Gregory Y. Lauwers

Detection of high-grade dysplasia in Barrett's esophagus by spectroscopy measurement of 5-aminolevulinic acid-induced protoporphyrin IX fluorescence.

BACKGROUND Preliminary studies with qualitative detection methods suggest that 5-aminolevulinic acid-induced protoporphyrin IX fluorescence might improve the detection of dysplastic Barretts epithelium. This study used quantitative methods to determine whether aminolevulinic acid-induced protoporphyrin IX fluorescence can differentiate between Barretts mucosa with and without dysplasia. METHODS Patients were given 10 mg/kg of aminolevulinic acid orally 3 hours before endoscopy. Quantitative fluorescence spectra were acquired by using a nitrogen-pumped dye laser (l 400 nm) spectrograph system. The protoporphyrin IX fluorescence intensity at 635 nm was compared with the histopathologic diagnosis for mucosal biopsy specimens taken immediately after the fluorescence measurements. RESULTS Ninety-seven spectra were obtained from 20 patients. The mean (+/- standard error) standardized protoporphyrin IX fluorescence intensity was significantly greater (p < 0.05) for high-grade dysplastic Barretts epithelium (0.29 +/- 0.07, n = 13) than for nondysplastic Barretts epithelium (0.11 +/- 0.02, n = 43). By using protoporphyrin IX fluorescence alone, high-grade dysplasia was distinguished from nondysplastic tissue types with 77% sensitivity and 71% specificity. Decreased autofluorescence was particularly found in nodular high-grade dysplasia. By using the fluorescence intensity ratio of 635 nm/480 nm, nodular high-grade dysplasia could be differentiated from nondysplastic tissue with 100% sensitivity and 100% specificity. CONCLUSION Protoporphyrin IX fluorescence may be useful for identifying areas of high-grade dysplasia in Barretts esophagus and for targeting of biopsies.

Histopathology of Barrett’s esophagus after ablation and endoscopic mucosal resection therapy

This review focuses on the histopathological evaluation of endoscopic mucosal resection (EMR) specimens in Barretts esophagus, and on the histopathological, biological, and molecular properties of postablation Barretts esophagus. EMR may be used for both diagnostic and therapeutic purposes. Diagnostic accuracy regarding the grade and stage of neoplasms is improved with the use of EMR, but the value of this technique for treatment is more controversial because of the high prevalence rate of positive margins and the rate of metachronous lesions found elsewhere in the esophagus during follow-up. Ablation techniques, such as argon plasma coagulation, photodynamic therapy, and radiofrequency ablation, are used increasingly for the treatment of Barretts esophagus and related neoplasms, often in combination with EMR. A common problem after use of these techniques is the development of islands of neosquamous epithelium (NSE) which can overlie buried Barretts (and/or dysplasia) epithelium. This is, therefore, concealed to the endoscopists view and may be allowed to progress to cancer without detection. NSE is histologically similar to normal esophageal squamous epithelium and does not possess the molecular aberrations characteristic of Barretts esophagus. In contrast, residual nonburied Barretts esophagus shows persistent pathologic and molecular abnormalities and may progress to cancer upon long term follow-up. The biological potential and rate of progression of nonburied residual Barretts esophagus following ablation is unclear, but some preliminary studies suggest that the risk may decrease. Buried nondysplastic Barretts esophagus appears to show decreased biological potential and this may be related to protection from the contents of the lumen by the barrier function of the overlying NSE. On the other hand, anecdotal reports have suggested that buried dysplasia may progress to cancer in some instances.

Comprehensive imaging of gastroesophageal biopsy samples by spectrally encoded confocal microscopy.

BACKGROUND Spectrally encoded confocal microscopy (SECM) is a high-speed reflectance confocal microscopy technique that has the potential to be used for acquiring comprehensive images of the entire distal esophagus endoscopically with subcellular resolution. OBJECTIVE The goal of this study was to demonstrate large-area SECM in upper GI tissues and to determine whether the images contain microstructural information that is useful for pathologic diagnosis. DESIGN A feasibility study. SETTING Gastrointestinal Unit, Massachusetts General Hospital. PATIENTS Fifty biopsy samples from 36 patients undergoing routine EGD were imaged by SECM, in their entirety, immediately after their removal. RESULTS The microstructure seen in the SECM images was similar to that seen by histopathology. Gastric cardia mucosa was clearly differentiated from squamous mucosa. Gastric fundic/body type mucosa showed more tightly packed glands than gastric cardia mucosa. Fundic gland polyps showed cystically dilated glands lined with cuboidal epithelium. The presence of intraepithelial eosinophils was detected with the cells demonstrating a characteristic bilobed nucleus. Specialized intestinal metaplasia was identified by columnar epithelium and the presence of goblet cells. Barretts esophagus (BE) with dysplasia was differentiated from specialized intestinal metaplasia by the loss of nuclear polarity and disorganized glandular architecture. LIMITATIONS Ex vivo, descriptive study. CONCLUSIONS Large-area SECM images of gastroesophageal biopsy samples enabled the visualization of both subcellular and architectural features of various upper GI mucosal types and were similar to the corresponding histopathologic slides. These results suggest that the development of an endoscopic SECM probe is merited.

Histopathologic features of colitis due to immunotherapy With Anti-PD-1 antibodies

Programmed cell death protein 1 (PD-1) blocking agents are novel immunotherapeutics used for treatment of advanced-stage malignancies. They have shown promise in the treatment of several malignancies, with greater efficacy and better tolerability than cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocking agents. However, as with anti-CTLA-4 agents, clinically significant colitis remains an important complication. Although there is growing awareness of the histopathologic features of anti-CTLA-4 therapy, there is little information on the pathologic features of anti-PD-1 colitis. We describe here the histopathologic findings in 8 patients who developed colitis while on anti-PD-1 monotherapy. The most common pattern of injury observed (5/8 cases) was an active colitis with neutrophilic crypt microabscesses and with prominent crypt epithelial cell apoptosis and crypt atrophy/dropout. These latter features are reminiscent of other colitides with prominent apoptosis such as acute graft-versus-host disease or certain drug-induced colitides. The remainder of cases (3/8) showed a lymphocytic colitis-like pattern, characterized by increased intraepithelial lymphocytes and surface epithelial injury. Apoptosis was also often increased in these cases but crypt atrophy/dropout was not present. In patients who experienced recurrence of anti-PD-1 colitis, histologic features were similar to the initial insult but, in addition, features of chronicity developed that mimicked inflammatory bowel disease (basal lymphoplasmacytosis and crypt architectural irregularity, and Paneth cell metaplasia in 1 case). Awareness of the clinical scenario, however, should allow pathologists to suggest anti-PD-1 colitis. Interestingly, recurrent colitis was observed in patients who had been off anti-PD-1 therapy for many months. As anti-PD-1 agents are increasingly used in oncology, we present this series to increase awareness of anti-PD-1 colitis among pathologists, to facilitate its timely diagnosis and treatment.

Biliary Adenofibroma of Liver: Morphology, Tumor Genetics, and Outcomes in 6 Cases

Biliary adenofibroma is a rare primary hepatic neoplasm, recognized in the World Health Organization classification, although only 14 cases have been reported to date. This series includes extended follow-up from 2 of the early case reports and 4 novel cases. Clinical history and histology were reviewed in all 6 cases. Tumor DNA was analyzed for point mutations by multiplex polymerase chain reaction and copy number alterations by array comparative genomic hybridization. The patients included 4 females and 2 males presenting between 46 and 83 years of age, with tumors ranging from 7 to 16 cm in diameter. The tumors had similar morphology, with tubules and cysts lined mainly by bland to mildly atypical cuboidal epithelium embedded in fibrous stroma. Multiplex polymerase chain reaction did not identify mutations in 4 tumors tested. Three tumors tested by array comparative genomic hybridization showed chromosomal copy number alterations, including 1 with amplifications of CCND1 and ERBB2. Three patients underwent resection with no recurrence at 21, 20, and 3 years of follow-up. One patient is alive after 14 months with no resection. Two patients with margin-positive resections had local recurrence at 1 and 6 years after surgery. No patient had distant metastasis. The distinct morphology and multiple clonal cytogenetic alterations in biliary adenofibromas indicate that the lesions are neoplastic. Amplifications of CCND1 and ERBB2 are not typical of benign neoplasms, and suggest that these tumors may have the ability to behave aggressively. However, the clinical outcomes in these patients suggest the neoplasms are only slowly progressive.

Lymphocytic colitis: pathologic predictors of response to therapy

Although the presence of intraepithelial lymphocytosis with surface epithelial damage is a unifying feature of lymphocytic colitis, there are nonclassical features that create morphologic heterogeneity between cases. Limited data on the significance of these secondary histologic features are available. Cases of lymphocytic colitis diagnosed between 2002 and 2013 were identified using the Research Patient Data Registry of a tertiary referral center. Diagnostic biopsy slides were reviewed and evaluated for histologic features of lymphocytic colitis. Clinical data including type of therapy and response to treatment were collected. χ2 Test (or Fisher exact test) and logistic regression analysis were used where appropriate. Thirty-two cases of lymphocytic colitis with complete clinical data and slides available for review were identified. The mean age was 56.4 years, and the female-to-male ratio was 3:2. Eleven patients improved with minimal intervention (group 1), 14 patients responded to steroid therapy (group 2), and 7 patients responded to mesalamine, bismuth subsalicylate, and/or cholestyramine therapy (group 3). Histologic differences in the characteristics of the subepithelial collagen table (P = .018), the severity of lamina propria inflammation (P = .042), and the presence of eosinophil clusters (P = .016) were seen between groups 2 and 3. Patients in group 1 were more likely to have mild crypt architectural distortion in their biopsies than patients in groups 2 and 3. Lymphocytic colitis is a heterogeneous disease, and the evaluation of histologic factors may help identify various subtypes and predict therapy response.

Inflammatory and infectious pathology of the gastrointestinal tract: an introduction

In this year’s Annual Review Issue, we have decided to focus our interest on inflammatory and infectious conditions of the gastrointestinal tract.While the last 20 years brought significant information onGI neoplasia, the access tomore biopsymaterial worldwide – coupled with increased recognition of the spectrum of underlying diseases – deeply impacts the growing field of non-neoplastic gastrointestinal pathology. Prompted also by a more intimate understanding of molecular inflammatory pathways, we have now gained a broader understanding of the mechanisms at play in the development of debilitating inflammatory and infectious gastrointestinal diseases. To cover such a large and diverse array of subjects we called upon a group of international experts hailing from Europe, Australia, South Africa and North America to produce a superb issue. In the first paper of the series Drs. Kumarasinghe and Brown (https://doi.org/10.1007/s00428-017-2210-3) present a timely review on the diagnosis of granulomas in the gut. Established on their boundless experience they offer diagnostic clues based on the nature, the appearance and locations of the granulomas. Following their approach, pathologists will be able in most cases to either define the aetiology with certainty or at least narrow the differential diagnosis before additional testing and clinical anamnesis lead to final diagnosis. Eosinophilic gastrointestinal diseases have been increasing in prevalence in Western countries in recent years. Drs. McCarthy and Sheahan (https://doi.org/10.1007/s00428-0172249-1) present an extensive review on the topic, ranging from normal to pathology or disease. Since physiologic values of eosinophilia vary widely between the different segments of the large bowel, location of the biopsy is critically important for the interpretation. No standard diagnostic criteria have been proposed for the diagnosis of eosinophilic gastroenteritis or eosinophilic colitis up to now. The authors present in detail the morphological features that may guide the diagnosis. Still, final assessment of eosinophilic gastrointestinal diseases requires careful histopathologic assessment, clinical correlation and exclusion of several differential diagnoses. Drs. Johncilla and Srivastava (https://doi.org/10.1007/ s00428-017-2238-4) have contributed an exhaustive review of the diagnosis of oesophageal inflammatory disorders at the exception of gastroesophageal reflux disease. Our colleagues present a unique approach of describing first the morphological patterns and later the differential diagnosis of common aetiologies related to each pattern of esophagitis. As the authors report, this approach is closer to clinical practice and offers the best benefit to trainees and practicing general pathologists. Dr. Biswas and colleagues (https://doi.org/10.1007/ s00428-018-2317-1) draw our attention to the pathologist’s role when handling surveillance biopsies from patients with Barrett’s oesophagus. The authors illustrate the complex mosaic of metaplastic glandular phenotypes that are frequently seen in these patients and also refer to the phenotypic dynamics of Barrett’s oesophagus across time and space. Understanding the ecological conditions that drive malignant evolution in Barrett’s may help us avoid burdensome and costly surveillance in patients at low risk of transformation and intervene in patients at increased risk. Dr. Umetsu and colleagues (https://doi.org/10.1007/ s00428-017-2243-7) present a thorough review on autoimmune enteropathy, a rare condition characterised by * Gregory Y. Lauwers Gregory.Lauwers@Moffitt.org