A Clinicopathologic Evaluation of Incidental Fundic Gland Polyps With Dysplasia: Implications for Clinical Management.

OBJECTIVES: Fundic gland polyps (FGPs) can rarely exhibit dysplasia of the surface epithelium. Based on retrospective data, FGPs with dysplasia (FGPDs) are thought to be a strong marker for familial adenomatous polyposis (FAP), although sporadic, non-syndromic FGPDs also occur. Owing to the significant syndromic association, diagnosis of an apparently sporadic FGPD may prompt clinical evaluation for FAP, especially its attenuated variant. We sought to evaluate the positive predictive value of incidental FGPDs for FAP. We also characterized the clinicopathologic features of incidental FGPDs to advance clinical management. METHODS: Incidental FGPDs were identified from 2004 to 2015 in patients without FAP at biopsy. All clinical follow-up data were reviewed, and germline analysis for APC and MUTYH mutations was performed in consenting patients. RESULTS: We identified 25 incidental FGPDs in patients not known to have FAP (11.6% of FGPDs, 1.0% of all FGPs). Four patients had a family history of gastric polyps or gastrointestinal cancers. Clinical management included completion polypectomy and gastric endoscopic surveillance (44%), endoscopic surveillance alone (32%), no follow-up (24%), colonoscopy referral (12%), and genetic counseling (4%). Colonoscopies on record revealed 0-7 cumulative adenomas. Follow-up averaged 4.4 years (range 0.3-10.6). No clinical evidence of FAP, gastric cancer, death, or surgery occurred. None of the 11 patients consenting to germline APC and MUTYH testing had genomic alterations. CONCLUSIONS: Incidental FGPDs in this series were all found to be sporadic (25/25) by endoscopic, clinical, and molecular findings, and thus FGPDs were not harbingers of FAP. As isolated findings, FGPDs do not appear to warrant follow-up genetic counseling or testing.

Glomerulonephritis With Masked Monotypic Immunoglobulin Deposits and Concurrent Lymphomatous Infiltration.

Kidney injury can be a complication of hematopoietic neoplasia by both direct and indirect mechanisms. Virtually all lymphomas and plasma cell dyscrasias can show kidney involvement, including parenchymal infiltration and by secondary injury. Recently, a unique form of glomerulonephritis with masked monotypic immunoglobulin deposits has been reported, which shows frequent association with hematopoietic neoplasia and a propensity for progressive kidney disease. In many instances, these cases are likely diagnosed as glomerulonephritis with dominant C3 due to the absence of immunoglobulin staining by routine immunofluorescence microscopy. The patient reported here showed lymphomatous infiltration on kidney biopsy and mesangial proliferative glomerulonephritis with dominant staining for C3 without immunoglobulins on initial immunofluorescence; however, monotypic immunoglobulin G κ light chain was revealed after additional immunofluorescence staining was performed on the paraffin-embedded tissue. This patient's case highlights the evolving state of kidney biopsy interpretation and the expanding spectrum of kidney disease in the setting of hematopoietic neoplasia.

Digital Whole Slide Imaging Compared With Light Microscopy for Primary Diagnosis in Surgical Pathology.

CONTEXT.­: The adoption of digital capture of pathology slides as whole slide images (WSI) for educational and research applications has proven utility. OBJECTIVE.­: To compare pathologists' primary diagnoses derived from WSI versus the standard microscope. Because WSIs differ in format and method of observation compared with the current standard glass slide microscopy, this study is critical to potential clinical adoption of digital pathology. DESIGN.­: The study enrolled a total of 2045 cases enriched for more difficult diagnostic categories and represented as 5849 slides were curated and provided for diagnosis by a team of 19 reading pathologists separately as WSI or as glass slides viewed by light microscope. Cases were reviewed by each pathologist in both modalities in randomized order with a minimum 31-day washout between modality reads for each case. Each diagnosis was compared with the original clinical reference diagnosis by an independent central adjudication review. RESULTS.­: The overall major discrepancy rates were 3.64% for WSI review and 3.20% for manual slide review diagnosis methods, a difference of 0.44% (95% CI, -0.15 to 1.03). The time to review a case averaged 5.20 minutes for WSI and 4.95 minutes for glass slides. There was no specific subset of diagnostic category that showed higher rates of modality-specific discrepancy, though some categories showed greater discrepancy than others in both modalities. CONCLUSIONS.­: WSIs are noninferior to traditional glass slides for primary diagnosis in anatomic pathology.

Characterization of PD-L1 Immunohistochemical Expression in Cell Blocks With Different Specimen Fixation and Processing Methods.

Interpretative criteria for programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) have been largely based on data from formalin-fixed, paraffin-embedded tissues, despite the fact that cytologic specimens, especially cell blocks, are often the only or most readily available tissue for testing. Unlike biopsy specimens, however, cytology sample processing methods can vary markedly. The purpose of this study was to evaluate the effects of several common preanalytic variables on PD-L1 IHC. Two cell lines with strong expression of PD-L1 (H441) and no expression (MCF7) were cultured in vitro. Harvested cells were collected in PreservCyt, CytoLyt, cell culture media (RPMI), saline, and formalin. Cell blocks were prepared by the plasma-thromboplastin method or Cellient automated system and stained with the FDA-approved 28-8 PD-L1 antibody per protocol. PD-L1 expression was scored manually by 3 pathologists for stain intensity and localization and compared across preparation methods. Several IHC staining patterns were observed: complete membranous, partial membranous, globular, and cytoplasmic, with some overlap. Cellient blocks had the best interobserver agreement and cytomorphology, highest proportion of strong complete membranous staining (82%), and least amount of cytoplasmic (11%) and globular staining (8%). RPMI, saline, and formalin samples demonstrated increased amounts of cytoplasmic and globular staining relative to Cellient, while CytoLyt exhibited the poorest performance overall. Interpretation of PD-L1 IHC on cell blocks is feasible for most processing methods examined, but may require recognition of increased cytoplasmic and globular staining in some sample types. Cellient cell blocks demonstrated superior performance compared with other methods.

De novo immune complex deposition in kidney allografts: a series of 32 patients.

Immune complex deposition in kidney allografts can include both recurrent and de novo processes. Recurrent glomerulonephritis is a well-recognized phenomenon and has been shown to be a common cause of allograft failure. De novo immune complex-mediated disease remains relatively poorly characterized, likely owing to the less frequent use of immunofluorescence and electron microscopy in the transplant setting. We performed a retrospective review of kidney allograft biopsies showing glomerular immune complex deposition. Cases with de novo deposits were identified and further organized into two groups depending on whether the immune complex deposition could be clinically and/or histologically classified. Thirty-two patients with de novo immune complex deposition were identified over a 7-year period. A broad range of immune complex-mediated injuries were observed, the majority (63%) of which could be readily classified either clinically or histologically. These included cases of membranous glomerulonephropathy, IgA nephropathy, infection-related glomerulonephritis and glomerulonephritis related to an underlying autoimmune process. A smaller subset of patients (37%) demonstrated immune complex deposition that was difficult to histologically or clinically classify. These patients typically showed mild mesangial immune complex deposition with co-dominant IgG and IgM staining by immunofluorescence microscopy. The presence of concurrent antibody-mediated rejection and donor-specific antibody positivity was significantly higher in the unclassifiable group. The significance of these deposits and their possible relationship to allograft rejection deserves further investigation.

X-Ray of Excised Cancerous Breast Tissue Does Not Affect Clinical Biomarker Expression.

CONTEXT: College of American Pathologists (CAP) and the American Society of Clinical Oncology have emphasized the need to reduce preanalytic variables for evaluating predictive biomarker expression in breast cancer. Postoperative x-ray of excised breast tissue is commonplace, yet is a variable that has not been investigated previously. We asked whether such radiation affects expression of relevant biomarkers. DESIGN: A previous study found that human breast cancers grown in mice demonstrate the same immunohistochemical and molecular profiles as the original tumors. Thirteen patient-derived xenografts were harvested fresh and divided for specimen radiography and a matched nonirradiated control, while following CAP/ASCO guidelines for cold ischemia time and fixation. Samples were processed in a tissue microarray for immunohistochemistry. Estrogen receptor (ER), progesterone receptor (PR), p53, and Ki67 staining was evaluated using an optimized scoring algorithm performed on digitally scanned slides. Samples were also scored manually by a blinded pathologist using the H-score method, and HER2 by the CAP/ASCO 2013 protocol. Histologic scores were compared by analysis of variance. RESULTS: There was no significant difference in quantity or intensity of staining between irradiated and nonirradiated samples for estrogen receptor (P=0.28), p53 (P=0.96), and Ki67 (P=0.94). A small but statistically significant difference was observed for PR (P=0.0058). HER2 staining was similarly unchanged in the 1 tumor exhibiting 3+ staining. CONCLUSIONS: Our study demonstrates that x-ray of breast carcinomas does not significantly affect the expression of predictive biomarkers, with the exception of PR for unclear reasons. It also highlights the utility of the patient-derived xenograft model for biomarker studies.

C3 glomerulopathy in adults: a distinct patient subset showing frequent association with monoclonal gammopathy and poor renal outcome.

BACKGROUND: C3 glomerulopathy (C3G) includes both C3 glomerulonephritis (C3GN) and dense deposit disease (DDD) and is defined by C3-dominant deposits on immunofluorescence. Dysfunction of the alternative pathway (AP) of complement is central to the pathophysiology of C3G and young patients often harbor genetic alterations of AP mediators. Recently, a link between C3G and paraproteinemia has been established. We performed this study to better characterize older patients with C3G where this association is more frequently seen. METHODS: Fourteen biopsies from 12 patients meeting diagnostic criteria for C3G were identified in patients > 49 years of age from 2005 to 2015 after exclusion of cases containing masked monotypic immunoglobulin deposits. Pathologic and clinical features were reviewed. RESULTS: The median age was 63.5 years and 75% of patients were male. All had renal insufficiency at presentation. Kidney biopsy showed DDD in three patients and C3GN in the remainder. Serum protein electrophoresis revealed a paraprotein in 10 patients, 8 of which had a plasma cell dyscrasia on bone marrow biopsy. A membranoproliferative pattern of glomerular injury was seen in 64% of biopsies, while mesangial proliferative and endocapillary proliferative patterns were seen less frequently. Among patients with at least 1 year of follow-up (n = 9), five were on renal replacement therapy, three showed stable (but impaired) kidney function and one demonstrated improvement. CONCLUSIONS: C3G is an uncommon but important cause of kidney injury in older adults and associates with a high prevalence of paraproteinemia. In adult patients with C3G, prognosis is guarded as most patients showed either progression to end-stage kidney disease or stable but impaired kidney function.

An unusual and challenging case of HIV-associated primary CNS Lymphoma with Hodgkin-like morphology and HIV encephalitis.

HIV-associated primary CNS lymphomas are well-recognized, almost exclusively EBV-driven neoplasms with poor clinical prognosis. We report a challenging, atypical case of an HIV-associated lymphoproliferative disorder with unusual morphologic features reminiscent of Hodgkin Lymphoma, accompanied by HIV encephalitis. A 52-year-old male presented with acute seizures after seven months of progressive neurocognitive decline that was clinically diagnosed as progressive supranuclear palsy. Clinical work-up revealed HIV infection along with two ring-enhancing lesions in the brain on MRI, and negative CSF EBV testing. Subsequent biopsy showed well-demarcated hypercellular regions in the brain comprised of scattered Reed-Sternberg-like cells in a background of small to medium-sized lymphocytes exhibiting focal angiocentricity and geographic necrosis. The atypical cells were positive for CD20, EBV, and CD79a, and negative for CD45, GFAP, CD15, CD30, and p24. These cells were admixed with numerous CD68-positive cells. The adjacent brain showed classic features of HIV encephalitis with perivascular, CD68 and p24-positive multinucleated giant cells. This case illustrates several diagnostic pitfalls in the work-up of HIV-associated brain lesions, as well as reporting a unique histomorphology for an HIV-related primary CNS lymphoproliferative disorder.

Two cases of Scimitar syndrome associated with multiple congenital skeletal anomalies and lacking abnormalities by genomic microarray analysis.

Scimitar syndrome is a congenital anomaly occurring in approximately 1/50,000 births, consisting of partial anomalous pulmonary venous return, right lung hypoplasia, and several associated defects. The condition generally has significant morbidity and mortality, but the underlying cause is poorly understood. In this report, we describe 2 autopsy cases of Scimitar syndrome associated with multiple skeletal anomalies and attempt to characterize possible genetic abnormalities in this condition. In light of these findings, we discuss the embryology and direct timing during development of the anomalies associated with this syndrome.

The tumor suppressor adenomatous polyposis coli controls the direction in which a cell extrudes from an epithelium.

Despite high rates of cell death, epithelia maintain intact barriers by squeezing dying cells out using a process termed cell extrusion. Cells can extrude apically into the lumen or basally into the tissue the epithelium encases, depending on whether actin and myosin contract at the cell base or apex, respectively. We previously found that microtubules in cells surrounding a dying cell target p115 RhoGEF to the actin cortex to control where contraction occurs. However, what controls microtubule targeting to the cortex and whether the dying cell also controls the extrusion direction were unclear. Here we find that the tumor suppressor adenomatous polyposis coli (APC) controls microtubule targeting to the cell base to drive apical extrusion. Whereas wild-type cells preferentially extrude apically, cells lacking APC or expressing an oncogenic APC mutation extrude predominantly basally in cultured monolayers and zebrafish epidermis. Thus APC is essential for driving extrusion apically. Surprisingly, although APC controls microtubule reorientation and attachment to the actin cortex in cells surrounding the dying cell, it does so by controlling actin and microtubules within the dying cell. APC disruptions that are common in colon and breast cancer may promote basal extrusion of tumor cells, which could enable their exit and subsequent migration.