Modern Pathology

Extraskeletal myxoid chondrosarcoma (EMC) is an ultrarare sarcoma typically exhibiting myxoid/reticular histology and NR4A3 translocation. However, morphologic variants and the relevance of non-EWSR1::NR4A3 fusions remain underexplored. Three challenging pan-Trk-expressing cases, featuring cellular to solid histology, were subjected to RNA exome sequencing (RES), unveiling different NR4A3-associated fusions. Alongside RES-analyzed cases, fluorescence in situ hybridization was performed to confirm 58 EMCs, with 48 available for pan-Trk immunostaining and KIT sequencing...

An accurate histopathologic diagnosis on surgical biopsy material is necessary for the clinical management of patients and has important implications for research, clinical trial design/enrollment, and public health education. This study used a mixed methods approach to isolate sources of diagnostic error while residents and attending pathologists interpreted digitized breast biopsy slides. Ninety participants including pathology residents and attendings at major United States medical centers reviewed a set of 14 digitized whole slide images of breast biopsies...

Malignant gastrointestinal neuroectodermal tumors (MGNET), also known as "gastrointestinal clear cell sarcoma-like tumor", are very rare, aggressive sarcomas characterized by enteric location, distinctive pathologic features, and EWSR1/FUS::ATF1/CREB1 fusions. Despite identical genetics, the clinicopathologic features of MGNET are otherwise quite different from clear cell sarcoma of soft parts (CCS). Only exceptional extra-enteric MGNET (E-MGNET) have been reported. We report a series of 11 E-MGNET, the largest to date...

Differential classification of prostate cancer (CaP) grade group (GG) 2 and 3 tumors remains challenging, likely due to the subjective quantification of percentage of Gleason pattern 4 (%GP4). Artificial intelligence assessment of %GP4 may improve its accuracy and reproducibility and provide information for prognosis prediction. To investigate this potential, a convolutional neural network (CNN) model was trained to objectively identify and quantify Gleason pattern (GP) 3 and 4 areas, estimate %GP4, and assess whether CNN-assessed %GP4 is associated with biochemical recurrence (BCR) risk in intermediate risk GG 2 and 3 tumors...

Programmed death-ligand 1 (PD-L1)antibody 22C3 is the approved companion diagnostic immunohistochemistry (IHC) test for treatment with pembrolizumab and cemiplimab in multiple cancer types. The 22C3 and 28-8 antibodies target the extracellular domain (ECD) of PD-L1 which is known to contain N-glycosylation sites. We hypothesize that antigenicity could be affected by degradation of the glycan part of the epitope and thus change the scoring of the assay over time. Here, we test samples over time and assess the effects of time and deglycosylation on PD-L1 signal by comparing an antibody with an extracellular domain (ECD) antigen to an antibody with an intracellular domain (ICD) antigen...

Reliable, reproducible methods to interpret programmed death ligand-1 (PD-L1) expression on tumor cells (TC) and immune cells (IC) are needed for pathologists to inform decisions associated with checkpoint inhibitor therapies. Our international study compared interpathologist agreement of PD-L1 expression using combined positive score (CPS) under standardized conditions on samples from patients with gastric/gastroesophageal junction/esophageal adenocarcinoma. Tissue sections from 100 adenocarcinoma pre-treatment biopsies were stained in a single laboratory using the PD-L1 IHC 28-8 and 22C3(Agilent) pharmDx immunohistochemical assays...

Fibrillar collagens are the most abundant extracellular matrix components in non-small cell lung cancer (NSCLC). Yet, the potential of collagen fiber descriptors as a source of clinically-relevant biomarkers in NSCLC is mainly unknown. Likewise, our understanding of the aberrant collagen organization and associated tumor-promoting effects needs to be better defined. To address these limitations, we identified a digital pathology approach that can be easily implemented in pathology units based on the Curvelet Transform filtering and single Fiber Reconstruction (CT-FIRE) software analysis of picrosirius (PSR) stains of fibrillar collagens imaged with polarized light (PL)...

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Women with Lynch syndrome (LS) are at increased risk of endometrial cancer (EC), among other tumors, and are characterized by mismatch repair (MMR) deficiency and microsatellite instability (MSI). While risk-reducing gynecological surgeries are effective in decreasing EC incidence, doubts arise regarding the appropriate timing of the surgery. We explored the usefulness of highly-sensitive MSI (hs-MSI) assessment in endometrial aspirates for the individualization of gynecological surveillance in LS carriers...

The diagnosis of oral epithelial dysplasia is based on the degree of architectural and cytological atypia in the squamous epithelium, with the conventional grading system of mild, moderate, and severe dysplasia considered by many to be the gold standard in predicting the risk of malignant transformation. Unfortunately, some low-grade lesions with or without dysplasia, progress to squamous cell carcinoma (SCC) in short periods of time. As a result, we are proposing a new approach to characterise oral dysplastic lesions that will help identify lesions at high risk for malignant transformation...

The precursor nature of papillary urothelial hyperplasia of the urinary bladder is uncertain. In this study, we investigated TERT promoter and FGFR3 mutations in 82 patients with papillary urothelial hyperplasia lesions. Thirty eight patients presented with papillary urothelial hyperplasia and concurrent non-invasive papillary urothelial carcinoma and 44 patients presented with de novo papillary urothelial hyperplasia. The prevalence of TERT promoter and FGFR3 mutation are compared between de novo papillary urothelial hyperplasia and those with concurrent papillary urothelial carcinoma...

Sertoli cell tumor (SCT) is the second most common type of sex cord-stromal tumor in men and ∼10% exhibit malignant behavior. Although CTNNB1 variants have been described in SCTs, only a limited number of metastatic cases have been analyzed, and the molecular alterations associated with aggressive behavior remain largely unexplored. This study evaluated a series of nonmetastasizing and metastasizing SCTs using next-generation DNA sequencing to further characterize their genomic landscape. Twenty-two tumors from 21 patients were analyzed...

Acinic cell carcinoma (AciCC) is a rare salivary gland cancer with excellent prognosis in most cases. However, a subset of patients will develop distant metastasis and die of disease. Recently, a two-tiered grading scheme in AciCC was proposed to recognize patients at risk for poor outcome. We performed a genetic analysis of AciCC to explore the underlying molecular correlates of the tumor grade and examined PD-L1 expression to identify potential candidates for immunotherapy. A retrospective cohort of 55 patients included 34 high-grade and 21 low-grade AciCCs...

We report a series of 58 melanocytic tumors that harbor an activating fusion of BRAF, a component of the MAP kinase signaling cascade. Cases were diagnosed as melanocytic nevus (n=12, 21%), diagnostically ambiguous favor benign (n=22, 38%), diagnostically ambiguous concerning for melanoma (n=12, 21%) or melanoma (n=12, 21%). Three main histopathological patterns were observed. The first pattern ("buckshot fibrosis") was characterized by large, epithelioid melanocytes arrayed as single cells or "buckshot" within marked stromal desmoplasia...

As the most common type of HPV-independent (HPVI) endocervical adenocarcinomas (ECAs), gastric-type endocervical adenocarcinomas (GEAs) account for approximately 10% of all ECAs Although anti-HER2 therapy has been proven effective in many cancers, it has not been utilized in ECAs including GEAs, which is at least partly due to the lack of a well-defined guideline. Limited available data regarding HER2 in GEAs and ECAs have considerable variations likely caused by variations in tumor types selection, testing methods, and scoring criteria...

Acinic cell carcinoma (AciCC) is a tumor that is recognized in both the breast and salivary glands. Recently, the recurrent genomic rearrangement, t(4;9)(q13;q31) was identified in salivary AciCC that results in constitutive upregulation of the nuclear transcription factor NR4A3, which can be detected by immunohistochemistry (IHC). Here we sought to evaluate NR4A3 expression in breast AciCC using IHC. Strong and diffuse nuclear staining was considered a positive result. Sixteen AciCC were studied including 8 pure AciCC and 8 AciCC admixed with other types (invasive carcinoma of no special type in 5 cases and metaplastic carcinoma in 3 cases)...

Positive surgical margins at radical prostatectomy are associated with an increased risk of biochemical recurrence (BCR). However, there is considerable variability in outcomes, suggesting that molecular biomarkers -- when assessed specifically at the margin tumor tissue -- may be useful to stratify prognosis in this group. We used a case-cohort design for the outcome of BCR, selecting 215 patients from a cohort of 813 prostatectomy patients treated at Johns Hopkins from 2008-2017 with positive margins and available clinical data...

Prostate cancer is a heterogeneous disease with several well-recognized morphologic subtypes and histologic variants - subsets of which are enriched for or associated with specific genomic alterations. Herein, we report a cohort of four unique prostate cancers characterized by intra-tumoral psammomatous calcification - which we have termed prostate cancer with psammomatous calcification (PCWPC). Clinicopathologic review demonstrates that PCWPC are high-grade [Grade Group 3 (GG3) or higher] tumors that involve the anterior prostate, and integrative targeted next-generation sequencing reveals recurrent hotspot IDH1 mutations...

There is emerging evidence that vulvar squamous cell carcinoma (VSCC) can be prognostically subclassified into 3 groups based on human papillomavirus (HPV) and p53 status: HPV-associated (HPV+), HPV-independent/p53 wild-type (HPV-/p53wt), or HPV-independent/p53 abnormal (HPV-/p53abn). Our goal was to assess the feasibility of separating VSCC and its precursors into these 3 groups using p16 and p53 immunohistochemistry (IHC). A tissue microarray (TMA) containing 225 VSCC, 43 usual vulvar intraepithelial neoplasia (uVIN/HSIL), 10 verruciform acanthotic vulvar intraepithelial neoplasia (vaVIN), and 34 differentiated VIN (dVIN), was stained for p16 and p53...

According to the American Joint Cancer Committee, pT3 renal pelvic carcinoma is defined as tumor invading the renal parenchyma and/or peripelvic fat and is the largest pT category, with notable survival heterogeneity. Anatomic landmarks within the renal pelvis can be difficult to discern. Using glomeruli as a boundary to differentiate renal medulla invasion from renal cortex invasion, this study aimed to compare patient survival of pT3 renal pelvic urothelial carcinoma based on the extent of renal parenchyma invasion and, thereafter, determine whether redefining pT2 and pT3 improves pT correlation with survival...