Differentiated squamous intraepithelial neoplasia associated with squamous cell carcinoma of the anal canal.

AIMS: Differentiated squamous intraepithelial neoplasia (DSIN) has been described in several sites, including the upper aerodigestive tract and vulva, so this study investigated whether it also occurred in the anal canal. METHODS AND RESULTS: All cases of squamous cell carcinoma (SCC) involving the anal canal diagnosed between 2009 and 2015 at our institution were reviewed. Eighty-six cases were included, and 13 (15%) showed features consistent with DSIN: 10 were 'pure' DSIN, and three were 'mixed' DSIN and squamous intraepithelial lesion. DSIN was characterized by atypical keratinocytes limited to the basal/parabasal layers, acanthosis, and a 'cobblestone' appearance. Among specimens with pure DSIN, the surface was flat in eight cases. In five cases, the DSIN was extensive, and associated with deeply invasive SCC requiring radical surgical resection. Immunohistochemically, the epithelia showing changes consistent with DSIN were p16-negative, whereas the invasive component was p16-positive in 12 cases. Both Ki67 and p53 showed strong nuclear positivity in the basal/parabasal layers of DSIN. CONCLUSIONS: Invasive SCC associated with DSIN often presents at an advanced stage of disease, requiring radical surgical treatment. The neoplastic changes in DSIN are limited to the basal/parabasal layers, which may account for the negative diagnoses by anal cytopathology and late clinical diagnosis. The recognition of anal DSIN is important in order to avoid underdiagnosis in superficial biopsies.

Perineural invasion on biopsy is associated with upstaging at radical prostatectomy in Gleason score 3 + 4 = 7 prostate cancer.

This study assesses if perineural invasion (PNI) detected on biopsy with Gleason score (GS) 3 + 4 = 7 prostate cancer (PCa) is associated with upstaging/upgrading of disease after radical prostatectomy (RP). 154 patients with GS 3 + 4 = 7 PCa diagnosed from biopsy who underwent RP were assessed for PNI. The percentage of biopsy sites with PNI (%PNI) was also calculated. Pattern 4 morphologies (ill-defined glands [IDG], fused, cribriform, and glomerulations) were also assessed. Clinical information, GS and stage after RP were retrieved from the medical records. 45 % (69/154) of patients were upstaged (≥pT3) and 29 % (44/154) were upgraded to GS >3 + 4 = 7 after RP. 37 % (57/154) of patients had PNI which was associated with upstaging (RR 1.4; P = 0.04) but not upgrading (RR 0.9; P = 0.7). There was higher %PNI in upstaged patients (12.1 % ± 1.8 vs. 7.1 % ± 1.5, P = 0.03) with a significant correlation between %PNI and ≥pT3 (r = 0.178, P = 0.027). After multivariate analysis, only cribriform formations were significantly associated with upstaging (P = 0.009). The presence of PNI in biopsies with GS 3 + 4 = 7 PCa is associated with upstaging at RP but is a weaker predictor of ≥pT3 disease than cribriform morphology.

Late-Onset Rejection in Liver Allograft Biopsies: An Analysis of Process, Pattern, and Clinical Implications.

OBJECTIVES: Both alloimmune and nonalloimmune factors affect the long-term survival of liver allograft recipients. Various patterns of late-onset rejection are recognized, including typical acute cellular rejection (tACR), ductopenic rejection (DuR), nonspecific hepatitis (NSH), isolated central perivenulitis (ICP), and plasma cell-rich rejection (PCRR). This study compares the clinicopathologic features of late-onset rejection (LOR) in a large-cohort context. METHODS: For-cause liver biopsies more than 6 months after transplant were included from the University of Minnesota between 2014 and 2019. Histopathologic, clinical, laboratory, treatment, and other data were analyzed in nonalloimmune and LOR cases. RESULTS: The study consisted of 160 patients (122 adults, 38 pediatric patients), with 233 (53%) biopsies showing LOR: 51 (22%) tACR; 24 (10%) DuR; 23 (10%) NSH; 19 (8%) PCRR; and 3 (1%) ICP. Mean onset of 80 vs 61 months was longer for nonalloimmune injury (P = .04), a difference lost without tACR (mean, 26 months). Graft failure was highest with DuR. Response to treatment, as measured by changes in liver function tests, was similar between tACR and other LORs, and NSH occurred more often in pediatric patients (P = .001); tACR and other LOR incidence was similar. CONCLUSIONS: LORs occur in pediatric and adult patients. Except for tACR, patterns overlap in many ways, with DuR having the greatest risk of graft loss, but other LORs respond well to antirejection treatments.

A descriptive study evaluating Health Canada's risk communications.

PURPOSE: Risk assessment for natural health products (NHPs) may not be evaluated similarly to therapeutic products by Health Canada in terms of notification of harms to consumers and health professionals. In this descriptive study, we evaluated risk communications (RCs) issued by Health Canada for NHPs and for therapeutic products, looking for differences in a number of variables. METHODS: Risk communications issued by Health Canada in 2006 were independently evaluated by two investigators for whether the harm was actual or potential, for the seriousness and nature of harm, the origin of report, publication type, and degree of association. Disagreements were brought before a third reviewer for adjudication. RESULTS: During the study period, Health Canada issued 42 RCs for each of NHPs and therapeutic products. Most (86%) NHP RCs were issued for potential harm from contamination and adulteration, whereas 69% of therapeutic product RCs were issued due to actual harms (p < 0.0001). Two deaths had been associated with NHP use, compared with 15 deaths associated with the use of therapeutic products (p = 0.0048). The degree of association between product and harm was higher among NHP RCs compared with that among therapeutic product RCs (p < 0.0001). All reports issued for NHPs originated from foreign sources or Health Canada, whereas 69% of therapeutic product RCs were issued by drug manufacturers. CONCLUSIONS: We identified important differences in the RCs issued for NHPs versus those for therapeutic products. Standardized formats for RCs are recommended.

Recent Advances in Digestive Tract Tumors: Updates From the 5th Edition of the World Health Organization "Blue Book".

CONTEXT.­: The World Health Organization Classification of Tumours: Digestive System Tumors, 5th edition, was published in 2019 and shows several impactful changes as compared with the 4th edition published in 2010. Changes include a revised nomenclature of serrated lesions and revamping the classification of neuroendocrine neoplasms. Appendiceal goblet cell adenocarcinoma is heavily revised, and intrahepatic cholangiocarcinoma is split into 2 subtypes. New subtypes of colorectal carcinoma and hepatocellular carcinoma are described. Precursor lesions are emphasized with their own entries, and both dysplastic and invasive lesions are generally recommended to be graded using a 2-tier system. Hematolymphoid tumors, mesenchymal tumors, and genetic tumor syndromes each have their own sections in the 5th edition. New hematolymphoid lesions include monomorphic epitheliotropic intestinal T-cell lymphoma; duodenal-type follicular lymphoma; intestinal T-cell lymphoma, not otherwise specified; and indolent T-cell lymphoproliferative disorder of the gastrointestinal tract. This paper will provide an in-depth look at the changes in the 5th edition as compared with the 4th edition. OBJECTIVE.­: To provide a comprehensive, in-depth update on the World Health Organization classification of digestive tumors, including changes to nomenclature, updated diagnostic criteria, and newly described entities. DATA SOURCES.­: The 5th edition of the World Health Organization Classification of Tumours: Digestive System Tumours, as well as the 4th edition. CONCLUSIONS.­: The World Health Organization has made many key changes in its newest update on tumors of the digestive system. Pathologists should be aware of these changes and incorporate them into their practice as able or necessary.

Phosphorylated transducer and activator of transcription-3 (pSTAT3) immunohistochemical expression in paired primary and metastatic colorectal cancer.

BACKGROUND: Signal Transducer and Activator of Transcription-3 (STAT3) mediates cellular functions. We assessed the IHC expression of phosphorylated STAT3 (pSTAT3) in paired primary tumors and liver metastases in patients with advanced stage colorectal cancer (CRC). METHODS: We included patients with tissue blocks available from both the primary CRC and a surgically resected liver metastasis. The IHC pSTAT3 expression agreement was measured using Cohen's kappa statistic. RESULTS: The study included 103 patients, 55% male, median age was 64. 43% tumors originated in rectum, and 63% of the primary tumors were synchronous. Expression of pSTAT3 was 76% in liver metastases and 71% in primary tumors. A difference in pSTAT3 staining between the primary tumor and liver metastases was noted in 64%. There was lost expression of pSTAT3 in the liver metastases in 28% and gained expression in 36% of cases compared to the primary. The kappa statistic comparing agreement between staining patterns of the primary tumors and liver metastases was a "less-than-chance", at -0.02. Median survival was 4.9 years, with no difference in survival outcomes by pSTAT3 expression in the primary tumor or liver metastases. DISCUSSION: STAT3 is not a prognostic marker in the selective setting of metastatic CRC to liver, but it may remain a potential therapeutic target given most liver metastases expressed pSTAT3. Discordant pSTAT3 expression in between primary tumors and paired liver metastases suggests that use of this class of drug to treat liver predominant metastatic colorectal cancer in a biomarker-driven approach may require confirmatory liver tumor biopsy.

Clear Cell Urothelial Carcinoma.

Clear cell urothelial carcinoma (CCUC) is a rare variant of urothelial carcinoma (UC) and its clinical significance has not been well elucidated. Consecutive cases of UC over a period of 5 years were reviewed. Histopathological tumor parameters, including the proportion of tumor cells with clear cell change, and patient outcomes were recorded. Expression of the following immunohistochemical markers was investigated: CK7, CK20, CK5, CD44, and PAX8. We also conducted a review of the literature for case reports/series of CCUC. Ten CCUCs were identified out of a total of 872 cases of UC. The clear cell component was characterized by prominent cytoplasmic membranes and voluminous clear cytoplasm, and accounted for 30% to 90% of the invasive tumor component. Of all the non-CCUC cases reviewed, at least 50% (noninvasive or invasive UC) showed focal areas of clear cell change that accounted for less than 5% of the neoplastic cells. Immunohistochemically, CCUC exhibited positive reactivity for CK5/CD44 (n = 9); CK20 (n = 5), PAX8 (very focal to extensive) (n = 6), and GATA3/CK7 (n = 10). Eight of 10 CCUC were of advanced clinical stage (pT3/pT4) and 6 of 10 experienced tumor recurrence and/or death due to disease. In conclusion, CCUC can be distinguished from non-CCUC by the extensive clear cell change in more than 30% of cells. This variant is associated with rapid progression to muscle invasion and metastasis, with an aggressive clinical course. Expression of CK5/CD44 may represent basal cell features in most CCUC cases, while PAX8 expression is suggestive of mesonephric derivation.

CAM use in pediatric neurology: an exploration of concurrent use with conventional medicine.

BACKGROUND: Previous studies have found that up to 60% of children with neurologic conditions have tried complementary and alternative medicine (CAM). OBJECTIVE: To assess the use of CAM among patients presenting to neurology clinics at two academic centers in Canada. METHODS: A survey instrument was developed to inquire about use of CAM products and therapies, including reasons for use, perceived helpfulness, and concurrent use with conventional medicine, and administered to patients or their parents/guardians at the Stollery Children's Hospital in Edmonton and the Children's Hospital of Eastern Ontario (CHEO) in Ottawa. RESULTS: Overall CAM use at the Stollery was 78%, compared to 48% at CHEO. The most common CAM products used were multi-vitamins (84%), vitamin C (37%), homeopathic remedies (24%), and fish oil/omega 3 s (22%). The most common CAM practices used were massage (47%), chiropractic (37%), faith healing (18%), aromatherapy (16%), homeopathy (16%), and relaxation (16%). Many patients used CAM products at the same time as conventional medicine but just over half (57%) discussed this concurrent use with their physician. CONCLUSION: CAM use is common in pediatric neurology patients and most respondents felt that it was helpful, with few or no harms associated. However, this use is often undisclosed, increasing possibility of interactions with conventional drugs. We urge clinicians to inquire about CAM use during routine history taking at every patient visit. Parents would clearly like more information about CAM from their specialty clinics; such information would be easier to share if more primary data were available about the safety and effectiveness of commonly used therapies.