Antibrush Border Antibody Disease: A Case Series.

Antibrush border antibody (ABBA) disease is a rare cause of kidney disease characterized by progressive renal tubular injury associated with immune complex deposition along the basement membranes of the proximal tubule and circulating autoantibodies to brush border antigens. Several antigens have been identified as targets of autoantibodies in this disease, including low-density lipoprotein receptor related protein 2 (LRP2), cubilin, and amnionless proteins. We present 9 patients from 2 academic medical centers and describe the clinicopathologic characteristics and outcome data. All patients presented with acute kidney injury and proteinuria. Pathology confirmed immune complex deposition along proximal tubular basement membranes in all patients, but the majority (6/8) also showed segmental glomerular subepithelial immune complexes. Two of 3 patients treated with rituximab demonstrated stabilization of kidney function; 1 of these patients had mantle cell lymphoma. One patient with lung cancer showed stabilization of disease after treatment of the malignancy. The remaining patients progressed to end-stage kidney disease with either conservative therapy (3 patients) or immunosuppression with glucocorticoids (2 patients). This series highlights the poor prognosis of ABBA disease, but a potential benefit of anti-B cell therapy or treatment of an underlying malignancy in some cases.

Characteristics and Outcomes of NELL1 Membranous Nephropathy in Lipoic Acid Users and Nonusers.

Introduction: Neural epidermal growth factor like 1 membranous nephropathy (NELL1 MN) is associated with various secondary etiologies. However, previous studies on the frequency of these associations and their impact on outcomes are limited. We report a large multiinstitutional series of patients with NELL1 MN with a focus on secondary associations, pathology findings, and their impact on outcome. Methods: We retrospectively reviewed clinicopathologic features of NELL1 MN from 3 institutions and analyzed clinical and histologic associations with outcome. Results: Of 70 patients, 53% were male with a median age of 66 years; median proteinuria was 5.9 g/d. NELL1 MN was associated with lipoic acid (36%), heavy nonsteroidal antiinflammatory drug (NSAID) use (27%), autoimmune disease (23%), malignancy (10% recent, 23% any), mercury exposure (1%), and 11% had no known secondary association. At median follow-up of 11 months, 72% achieved complete or partial remission. Remission rate was 91% in patients with lipoic acid-associated NELL1 MN and ≥6 months of follow-up. On multivariable analyses, patients with primary NELL1 MN (adjusted odds ratio [OR]: 19.7, P = 0.01) and increasing degree of tubular atrophy and interstitial fibrosis (IFTA) (adjusted OR 1.1, P = 0.01) were less likely to achieve any remission, whereas complete remission (CR) was associated with lipoic acid use (adjusted OR: 10.9, P = 0.04, 95% confidence interval [CI]: 1.2-100) and lesser degrees of IFTA (adjusted OR: 0.79, P = 0.16, 95% CI: 0.66-0.96). Conclusion: Our findings strengthen the association between lipoic acid and NELL1 MN. Furthermore, our findings suggest that discontinuation of lipoic acid without immunosuppression should be considered as the first-line treatment.

Fit-for-Purpose Ki-67 Immunohistochemistry Assays for Breast Cancer.

New therapies are being developed for breast cancer, and in this process, some "old" biomarkers are reutilized and given a new purpose. It is not always recognized that by changing a biomarker's intended use, a new biomarker assay is created. The Ki-67 biomarker is typically assessed by immunohistochemistry (IHC) to provide a proliferative index in breast cancer. Canadian laboratories assessed the analytical performance and diagnostic accuracy of their Ki-67 IHC laboratory-developed tests (LDTs) of relevance for the LDTs' clinical utility. Canadian clinical IHC laboratories enrolled in the Canadian Biomarker Quality Assurance Pilot Run for Ki-67 in breast cancer by invitation. The Dako Ki-67 IHC pharmDx assay was employed as a study reference assay. The Dako central laboratory was the reference laboratory. Participants received unstained slides of breast cancer tissue microarrays with 32 cases and performed their in-house Ki-67 assays. The results were assessed using QuPath, an open-source software application for bioimage analysis. Positive percent agreement (PPA, sensitivity) and negative percent agreement (NPA, specificity) were calculated against the Dako Ki-67 IHC pharmDx assay for 5%, 10%, 20%, and 30% cutoffs. Overall, PPA and NPA varied depending on the selected cutoff; participants were more successful with 5% and 10%, than with 20% and 30% cutoffs. Only 4 of 16 laboratories had robust IHC protocols with acceptable PPA for all cutoffs. The lowest PPA for the 5% cutoff was 85%, for 10% was 63%, for 20% was 14%, and for 30% was 13%. The lowest NPA for the 5% cutoff was 50%, for 10% was 33%, for 20% was 50%, and for 30% was 57%. Despite many years of international efforts to standardize IHC testing for Ki-67 in breast cancer, our results indicate that Canadian clinical LDTs have a wide analytical sensitivity range and poor agreement for 20% and 30% cutoffs. The poor agreement was not due to the readout but rather due to IHC protocol conditions. International Ki-67 in Breast Cancer Working Group (IKWG) recommendations related to Ki-67 IHC standardization cannot take full effect without reliable fit-for-purpose reference materials that are required for the initial assay calibration, assay performance monitoring, and proficiency testing.

Principles of Analytic Validation of Immunohistochemical Assays: Guideline Update.

CONTEXT.­: In 2014, the College of American Pathologists developed an evidence-based guideline to address analytic validation of immunohistochemical assays. Fourteen recommendations were offered. Per the National Academy of Medicine standards for developing trustworthy guidelines, guidelines should be updated when new evidence suggests modifications. OBJECTIVE.­: To assess evidence published since the release of the original guideline and develop updated evidence-based recommendations. DESIGN.­: The College of American Pathologists convened an expert panel to perform a systematic review of the literature and update the original guideline recommendations using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS.­: Two strong recommendations, 1 conditional recommendation, and 12 good practice statements are offered in this updated guideline. They address analytic validation or verification of predictive and nonpredictive assays, and recommended revalidation procedures following changes in assay conditions. CONCLUSIONS.­: While many of the original guideline statements remain similar, new recommendations address analytic validation of assays with distinct scoring systems, such as programmed death receptor-1 and analytic verification of US Food and Drug Administration approved/cleared assays; more specific guidance is offered for validating immunohistochemistry performed on cytology specimens.

AA amyloidosis With Ig-Dominant Staining and Diagnostically Unusual Features.

Introduction: Although serum amyloid A (AA) amyloid may occasionally show nonspecific staining by immunofluorescence (IF), the correct diagnosis can usually be determined by integrating pathologic features and clinical scenario, and using AA amyloid immunohistochemistry (IHC) and/or mass spectrometry. A recent mass spectrometry-based study described false-positive Ig IF staining in a subset of AA amyloid cases. Methods: We sought to delineate clinicopathologic features of AA amyloid with Ig-dominant staining by using a retrospective review. Results: AA amyloid with Ig-dominant staining was identified in 10 patients from 5 institutions, representing 1.2% to 4% of AA amyloid kidney biopsies. Evidence of a monoclonal protein was documented in 0% to 2.7% of patients with AA amyloid screened for inclusion, but 30% of those with Ig-dominant staining. The patient population had equal sex distribution and presented at median age of 68.5 years with nephrotic proteinuria and kidney impairment. Etiologies of AA amyloid included injection drug use (30%), autoimmune disease (20%), and chronic infection (10%); 40% had no identified clinical association. On biopsy, heavy chain (co)dominant staining by IF (in 80%), discordant distribution in Ig staining (in 20%), tubulointerstitial nephritis (in 30%), and/or crescents (in 10%) were present. Two of 3 patients with paraproteinemia had concordant heavy and/or light chain dominant staining within the AA amyloid. Two cases were initially misdiagnosed as Ig-associated amyloidosis. Conclusion: We describe the morphologic spectrum of AA amyloidosis with Ig-dominant staining which may have clinical, laboratory, and pathologic overlap with amyloid light chain (AL), amyloid heavy chain, and heavy and light chain (AHL) amyloidosis.

Genetic and Immunohistochemical Profiling of Mammary Hidradenoma and Comparison to Mucoepidermoid Carcinoma.

Mucoepidermoid carcinoma (MEC) is exceedingly rare in the breast, with <45 cases reported in the literature. Although estrogen receptor/progesterone receptor/human epidermal growth factor 2 triple-negative, MEC is characterized as a special subtype of breast carcinoma with significantly better prognosis than conventional basal-type tumors. Cutaneous hidradenoma (HA) is considered a benign adnexal neoplasm showing histomorphologic overlap with MEC. Rare cases of HA have also been reported in the breast, but these are relatively uncharacterized. In this study, we examined the clinicopathologic, immunohistochemical (IHC), and genetic features of 8 breast HAs, in comparison to 3 mammary MECs. All cases were positive for MAML2 break-apart fluorescence in situ hybridization. Eight cases demonstrated a CRTC1::MAML2 fusion, and one MEC harbored a CRTC3::MAML2 fusion; the latter is a novel finding in the breast. Mutational burden was very low, with only one HA exhibiting a MAP3K1 pathogenic alteration. By IHC, both MEC and HA demonstrated cell type-dependent expression of high- and low-molecular-weight keratins and p63, as well as negative to low-positive estrogen receptor and androgen receptor. Smooth muscle myosin and calponin highlighted an in situ component in the 3 cases of MEC; expression of these myoepithelial markers was negative in HAs. Additional distinguishing characteristics included the growth pattern and tumor architecture, the presence of glandular/luminal cells in HA, and overall higher IHC expression of SOX10, S100 protein, MUC4, and mammaglobin in MEC. Morphologic findings were also compared to a series of 27 cutaneous nonmammary HAs. Mucinous and glandular/luminal cells were identified in significantly more mammary HAs than nonmammary lesions. The findings provide insight into the pathogenesis of MAML2-rearranged neoplasms of the breast, underscore the overlapping genetic features of MEC and HA, and highlight similarities to their extramammary counterparts.

Polyacrylamide-based hydrogel coatings improve biocompatibility of implanted pump devices.

The introduction of transcutaneous and subcutaneous implants and devices into the human body instigates fouling and foreign body responses (FBRs) that limit their functional lifetimes. Polymer coatings are a promising solution to improve the biocompatibility of such implants, with potential to enhance in vivo device performance and prolong device lifetime. Here we sought to develop novel materials for use as coatings on subcutaneously implanted devices to reduce the FBR and local tissue inflammation in comparison to gold standard materials such as poly(ethylene glycol) and polyzwitterions. We prepared a library of polyacrylamide-based copolymer hydrogels, which were selected from materials previously shown to exhibit remarkable antifouling properties with blood and plasma, and implanted them into the subcutaneous space of mice to evaluate their biocompatibility over the course of 1 month. The top performing polyacrylamide-based copolymer hydrogel material, comprising a 50:50 mixture of N-(2-hydroxyethyl)acrylamide (HEAm) and N-(3-methoxypropyl)acrylamide (MPAm), exhibited significantly better biocompatibility and lower tissue inflammation than gold standard materials. Moreover, when applied to polydimethylsiloxane disks or silicon catheters as a thin coating (45 ± 1 µm), this leading copolymer hydrogel coating significantly improved implant biocompatibility. Using a rat model of insulin-deficient diabetes, we showed that insulin pumps fitted with HEAm-co-MPAm hydrogel-coated insulin infusion catheters exhibited improved biocompatibility and extended functional lifetime over pumps fitted with industry standard catheters. These polyacrylamide-based copolymer hydrogel coatings have the potential to improve device function and lifetime, thereby reducing the burden of disease management for people regularly using implanted devices.

Using American Type Culture Collection Cell Lines to Evaluate Interlaboratory Variables for Estrogen Receptor and Human Epidermal Growth Factor Receptor 2 Immunostaining.

CONTEXT.­: Most laboratories currently use patient tissues for validating immunohistochemical stains. OBJECTIVE.­: To explore advantages of using cell lines with known antigenicity as a validation method. DESIGN.­: Five American Type Culture Collection (ATCC) cell lines with known negative, low positive, and moderate to strong estrogen receptor (ER) expression as well as negative, equivocal, and positive human epidermal growth factor receptor 2 (HER2) expression were cultured and made into cell blocks. One block from each cell line was fixed in formalin and another in ethanol before cell block preparation. Two sets of paired unstained slides from each block were sent to 10 different laboratories for HER2 and ER staining to be stained on runs from different days according to each laboratory's defined protocol. RESULTS.­: The 10 study participants evaluated 40 slides in a blinded fashion. For ER expression, all 80 interpretations for the ER strong and moderate positive cell lines had the target ER-positive result, and 74 of 80 ER-negative cell lines (92.5%) had agreement with the intended negative result. The ER low positive cell line showed varied but positive expression among all observers. The HER2 (3+)-positive cell lines yielded a target interpretation of 3+ in 65 of 80 interpretations (81.2%). For the HER2-negative cell line 69 of 78 interpretations (88.5%) were consistent with the target response (0 or 1+). No significant variation was observed between the ethanol- and non-ethanol-exposed cell lines, or between runs by the same laboratory. Variation from target results clustered within laboratories. CONCLUSIONS.­: This study indicates that variability between laboratories can be identified by using cell lines for quantitative or semiquantitative immunohistochemistry when using cultured cell lines of known antigenicity. These cell lines could potentially play a role in aiding anatomic pathology laboratories in validating immunohistochemistry tests for formalin- and ethanol-fixed tissues.

Systemic Lupus Erythematosus and ANCA-Associated Vasculitis Overlap Syndrome: A Case Report.

Concomitant lupus nephritis and antineutrophil cytoplasmic antibody-positive crescentic glomerulonephritis is rare, and there is little guidance on the management and outcomes of these patients. A Hispanic woman in her early 40s with no contributory medical history presented with 3 weeks of cough, shortness of breath, fever, and malaise. Laboratory test results were notable for serum creatinine level of 17.4 mg/dL (previously normal), urinalysis with a high hemoglobin level, >182 red blood cell count, and urinary protein-creatinine ratio of 5.72 g/g. Serologies showed elevated dsDNA, ribonucleoprotein antibody, Smith antibody, myeloperoxidase antibody, positive antinuclear antibody, and low complement levels. She was urgently started on hemodialysis and solumedrol 1 g for 3 days. On day 2, she had a kidney biopsy, which showed necrotizing crescentic glomerulonephritis and immunofluorescence with "full house" pattern, immune complex deposits, and strong antinuclear antibody staining of nuclei. She developed diffuse alveolar hemorrhage and was initiated on plasmapheresis and cyclophosphamide. She improved and was discharged without needing further dialysis. Clinicians should consider systemic lupus erythematosus and antineutrophil cytoplasmic antibody disease overlap syndrome when a young, female patient presents with new kidney failure and alveolar hemorrhage. Early biopsy and aggressive treatment are essential in preserving kidney function, and plasmapheresis should be considered in severe cases. This is a severe case with a positive outcome.

Digital Image Analysis and Quantitative Bead Standards in Root Cause Analysis of Immunohistochemical Staining Variability: A Real-world Example.

Assessment of automated immunohistochemical staining platform performance is largely limited to the visual evaluation of individual slides by trained personnel. Quantitative assessment of stain intensity is not typically performed. Here we describe our experience with 2 quantitative strategies that were instrumental in root cause investigations performed to identify the sources of suboptimal staining quality (decreased stain intensity and increased variability). In addition, these tools were utilized as adjuncts in validation of a new immunohistochemical staining instrument. The novel methods utilized in the investigation include quantitative assessment of whole slide images (WSI) and commercially available quantitative calibrators. Over the course of ~13 months, these methods helped to identify and verify correction of 2 sources of suboptimal staining. One root cause of suboptimal staining was insufficient/variable power delivery from our building's electrical circuit. This led us to use uninterruptible power managers for all automated immunostainer instruments, which restored expected stain intensity and consistency. Later, we encountered one instrument that, despite passing all vendor quality control checks and not showing error alerts was suspected of yielding suboptimal stain quality. WSI analysis and quantitative calibrators provided a clear evidence that proved critical in confirming the pathologists' visual impressions. This led to the replacement of the instrument, which was then validated using a combination of standard validation metrics supplemented by WSI analysis and quantitative calibrators. These root cause analyses document 2 variables that are critical in producing optimal immunohistochemical stain results and also provide real-world examples of how the application of quantitative tools to measure automated immunohistochemical stain output can provide a greater objectivity when assessing immunohistochemical stain quality.

A Diverse Spectrum of Immune Complex- and Complement-Mediated Kidney Diseases Is Associated With Mantle Cell Lymphoma.

Introduction: There are limited reports on kidney biopsy findings in patients with mantle cell lymphoma (MCL). Methods: We initiated a multi-institutional, retrospective review of kidney biopsy findings in patients with active and treated MCL. Results: A total of 30 patients with MCL and kidney biopsies were identified, with a median age of 67 (range 48-87) years, 73% of whom were men. A total of 20 patients had active MCL at the time of biopsy, of whom 14 (70%) presented with acute kidney injury (AKI), proteinuria and/or hematuria, and biopsy findings potentially attributable to lymphoma. Of the 14, 11 had immune complex (IC) or complement-mediated (C3) disease including proliferative glomerulonephritis (GN) with monotypic Ig deposits (PGNMID [2]), C3GN, (2), secondary membranous nephropathy (MN [3]), tubular basement membrane (TBM) deposits (2), and modest lupus-like GN (2). Lymphomatous infiltration was present in 8 of the 20 patients, 5 with coincident IC or C3 lesions. A total of 6 patients with available follow-up were treated for MCL, all with clinical remission of GN (2 PGNMID, 2 C3GN, and 2 MN). Conclusion: MCL is associated with diverse monoclonal and polyclonal glomerular and extra-glomerular IC and C3 disease. For patients with active MCL and kidney dysfunction requiring biopsy, 70% had findings due or potentially due to lymphoma, including 55% with IC or C3 disease and 40% had lymphomatous kidney infiltration. IC and C3GN in the setting of active MCL was responsive to lymphoma-directed therapy.

Neoadjuvant Therapy in Breast Cancer: Histologic Changes and Clinical Implications.

Cytotoxic or endocrine therapy before surgery (neoadjuvant) for breast cancer has become standard of care, affording the opportunity to assess and quantify response in the subsequent resection specimen. Correlation with radiology, cassette mapping, and histologic review with a semi-quantitative reporting system such as residual cancer burden (RCB) provides important prognostic data that may guide further therapy. The tumor bed should be identified histologically, often as a collagenized zone devoid of normal breast epithelium, with increased vasculature. Identification of residual treated carcinoma may require careful high power examination, as residual tumor cells may be small and dyscohesive; features are widely variable and include hyperchromatic small, large, or multiple nuclei with clear, foamy, or eosinophilic cytoplasm. Calculation of RCB requires residual carcinoma span in 2 dimensions, estimated carcinoma cellularity (% area), number of involved lymph nodes, and span of largest nodal carcinoma. These RCB parameters may differ from AJCC staging measurements, which depend on only contiguous carcinoma in breast and lymph nodes.

Clinicopathologic features of non-lupus membranous nephropathy in a pediatric population.

BACKGROUND: Membranous nephropathy is an uncommon cause of nephrotic syndrome in pediatrics. METHODS: We reviewed our kidney biopsy records for patients ≤ 20 years of age with membranous nephropathy without evidence of systemic lupus erythematosus within 6 months of biopsy (January 1995-September 2020). Staining for PLA2R, NELL1, THSD7A, SEMA3B, EXT2 (3 biopsies), and IgG-subclass were performed. RESULTS: Sixteen children (≤ 12 years) and 25 adolescents (13-20 years) were identified. Four children and 15 adolescents showed autoantigen positivity: PLA2R+/SEMA3B- (13), SEMA3B+/PLA2R+ (2), SEMA3B+/PLA2R- (1), NELL1 (1), EXT2+ (2), and THSD7A (0). Co-morbidities associated with PLA2R positivity included IPEX syndrome, active hepatitis B, Von Hippel Lindau syndrome, solitary kidney, type 1 diabetes, hyperuricemia, pregnancy (1), obesity (3), type II diabetes, H. pylori, viral prodrome, and nephrolithiasis. The SEMA3B+/PLA2R- adolescent was pregnant, the NELL1+ adolescent was obese, and the two EXT2+ adolescents eventually met the clinical criteria for lupus (4, 9 years post-biopsy). Co-morbidities among the remaining 24 patients included remote hepatitis B (2), Down's syndrome, lysinuric protein intolerance, recurrent UTIs, hypothyroidism, pregnancy (3), and obesity (2). Follow-up data was available for 12 children and 16 adolescents. Of the 12 children, 6 achieved complete remission, 4 achieved partial remission, and 2 had no response to treatment (1 transplant). Of the 16 adolescents, 4 achieved complete remission, 4 achieved partial remission, and 8 had no response to treatment (3 transplants). A child with "full-house" immunofluorescence staining achieved spontaneous disease remission. CONCLUSION: Our non-lupus membranous nephropathy cohort represents one of the largest pediatric studies to date. A higher resolution version of the Graphical abstract is available as Supplementary information.

Immune imprinting, breadth of variant recognition, and germinal center response in human SARS-CoV-2 infection and vaccination.

During the SARS-CoV-2 pandemic, novel and traditional vaccine strategies have been deployed globally. We investigated whether antibodies stimulated by mRNA vaccination (BNT162b2), including third-dose boosting, differ from those generated by infection or adenoviral (ChAdOx1-S and Gam-COVID-Vac) or inactivated viral (BBIBP-CorV) vaccines. We analyzed human lymph nodes after infection or mRNA vaccination for correlates of serological differences. Antibody breadth against viral variants is lower after infection compared with all vaccines evaluated but improves over several months. Viral variant infection elicits variant-specific antibodies, but prior mRNA vaccination imprints serological responses toward Wuhan-Hu-1 rather than variant antigens. In contrast to disrupted germinal centers (GCs) in lymph nodes during infection, mRNA vaccination stimulates robust GCs containing vaccine mRNA and spike antigen up to 8 weeks postvaccination in some cases. SARS-CoV-2 antibody specificity, breadth, and maturation are affected by imprinting from exposure history and distinct histological and antigenic contexts in infection compared with vaccination.

Pathology findings in pediatric patients with COVID-19 and kidney dysfunction.

BACKGROUND: Acute kidney injury (AKI) is seen in one-fifth of pediatric patients with COVID-19 requiring hospital admission, and is associated with increased morbidity, mortality, and residual kidney impairment. The majority of kidney pathology data in patients with COVID-19 is derived from adult case series and there is an overall lack of histologic data for most pediatric patients with COVID-19. METHODS: We assembled a multi-institutional cohort of five unvaccinated pediatric patients with COVID-19 and associated kidney dysfunction with available histology. RESULTS: Three complex patients with current or prior SARS-CoV-2 infection had multifactorial thrombotic microangiopathy with clinical features of hemolytic uremic syndrome (in two) or disseminated intravascular coagulation (in one); one died and another developed chronic kidney disease stage 5. Two with recently preceding SARS-CoV-2 infection presented with nephrotic syndrome; one had IgA vasculitis and one had minimal change disease. Within a short follow-up time, none has returned to baseline kidney function. CONCLUSION: Although uncommon, COVID-19-associated kidney injury can have significant morbidity in the unvaccinated pediatric and adolescent population. A higher resolution version of the Graphical abstract is available as Supplementary information.

NELL1-Positive HIV-Associated Lupus-Like Membranous Nephropathy with Spontaneous Remission.

Introduction: Kidney biopsy findings in patients with human immunodeficiency virus (HIV) are diverse, and optimal therapy for the various immune complex diseases in the setting of HIV is unknown. Case Presentation: A man with well-controlled HIV developed nephrotic range proteinuria, and kidney biopsy revealed lupus-like glomerulonephritis with a predominantly membranous pattern of injury. He opted for conservative therapy and experienced spontaneous and sustained remission. Subsequent testing revealed neural epidermal growth factor-like 1 (NELL1)-positive glomerular immune deposits. NELL1-positive glomerular immune deposits were identified in a total of 2 of 5 tested HIV-associated membranous nephropathy (MN), which were morphologically dissimilar and one of which weakly co-expressed phospholipase A2 receptor (PLA2R). Discussion: This case suggests potentially different outcomes in patients with immune complex diseases in the setting of HIV based on disease etiology and histopathology. HIV-associated MN is occasionally NELL1-positive.

Mammary Lobular Carcinoma-Like Salivary Gland Carcinoma: Report of a Rare Case.

Salivary and mammary glands are both exocrine organs sharing multiple tumorigenic processes. To the best of our knowledge, salivary gland tumors mimicking invasive lobular carcinoma of the breast have not yet been described. Herein, we report a case of a 62-year-old male who presented with progressive facial paralysis. Pathologic examination revealed an ill-defined epithelial neoplasm exhibiting discohesive growth set within an extensively fibrotic stroma. Both perineural and intraneural invasion were present. E-cadherin and p120 immunostaining showed aberrant cytoplasmic expression. Targeted next-generation sequencing detected a frameshift mutation of the CTNNA1 gene as the only known pathogenic variant. The patient was treated with surgical resection, immunotherapy, and chemotherapy. Currently, he is alive with disease twenty months after disease onset.

One Hundred Years of the Pathology Medical Student Fellowship.

CONTEXT.­: The Pathology Medical Student Fellowship (PSF) is a unique, year-long immersive educational experience. Review of institutional archives describes a medical student "Fellowship in Pathology" founded in 1919. OBJECTIVE.­: To characterize the impacts of this 100-year-old program. DESIGN.­: We determined the subsequent medical specialty of each PSF graduate in our department and surveyed those with available contact information. RESULTS.­: Of 145 pathology student fellows graduating between 1924 and 2020, a total of 50 (34.4%) matched into pathology; medical, surgical, and radiology subspecialties were also well-represented career choices. Between 2001 and 2020, of 36 students who matched into pathology from our institution, 19 (52.8%) had completed the fellowship. Survey respondents (n = 42) indicated that before the PSF, 11 of 42 students (26.2 %) were undecided in their specialty, with only 6 (14.3%) identifying pathology as their primary field of interest. Of survey respondents who had completed training, 26 (61.9%) practice in academic settings. Nonpathology physicians reported frequent utilization of skills gained during the PSF year, with 5 of 23 (21.7%) responding "daily," and 9 (39.1%) responding "weekly." The most useful skills included knowledge of pathophysiology of disease and anatomy, improved communication with multidisciplinary teams, and/or interpretation of pathology results (each selected by 17 to 20 students, 73.9%-87.0%). Free-text responses on impacts of the PSF described enhanced knowledge of disease pathobiology and diagnostic complexity and increased confidence and autonomy. CONCLUSIONS.­: We describe the program structure, educational benefits, graduate specialty choices, and career impacts of 100 years of the PSF at our institution. Although undecided before pathology exposure, many PSF graduates subsequently enter pathology careers. Regardless of specialty choice, PSF graduates have a high rate of subsequently pursuing academic medical careers.