Andrea L. Barbieri

Translocation of a gut pathobiont drives autoimmunity in mice and humans

Bacterial involvement in autoimmunity The composition of the commensal microbiota is known to influence autoimmune disease development and persistence. Manfredo Vieira et al. identified a gut microbe, Enterococcus gallinarum, that translocates from the gut into the organs of mice with a genetic predisposition to lupus-like autoimmunity (see the Perspective by Citi). Molecular signatures of gut barrier disintegration and pathogenic T helper cells were evident in the gut, liver, and lymphoid organs during colonization with the pathobiont. The ensuing pathology could be reversed by vancomycin treatment and by vaccination against E. gallinarum. The same bug was also found in liver biopsies of autoimmune patients, but not in healthy controls. Science, this issue p. 1156; see also p. 1097 Enterococcus gallinarum is implicated in the exacerbation of autoimmune pathology in genetically predisposed mice and humans. Despite multiple associations between the microbiota and immune diseases, their role in autoimmunity is poorly understood. We found that translocation of a gut pathobiont, Enterococcus gallinarum, to the liver and other systemic tissues triggers autoimmune responses in a genetic background predisposing to autoimmunity. Antibiotic treatment prevented mortality in this model, suppressed growth of E. gallinarum in tissues, and eliminated pathogenic autoantibodies and T cells. Hepatocyte–E. gallinarum cocultures induced autoimmune-promoting factors. Pathobiont translocation in monocolonized and autoimmune-prone mice induced autoantibodies and caused mortality, which could be prevented by an intramuscular vaccine targeting the pathobiont. E. gallinarum–specific DNA was recovered from liver biopsies of autoimmune patients, and cocultures with human hepatocytes replicated the murine findings; hence, similar processes apparently occur in susceptible humans. These discoveries show that a gut pathobiont can translocate and promote autoimmunity in genetically predisposed hosts.

Wagner-Meissner corpuscle proliferation: a unique cause of colon polyps.

Introduction Wagner-Meissner corpuscles (WMCs) are Schwannianderived specialized nerve endings typically found in the dermal papillae of glabrous skin (ie, hairless skin found on the plantar and palmar surfaces), where they function as mechanoreceptors. Previous reports in the literature have used a multitude of terms (tactile corpuscle-like bodies, tactoid bodies, Wagner-Meissner bodies, pseudoMeissner corpuscles, and Meissneroid corpuscles) to describe morphologically identical structures found outside this normal histological realm. WMCs have been recognized as a minor component in some benign neural neoplasms, including neurofibromas, schwannomas, and cellular nevi. Lesions composed predominantly of WMCs have also been infrequently described in several locations, including the vulva, cheek, periaortic tissue, finger, and lower extremity. It is important to note that although WMCs are incidentally identified in a variety of tissues in histological sections and occasionally in the above-mentioned neoplasms, they are not seen normally in the lamina propria of the gastrointestinal (GI) tract. We report 2 patients with colonic polyps composed entirely of S100-positive spindle cells with differentiation toward WMC. This unique morphology was initially a cause of diagnostic confusion. Awareness of this entity may prevent mischaracterization with other types of unusual colon polyps. Additionally, in our experience, we believe that these lesions, in isolation, should not raise clinical concern for a syndromic association, which may otherwise be elicited given their neural origin and distinct morphology.

Comparison of PCR-based detection of chromogranin A mRNA with traditional histological lymph node staging of small intestinal neuroendocrine neoplasia

BackgroundAccurate neuroendocrine neoplasia (NEN) staging is vital for determining prognosis and therapeutic strategy. The great majority of NENs express chromogranin A (CgA) which can be detected at a protein or transcript level. The current standards for lymph node metastasis detection are histological examination after Hematoxylin and Eosin (H&E) and CgA immunohistochemical (IHC) staining. We hypothesized that detection of CgA mRNA transcripts would be a more sensitive method of detecting these metastases.FindingsWe compared these traditional methods with PCR for CgA mRNA extracted from formalin fixed paraffin embedded slides of lymph nodes (n = 196) from small intestinal NENs, other gastrointestinal cancers and benign gastrointestinal disease. CgA PCR detected significantly more NEN lymph nodes (75%) than H&E (53%) or CgA IHC (57%) (p = 0.02). PCR detected CgA mRNA in 50% (14 of the 28) of SI-NEN lymph nodes previously considered negative. The false positive rate for detection of CgA mRNA was 19% in non-neuroendocrine cancers, and appeared to be due to occult neuroendocrine differentiation or contamination by normal epithelium during histological processing.ConclusionsMolecular pathological analysis demonstrates the limitations of observer-dependent histopathology. CgA PCR analysis detected the presence of CgA transcripts in lymph nodes without histological evidence of tumor metastasis. Molecular node positivity (stage molN1) of SI-NEN lymph nodes could confer greater staging accuracy and facilitate early and accurate therapeutic intervention. This technique warrants investigation using clinically annotated tumor samples with follow-up data.

Comprehensive Genetic Analysis of Follicular Thyroid Carcinoma Predicts Prognosis Independent of Histology

Context Follicular thyroid carcinoma (FTC) is classified into minimally invasive (miFTC), encapsulated angioinvasive (eaFTC), and widely invasive (wiFTC) subtypes, according to the 2017 World Health Organization guidelines. The genetic signatures of these subtypes may be crucial for diagnosis, prognosis, and treatment but have not been described. Objective Identify and describe the genetic underpinnings of subtypes of FTC. Methods Thirty-nine tumors, comprising 12 miFTCs, 17 eaFTCs, and 10 wiFTCs, were whole-exome sequenced and analyzed. Somatic mutations, constitutional sequence variants, somatic copy number alterations, and mutational signatures were described. Clinicopathologic parameters and mutational profiles were assessed for associations with patient outcomes. Results Total mutation burden was consistent across FTC subtypes, with a median of 10 (range 1 to 44) nonsynonymous somatic mutations per tumor. Overall, 20.5% of specimens had a mutation in the RAS subfamily (HRAS, KRAS, or NRAS), with no notable difference between subtypes. Mutations in TSHR, DICER1, EIF1AX, KDM5C, NF1, PTEN, and TP53 were also noted to be recurrent across the cohort. Clonality analysis demonstrated more subclones in wiFTC. Survival analysis demonstrated worse disease-specific survival in the eaFTC and wiFTC cohorts, with no recurrences or deaths for patients with miFTC. Mutation burden was associated with worse prognosis, independent of histopathological classification. Conclusions Though the number and variety of somatic variants are similar in the different histopathological subtypes of FTC in our study, mutational burden was an independent predictor of mortality and recurrence.

Successful treatment of primary donor-derived human herpesvirus-8 infection and hepatic Kaposi Sarcoma in an adult liver transplant recipient

Kaposi sarcoma (KS) may rarely occur in transplant recipients through primary human herpesvirus‐8 (HHV‐8) infection from a seropositive donor. This report describes a patient who developed hepatic KS after receiving a split liver transplant from an HHV‐8‐positive donor. The recipient was treated with liposomal doxorubicin after reduction in immunosuppression led to acute cellular rejection. This treatment achieved regression of KS while preserving allograft function, demonstrating a successful therapeutic strategy for this malignancy.

Challenges in communication from referring clinicians to pathologists in the electronic health record era

We report on the role played by electronic health record inbox messages (EHRmsg) in a safety event involving pathology. Evolving socio-cultural norms led to the coopting of EHRmsg for alternate use and oversight of a clinician to pathologist request. We retrospectively examined EHR inbox messages to pathologists over a 3 month block. 36 messages from 22 pathologists were assessed. 26 pertained to patient care including requests for report corrections and additional testing. 88% of requests had gone unaddressed. Clinicians assumed that pathologists used EHRmsg as clinical care team members, however, pathologists rarely did. Communication gaps exist between primary clinicians and pathologists in the EHR era and they have potential to result in patient harm. Different sociocultural norms and practice patterns between specialties underlie some of the breakdowns. Health information technology implementation needs to proactively look for new sociotechnical failure modes to avoid patient harm from communication lapses.

Clonal evolution analysis of paired anaplastic and well-differentiated thyroid carcinomas reveals shared common ancestor

Foci of papillary or follicular thyroid carcinoma are frequently noted in thyroidectomy specimens of anaplastic thyroid carcinoma (ATC). However, whether ATCs evolve from these co‐existing well‐differentiated thyroid carcinomas (WDTCs) has not been well‐understood. To investigate the progression of ATC in patients with co‐existing WDTCs, five ATC tumors with co‐existing WDTCs and matching normal tissues were whole‐exome sequenced. After mapping the somatic alteration landscape, evolutionary lineages were constructed by sub‐clone analysis. Though each tumor harbored at least some unique private mutations, all five ATCs demonstrated numerous overlapping mutations with matched WDTCs. Clonal analysis further demonstrated that each ATC/WDTC pair shared a common ancestor, with some pairs diverging early in their evolution and others in which the ATC seems to arise directly from a sub‐clone of the WDTC. Though the precise lineal relationship remains ambiguous, based on the genetic relationship, our study clearly suggests a shared origin of ATC and WDTC.

Optimal Intraoperative Assessment of Gastric Margins

Objectives Intraoperative pathology consultation (IOC) to assess margins is frequently requested during surgery of the stomach and gastroesophageal junction. Methods We studied 110 consecutive patients undergoing gastrectomy with IOC margin assessment. Results Gastric margins at IOC utilized the most blocks but were least often positive. In 64% of patients, the entire gastric margin was examined using average six blocks; representative sections were examined in 25% of patients using two blocks. There was no difference in patient outcome between those who had entire vs representative sections of margin examined. Gross variables showing strongest associations with positive margins were tumor size and tumor distance to margin. Tumors sized greater than 2.3 cm had significantly increased risk of positive margin, and tumor distance greater than 4.5 cm to margin was associated with negative margins. Conclusions We conclude representative sections of the closest gastric margin are sufficient to ensure R0 resection in the majority of cases.

Two Cases of Primary Hepatic Neuroendocrine Tumors and a Review of the Current Literature

Neuroendocrine tumors comprise approximately 1-2% of all gastrointestinal tumors, and while the liver is the most common site for metastasis of these tumors, primary hepatic neuroendocrine tumors are very rare entities. Since first being reported in 1958, there have been less than 150 cases reported in the literature. Because of the infrequent occurrence of these tumors, the pool of data available for analysis regarding these tumors is small. As such, the medical community must rely on the publication of case report data to further enlarge this data pool, with the hopes of eventually having enough data to draw meaningful, statistically significant conclusions with regard to diagnosis and management of these rare tumors. We have encountered two patients at our institution within the last year with primary hepatic neuroendocrine tumors. We present their cases in this manuscript in an effort to contribute to the available data on the disease. We also provide a concise review of the literature available to date regarding primary hepatic neuroendocrine tumors.Neuroendocrine tumors comprise approximately 1-2% of all gastrointestinal tumors, and while the liver is the most common site for metastasis of these tumors, primary hepatic neuroendocrine tumors are very rare entities. Since first being reported in 1958, there have been less than 150 cases reported in the literature. Because of the infrequent occurrence of these tumors, the pool of data available for analysis regarding these tumors is small. As such, the medical community must rely on the publication of case report data to further enlarge this data pool, with the hopes of eventually having enough data to draw meaningful, statistically significant conclusions with regard to diagnosis and management of these rare tumors. We have encountered two patients at our institution within the last year with primary hepatic neuroendocrine tumors. We present their cases in this manuscript in an effort to contribute to the available data on the disease. We also provide a concise review of the literature available to date regarding primary hepatic neuroendocrine tumors.

Evaluating Intestinal Infections: A Systematic Approach.

Endoscopic biopsies of the mucosa of the large and small intestines can present the pathologist with daunting challenges, in particular because of the breadth of the differential diagnosis, which may include neoplastic, ischemic, iatrogenic (notably medication related), autoimmune, idiopathic, and infectious entities. The purpose of the present study was to develop a logical and systematic approach to the diagnosis of mucosal infections by identifying several morphologic compartments in the intestinal mucosa, and establishing a differential diagnosis for the organisms that are associated with each compartment. The organisms involved may be identified by their appearances in histologic sections, or by the nature of the host reaction to their presence. The process of systematically examining each compartment of the mucosa and scanning for evidence of infection is performed subconsciously by many pathologists, and we have found this approach to be particularly appreciated by pathologists in training.