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Endoscopic evidence of disease is a critical predictor of relapse in patients with Crohn’s disease (CD). While histologic disease activity is evolving as a similarly important end point, classical morphologic features of CD may overlap with postoperative inflammatory changes, confounding the evaluation of anastomotic biopsies. In this episode, Dr, John Hart, Professor and Vice Chair of Anatomic Pathology at the University of Chicago discusses his team’s critical recent study in Modern Pathology showing that due to the above extensive morphologic overlap and the lack of specific histologic features of relapse, biopsies from anastomotic sites are of no value in predicting clinical CD progression. On the other hand, CD activity in biopsies obtained away from anastomotic sites should be used for guiding endoscopic sampling and clinical management.

This episode features Dr. Laura Lamps , a leader in the field of gastrointestinal pathology. Dr. Lamps is the Godfrey D. Stobbe Professor and Director of Gastrointestinal Pathology and Assistant Chair for Faculty Development and Program Director of GI Pathology Fellowship at the Department of Pathology, Michigan Medicine, at the University of Michigan. The former President of US and Canadian Academy of Pathology (USCAP) shares with the audience her perspectives as a brilliant leader on the importance of seeking a diverse mentorship and investing in leadership development resources. The informative discussion centers on how to build and empower the next generation of pathologists.

In this episode, Dr. Tamara Lotan from Johns Hopkins University discusses the potential of deep-learning (DL) algorithms trained on H and E-stained whole slide images (WSI) to screen for clinically relevant genomic alterations in prostate cancer (PCA). Dr. Lotan reviews her team’s recent publication in Modern Pathology, where they were able to create DL algorithms to identify PCA with underlying ERG fusions or PTEN deletions. By applying the algorithms to multiple radical prostatectomy and needle biopsy cohorts, the authors demonstrated the ability of DL models to accurately predict ERG/PTEN status from H and E stained WSI.

In this episode, Dr. Arnaud de la Fouchardiere, from the Universite Claude Bernard in Lyon France, discusses his multinational team’s recent study on the clinical and histologic presentation of 51 cutaneous melanocytic neoplasms with a PKC fusion gene. Most tumors occurred in young adults (median age, 29.5 years) and some presented in newborns. Histologically, 42 tumors were classified as benign, presenting predominantly as biphasic dermal proliferation with nests of small melanocytes surrounded by fibrosis with haphazardly arranged spindled and dendritic melanocytes, resembling those reported as “combined blue nevi.” Six tumors had sheets of atypical melanocytes infiltrating the dermis and were classified as melanomas. Two of the melanomas displayed loss of BAP1 nuclear expression with one patient developing metastatic disease and another dying of their melanoma.

ROS1 alterations are uncommon in gliomas and are primarily described in infants. In this episode, our host discusses with Dr. Xinyan Lu from the Feinberg School of Medicine in Chicago her team’s recent study on characterizing the clinicopathological features and molecular signatures of the full spectrum of ROS1 fusion–positive gliomas across all age groups. A multi-institutional cohort of 32 new and 58 published cases was divided into 3 age groups (19 infants, 40 pediatric patients, and 31 adults). Tumors in infants and adults showed uniformly high-grade morphology; however, tumors in pediatric patients exhibited diverse histologic features. The GOPC::ROS1 fusion was prevalent (61/79, 77%) across all age groups. Adult tumors showed recurrent genomic alterations characteristic of IDH wild-type glioblastoma, including the +7/-10/CDKN2A deletion and amplification of CDK4, MDM2, and PDGFRA. The outcomes were significantly poorer in adult patients. The authors conclude that ROS1 likely acts as a driver in infant and pediatric gliomas and as a driver or codriver in adult gliomas. Integrated comprehensive clinical testing might be helpful in identifying such patients for possible targeted therapy.

Estrogen receptor (ER) status in breast cancer (BC) is determined using immunohistochemical nuclear expression. Currently, tumors with 1% or more positive cells are defined as ER-positive. BC, with 1%-9% expression (ER-low-positive), is a clinically and biologically unique subgroup. In this episode of Mod Path CHAT, Dr. Emad Rakha discusses his team’s study on the subject. A large BC cohort (8171) was investigated and categorized into 3 groups: ER low-positive (1%-9%), ER-positive (≥10%), and ER-negative (ER low-positive tumors constituted The authors recommend repeat testing of BC showing 1%-9% ER expression and using a cutoff ≥10% expression to define ER positivity to help better inform treatment decisions.

Borderline hepatocellular adenomas (BL-HCA) are characterized by focal architectural/cytologic atypia and reticulin loss, features that are insufficient for a definitive diagnosis of hepatocellular carcinoma (HCC). The diagnosis and management of BL-HCA are challenging as their biological behavior, especially in terms of malignant potential, is still debated. Our guest, Dr. Nicolas Poté, from the Université Paris Cité in Paris, France, discusses his team's recent study comparing the clinicopathologic and molecular features of BL-HCA with those of typical HCA (T-HCA), HCA with malignant transformation (HCC on HCA), and HCC to assess the risk of malignancy. Somatic mutations, including TERT promoter mutations associated with HCA malignant transformation and gene expression levels of 96 genes, were investigated. In comparison with T-HCA, BL-HCA were significantly enriched for exon 3 mutations of β catenin gene (41% vs 6%; P .001). By gene expression profiling BL-HCA overlapped with T-HCA and HCC on HCA, favoring a molecular continuum of the tumors. TERT promoter mutations were observed only in HCC on HCA (42%) and in HCC (38%). The authors propose a decision algorithm for the management of BL-HCA based on their morphologic and molecular features in biopsy samples.

Stimulated Raman Histology for Rapid Intraoperative Diagnosis of Central Nervous System Tumors Stimulated Raman histology (SRH) is an ex-vivo optical imaging method that enables the microscopic examination of fresh tissue intraoperatively. SRH imaging allows rapid microscopic imaging, avoids tissue loss, and enables remote telepathology review. Our guest, Dr. Matija Snuderl from New York University Langone Health, New York, discusses his team’s recent blinded, retrospective two-arm telepathology study on clinical validation of SRH for rapid intraoperative diagnosis of central nervous system tumors. All SRH images were of sufficient quality and showed high accuracy in distinguishing glial from nonglial tumors (96.5% SRH vs 98% whole slide images) and predicting final diagnosis (85.9% SRH vs 93.1% whole slide images). The median turnaround time for prospectively SRH-rendered diagnosis was 3.7 minutes, 10-fold shorter than the median for frozen sections.

Distinguishing grade 3 pancreatic neuroendocrine tumor (G3 PanNET) from neuroendocrine carcinoma (PanNEC) is a known diagnostic challenge, and accurate classification is critical because clinical behavior and therapies differ. Dr. Nancy Joseph from the University of California San Francisco discusses her group’s recent study on high-grade neoplasms originally diagnosed as pancreatic neuroendocrine neoplasms. In addition to the currently recommended stains (p53, Rb, ATRX, and DAXX), 500 NGS panel and immunohistochemistry for p16 and trypsin or chymotrypsin were also performed. The authors were able to classify 89% of cases as either G3 PanNET, PanNEC or mixed acinar-NEC. G3 PanNETs demonstrated frequent alterations in MEN1 (71%), DAXX (47%), ATRX (24%), TSC2 (35%), SETD2 (42%), and CDKN2A (41%). Contrary to prior reports, TP53 alterations were also common in G3 PanNETs (35%) but were always mutually exclusive with CDKN2A alterations in this group. PanNECs demonstrated frequent alterations in TP53 (88%), cell cycle genes RB1 (47%), CCNE1/CCND1 (12%), CDKN2A (29%), and in KRAS (53%) and SMAD4 (41%); TP53 was co-altered with a cell cycle gene in 76% of PanNECs. Diffuse strong p16 staining was observed in 69% of PanNECs in contrast to 0% of G3 PanNETs. Acinar-NECs had recurrent alterations in ATM (25%), APC (25%), and STK11 (25%). Molecular profiling and immunohistochemistry for p16 greatly improve the diagnostic accuracy of high-grade pancreatic neuroendocrine neoplasms and identify a subset of rare cases with overlapping features of both PanNET and PanNEC.

Dr. Matthew Cecchini from the University of Western Ontario discusses his team’s study on the prognostic role of digitally assessed cell density in non-small cell lung carcinoma (NSCLC). Recently, a revised reporting system for lung adenocarcinoma incorporates high-risk histologic patterns, which may have increased cellular density. Digital slides from The Cancer Genome Atlas (TCGA) lung adenocarcinoma (ADC) and lung squamous cell carcinoma (SCC) data sets were obtained and analyzed using QuPath. High-grade histologic patterns in the ADC and SCC cases were associated with greater tumor densities compared with low-grade patterns. Cases with lower tumor cellularity had improved overall and progression-free survival compared with cases with higher cellularity.

In this episode, Dr. Brooke Howitt from Stanford University discusses her team’s recent study on PTEN expression in tubo-ovarian high-grade serous carcinoma (HGSCs). PTEN deficiency (complete or sub-clonal loss) as detected by immunohistochemistry was identified in 13 of the 62 HGSCs (21%) and was significantly correlated with reduced expression of estrogen receptor and worse first progression-free survival (P .05) but not with PD-L1 expression, or overall survival. Additionally, tumor progression within 1 year of PARP inhibitor therapy was found more frequently in PTEN-deficient cases than in PTEN-intact cases (100% vs 52%). These findings indicate that PTEN deficiency defines a distinct clinically significant subgroup of HGSCs with a tendency for estrogen receptor negativity, inferior clinical outcomes, and potential drug resistance. These tumors may benefit from PI3K pathway inhibitors in combination with other ovarian cancer regimens.

Screening lymph nodes for metastases in colorectal cancer (CRC) can be a cumbersome task, but it is amenable to artificial intelligence (AI)-assisted diagnostic solutions. Prof. Inti Zlobec and Dr. Amjad Kahn from the Institute of Pathology in Bern, Switzerland discuss their newly proposed deep learning-based tool for the evaluation of CRC lymph node metastases in digitized whole-slide images. Their approach showed excellent performance, with high sensitivity (0.99) and specificity (0.96) in two validation cohorts of CRC cases (3836 slides) when comparing slide-level labels with the ground truth (pathologist reports). The overlays of AI-based prediction within lymph node regions matched 100% when compared with a microscope evaluation by expert pathologists!