ModPath Chat

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 (<1%). A subset of ER low-positive cases was further evaluated using IHC, RNAscope, and RT-qPCR.

ER low-positive tumors constituted <% of BC cases examined and showed significant clinicopathological similarity to ER-negative tumors. Further validation of ER status revealed that 45% of these tumors were ER-negative with repeated IHC staining and confirmed by RNAscope and RT-qPCR. BCs with 10% ER behaved similarly to ER-positive BCs.

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!

Fundic gland polyps (FGPs) develop sporadically (frequently after proton pump inhibitor therapy) or in the setting of a hereditary polyposis syndrome, such as familial adenomatous polyposis (FAP). In the later setting, FGPs often demonstrate low-grade dysplasia and are frequently associated with APC mutations. Sporadic FGPs with dysplasia also demonstrate frequent APC mutations.

Our guest, Dr. Won-Tak Choi, discusses the finding of his recent study on the topic where clinicopathologic features of 192 patients with FGPs were analyzed and DNA flow cytometry was performed.

Progression to advanced gastric neoplasia was rare in FGPs. None of the FAP-related and sporadic FGP biopsies, regardless of the presence or absence of dysplasia, demonstrated DNA content abnormality. This indicates that FGPs lack large-scale chromosomal changes that are characteristic of the typical adenoma-carcinoma sequence in gastrointestinal malignancies.

Psammomatoid ossifying fibroma (PsOF) is a benign fibro-osseous neoplasm that predominantly affects frontal and ethmoid bones, with a preference for adolescents and young adults. The clinical and morphologic features of PsOF overlap with other fibro-osseous lesions, and additional molecular markers may help increase their diagnostic accuracy. Chromosomal breakpoints at bands Xq26 and 2q33 have been previously described. Our guest, Dr. Arjen Cleven, discusses his group’s recent identification of a SATB2 rearrangement in PsOF.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Over the previous two decades, tremendous progress has been made in our understanding of the molecular pathogenesis of DLBCL. Unfortunately, these advances have not yet been translated into improvements in targeted therapy. In this podcast, our guest, Dr. Daniel J. Hodson of Cambridge University, discusses recent major genetic subtyping studies and their implications for diagnostic pathology services and the management of DLBCL.