Clinicopathologic Features of Gastrointestinal Tract Langerhans Cell Histiocytosis.

Gastrointestinal (GI) tract involvement by Langerhans cell histiocytosis (LCH) is rare and its clinicopathologic characteristics have only been described in case reports and small series. We reviewed hematoxylin and eosin and CD1a, S100, and Langerin immunohistochemical-stained slides from 47 patients with well-documented demographic and clinical findings. Our cases included 8 children and 39 adults, with a mean follow-up of 63 months. All pediatric patients had concurrent multisystem LCH, presented with GI symptoms, and showed nonpolypoid lesions. Seven (88%) showed multifocal GI disease, including 5 with multiple GI organ involvement. All sampled lesions from children exhibited infiltrative growth. More than half had died of the disease or manifested persistent LCH at last follow-up. Twenty-five of 39 (64%) adults had LCH involving only the GI tract (single system), with the remaining 14 (36%) exhibiting multisystem disease. Adult single-system GI LCH was typically encountered incidentally on screening/surveillance endoscopy (72%). Most exhibited isolated colorectal involvement (88%) as a solitary polyp (92%), with a well-demarcated/noninfiltrative growth pattern (70%), and excellent prognosis (100%). In comparison, adult patients with multisystem LCH more frequently presented with GI symptoms (92%, P < .001), noncolorectal GI site involvement (50%, P = .02), multifocal GI lesions (43%, P = .005), nonpolypoid lesions (71%, P < .001), infiltrative histologic growth pattern (78%, P = .04), and persistent disease (57%, P < .001). Adult patients with multisystem LCH appear to exhibit similar clinicopathologic features to those of pediatric patients. These results demonstrated that adults with single-system LCH involving the GI tract have an excellent prognosis, whereas multisystem LCH occurring at any age carries an unfavorable prognosis. High-risk features of GI LCH include pediatric age, GI symptomatology, noncolorectal GI involvement, multifocal GI disease, nonpolypoid lesions, and infiltrative growth pattern.

Clinicopathologic Characterization of Invasive Fungal Intestinal Infections in Pediatric Patients.

BACKGROUND: Invasive fungal intestinal infections are rare in pediatric patients with limited studies reported to date. METHODS: Retrospective study of invasive intestinal fungal infections in pediatric patients. For fungal specification, 18S rRNA gene PCR was performed using formalin-fixed paraffin-embedded tissues. RESULTS: A total of 19 cases from 18 patients were included (13 males, 72%) with a median age of 20 days (8 days-14 years). About 13 patients (72%) presented within 67 days of birth and 11 patients (61%) were premature and 14 patients (78%) had a significant medical history. The most common location was the jejunum/ileum (56%) followed by the right colon and terminal ileum (22%). In 10 patients, the fungal elements were seen in the mucosa with 3 extending into the submucosa, and only 3 patients showed full-thickness involvement. Tissue necrosis and angioinvasion were seen in 13 (72%) and 8 (44%) patients, respectively. Morphologically, organisms consistent with Candida spp. were seen in 17 patients and with a mucoraceous mold in 1 patient. A 18S rRNA gene sequencing performed in 18 cases identified Candida dubliniensis in 16 cases and Candida spp. in 2 cases. During the study follow-up period, 56% of the patients died. CONCLUSION: In our experience, most cases were due to Candida spp. and predominantly in premature infants and associated with poor outcomes.

Clinicopathologic Characterization of Lymphocytic Colitis in the Pediatric Population.

BACKGROUND: Lymphocytic colitis (LC) in the pediatric population has been associated with immune dysregulation. METHODS: Single-center retrospective study of pediatric LC. RESULTS: 50 patients (35 female, 70%) with a median age of 12 years at diagnosis (interquartile range: 5.7-15.8) of LC were identified. At presentation, 11 patients (22%) had malnutrition, 16 (32%) had a known underlying immune dysregulation, 4 (8%) had celiac disease (CD), and none had a diagnosis of inflammatory bowel disease. The most common medications prior to diagnosis were non-steroidal anti-inflammatory drugs, proton pump inhibitor, and selective serotonin reuptake inhibitors (10% each). Colonic biopsies showed a median number of intraepithelial lymphocytes (IELs)/100 epithelial cells of 48 (range: 25-85), and only 10% of cases had neutrophilic cryptitis. Upper gastrointestinal tract findings included lymphocytic esophagitis (4%), and duodenal IELs without and with villous blunting (9% each) (n: 47). Ten patients (23%) had increased IELs in the terminal ileum (n: 43). Treatments including 5-ASA, budesonide, prednisone, and gluten-free diet improved symptoms in <50% of patients (n: 42), and all follow-up colonoscopies showed persistent LC (n: 13). CONCLUSION: Our study supports the association of LC with immune-mediated conditions, most commonly celiac disease. Symptomatic improvement was seen in <50% of patients with none of the patients with repeat colonoscopy showing histologic improvement.

Gastrointestinal Tract Granular Cell Tumor in the Pediatric Population: A Multicenter Experience.

BACKGROUND: Pediatric granular cell tumors (GCT) involving the gastrointestinal tract (GIT) are rare with limited case report/series reported to date. METHODS: Multicenter retrospective study of pediatric GIT GCT. RESULTS: A total of 10 cases were included in the study with a median age of 13.5 years (range: 7-18 years) and were predominantly female patients (60%). In half of the patients no significant medical history was present with the remaining 5 having Crohn disease (10%), eosinophilic esophagitis (EoE) (10%), Crohn disease and EoE (10%), growth hormone deficiency (10%), and aplasia cutis congenita (10%). The GCT median size was 1.3 cm (range: 1-1.6 cm) and were more commonly located in the esophagus (70%) followed by the stomach (20%) and rectum (10%). Most of the cases showed round/polygonal tumor cells with abundant granular cytoplasm, and none of the cases had nuclear atypia, increased mitotic activity, or tumor cell necrosis. None of our cases received specific therapy for GCT other than clinical follow-up, and none of the patients had evidence of local recurrence or metastatic disease. CONCLUSION: We present our multicenter experience with GIT GCT, all cases had a benign course. Interestingly, 4 of the esophageal GCT cases (including 2 patients with EoE) showed an eosinophil-rich esophagitis in the underlying mucosa.

Granulomas in Pediatric Liver Biopsies: Single Center Experience.

BACKGROUND: Granulomas in pediatric liver biopsies (GPLB) are rare with the largest pediatric cohort reported over 25 years ago. METHODS: Single-center retrospective study of GPLB. RESULTS: Seventeen liver biopsies from 16 patients with granulomas were identified (9 boys, 56%) with a median age of 13 years (range: 1-18) for which the most common indication was the presence of a nodule/mass (47%). Significant comorbidities were seen in 13 patients (81%) and included: liver transplant (25%), history of a neoplasm (25%), autoimmune hepatitis (6%), Crohn disease (6%), bipolar disorder (6%), severe combined immunodeficiency (6%), and sickle cell disease (6%). Eleven patients were taking multiple medications at the time of biopsy. Granulomas were more commonly pan-acinar (11 cases) followed by subcapsular (4 cases), portal (1 case), and periportal (1 case). Necrosis was seen in 10 cases (59%). GMS stain was positive in 2 cases for Histoplasma-like yeast; microbiological cultures were negative in all cases (no: 4). A 18S and 16S rRNA gene sequencing performed in 15 cases revealed only 1 with a pathogenic microorganism, Mycobacterium angelicum. CONCLUSION: In our experience, GPLB are heterogenous with only 3 cases having an identifiable infectious etiology and many of the remaining cases being associated to multiple medications, suggesting drug-induced liver injury as possible etiology.

Liver manifestation of patients with celiac disease: A single center experience.

OBJECTIVES: Characterize the clinicopathologic features of liver biopsies from patients with celiac disease (CD). METHODS: Single center, retrospective search for liver biopsies from patients with CD. RESULTS: 36 unique patients were included, median age of 46 years (range: 2-75), including 5 pediatric patients, with an overall female predominance (25, 69 %) but in in children a male predominance was seen (p = 0.023). Most cases (75 %) had an underlying condition including autoimmune hepatitis (AIH) (11 %), AIH/primary biliary cholangitis (PBC) overlap (3 %) and PBC (3 %). The median body mass index was 28, with 4 (11 %) underweight and 22 (61 %) overweight/obese patients. The most common histologic pattern was steatosis (18, 50 %), considered severe in 5 (14 %) and in 7 (19 %) regarded as steatohepatitis. The other histologic patterns included a nonspecific portal and/or lobular inflammation ("celiac hepatitis") in 9 cases (25 %), autoimmune hepatitis (3, 8 %), chronic cholestatic pattern (3, 8 %), chronic hepatitis (1, 3 %), acute lobular hepatitis (1, 3 %) and stablished cirrhosis (1, 3 %). Additionally, 2 of the cases with steatosis show cirrhosis. CONCLUSIONS: The biopsy findings from patients with CD are heterogenous and in most represent a concomitant underlying disease, particularly metabolic dysfunction-associated steatotic liver disease. Additionally, CD injury should remain in the differential diagnosis in liver biopsies with a nonspecific portal and/or lobular inflammation.

Incidental findings during donor liver assessment: Single center experience.

Intraoperative consultation of donor liver is an important part of transplant evaluation and determination of liver eligibility. In this study, we describe incidental pathologic findings discovered during the pretransplant evaluation of liver donors in our Institution from 1/2010 to 12/2022. During this 13-year period 369 intraoperative consultations from 262 liver donors were performed. Of those cases, incidental findings were identified in 22 cases (5.9 %) from 19 donors (7.3 %); two donors had more than one lesion. The median age of this subset of patients was 53 years (range: 18-70) and females predominated (63 %). Sixteen of the donors had abnormal findings in the liver: 6 bile duct hamartoma (BDH), 5 hyalinized nodule with Histoplasma capsulatum, 5 focal nodular hyperplasia (FNH), 2 bile duct adenomas (BDA), 1 biliary cyst and 1 hemangioma. One donor had both FNH and a BDH. One BDH and 1 BDA case was misdiagnosed as malignancy during the frozen section evaluation. Three donors had extrahepatic pathologies: a pancreatic tail schwannoma, a low-grade appendiceal mucinous neoplasm, and a lymph node with metastatic endometrial endometrioid adenocarcinoma. Of the 19 livers, the final organ disposition was available for 9: 6 were transplanted (67 %) and 3 were discarded (33 %). Two of the 3 discarded organs were misdiagnosed BDH and BDA cases, and one was incorrectly reported as having 90 % microvesicular steatosis during the frozen assessment. We present the clinicopathologic characteristics of liver donors with incidental findings during the pre-transplant evaluation which could lead to unwarranted graft dismissal if misdiagnosed. Additionally, incidental fungal infections can have implications for immunosuppressive therapy and the decision to use or reject the graft.

Focal Nodular Hyperplasia in the Pediatric Population: A Multicenter Experience.

BACKGROUND: Focal nodular hyperplasia (FNH) is a benign liver lesion classically presenting in young females. In children, FNH is rare and its detailed clinicopathologic characteristics remain largely unknown. Furthermore, there are no studies comparing pediatric FNH features to those presenting in adults. METHODS: In this study, we analyzed a total of 47 FNH cases in pediatric patients (age range: 23 days to 18 years) from 3 centers and compared them to a cohort of 31 FNH cases in adult patients (age range: 20-64 years). RESULTS: Of the pediatric cases, 13 cases (28%) had a history of a prior malignancy of which 4 were treated with chemoradiation and stem cell transplantation (SCT), 5 with chemoradiation alone and 3 with chemotherapy and SCT. In the pediatric cases 41 (87%) had a central scar and 46 (98%) had fibrous septa. Both pediatric and adult FNH were more common in female patients. Cases in pediatric patients were also significantly associated with larger size (P = .047), absence of dystrophic vessels (P = .001), absence of sinusoidal dilatation (P = .029), pseudoacini formation (P = .013), and steatosis (P = .029). CONCLUSION: In our experience although most cases of pediatric FNH show the classic histologic features seen in adults, some significant differences exist, and awareness of these findings could aid in the evaluation of these rare cases.

Multi-institutional development and validation of a novel histologic grading system for colonic graft-versus-host disease.

Graft-versus-host disease (GVHD) remains a major complication for patients who have undergone hematopoietic stem cell transplantation. The Lerner system is the most widely used histologic grading score for gastrointestinal GVHD but its clinic utility is debated. The aim of our study was to develop a novel histologic grading system for gastrointestinal GVHD that incorporates independent evaluation of both apoptotic counts and crypt destruction. Colonic biopsies taken to assess for GVHD were retrospectively assessed for: Crypt damage (No crypt dropout or ulceration-0; crypt dropout without ulceration-1; ulceration-2) and crypt apoptotic counts (No apoptosis-0; 1-6 apoptotic bodies per 10 contiguous crypts-1; >6apoptotic bodies per 10 contiguous crypts-2). The two scores were added together to get an overall grade (0-4). Alternative apoptotic cutoff points were examined. An apoptotic cutoff of >9 apoptotic bodies per 10 contiguous crypts marginally improved the area under the curve (AUC), but the AUCs from the resulting novel grade calculations were not significantly different (p = 0.10). Lerner grading was also applied. The study group consisted of an initial analysis cohort (n = 191) and a second validation cohort from a separate institution (n = 97). In the initial analysis cohort, our histologic grading system provided prognostic stratification for GVHD-related death within 6 months (p = 0.0004, AUC = 0.705). The Lerner system performed similarly in terms of providing prognostic stratification for GVHD-related death (p = 0.0001, AUC = 0.707). In the external validation cohort, our histologic grading system was not associated with GVHD-related death (p = 0.14, AUC = 0.621), but the Lerner system was associated with GVHD-related death (p = 0.048, AUC = 0.663). While our grading system may have some advantages compared to the Lerner system, due to lack of reproducibility we do not currently recommend widespread adoption of this system. Nonetheless, we present a standardized tool for assessing both apoptosis and crypt damage. Future studies assessing alternative histologic grading systems with external validation and further examination the lower apoptotic threshold for GVHD diagnosis are warranted.

DICER1 tumor predisposition syndrome: an evolving story initiated with the pleuropulmonary blastoma.

DICER1 syndrome (OMIM 606241, 601200) is a rare autosomal dominant familial tumor predisposition disorder with a heterozygous DICER1 germline mutation. The most common tumor seen clinically is the pleuropulmonary blastoma (PPB), a lung neoplasm of early childhood which is classified on its morphologic features into four types (IR, I, II and III) with tumor progression over time within the first 4-5 years of life from the prognostically favorable cystic type I to the unfavorable solid type III. Following the initial report of PPB, its association with other cystic neoplasms was demonstrated in family studies. The detection of the germline mutation in DICER1 provided the opportunity to identify and continue to recognize a number seemingly unrelated extrapulmonary neoplasms: Sertoli-Leydig cell tumor, gynandroblastoma, embryonal rhabdomyosarcomas of the cervix and other sites, multinodular goiter, differentiated and poorly differentiated thyroid carcinoma, cervical-thyroid teratoma, cystic nephroma-anaplastic sarcoma of kidney, nasal chondromesenchymal hamartoma, intestinal juvenile-like hamartomatous polyp, ciliary body medulloepithelioma, pituitary blastoma, pineoblastoma, primary central nervous system sarcoma, embryonal tumor with multilayered rosettes-like cerebellar tumor, PPB-like peritoneal sarcoma, DICER1-associated presacral malignant teratoid neoplasm and other non-neoplastic associations. Each of these neoplasms is characterized by a second somatic mutation in DICER1. In this review, we have summarized the salient clinicopathologic aspects of these tumors whose histopathologic features have several overlapping morphologic attributes particularly the primitive mesenchyme often with rhabdomyoblastic and chondroid differentiation and an uncommitted spindle cell pattern. Several of these tumors have an initial cystic stage from which there is progression to a high grade, complex patterned neoplasm. These pathologic findings in the appropriate clinical setting should serve to alert the pathologist to the possibility of a DICER1-associated neoplasm and initiate appropriate testing on the neoplasm and to alert the clinician about the concern for a DICER1 mutation.

Hepatocellular Adenoma in an Infant With Burn-McKeown Syndrome: Report of a Case.

Hepatocellular adenomas (HCA) in infants are exceedingly rare with only 5 cases reported to the best of our knowledge, all of them preceding the classification of HCA. Here we present an autopsy case of a 9-month-old girl with Burn-McKeown syndrome with an incidental liver nodule in the right lobe measuring 1.5 cm in greatest dimension. The lesion was composed of an unencapsulated proliferation of hepatocytes with multiple unaccompanied arteries without well-formed portal tracts, and an intact reticulin framework without thickened hepatic plates, findings consistent with an HCA. Glutamine synthetase (GS), lipid fatty acid-binding protein (LFABP), c-reactive protein (CRP), serum amyloid-a (SAA), beta-catenin and CD34 immunostains were performed. GS was diffusely and strongly positive in the lesion, CD34 showed heterogenous staining of sinusoids within the lesion without a well-formed rim from the background liver and beta-catenin was negative for nuclear staining. CRP and SAA were considered negative, and LFABP was retained. Molecular testing showed no CTNNB1 variants and found two tier 3 variants involving CHEK2 and PTEN genes. These findings are consistent with an unclassified HCA (U-HCA) per the 2019 WHO Classification of Tumors, representing the youngest patient reported. This raises the possibility that some HCAs are congenital or develop very early in life, remaining undiagnosed until later in life.

Solid-Tubulocystic Variant of Intrahepatic Cholangiocarcinoma: Report of a Pediatric Case With Molecular Characterization.

We present a case of solid-tubulocystic variant of intrahepatic cholangiocarcinoma (also called cholangioblastic variant of intrahepatic cholangiocarcinoma) in a 15-year-old girl, the youngest patient reported to date. The tumor was located in the left lobe of the liver, predominantly solid with cystic areas, and measured 16 cm in greatest dimension. Microscopic examination showed 2 major histologic patterns: a mixed pattern with solid, tubulocystic, macrocystic, trabecular, and nested growth, diffuse cytokeratin 7/19 and weak neuroendocrine immunoreactivity, and low Ki-67 index; and a more compact, macrotrabecular/gyriform pattern with focal CK7/19, stronger neuroendocrine reactivity, and higher Ki-67 index. Inhibin immunoreactivity was diffuse throughout both patterns. Treatment included tumor resection with negative margins and 8 cycles of capecitabine chemotherapy; the patient is alive with no evidence of tumor 2.5 years after resection. Although molecular characterization of the tumor at the time of resection was unrevealing, a recent study has identified a novel NIPBL-NACC1 fusion transcript in this tumor type, which we have confirmed in this case. This case expands the reported age range of this rare tumor type and confirms a recently-reported diagnostic genomic alteration. Awareness of this rare entity affecting pediatric patients is crucial to avoid confusion with similar-appearing neoplasms.

Expression of p53 is significantly associated with recurrence-free survival and overall survival in pleuropulmonary blastoma (PPB): a report from the International Pleuropulmonary Blastoma/DICER1 Registry.

Pleuropulmonary blastoma (PPB) is a primary embryonal malignancy of childhood that is characterized by distinct morphologic types: type Ir (regressed), type I (cystic), type II (cystic and solid), and type III (solid). Prognosis varies by PPB type. Most cases are associated with a germline pathogenic mutation in DICER1; however, there is limited data on the factor(s) at a cellular level that drive progression from type I to type III. In this study, we evaluated the expression of p53 and its prognostic implications. A total of 143 PPB cases were included in the study with the following distribution in PPB types: Ir (14%), I (23%), II (32%), and III (31%). P53 expression by immunohistochemistry (IHC) was recorded as four groups: 0%, 1-25%, 26-75%, and 76-100%. All type I PPBs showed 0-25% p53 expression compared to the higher p53 expression (>25%) in type III PPB (p < 0.0001), to support the argument that p53 has a role in tumor progression. In addition, type Ir with the architectural hallmarks of type I PPB, but lacking the primitive cell population, has negligible p53 expression. High p53 expression (staining observed in >25% of the tumor cells) was significantly associated with age over 1 year (p = 0.0033), neoadjuvant therapy (p = 0.0009), positive resection margin (p = 0.0008) and anaplasia (p < 0.0001). P53 expression was significantly associated with recurrence-free survival (p < 0.0001) and overall survival (p = 0.0350), with higher p53 expression associated with worse prognosis. Comparisons of concordance statistics showed no significant difference in prognostication when using morphologic types compared to p53 expression groups (p = 0.647). TP53 sequence was performed in 16 cases; the most common variant identified was a missense variant (12 cases), and in one case a frameshift truncating variant was noted. Based on these findings, we recommend performing p53 IHC in all newly diagnosed cases of types II and III PPB to further aid in risk stratification.

Clinicopathologic Characteristics of Centrilobular Injury in Pediatric Liver Transplantation.

Centrilobular injury (CLI) is defined as the presence of perivenular mononuclear inflammation, hepatocyte dropout, and extravasated erythrocytes. In pediatric liver allografts, CLI has been associated with advanced fibrosis and chronic rejection (CR). We sought to better characterize the clinicopathologic features of CLI in the setting of T cell-mediated rejection (TCMR) and its association with complement component 4d (C4d) deposition. A total of 206 posttransplant pediatric patients (491 allograft liver biopsies) were available from 2000 to 2018, of which 63 patients (102 biopsies) showed evidence of TCMR and were included in the study. Of the patients, 35 (55.6%) had CLI on their initial episode of TCMR; those patients with CLI were significantly associated with the type of immunosuppression treatment (P = 0.03), severity of TCMR (P < 0.001), higher gamma-glutamyltransferase (P = 0.01), and advanced fibrosis (P = 0.03). There was a trend to shorter time interval from transplantation to presentation of CLI compared with those without CLI (P = 0.06). No difference was observed in graft or overall survival in the patients with CLI. In 20 patients with CLI, additional biopsies were available; in 45% of these patients, CLI was a persistent/recurrent finding. C4d deposition was noted in 12% of all biopsies (6 patients) with CLI. No significant correlation was noted in C4d deposition and CLI, CR, or graft/overall survival. In conclusion, CLI, although not significantly associated with worse graft survival, was significantly associated with severe TCMR and degree of fibrosis, which highlights the importance of active clinical management and follow-up for these patients.

Describing universal Strongyloides serologic screening among pediatric intestinal and liver transplant recipients.

BACKGROUND: Strongyloides spp hyperinfections are a worldwide phenomenon that proves fatal for solid organ transplant recipients. Screening protocols to guide prophylaxis management vary institution to institution from universal to epidemiology driven. Our institution initiated a universal screening protocol regardless of travel history and exposure to ensure no cases were missed. METHODS: In this study, we describe the outcomes of three Strongyloides sero-positive children whom underwent intestinal or liver transplantation and the experience of universal screening at a tertiary care county hospital in South Florida. RESULTS: Among the 66 intestine and liver pediatric transplant recipients who were screened for Strongyloides antibodies, only three were identified to be sero-positive via the screening mechanism. Two of three had significant epidemiology risk factors. None of the patients reviewed were found to have developed hyperinfection. However, reflecting on the experience represented by our series of pediatric patients, the risk of any complication related to Strongyloides status appears low. Even among this South Florida population whom come from or travel to endemic regions are in contact with sero-positive individuals, very few illustrate sero-positivity. CONCLUSION: While institutions continue to analyze the cost-benefit of universal testing vs. universal prophylaxis vs. targeted screening, the decision must encompass the patient population, rolling cumulative incidence, and morbidity and mortality related to this disease.

Smooth muscle hamartoma and striated muscle hamartoma: Clinicopathologic characterization of two rare entities and literature review.

Smooth muscle hamartoma (SMH) and striated muscle hamartoma (STH) are anomalous proliferations of smooth muscle or striated muscle, respectively, in anatomic sites where these tissues are normally present. To date, only limited cases have been reported describing these lesions. In this study, we sought to characterize the clinicopathologic features of both SMH and STH. A total of 27 cases of SMH and 12 cases of STH from 1990 to 2020 were identified. SMH cases had a slight male predominance (63%) and a mean age of presentation of 20 years (range: 4 months-91 years), with a mean size of 9.3 mm (±13.3). In contrast, STH were equally distributed in gender, with a mean age of presentation of 40 years (range: 3 months-66 years) and a mean size of 5.7 mm (±3.6). SMH were more commonly located in the torso and extremities (70%) and STH in the head and neck area (92%). One case of SMH recurred after 1.1 years and in the initial diagnosis the lesion was present at the tissue edge. None of the cases of STH had a recurrence. We present the largest cohort of SMH and STH, and report the first case of a recurrent SMH, suggesting the importance of obtaining a clean margin for these lesions.

Programmed Death Ligand 1 Expression and Related Markers in Pleuropulmonary Blastoma.

INTRODUCTION: Pleuropulmonary blastoma (PPB), a rare childhood neoplasm of the lung, is linked to pathogenic DICER1 variants. We investigated checkpoint inhibitor markers including Programmed Death Ligand 1 (PD-L1), PD1, CD8 and tumor mutational burden (TMB) in PPB. MATERIAL AND METHODS: Cases were collected from departmental archives and the International PPB/DICER1 Registry. Immunohistochemistry (IHC) for PD-L1, PD-1, CD8 and DNA mismatch repair (MMR) genes were performed. In addition, normal-tumor paired whole exome sequencing (WES) was performed in two cases. RESULTS: Twenty-five PPB cases were studied, consisting of Type I (n = 8, including 2 Ir), Type II (n = 8) and Type III (n = 9). PD-L1 combined positive score (CPS) of 1, 4 and 80 was seen in three (3/25, 12.0%) cases of Type II PPB with negative staining in the remaining cases. PD-1 and CD8 stains demonstrated positive correlation (P < .05). The density of PD1 and CD8 in the interface area was higher than within tumor (P < .05). The MMR proteins were retained. TMB was 0.65 mutations/Mb in type II PPB with high expression of PD-L1, and 0.94 mutations/Mb in one negative PD-L1 case with metastatic tumor. CONCLUSION: A small subpopulation of PPB patient might benefit from checkpoint immunotherapy due to positive PD-L1 staining.

Ground-glass hepatocellular inclusions are associated with polypharmacy.

Ground-glass (GG) hepatocytes are classically associated with chronic hepatitis B (HBV) infection, storage disorders, or cyanamide therapy. In a subset of cases, an exact etiology cannot be identified. In this study, we sought to characterize the clinical, histological, and ultrastructural findings associated with HBV-negative GG hepatocytes. Our institutional laboratory information system was searched from 2000 to 2019 for all cases of ground-glass hepatocytes. Ten liver biopsies with GG hepatocellular inclusions and negative HBV serology, no known history of storage disorders, or cyanamide therapy were reviewed. Half of the patients had history of organ transplantation and/or malignancy. These patients took on average 8.1 medications (range: 3-14) with the most common medications being immunosuppressive and health supplements. Histologically, GG hepatocytes show either peri-portal or centrizonal distribution. The inclusions are PAS-positive and diastase sensitive. Electron microscopy showed intracytoplasmic granular inclusions with low electron density, consistent with unstructured glycogen. In summary, GG hepatocytes are a rare finding in liver biopsies, but are more common in patients with hepatitis B. They can also be seen in HBV-negative patients who have polypharmacy. In these cases, they are the result of unstructured glycogen accumulation putatively due to altered cell metabolism.

GCV/VCVG prophylaxis against CMV DNAemia in pediatric renal transplant patients: A systematic review and meta-analysis.

CMV disease continues to stand as a significant threat to the longevity of renal transplants in children. More pediatric recipients are CMV-negative with CMV-positive donor serologies resulting in a HR mismatch. The length of prophylaxis with GCV or VGCV required to optimally prevent recurrence of CMVDNAemia remains unknown. This study is a meta-analysis comparing GCV/VGCV prophylaxis regimens provided for <6 months, from 6 to <12 months, and ≥12 months after transplant in order to prevent CMVDNAemia. The search conducted involved PubMed, EMBASE, ISI Web of Science, and Cochrane Central Register from inception through December 2017. Search terms Kidney Transplantation, CMV, GCV, and VGCV provided 204 studies for abstract review. Studies excluded were those which did not itemize pediatric data separately, single case reports, and duplicate studies. Pooled analysis of five retrospective studies and one prospective study identified that there is no statistically significant difference in the incidence of CMV DNAemia when comparing <6 months of prophylaxis and >12 months of prophylaxis (23% and 15%, respectively, P = 0.23). Regardless of the length of prophylaxis, there was no statistical difference in the incidence of CMV DNAemia in the HR patients (6 to <12 months vs <6 months, P = 0.62; 6 to <12 months vs ≥12 months, P = 0.78; ≥12 months vs <6 months, P = 0.83). This study identifies no optimal length of prophylaxis for HR mismatch pediatric renal transplant patients as many develop CMV DNAemia.

Comparison in outcome with tailored antibiotic prophylaxis postoperatively in pediatric intestinal transplant population.

BIs are ubiquitous among the pediatric intestinal transplant patient population. Personalizing postoperative prophylaxis antibiotic regimens may improve outcomes in this population. A retrospective analysis of all pediatric patients who underwent intestinal transplantation was evaluated to compare standardized and tailored regimens of antibiotics provided as prophylaxis postoperatively. Patients in the standard group have both shorter time to and higher rate of BIs, which was statistically significant (P < 0.001). Of the children who developed a BI, there was no statistical difference in average times to the development of a second BI (293 vs 119 days, P = 0.211). The tailored group had prolonged times until the development of a MDRO (52.6 vs 63.9 days, P = 0.677). Although not statistically significant, the tailored group had a propensity to present with gram-negative pathogens after transplant as compared to the standard regimen group, which presented with gram-positive pathogens (P = 0.103). Children with a history of an MDRO held a 7.3 (P < 0.01) times more likelihood of death within a year of transplant. A tailored prophylactic antibiotic regimen in the post-transplant period appears to prolong the time to the first BI. Although the data do not show differences in mortality, further study may prove the impact of a tailored antibiotic regimen on morbidity and mortality rates.