Data regarding the clinical impact of subspecialist pathology review of appendiceal neoplasms are limited.
To determine whether pathology review by gastrointestinal pathologists at a tertiary-care ...referral center resulted in significant changes in the diagnosis and clinical management of appendiceal neoplastic lesions.
We conducted a retrospective review of all patients with an initial diagnosis of appendiceal neoplasm referred to a tertiary-care referral center in Ontario, Canada, from 2010-2016. The discordance rate between original and review pathology reports, the nature of discordances, and the impact of any discordance on patient management were recorded.
A total of 145 patients with appendiceal lesions were identified (low-grade mucinous appendiceal neoplasm n = 79, invasive mucinous adenocarcinoma n = 12, "colorectal type" adenocarcinoma n = 12, goblet cell carcinoid and adenocarcinomas ex goblet cell carcinoid n = 24, and other lesions/neoplasms n = 20). One or more changes in diagnoses were found in 36 of 145 cases (24.8%), with changes within the same category of interpretation (n = 10), stage (n = 7), grade (n = 6), and categoric interpretation (n = 5) being the most common. In 10 of 36 patients (28%), the diagnostic change led to a significant change in management, including recommendation for additional surveillance, systemic chemotherapy, additional surgery, or discontinuation of surveillance.
Subspecialist pathology review of appendiceal neoplastic lesions led to a change in diagnosis in 36 of 145 cases (24.8%), of which nearly 30% (10 of 36 cases) led to a change in clinical management. The overall rate of clinically significant discordances was 7% (10 of 145). Our findings suggest that subspecialist pathology review of appendiceal neoplasms referred to specialized centers is justified.
Failure of liver stiffness measurement (LSM) by transient elastography (TE, FibroScan) and unreliable results occur in ≈5% and 15% of patients, respectively, mainly due to obesity. In this ...multicenter study, we evaluated the feasibility and performance of the novel FibroScan XL probe in 276 patients with chronic liver disease (42% viral hepatitis, 46% nonalcoholic fatty liver disease NAFLD) and a body mass index (BMI) ≥28 kg/m2. Patients underwent liver biopsy and TE with the standard M and XL probes. TE failure was defined as no valid LSMs and unreliable examinations as <10 valid LSMs or an interquartile range (IQR)/LSM >30% or success rate <60%. Probe performance for diagnosing ≥F2 fibrosis and cirrhosis (F4) versus biopsy were examined using areas under receiver operating characteristic curves (AUROC). FibroScan failure was less frequent with the XL probe than the M probe (1.1% versus 16%) and the XL probe was more often reliable (73% versus 50%; both P < 0.00005). Reliable results with the XL probe were obtained in 61% of patients in whom the M probe was unreliable. Among 178 patients with ≥10 valid LSMs using both probes, liver stiffness was highly correlated between probes (ρ = 0.86; P < 0.0005); however, median liver stiffness was lower using the XL probe (6.8 versus 7.8 kPa; P < 0.00005). The AUROC of the XL and M probes were similar for ≥F2 fibrosis (0.83 versus 0.86; P = 0.19) and cirrhosis (0.94 versus 0.91; P = 0.28). Conclusion: Compared with the M probe, the FibroScan XL probe reduces TE failure and facilitates reliable LSM in obese patients. Although the probes have comparable accuracy, lower liver stiffness cutoffs will be necessary when the XL probe is used to noninvasively assess liver fibrosis. (HEPATOLOGY 2012)
Intratumoral heterogeneity arises through the evolution of genetically diverse subclones during tumor progression. However, it remains unknown whether cells within single genetic clones are ...functionally equivalent. By combining DNA copy number alteration (CNA) profiling, sequencing, and lentiviral lineage tracking, we followed the repopulation dynamics of 150 single lentivirus-marked lineages from 10 human colorectal cancers through serial xenograft passages in mice. CNA and mutational analysis distinguished individual clones and showed that clones remained stable upon serial transplantation. Despite this stability, the proliferation, persistence, and chemotherapy tolerance of lentivirally marked lineages were variable within each clone. Chemotherapy promoted the dominance of previously minor or dormant lineages. Thus, apart from genetic diversity, tumor cells display inherent functional variability in tumor propagation potential, which contributes to both cancer growth and therapy tolerance.
Background
Accurate tools for the noninvasive detection of hepatic steatosis are needed. The Controlled Attenuation Parameter (CAP) specifically targets liver steatosis using a process based on ...transient elastography.
Methods
Patients with chronic liver disease and body mass index (BMI) ≥28 kg/m2 underwent biopsy and liver stiffness measurement (LSM) with simultaneous CAP determination using the FibroScan® M probe. The performance of the CAP for diagnosing steatosis compared with biopsy was assessed using areas under receiver operating characteristic curves (AUROC).
Results
A total of 153 patients were included: 69% were male, median BMI was 32 kg/m2; 47% had nonalcoholic fatty liver disease (NAFLD); and 65% had significant (≥10%) steatosis. The CAP was significantly correlated with the percentage of steatosis (ρ = 0.47) and steatosis grade (ρ = 0.51; both P < 0.00005). The median CAP was higher among patients with significant steatosis (317 IQR 284–339 vs. 250 227–279 dB/m with <10% steatosis; P < 0.0005) and the AUROC for this outcome was 0.81 (95% CI 0.74–0.88). At a cut‐off of 283 dB/m, the CAP was 76% sensitive, 79% specific, and had positive and negative predictive values of 87% and 64%, respectively. CAP performance was not influenced by measurement variability, but was higher in patients with mild (F0‐F1) fibrosis (AUROC 0.89 vs. 0.72 with F2‐F4; P = 0.03). The AUROCs of the CAP for ≥5%, >33% and >66% steatosis were 0.79, 0.76 and 0.70, respectively.
Conclusions
The CAP is a promising tool for the noninvasive detection of hepatic steatosis. Advantages of CAP include its ease of measurement, operator‐independence and simultaneous availability with LSM for fibrosis assessment.
Here, we demonstrated the differentiation potential of murine muscle-derived stem/progenitor cells (MDSPCs) toward myogenic, neuronal, and glial lineages. MDSPCs, following transplantation into a ...critical-sized sciatic nerve defect in mice, showed full regeneration with complete functional recovery of the injured peripheral nerve at 6 weeks post-implantation. However, several weeks after regeneration of the sciatic nerve, neoplastic growths were observed. The resulting tumors were malignant peripheral nerve sheath tumors (MPNSTs) with rhabdomyoblastic differentiation, expressing myogenic, neurogenic, and glial markers, common markers of human malignant triton tumors (MTTs). No signs of tumorigenesis were observed 17 weeks post-implantation of MDSPCs into the gastrocnemius muscles of dystrophic/mdx mice, or 1 year following subcutaneous or intravenous injection. While MDSPCs were not oncogenic in nature, the neoplasias were composed almost entirely of donor cells. Furthermore, cells isolated from the tumors were serially transplantable, generating tumors when reimplanted into mice. However, this transformation could be abrogated by differentiation of the cells toward the neurogenic lineage prior to implantation. These results establish that MDSPCs participated in the regeneration of the injured peripheral nerve but transformed in a microenvironment- and time-dependent manner, when they likely received concomitant neurogenic and myogenic differentiation signals. This microenvironment-specific transformation provides a useful mouse model for human MTTs and potentially some insight into the origins of this disease.
Background & Aims: The revised Bethesda guidelines for Lynch syndrome recommend microsatellite instability (MSI) testing all colorectal cancers in patients diagnosed before age 50 years and ...colorectal cancers diagnosed in patients between ages 50 and 59 years with particular pathology features. Our aim was to identify pathology and other features that independently predict high MSI (MSI-H). Methods: Archival tissue from 1098 population-based colorectal cancers diagnosed before age 60 years was tested for MSI. Pathology features, site, and age at diagnosis were obtained. Multiple logistic regression was performed to determine the predictive value of each feature, as measured by an odds ratio (OR), from which a scoring system (MsPath) was developed to estimate the probability a colorectal cancer is MSI-H. Results: Fifteen percent of tumors (162) were MSI-H. Independent predictors were tumor-infiltrating lymphocytes (OR, 9.1; 95% confidence interval CI, 5.9–14.1), proximal subsite (OR, 4.7; 95% CI, 3.1–7.3), mucinous histology (OR, 2.8; 95% CI, 1.7–4.8), poor differentiation (OR, 1.9; 95% CI, 1.2–3.1), Crohn’s-like reaction (OR, 1.9; 95% CI, 1.2–2.9), and diagnosis before age 50 years (OR, 1.9; 95% CI, 1.3–2.9). MsPath score ≥1.0 had a sensitivity of 93% and a specificity of 55% for MSI-H. Conclusions: The probability an individual colorectal cancer is MSI-H is predicted well by the MsPath score. There is little value in testing for DNA mismatch repair loss in tumors, or for germline mismatch repair mutations, for colorectal cancers diagnosed in patients before age 60 years with an MSPath score <1 (approximately 50%). Pathology can identify almost all MSI-H colorectal cancers diagnosed before age 60 years.
Background & Aims The FibroScan XL probe facilitates liver stiffness measurement (LSM) by transient elastography (TE) in obese patients, yet factors affecting its accuracy have not been described. ...Our objectives were to examine the prevalence, risk factors, and causes of discordance between fibrosis estimated by the FibroScan XL probe and biopsy. Methods Two hundred and ten patients with chronic liver disease (45% viral hepatitis, 55% nonalcoholic fatty liver disease (NAFLD) and a body mass index (BMI) ⩾28 kg/m2 ) underwent liver biopsy and TE with the FibroScan XL probe. Predictors of discordance ⩾2 fibrosis stages between measures, which occurred in 11% of patients (n = 24), were identified by comparing patient, TE, and biopsy characteristics of discordant and non-discordant cases. Results Fibrosis estimated by the FibroScan XL probe was greater than biopsy in 75% (18/24) of discordant cases. Although biopsy quality was not associated with discordance, discordant cases were less likely to have ⩾10 valid shots (75% vs . 97%; p = 0.001), a success rate ⩾60% (67% vs . 95%; p <0.0005), and an interquartile range over median liver stiffness (IQR/M) <21% (37% vs . 57%; p = 0.07) than non-discordant cases. However, only increased BMI (odds ratio OR 1.09 per kg/m2 ; 95% confidence interval CI 1.01–1.18; p = 0.04) was independently associated with discordance; liver stiffness was of borderline significance (OR 1.73 per log10 -transformed value; 95% CI 0.95–3.18; p = 0.08). Discordance was 4- to 5-fold more frequent among patients with severe obesity (BMI ⩾40 kg/m2 : 32% vs . 8%) and liver stiffness above the median of 7.0 kPa (20% vs . 4%; both p <0.0005). Conclusions Discordance between liver fibrosis estimated by biopsy and TE using the FibroScan XL probe was infrequent in this obese population. Patients with severe obesity and elevated liver stiffness have the greatest risk of discordance.
In embryonic stem cells, promoters of key lineage-specific differentiation genes are found in a bivalent state, having both activating H3K4me3 and repressive H3K27me3 histone marks, making them ...poised for transcription upon loss of H3K27me3. Whether cancer-initiating cells (C-ICs) have similar epigenetic mechanisms that prevent lineage commitment is unknown. Here we show that colorectal C-ICs (CC-ICs) are maintained in a stem-like state through a bivalent epigenetic mechanism. Disruption of the bivalent state through inhibition of the H3K27 methyltransferase EZH2, resulted in decreased self-renewal of patient-derived C-ICs. Epigenomic analyses revealed that the promoter of Indian Hedgehog (IHH), a canonical driver of normal colonocyte differentiation, exists in a bivalent chromatin state. Inhibition of EZH2 resulted in de-repression of IHH, decreased self-renewal, and increased sensitivity to chemotherapy in vivo. Our results reveal an epigenetic block to differentiation in CC-ICs and demonstrate the potential for epigenetic differentiation therapy of a solid tumour through EZH2 inhibition.
Germline activating platelet-derived growth factor receptor alpha (PDGFRA) mutations have been described in four families. All the index patients have presented with multiple mesenchymal tumors of ...the gastrointestinal tract. We identified a fifth family with four first-degree relatives that harbor a PDGFRA exon 18 (D846V) germline mutation. The affected kindred have a unique phenotype including coarse facies and skin, broad hands and feet, and previously undescribed premature tooth loss. While the index patient presented with multiple small bowel inflammatory fibroid polyps (IFPs) and has a gastric gastrointestinal stromal tumor (GIST), no tumors have yet been identified in other family members. We describe the pathology, genetics, the incomplete penetrance and variable expressivity of the familial PDGFRA-mutation syndrome referencing the mouse knock-in Pdgfra model. We speculate on the role of the telocyte, a recently described CD34, PDGFRA+ stromal cell, in the development of inflammatory fibroid polyps and the somatic phenotype.
•Description of family with PDGFRA mutation.•Novel dysmorphic features described and shown through picture.•Pathology of GI polyp.•Discussion of telocytes as possible role in IFPs.•Discussion of the role of environmental factors in phenotype.
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