Explorez tous les épisodes du podcast ModPath Chat

Drs. Guido Martignoni and Anna Caliò from the University of Verona in Italy discuss their recent study on primary and metastatic fumarate hydratase (FH)-deficient renal cell carcinomas. Six metastatic tumors were histologically documented with high frequency of involvement of lymph nodes, liver and peritoneal cavity. Metastases were morphologically heterogeneous often differing from corresponding primary. Interestingly, some peritoneal metastases morphologically resembled a benign reactive mesothelial process or primary peritoneal mesothelioma, a pitfall that can be avoided by performing IHC panels that include PAX8 and FH. As for therapeutic predictors, significant PD-L1 labeling was found in 60% of primary renal tumors, whereas none of them carried pathogenetic EGFR mutations.

Dr. Claudio Luchini from the University of Verona and Dr. Gaetano Paolini from Brescia University Hospital in Italy discuss their systematic review article, published in Modern Pathology, on Intraductal oncocytic papillary neoplasm (IOPN) of the pancreas.

Our host discusses with Drs. Shaomin Hu from Cleveland Clinic and Yue Xue MD PhD, from Case Western Reserve in Cleveland Ohio, their multi-institutional study on gastrointestinal (GI) tract involvement by Langerhans cell histiocytosis (LCH). The authors highlight new insights from their large study showing that adult patients with multisystem LCH exhibit similar clinicopathologic features to those of pediatric patients. Adults with single-system LCH involving the GI tract have an excellent prognosis, whereas multisystem LCH occurring at any age carries an unfavorable prognosis. High-risk features of GI LCH include pediatric age, GI symptomatology, noncolorectal GI involvement, multifocal GI disease, nonpolypoid lesions, and infiltrative growth pattern.

Our host discusses with Dr. Anna Laury, from the Department of Pathology, University of Helsinki, Finland, her team's study on the utilization of AI-guided spatial transcriptomic analysis to allow for the biological interpretation of morphologic features detected by AI algorithms when applied to WSI of standard H&E sections.

The authors previously trained an AI model to identify HGSC (high-grade serous carcinoma of the ovary) tumor regions that are highly associated with outcome status but are indistinguishable by conventional morphologic methods. In the here discussed study, Dr. Laury’s team applied spatially resolved transcriptomics to further profile the AI-identified tumor regions in 16 patients (8 per outcome group) and identify molecular features related to disease outcome in patients who underwent primary debulking surgery and platinum-based chemotherapy.

Our host discusses with Drs. Prendeville and Selvarajah, from the departments of Laboratory Medicine and Pathobiology at the University of Toronto, their recent study on Pathologist-Driven somatic testing for DNA Damage Repair (DDR) in prostate carcinoma (PCa).

516 FFPE samples from metastatic and localized high risk PCa cases including needle biopsies, TURP and RP specimens were tested using a custom NGS panel of 83 cancer predisposition genes encompassing 4 Homologous Recombination Repair (HRR) genes [BRCA1/2, ATM, PALB2] and 4 Mismatch Repair (MRR) [MLH1, MSH2, MSH6, PMS2]. 13.9% of patients had at least one AMP/ASCO/CAP tier I or tier II variant, whereas 21.5% patients had a tier III variant. Tier I/II variant(s) were identified in 27% of metastatic biopsy samples and 13% of primary samples.

The presence of a tier I/II variant was not significantly associated with the grade group (GG) or presence of intraductal (IDC-P) /cribriform carcinoma in the primary tumor and therefore may not be reliable to guide patient selection.

Non-small cell lung carcinomas (NSCLCs) commonly present as 2 or more separate tumors. They encompass separate primary lung carcinomas (SPLCs), representing independently arising tumors, or intrapulmonary metastases (IPMs), representing intrapulmonary spread of a single tumor. In this episode, Dr. Natasha Rekhtman, from Memorial Sloan Kettering Cancer Ctr, NY provides an update on the growing applications of genomic testing as a clinically relevant benchmark for determining clonal relationships in multiple NSCLCs. She discusses the limitations of morphology-based distinction of SPLCs vs IPMs and the pivotal insights that have emerged from studying multiple NSCLCs using genomic approaches as a gold standard.

Our host discusses with Drs. Djerroudi and Vincent-Salomon, from the Institut Curie in Paris France, their recent study comparing HER2-negative invasive breast cancer of no special type (IBC-NST), with HER2-negative ILC. HER2-negative ILC had a higher frequency of HER2-zero cases (59.4% vs 53.7%) and a lower frequency of HER2-low (40.6% vs 46.3%). Clinicopathological features associated with HER2-low status (vs HER2-zero) in ILC were older age, postmenopausal status, non-classic ILC histological types, higher grade, and ER expression. While HER2-low ILC patients had a lower risk of local recurrence (vs HER2-zero) there was no association between HER2 status and either breast cancer specific survival or distant metastasis-free interval. ERBB3 was the unique mutated gene exclusively associated with HER2-low ILCs, albeit mutated at a low frequency (7.1%). The guests highlighted the potential therapeutic significance of their findings that HER2-low ILCs exhibit unique molecular and clinical attributes.

A most exciting conversation with some of the many engaged listeners of our podcast around the globe. Our host is joined by Dr. Zeeshan Ansar from Karachi, Pakistan; Dr. Emilian Olteanu, from Timisoara, Romania; Dr. Sanam Loghavi from Houston, USA and Dr. Sanjay Mukhopadhyay, from Clevland, USA.

In this episode, our host and Dr. Lisa Rooper from Johns Hopkins University, on behalf of her group of esteemed coauthors, discuss their recent study on the molecular characteristics of “Olfactory Carcinoma.” Targeted molecular profiling of 23 cases of the rare sinonasal tumor was performed to help clarify their pathogenesis and classification. The authors found recurrent Wnt pathway and ARID1A alterations, suggesting that sinonasal neuroendocrine and epithelial tumors may be best regarded as a histologic and molecular spectrum.

Integration of molecular analyses in routine diagnostics is the new practice paradigm of surgical pathology practice. The 2024 USCAP Long Course led by Dr. John Hart from the University of Chicago and Daniela Allende of Cleveland Clinic focuses on hepatic neoplasms and medical diseases where there are opportunities for ancillary molecular testing to refine the diagnosis and provide clinically relevant prognostic information. In this episode, the guests offer a preview of the long course sessions encompassing the utility of germline testing to identify liver disease risk alleles and the exciting potential of emerging technologies.

In this meet the expert episode, ModPath CHAT host Dr. George Netto discusses with Dr. Liron Pantanowitz, Chair of Pathology at UPMC and a pioneer leader in the field, his views on the current status and future direction of Digital Pathology. The conversation touches the various aspects of the digital transformation journey in AP, from infrastructure requirement to talent acquisition and training, regulatory hurdles and expectation of financial return on investments.

Flow cytometric analysis of blood & bone marrow for diagnosis of acute myelogenous leukemia (AML) relies heavily on manual intervention in the processing & analysis steps. Attention-based multi-instance learning models (ABMILMs) are deep learning models that make accurate predictions & generate interpretable insights regarding the classification of a sample from individual events.
The Drs. Olga Pozdnyakova and Joshua Lewis discuss their newly developed computational pipeline using ABMILMs for the automated diagnosis of AML cases based exclusively on flow cytometric data. The study is the first to illustrate the feasibility of using deep learning-based analysis of flow cytometric data for automated AML diagnosis & molecular characterization.

Modern Pathology is publishing a seminal series of review articles highlighting the recently completed fifth edition of the World Health Organization classification of hematolymphoid tumors (WHO-HEM5). In this episode of ModPath CHAT, Dr. Sanam Loghavi from The MD Anderson Cancer Center in Houston, discusses the major updates in the classification of myeloid neoplasms, providing a comparison with WHO-HEM4R, and offering guidance on how the new classification can be applied to the diagnosis of myeloid neoplasms in routine practice.

Polymorphous adenocarcinoma (PAC) is a common, usually low-grade salivary gland carcinoma. While conventional PACs are most associated with PRKD1 p.E710D hotspot mutations, the cribriform subtype is often associated with gene fusions in PRKD1, PRKD2, or PRKD3. The guest, Dr. Justin Bishop from UT Southwestern Medical Center in Dallas, discusses his team’s recent study characterizing the fusions associated with PAC with NGS. A diverse group of fusion partners, including 13 novel partners, were identified. The most common partners for the PRKD genes were ARID1A and ARID1B.

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 (<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.

Currently, PAX8 is the most commonly used immunomarker for gynecologic carcinomas; however, it lacks specificity. By mining The Cancer Genome Atlas mRNA expression profile data, Drs. Ding and Liu’s team identified SOX17 as a potential specific marker for gynecologic tumors. The authors performed immunohistochemical staining on tissue microarrays from 416 ovarian and endometrial cancer cases and 1544 solid tumors from other organs. Like PAX8, SOX17 was highly expressed in most subtypes of ovarian carcinoma (97.5% vs 97% for PAX8 in serous carcinoma, 90% vs 90% in endometrioid carcinoma, and 100% vs 100% in clear cell carcinoma), except for mucinous carcinoma (0% vs 27%). SOX17 was also highly expressed in endometrial carcinoma subtypes (88% vs 84% in endometrioid carcinoma, 100% vs 100% in serous and clear cell carcinoma). Importantly, SOX17 was not expressed in thyroid carcinomas, renal cell carcinomas, and mesotheliomas.

Primary ovarian mucinous tumors represent a heterogeneous group of neoplasms that can be diagnostically challenging. Our guest, Dr. Pavel Dundr and his coauthors analyzed 124 tumors that were originally diagnosed as mucinous borderline tumors (MBTs) or mucinous carcinomas (MCs), with an emphasis on interobserver diagnostic agreement and assessment of the potential utility of molecular profiling.

Only a moderate agreement in diagnosis was found between the 13 observers on the study (k 0.524, for mucinous cystadenoma vs MBT vs MC). A perfect agreement for the distinction between mucinous cystadenoma/MBT - as a combined category - and MC was found in only 36.3% of cases. Differentiating between MBTs and MCs with expansile invasion was particularly problematic.

A comparison of molecular findings between the MBT and MC groups did not show major unequivocal differences. Interestingly, HER2 overexpression or amplification was found in 5.3% of MBTs, 35.3% of all MCs and in 45% of MCs with expansile invasion.

Extranodal extension (ENE) is a significant prognostic factor for human papillomavirus (HPV)-negative head and neck squamous cell carcinoma. However, it remains controversial whether ENE is prognostically relevant in HPV-positive oropharyngeal squamous cell carcinoma (OPSCC). The host discusses with Dr. Nora Katabi from Memorial Sloan Kettering Cancer Center her team’s recent study on the topic.

Patients with ENE had shortened overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS). The 5-year OS, DSS, and DFS were 95%, 97%, and 90% for the group without ENE, and 64%, 71%, and 65% respectively for the group with ENE. On multivariate survival analysis, the presence of ENE was an independent adverse prognostic factor for OS, DSS, and DFS. The authors propose to document the presence and extent of ENE for these tumors and give consideration for the American Joint Committee on Cancer (AJCC) 9th edition to include ENE into pN stage of HPV-positive OPSCC.

Immunohistochemistry (IHC) and microsatellite instability (MSI) testing constitute the two major test modalities currently in use for detecting deficient mismatch repair (dMMR). Each is associated with caveats and limitations that can be consequential. Most notably, the traditional approach of defining mismatch repair protein IHC abnormality by complete loss of staining in all tumor cells is evolving. Partial or clonal loss is becoming recognized as a manifestation of gene abnormality; in some cases, such clonal loss is associated with germline pathogenic variants. Non-colorectal cases, and occasionally even colorectal tumors, that are MMR deficient by IHC but not MSI-high by current standards are being recognized. Recent data suggest that these immunohistochemistry abnormal/non-microsatellite instability-high cases warrant further genetic workup for Lynch syndrome detection. In this episode, we discuss with Dr. Jinru Shia of Memorial Sloan Kettering Cancer Center her team's view on what constitutes the most optimal strategy in test selection and how best to utilize case context to enhance the interpretation of the dMMR test results.

The group of precursors that lead to HPV-independent, p53-wild-type squamous cell carcinoma is largely unexplored. Nonetheless, a subset of lesions with verruciform acanthosis and altered squamous maturation has been characterized using diverse nomenclature such as VAAD, vLSC, DEVIL, and VAM. These lesions are associated with invasive squamous cell carcinoma and verrucous carcinoma of the vulva, and they harbor recurrent alterations in oncogenes like PIK3CA, HRAS, and NOTCH1.

Dr. Carlos Parra-Herran from the department of Pathology at Brigham and Women's Hospital discusses the importance of reproducibly in distinguishing these lesions from other squamous vulvar precursors and non-neoplastic mimickers with acanthosis or verruciform growth. In order to align with the WHO classification, his group proposes the unifying term of HPVi (p53wt) vaVIN.

Adenoid Ameloblastoma is a very rare benign odontogenic tumor characterized microscopically by epithelium resembling conventional ameloblastoma, with additional duct-like structures, epithelial whorls, and cribriform architecture. Dentinoid deposits, clusters of clear cells, and ghost-cell keratinization may also be present.These tumors do not harbor BRAF or KRAS mutations and their molecular basis appears distinct from conventional ameloblastoma but remains unknown. Dr. Carolina Cavalieri Gomes from the Universidade Federal de Minas Gerais in Brazil, discusses her team’s discovery of CTNNB1 (beta-catenin) exon 3 mutations in 4 of 9 primary cases and 2 additional recurrences.

While the occasional presence of ghost cells keratinization was the feature that led the team to initially investigate beta-catinin, this feature was present in only 2/6. Furthermore, nuclear beta-catenin immunoexpression (IHC) was found in 7 of 8 tested samples including some with wild type CTNNB1. The findings support the classification of adenoid ameloblastoma as a separate entity, and not as a subtype of ameloblastoma. The use of beta-catenin IHC could help in establishing the diagnosis in challenging cases.

Although prophylactic lymph node dissections do not improve survival, the prognostic implications of a positive sentinel node and the benefits of removing nodal metastases for loco-regional disease control remain important. There is a strong interest in novel approaches that can improve patients’ selection for sentinel lymphnode biopsies(SLNB) given that 85% of these procedures are negative and non-therapeutic. The host discusses with Dr. Alexander Meves his recent review in Modern Pathology on the role of gene expression profiling in this setting when combined with clinicopathologic parameters.

Flat lesions of the urothelium with histologic features that falls short of the threshold for urothelial carcinoma in situ (CIS) remains a challenging problem in diagnostic surgical pathology. Among these are flat urothelial hyperplasia, urothelial dysplasia, and atypia of unknown significance; lesions that have struggled under evolving classifications, changing criteria, and limited clinical actionability, all confounded by the recognized lack of diagnostic reproducibility.

In this episode of ModPath Chat, Dr. Gladell Paner discusses with the host his recently published "Controversies in Pathology" article in Modern Pathology on the pros and cons of keeping the previous terminology of this group of lesions. 

Locally recurrent prostate cancer from 53 patients that failed radiation therapy and underwent salvage radical prostatectomy was analyzed for clinicopathological and genomic characteristics. Most radiorecurrent tumors were enriched in cribriform morphologies (invasive cribrifom PCa and intraductal carcinoma with cribriform pattern) and demonstrated potentially targetable genomic alterations (defects in DDR genes: TP53, BRCA2, PALB2, ATR etc.). The guest, Dr. Rajal Shah of UTSW, discusses how understanding this phenotypic and genotypic diversity of radiorecurrent PCa is critically important for future management of such patients.

Establishing an efficient and standardized workflow for performing molecular classification on ECs, and reporting both the molecular and histologic findings in an integrative manner, is imperative. Dr. Brooke Howitt discusses with the host her institution’s effort to implement rapid and routine molecular classification on all ECs diagnosed at Stanford.

Most succinate dehydrogenase (SDH)-deficient RCCs demonstrate classic morphology characterized by bland eosinophilic cells with intracytoplasmic inclusions. Increasingly, "variant" morphologic features are recognized. Drs. Anthony Gill and Talia Fuchs discuss with the host their findings in a recent publication in Modern pathology where features such as high-grade nuclear features, necrosis, papillary, solid, and tubular architecture are present. These features appear to be associated with more aggressive behavior emphasizing the need for a low threshold for performing SDHB immunohistochemistry in any difficult to classify renal tumor; particularly if occurring at a younger age.

The vast majority of image-detected breast abnormalities are currently diagnosed by percutaneous core needle biopsy (CNB). While management of frankly malignant lesions diagnosed by CNB is now well-defined, there is less consensus on the optimal management of high-risk and selected benign lesions diagnosed by CNB. In this episode, Dr. Benjamin Calhoun from University of North Carolina in Chapel Hill eloquently discusses the evidence for and against immediate excision of such lesions.

Modern Pathology have recently launched a new series of reviews addressing controversial issues in pathology. In this episode of ModPath CHAT, Dr. Elizabeth Montgomery, a world renowned expert in gastrointestinal pathology gives her point of view on the utility of ancillary testing for risk stratification of Barrett’s esophagus and dysplasia. 

Ki-67 assessment is a key step in the diagnosis of neuroendocrine neoplasms (NENs) from all anatomic locations.

The application of digital pathology coupled with machine learning has been shown to be highly accurate and reproducible for the evaluation of Ki-67 in NENs. The guest, Dr. Claudio Luchini from the University of Verona in Italy, discusses his recently published systematic review on the subject of Ki-67 assessment in pancreatic NENs (PanNENs) employing digital image analysis (DIA). The most common advantages and disadvantage of using DIA are highlighted.

In a subset of patients with metastatic colorectal cancer (mCRC), the peritoneum is the predominant site of dissemination. While cure can be achieved by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), this procedure is associated with long-term morbidity and high relapse rates.

In this episode of ModPath CHAT, Drs. Siesing and Jirstrom from Lund University in Sweden discuss their recent study in Modern Pathology on the topic. Multi-region immunohistochemical profiling and deep targeted DNA-sequencing was performed on 7 mCRC patients with peritoneal carcinomatosis (PC). SATB2 was lacking in the majority of cases, and a conspicuous intra-patient heterogeneity was denoted for expression of (RBM3). Mutations in key CRC driver genes, i.e., KRAS, APC and TP53, were homogenously distributed across all samples. The authors conclude that their findings should trigger additional studies addressing the potential distinctiveness of mCRC with PC, which might pave the way for improved personalized treatment of these patients.

Uterine leiomyosarcoma is the most common uterine mesenchymal malignancy. The majority present at stage I with variable clinical outcome.

In this episode of ModPath Chat, Dr. David Chapel discusses his recently published multi-institutional study proposing a novel risk stratification model (shown below) for low stage uterine leiomyosarcoma.

Risk score = (coagulative necrosis)(1) + (mitoses > 25 per 2.4mm2)(2) + (atypical mitoses)(2) + (lymphovascular invasion)(3) + (serosal abutment)(5)

In this episode the audience will enjoy a great discussion of the growing potential of methylome and copy number profiling, a technique well established for the classification of brain tumors, in bone and soft tissue tumors diagnosis.

Nuclear overexpression of FOS and FOSB have emerged as a reliable surrogate markers to detect rearrangements of the transcription factors FOS and FOSB in osteoid osteoma and osteoblastoma. Limitations in specificity and sensitivity remains with some osteosarcoma showing nuclear FOS expression and a small number of osteoblastomas lacking rearrangements. Aggressive appearing osteoblastomas and osteoblastoma-like osteosarcoma can be difficult to distinguish.

The guest, Dr. Daniel Baumhoer, discusses the potential use of methylation and copy number profiling in this setting. Osteoblastomas were found to be uniformly characterized by flat copy number profiles that can add certainty to their diagnosis. 

While AML and cysts are the most common renal manifestations in patients with inherited TSC syndromes, approximately 4% will develop renal cell carcinoma (RCC). These include RCC with clear cytoplasm, papillary architecture, and prominent smooth muscle stroma; RCC with granular eosinophilic cytoplasm and macrocystic architecture; and RCC resembling the eosinophilic variant of chromophobe RCC. In recent years and in five studies in the March 2022 issue of Modern Pathology, sporadic counterparts to the hereditary tuberous sclerosis complex-associated RCC that are associated with somatic TSC/MTOR pathway mutations have now been described. 

The host discusses with Dr. Sanjay Mukhopadhyay and Dr. Monisha Sudarshan from Cleveland Clinic their recent Modern Pathology editorial on the findings by F. Zhou et al. (https://doi.org/10.1038/s41379-021-00875-x). The concept of tumor spread through air spaces (STAS) has been recently introduced and is gaining momentum. On permanent sections, STAS has been associated with an increased likelihood of lymph node metastases and aggressive behavior. However, the validity of using STAS diagnosis on frozen section to guide management is controversial. The guests argue that expecting pathologists to diagnose STAS on frozen section and bear responsibility for an aggressive surgical resection is fraught with risk. In their opinion, it is too much, too soon.

Dr. Inti Zlobec, professor of digital pathology at the Institute of Pathology in the University of Bern, discusses her team’s recent publication in Modern Pathology on the role of image analysis in assessing area of extracellular mucin and predicting consensus molecular subtypes (CMS) in colorectal carcinoma. The utilized deep learning algorithm had an excellent agreement with pathologists’ estimates of mucin areas. Coupled with MSI, mucinous area estimates may predict CMS classification using only histopathology. This highlights the great potential of Image based classifier of molecular subtypes of colon cancer. Study by Nguyen, HG., Lundström, O., Blank, A. et al. Image-based assessment of extracellular mucin-to-tumor area predicts consensus molecular subtypes (CMS) in colorectal cancer. Mod Pathol 35, 240–248 (2022)

An informative discussion with Dr. Buttner on the significance of newly acquired genetic insights into pulmonary invasive mucinous adenocarcinoma (IMA).

In the latest WHO classification, IMA is defined as a primary lung adenocarcinoma with tumor cells showing goblet cell- or columnar cell-morphology with abundant intracytoplasmic mucin. Due to its distinctive clinical features, i.e., peripheral location and a high frequency of multifocal, multilobular, and bilateral occurrence it has been defined as a distinct entity with dismal outcome. Two recent studies, including that of Kim et al. Mod Pathol 35, 202–209 (2022), shed some light on the genetic alterations of IMA and are discussed.