83, 95% CI 0.73, 0.92), respectively. Mean intraobserver agreement with the 6 diagnostic categories was 83% (κ = 0.77). Mean intraobserver agreement with the final diagnostic categories of microscopic colitis versus nonmicroscopic colitis was 95% (κ = 0.89). Conclusions: Both interobserver and intraobserver agreement were good in distinguishing among the 6 diagnostic categories, and excellent in distinguishing between microscopic colitis and nonmicroscopic colitis diagnoses. The histologic criteria for microscopic colitis provide for consistent and reproducible interindividual and intraindividual diagnoses in the evaluation of colonic biopsies. (Inflamm Bowel Dis 2008)

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.

Background: The risk for subsequent breast cancer in women diagnosed with radial scar lesions (RS) on benign breast biopsy remains controversial. We studied the relative risk of radial scar lesions in a large cohort of patients with benign breast disease (BBD). Methods: Radial scars were identified in a BBD cohort of 9,262 patients biopsied at Mayo Clinic between 1967 and 1991. Radial scar lesions were classified as proliferative disease without atypia (PDWA) unless atypia was present (classified as atypical hyperplasia [AH]). The observed number of breast cancers developing among those with RS was compared to that expected in the general population using standardized incidence ratios (SIRs, mean follow-up interval 17 years). Results: RS were identified in 439 (4.7%) of the cohort members; 382 (87.0%) contained one RS, 42 (9.6%) contained two, 9 (2.0%) contained three, and 6 (1.4%) contained four or more. The majority of RS (356, 82.4%) were less than 5.0 mm in diameter; 60 (13.9%) were 5.0–9.9 mm, and 16 (3.7%) were 10.0 mm or greater. The relative risk for women with PDWA and RS was 1.88 (95% CI, 1.36–2.53), no different than PDWA without RS [relative risk 1.57 (95% CI, 1.37–1.79) (P = 0.29)]. Women with atypical hyperplasia and RS (n = 60) had a relative risk of 2.81 (95% CI, 1.29–5.35), while those with atypia but without RS had a relative risk of 3.97 (95% CI, 2.99–5.19). Conclusions: RS imparts no increased breast cancer risk above that of PDWA or AH without RS.

Crystal-storing histiocytosis is a rare diagnosis that to date has only been associated with 2 conditions: intracytoplasmic accumulation of crystallized immunoglobulins in patients with lymphoproliferative disorders or plasma cell dyscrasias, and histiocytic accumulations of phagocytosed clofazimine, a drug used to treat lepromatous leprosy. We describe a 78-year-old woman with a past medical history of dermatologic mastocytosis and peripheral eosinophilia who presented with diarrhea and weight loss, and was found at colonoscopy to have polyposis limited to the right and transverse colon. She eventually underwent subtotal colectomy to remove the segment of polyposis. At gross examination, the colonic mucosa contained numerous polyps ranging from 1 to 7 mm which on histologic evaluation proved to represent mucosal and submucosal collections of histiocytes whose cytoplasm was distended by numerous brightly eosinophilic crystals. An intense eosinophilic infiltrate surrounded the histiocyte collections and also mildly involved the intervening colonic mucosa and superficial submucosa. Electron microscopy confirmed the presence of intracytoplasmic material identical to Charcot-Leyden crystals within histiocytes, representing the breakdown products of degranulated eosinophils. This is the first reported case of crystal-storing histiocytosis produced by massive accumulation of Charcot-Leyden crystals in eosinophilic colitis.

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.

Fluorescence in situ hybridization (FISH) and immunohistochemical analysis for assessment of HER-2 status in breast carcinomas are discordant in a significant proportion of cases with equivocal (2+) immunostaining. To evaluate the role of intratumoral heterogeneity and degree of amplification, we performed additional HER-2 immunostains and FISH on tumor-bearing blocks from 20 invasive breast carcinomas with immunohistochemical scores of 2+ with gene amplification and in 18 cases without amplification. Of the amplified cases, 11 (55%) had a 3+ immunohistochemical score on at least 1 additional slide, 8 (40%) remained 2+, and 1 (5%) had a slide scored 1+. All cases rescored 3+ showed high-level amplification in original and repeated FISH; cases remaining 2+ had a heterogeneous FISH profile (low-level amplification or a mosaic mixture of high-level amplified and nonamplified cells) in original and repeated FISH. Of nonamplified cases, 13 (72%) had a 1+ score on at least 1 additional slide, 4 (22%) remained 2+, and 1 (6%) had 1 slide scored 3+. In the nonamplified cases, 17 (94%) showed no amplification in repeated FISH. Significant intratumoral heterogeneity and minimal (low-level) HER-2 amplification account for many breast cancers with 2+ HER-2 protein expression.

Glomus tumor of the trachea is extremely rare. We report a case of tracheal glomus tumor in a 39-year-old man who presented with hemoptysis. The diagnosis was made after bronchoscopic biopsy of a tumor involving the posterior wall of the upper trachea. Thin-section multidetector computed tomography of the chest was performed before surgical resection, with multiplanar re-formations and 3-dimensional virtual bronchoscopic reconstruction. Tracheal sleeve resection with reconstruction was successful, and pathological studies confirmed complete resection and the diagnosis of glomus tumor. The patient was disease-free 3 months postoperatively. To our knowledge, this is the first reported case in which additional computed postprocessing was used to help evaluate the extent of such a tumor.

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.

Background & Aims Superficial (T1) esophageal adenocarcinoma (EAC) commonly is treated by endoscopic resection, yet little is known about factors that predict outcomes of this approach. We assessed clinical and histologic variables associated with the overall survival times of patients with T1 EAC who received therapy. Methods In a retrospective analysis, we collected data from patients who underwent endoscopic mucosal resection (EMR) for T1 EAC (194 patients with T1a and 75 patients with T1b) at the Mayo Clinic, from 1995 through 2011. EMR specimens were reviewed systematically for depth of invasion, presence of lymphovascular invasion, grade of differentiation, and status of resection margins. Kaplan–Meier curves and proportional hazards regression models were used in statistical analyses. Results Demographic characteristics were similar between patients with T1a and T1b EAC. Overall survival at 5 years after EMR was 74.4% for patients with T1a (95% confidence interval [CI], 67.6%−81.8%) and 53.2% for patients with T1b EAC (95% CI, 40.3%–70.1%). Of surviving patients with T1a EAC, 94.1% remained free of cancer (95% CI, 89.8%–98.5%), and 94.7% of surviving patients with T1b EAC remained free of cancer (95% CI, 85.2%−100%). A multivariable model associated older age (per 10-year increment), evidence of lymphovascular invasion, and deep margin involvement with reduced overall survival in patients with T1 EAC. Conclusions Systematic assessment of EMR specimens can help predict mortality and potentially guide treatment options for patients with T1 EAC.

Background There are currently 2 existing confocal laser endomicroscopy (CLE) platforms: probe-based CLE (pCLE) and endoscope-based CLE (eCLE) systems, each with its own criteria for identifying dysplasia in Barrett's esophagus (BE). The diagnostic performance of these 2 systems has not been directly compared. Design Preclinical, feasibility study. Objectives We compared the interrater agreement and diagnostic performance of the pCLE and eCLE systems. In addition, we evaluated a new BE endomicroscopy criteria based on fluorescent glucose intensity uptake. Patients Thirteen patients with Barrett's esophagus and high-grade dysplasia or early cancer undergoing 16 EMR. Intervention CLE imaging was performed using two different probes with 2-[N-(7-nitrobenz-2-oxa-1,3-diaxol-4-yl)amino]-2-deoxyglucose, a fluorescent glucose analog with preferential uptake in dysplastic mucosa to supply contrast. Four quadrants were imaged per specimen with a total of 64 imaged mucosal sites presented to three gastroenterologists. Main Outcome Measurements Interobserver agreement and accuracy for dysplasia was assessed of images classified according to Miami criteria, stacked eCLE images classified using the Mainz criteria and a novel fluorescence intensity criteria. Results The interrater agreements were 0.17, 0.68, and 0.87 for the Miami, Mainz, and the fluorescence intensity criteria, respectively. Overall accuracy in detecting dysplasia was 37% (95% CI, 30.3-43.9), 44.3% (95% CI, 37.3-50.9), and 78.6% (95% CI, 72.2-83.3) for the Miami, Mainz, and the fluorescence intensity criteria, respectively. Limitations This imaging technique and proposed fluorescence intensity criteria using 2-[N-(7-nitrobenz-2-oxa-1,3-diaxol-4-yl)amino]-2-deoxyglucose in EMR tissue will require in vivo validation and cannot be directly used with the current eCLE and pCLE clinical applications. Conclusions In this preclinical feasibility study, the use of an eCLE system with a topical fluorescent contrast in ex vivo EMR tissue demonstrated higher interrater agreement and accuracy.

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 (>or=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.

Esophageal food impaction (FI) is a distressing condition requiring urgent endoscopic intervention, with a reported recurrence rate between 10% and 20%. Knowledge of factors predisposing to recurrent FI may enable preventive measures to minimize the risk of recurrence.To identify risk factors associated with recurrent FI.Retrospective case-control study.Tertiary referral center.A prospectively maintained database and medical records of all patients undergoing emergent endoscopy for FI from 1989 to 2000 were reviewed. Cases were defined as those presenting with more than 1 episode of FI, whereas controls were defined as those without recurrence within 5 years of the index episode. Several demographic, clinical, endoscopic, and follow-up variables were extracted. Statistical analysis included chi2 tests and t tests for univariate analysis, and stepwise logistic regression for multivariate analysis.NA.Predictors of recurrent FI.A total of 52 cases and 124 controls were identified (recurrence rate 30%). Presence of a diaphragmatic hernia [odds ratio (OR) 2.65; confidence interval (CI) 1.19-5.89], disimpaction by piecemeal extraction (OR 2.32; CI 1.09-4.97), and acquisition of esophageal biopsies (OR 3.69; CI 1.42-9.66) increased odds for recurrent FI. Physician follow-up after FI decreased the odds for recurrent FI (OR 0.38; CI 0.18-0.80).Retrospective study.The presence of a diaphragmatic hernia, complexity of endoscopic disimpaction technique, and lack of follow-up increased risk for recurrent FI. Collection of esophageal biopsies as a risk factor suggests a visibly more severe esophageal disorder as a potential cause for recurrent FI.

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.

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.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.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.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%).

Purpose To assess immunohistologic features of angiogenesis of T1N0M0 oral squamous cell carcinoma (OSCC), and to identify predictors of regional recurrence. The identification of prognostic markers of early lymph node involvement in OSCC could allow for the use of more targeted biologic therapies for patients with early-stage tumors. Patients and Methods The study included patients treated for T1N0M0 OSCC at the Mayo Clinic from 1986 to 2001. All patients had initial surgical resection without neck dissection, and all had adequate follow-up with histologic specimens for review. Patients with lip, pharyngeal, or salivary gland tumors were excluded. Patient specimens were regraded and assessed for the histologic markers p53 and CD34 (penetrating and circumscribing patterns). The Kaplan-Meier method was used to estimate patient survival and survival free of regional recurrence. Results The study included 175 patients. The overall 5-year survival was 75%, and 5-year survival free of regional recurrence was 80.3%. Twenty-eight patients had regional recurrence. High-grade tumors ( P = .03) and the penetrating pattern of CD34 ( P = .02) were significantly associated with early regional metastasis from early-stage OSCC. The presence of p53 was not independently associated as a marker for regional metastasis. Conclusion Early-stage T1 OSCC with high-grade lesions and a penetrating pattern of CD34 was associated with a statistically significant risk of cervical lymph node metastasis, compared with a circumscribing pattern of CD34.

The majority of the facial skeleton myxomas are diagnosed between the second and third decades of life, with the average age of diagnosis between 25 to 30 years. Some authors suggest that there is a slight female predilection (male to female ratio 1:1.5); whereas others report an equal gender predilection between males and females. 6-8 Approximately two thirds of myx omas are located in the mandible, and one third are located in the maxilla. There is a wide variety in clinical and radiologic appearance; however, the most common presentation is as an asymptomatic jaw expansion and as a multilocular radiolucency. We present an unusual case of pediatric myxoma of the maxilla and discuss the presentation, histopathology, and treatment management.

Background & Aims: The aim of this study was to assess the validity of frozen section analysis of endoscopic mucosal resection (EMR) specimens from Barrett's esophagus as compared with permanent sections for the detection of neoplasia. Frozen sections help to give immediate feedback for surgical procedures. It has not been determined whether EMR can be adequately interpreted by using frozen sections to aid endoscopists in completely resecting neoplastic lesions. Methods: EMR specimens from Barrett's esophagus with high-grade dysplasia (HGD) and/or carcinoma were tested by frozen section. Pathologists evaluated EMR specimens for the depth of invasion as well as the appearance of clear margins of resection. The κ statistic was calculated to assess the degree of agreement between the frozen section and permanent section diagnoses. Results: Twenty-three consecutive patients underwent 30 EMRs with frozen section diagnosis. Frozen section revealed a carcinoma in 7 specimens (23%) and dysplasia in 20 (66%). Permanent sections found carcinoma in 8 specimens (26%), dysplasia in 19 specimens (63%), and normal or nondysplastic Barrett's esophagus in the remainder. The κ statistic for the depth of invasion of EMR specimens was 0.93 (near perfect agreement). The κ statistic for the margins of the EMR specimens was 0.80 (excellent agreement). Conclusions: This study indicated that frozen section analysis of esophageal EMR specimens is valid as compared with permanent section. This technique might allow rapid evaluation about the degree and depth of involvement of cancers. This allows physicians to make decisions regarding further therapy if margins are involved or decrease the use of EMR for histologically benign–appearing lesions.

Double Trouble: Two Cases of Squamous Carcinoma Arising From Barrett's Dysplasia After Endoscopic Mucosal Resection