ModPath Chat
Apple podcasts: https://podcasts.apple.com/us/podcast/modpath-chat/id1530197705
Google podcasts: https://podcasts.google.com/search/ModPath%20Chat
Episode 71: 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.
Episode 70: An integrated approach to differentiate Grade 3 PanNET from PanNEC
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.
Episode 69: Digitally quantitated tumor cellularity as a prognostic factor in NSCLC
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.
Episode 68: PTEN Deficiency in Tubo-Ovarian High-Grade Serous Carcinoma
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.
Episode 67: Computer-Assisted Diagnosis of Lymph Node Metastases in Colorectal Cancers
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!
Episode 66: Fundic Gland Polyps in FAP and Sporadic Patients
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.
https://modernpathology.org/audio-do/episode-66-fundic-gland-polyps-fap-and-sporadic-patients
Episode 65: SATB2 Rearrangement in Psammomatoid Ossifying Fibroma
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.
Episode 64: Genetic Profiling in Diffuse Large B-Cell Lymphoma
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.
https://modernpathology.org/audio-do/episode-64-genetic-profiling-diffuse-large-b-cell-lymphoma
Episode 63: SOX17: A Highly Sensitive and Specific Immunomarker for Ovarian and Endometrial Carcinomas
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.
Episode 62: Ovarian Mucinous Neoplasms: How Reproducible are Current Diagnostic Categories?
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.
Episode 61: Extranodal extension in HPV-positive oropharyngeal squamous cell carcinoma
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.
Episode 60: Detecting deficient mismatch repair in solid neoplasms
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.
https://modernpathology.org/audio-do/episode-60-detecting-feficient-mismatch-repair-solid-neoplasms
Episode 59: Verruciform and Acanthotic Vulvar Precursor Lesions
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.
https://modernpathology.org/audio-do/verruciform-and-acanthotic-vulvar-precursor-lesions
Episode 58: Morphologic Feature Guiding Discovery of Driver Genetic Alteration in Rare Entity
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.
Episode 57: Risk Stratification for SLNB in Melanoma
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.
Episode 56: Flat urothelial lesions of the urinary bladder: Who is in who is out?
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.
https://modernpathology.org/audio-do/episode-56-flat-urothelial-lesions-urinary-bladder-out
Episode 55: Radio-Resistant Prostate Carcinoma: “Cribriform” morphologies and DNA Damage Response and Repair defects
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.
Episode 54: The Stanford Experience in Implementation of the Molecular Classification of Endometrial carcinomas (EC)
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.
Episode 53: Expanding the clinico-pathological spectrum of SDH Deficient RCC
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.
Episode 52: High Risk and Selected Benign Breast Lesions on Core Biopsy: Excision Vs Surveillance?
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.
Episode 51: Are ancillary studies of any utility in risk assessment of Barrett’s esophagus and dysplasia?
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.
Episode 50: Ki-67 assessment in pancreatic neuroendocrine neoplasms manual vs. digital?
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.
Episode 49: Heterogeneity of molecular alterations in CRC with peritoneal carcinomatosis
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.
Episode 48: A Risk Stratification Model for Low Stage Uterine leiomyosarcoma
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)
Episode 47: A promising role for methylome and copy number profiling in classifying bone and soft tissue tumors
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.
Episode 46: Pink sporadic RCCs associated with TSC/MTOR alterations
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.
Episode 45: Spread through airspaces (STAS) on frozens: too much, too soon
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.
https://modernpathology.org/audio-do/episode-45-spread-through-airspaces-frozens-too-much-too-soon
Episode 44: Image-based assessment of extracellular mucin in colorectal cancer
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)
Episode 43: Meet the Expert: A Conversation with Professor Reinhard Buttner
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.
https://modernpathology.org/audio-do/episode-43-meet-expert-conversation-professor-reinhard-buttner
Episode 42: DP, WSI, AI, DL: The Alphabet Soup of the Third Revolution in Pathology
Traditional pathology have played an integral role in the delivery of diagnosis, semi-quantitative or qualitative assessment of protein expression, and classification of disease. Technological advances have recently paved the way for the development of digital pathology-based approaches for quantitative pathologic assessments, namely whole slide imaging (WSI) and artificial intelligence (AI)–based solutions, allowing us to explore and extract information beyond human visual perception. In this episode, two distinguished leaders in the space: Vipul Baxi, Senior Scientific Director of Digital Pathology at Bristol Meyers Squibb and Michael Montalto, Chief Scientific Officer at Path AI discuss their recent review article in Modern Pathology. The share their thoughts on the promise of Digital Pathology and the challenges and opportunities that lie ahead. Study by Baxi and Montalto et al. Digital pathology and artificial intelligence in translational medicine and clinical practice. Modern Pathology, 25, 23-32.
Episode 41: Atypical Uterine Polyps: A benign clinical course despite morphologic and molecular overlap with Adenosarcomas.
A subset of clinically benign uterine polyps shows atypical morphologic features worrisome for, but not diagnostic of, Mullerian adenosarcoma. The guest, Dr Marisa Nucci discusses her team’s finding in their recently published study in Modern Pathology. The authors propose the term “atypical uterine polyps” for these lesions, which show biologic overlap with early Mullerian adenosarcoma but lack molecular alterations characteristic of clinically aggressive adenosarcoma. Study by Nucci et al. Atypical uterine polyps show morphologic and molecular overlap with mullerian adenosarcoma but follow a benign clinical course. Modern Pathology, 35, 106-116.
Episode 40: Breast Implant Associated Lymphomas: EBV positivity pathogenic role?
Breast implant anaplastic large cell lymphoma (ALCL) is a T-cell neoplasm arising around textured breast implants. Our host discusses with Drs. Medeiros and Miranda their recent report on eight cases of Epstein–Barr virus (EBV)-positive large B-cell lymphoma associated with breast implants. Their data suggest a pathogenetic role for breast implants (as well as EBV) in the pathogenesis of this type of implant-associated lymphomas. Study by Medeiros and Miranda et al. Epstein–Barr-virus-positive large B-cell lymphoma associated with breast implants: an analysis of eight patients suggesting a possible pathogenetic relationship. Modern Pathology, 34, 2154–2167.
Episode 38: Machine Learning facilitates assessment of shaved lumpectomy margins
Drs. Timothy D’Alfonso, David Ho, and Lee K.Tan from Memorial Sloan Kettering in NY discuss their recent Modern Pathology study describing a new machine learning algorithm that can help pathologists assess shaved margins from lumpectomy specimens. A uniquely developed Deep Multi-Magnification Network (DMMN) was utilized in Whole Slide Images (WSI) in the hope to triage negative margins and allow pathologists to focus on shaves that are positive for DCIS and/or Invasive carcinoma.
Episode 37: Meet the Expert: A Conversation with Professor Holger Moch
Professor Holger Moch shares with our audience his most inspiring career journey as a physician scientist and a luminary in the field of renal cancers. An enjoyable historical look back at the evolution of the field and the progress in renal tumor classifications.
https://modernpathology.org/audio-do/episode-37-meet-expert-conversation-professor-holger-moch
Episode 36: 2021 Year in Review
In this episode of ModPath CHAT, Dr. George J Netto reviews five of the highly cited manuscripts that were published in Modern Pathology in 2021.
https://podcasts.apple.com/us/podcast/2021-year-in-review/id1530197705?i=1000618779566
https://modernpathology.org/audio-do/episode-36-2021-year-review
Episode 35: NTRK Fusions
Identification of molecular alterations in NTRK 1-3 has become increasingly important with the emergence of histology-agnostic, US Food and Drug Administration-approved, effective inhibitors. The host discusses with Dr. Jaclyn Hechtman, director of clinical diagnostic development at Neogenomics, her practical insights on how testing for NTRK fusion can best be implemented and communicated within the multidisciplinary healthcare team.
https://podcasts.apple.com/us/podcast/ntrk-fusions/id1530197705?i=1000618779807
https://modernpathology.org/audio-do/episode-35-ntrk-fusions
Episode 34: DICER1 Tumor Predisposition Syndrome: A chat with Pepper Dehner!
Dr. Dehner discusses his four decades journey with an entity that he first described in 1977. Since his initial description of Pleuropulmonary Blastoma (PPB), the neoplasm has become one of the defining entities of DICER1 Syndrome, a rare autosomal dominant familial tumor predisposition disorder with heterozygous DICER1 germline mutation. A fascinating historical perspective and most informative ModPath Chat episode on the wide spectrum of neoplasms that can be encountered in the syndrome awaits the listener. Study by Dehner et al.DICER1 tumor predisposition syndrome: an evolving story initiated with the pleuropulmonary blastoma. Modern Pathology (2021).
Episode 33: Re-evaluating tumors of purported specialized prostatic stromal origin: Distinct entities or Heterogenous mesenchymal neoplasms?
The host is joined by Dr. Andres Acosta from the Brigham and Women Hospital. Dr Acosta discusses, on behalf of a distinguished group of coauthors, their recent somewhat provocative modern pathology publication proposing that mesenchymal neoplasms of the prostate are morphologically and molecularly heterogeneous lesions that include neoplasms that harbor genetic aberrations seen in specific mesenchymal tumors arising in other anatomic sites, such as soft tissue and the uterus. Study by Acosta et al, Re-evaluating tumors of purported specialized prostatic stromal origin reveals molecular heterogeneity, including non-recurring gene fusions characteristic of uterine and soft tissue sarcoma subtypes. Modern Pathology, 34, 1763–1779 (2021).
Episode 32: “AstroPath” Substituting cells for cosmic stars, the sky is the limit for digital and computational pathology!
In this special “Meet the Expert” episode, two distinguished guests from Johns Hopkins University discuss their pioneering approach of applying methodologies, initially developed for astronomy, to the assessment of biomarkers of tumor microenvironment (TME). The guests are Dr. Janis Taube, director of Dermatopathology at Hopkins, and a co-Director of the TME Core at the Bloomberg-Kimmel Institute of Immunotherapy, and Dr. Alex Szalay, Bloomberg Distinguished Professor of Astronomy and Computer Science at Hopkins and the architect for the Science Archive of the Sloan Digital Sky Survey. The fascinating discussion focuses on an innovative multiplex imaging platform that they co-developed (AstroPath) for multidimensional assessment of spatially resolved interactions at the single-cell level of lung cancer and melanoma.
Episode 31: Counting Mitoses: SI(ze) matters!
In this episode, Dr. Ian Cree, Head of The WHO Tumour Classification discusses his team’s recent open access publication in Modern Pathology. Historically, mitotic figures counting has been done by expressing the number of mitoses per n high power fields (HPFs), ignoring the fact that microscope fields may differ substantially, even at the same high power (×400) magnification. Dr. Cree and coauthors remind all of this variation and its implication on the accuracy of our diagnostic and tumor grading practices. While the expanding adoption of computational digital pathology algorithm will help bring consistency to assessing proliferation activity, our MODPATH Chat guest recommends that counting should be performed per standard international unit of (mm2); with an indication of the area to be counted and the method used (“hotspot” vs “average”). Study by Cree et al, Counting mitoses: SI(ze) matters! Modern Pathology, 34, 1651–1657 (2021).
https://podcasts.apple.com/us/podcast/counting-mitoses-si-ze-matters/id1530197705?i=1000618779785
https://modernpathology.org/audio-do/episode-31-counting-mitoses-si-ze-matters
Episode 30: The Role of Genotyping in the Diagnosis and Prognostication of Gestational Trophoblastic Disease
In this episode of MODPATH CHAT, our guests Dr. Natalia Buza and Dr. Pei Hui from the department of Pathology at Yale University share their approach to the application of DNA genotyping to the diagnosis and prognostication of Hydatidiform moles and Gestational trophoblastic tumors. Genotyping is now the gold standard in the confirmation and subtyping of sporadic hydatidiform moles. DNA genotyping is critical to the separation of gestational trophoblastic neoplasia from non-gestational counterparts/mimics of either germ cell or somatic origin. Modern Pathology, 34, 1658–1672 (2021).
https://podcasts.apple.com/us/podcast/the-role-of-genotyping-in-the/id1530197705?i=1000618779681
Episode 29: Regression predicts Sentinel Lymph Node (SLN) status
The prognostic significance of regression has long been a matter of debate. Our guest, Professor Richard Scolyer, co-director of the Melanoma Institute Australia discussed his team’s recent findings on the prognostic value of regression, and the presence of regression and/or tumor infiltrating lymphocytes (TIL) in primary cutaneous melanomas predicted sentinel lymph node (SLN) status and survival outcomes. Study by Scolyer et al, Histological regression in melanoma: impact on sentinel lymph node status and survival. Modern Pathology, 2021.
https://modernpathology.org/audio-do/episode-29-regression-predicts-sentinel-lymph-node-status
Episode 28: A Novel Prognostic Score for NSCLC following Neoadjuvant therapy
Dr. Sabina Berezowka, from the university of Lausanne Switzerland, discusses with our host her team’s recent study describing a novel “Prognostic Score” for assessing tumor regression following Neaodjuvant therapy in non-small cell lung cancer (NSCLC). The proposed combined prognostic score (PRSC) performed better than pTNM staging and previously published Major Pathologic Response (MPR) approach. Study by Berezowka et al, A prognostic score for non-small cell lung cancer resected after neoadjuvant therapy in comparison with the tumor-node-metastases classification and major pathological response. Modern Pathology, 34, 1333–1344, 2021.
Episode 27: DDIT3 Immunohistochemical expression as a diagnostic marker for Myxoid Liposarcoma
Dr. Jason Hornick discusses his team recent study finding that a monoclonal antibody directed against the N-terminus of DDIT3 is a highly sensitive and specific for high-grade MLPS. DDIT3 immunostains could replace molecular genetic testing in many cases, although limited labeling may be seen in a range of other tumor types. Study by Hornick et al, Nuclear expression of DDIT3 distinguishes high-grade myxoid liposarcoma from other round cell sarcomas. Modern Pathology, 34, 1367–1372, 2021
Episode 26: TRIM63 as a biomarker for MiT family RCC
In this episode Dr. Rohit Mehra of University of Michigan discusses the utility of TRIM63 as a diagnostic marker to distinguish MiTF-RCC from other renal tumor subtypes with overlapping morphology. In combination with TFE3/TFEB FISH, TRIM63 RNA-ISH assays can improve the accuracy and efficiency of MiTF-RCC diagnosis. Study by Mehra et al, TRIM63 is a sensitive and specific biomarker for MiT family aberration-associated renal cell carcinoma. Modern Pathology, 34, 1596-1607, 2021.
https://modernpathology.org/audio-do/episode-26-trim63-biomarker-mitf-family-renal-cell-carcinoma
Episode 25: A MODPATH Chat with Dr. Victor Reuter: The Digital Transformation of Anatomic Pathology
Always a visionary, Dr. Reuter was one of the earliest Anatomic Pathologists to embrace and advance the genomic and more recently the digital transformation of our field. In this episode of Meet The Expert series, Dr. Reuter shares his perspective and vision on the current and future impact of digital pathology.
Episode 24: Artificial intelligence for advance requesting of IHC in diagnostically uncertain prostate biopsies
Dr. Clare Verrill and Andrea Chatrian of Oxford University in England discuss their team’s study on AI for advance ordering of IHC in difficult prostate biopsy. Their elegant work shows that an AI tool making automated IHC request prior to the pathologist read of H&E could create leaner workflow and result in pathologist time savings and shorten overall Turnaround time from accession to final diagnosis. Study by Chatrian et al, Artificial intelligence for advance requesting of immunohistochemistry in diagnostically uncertain prostate biopsies.
Episode 23: Synchronous Endometrial and Ovarian Carcinomas: Clonal relationship and directionality of progression
Dr. Britta Weigelt of MSKCC discusses her team’s study on synchronous endometrial (EC) and ovarian carcinomas (OC) in Lynch syndrome and constitutional Mismatch Repair Deficiency Syndrome (CMMRD). Contrary to sporadic synchronous ECs/OCs, which are almost invariably clonally related, ECs/OCs simultaneously involving the uterus and ovary in LS patients may represent two independent primary tumors. Like their sporadic counterparts, a subset of MMR deficiency syndrome-related synchronous ECs/OCs may also originate from a single with the endometrium being the likeliest site of origin. Study by Weigelt et al, Clonal relationship and directionality of progression of synchronous endometrial and ovarian carcinomas in patients with DNA mismatch repair-deficiency associated syndromes. Modern Pathology, 34, 994-1007, 2021.
Episode 22: Deciphering the Molecular Underpinning of Ulcerative Colitis Associated Colorectal Cancer
Dr. Daniela Hirsch, from the Institute of Pathology at the University of Heidelberg in Germany, discusses her findings on the molecular alterations associated with colorectal cancer in the setting of Ulcerative Colitis. Using aCGH, a 48 gene panel and MSI analysis and IHC for TP53, the author and her team revealed high rate of TP53 mutations and gains in chromosome 5p in these predominantly Microsatellite stable tumors. Phylogenic clues about ontogenesis and field effect are discerned from synchronous tumors.
Episode 21: Post Neo-adjuvant Chemotherapy Patterns of Residual Breast Cancer
Dr. Stuart Schnitt from Brigham and Women Hospital in Boston discusses his team’srecent findings of variable architectural and cytological patterns of residual disease in breast cancer patients with incomplete pathologic response. The relationship of pattern of residual disease to pre-treatment clinicopathologic parameters and the potential impact on management are discussed. Study by Pastorello et al, Clinico-pathologic predictors of patterns of residual disease following neoadjuvant chemotherapy for breast cancer. Modern Pathology, 34, 875-882, 2021.
Episode 20: “Rebranding” Hematopathology Using Twitter: The MD Anderson Experience
In this episode, our guests, Dr. Siba El Hussein and Dr. Sanam Loghavi from the department of hematopathology at MD Anderson Cancer Ctr, discuss their experience on the role of social media in the dissemination of knowledge in hematopathology and establishing networks of collaborators and followers. Editorial by El Hussein et al, Next-Generation Scholarship: Rebranding Hematopathology Using Twitter: The MD Anderson Experience. Modern Pathology, 34, 854-861, 2021.
Episode 19: USCAP 2021 Long Course: Biomarkers of Response to Check Point Inhibitors – beyond PD-L1
In this fourth and final episode of our special series covering this year’s USCAP Long Course on lung disease, our guest, Dr. Lynette Sholl, chief of pulmonary pathology at the Brigham and Women Hospital discusses her presentation on “Biomarkers of Response to Checkpoint Inhibitors”. Dr. Sholl touches upon the potential role of CD8+ T cell count, Multiplex IF based spatial profiling and novel genomic determinants as markers beyond PD-L1.
Episode 18: USCAP 2021 Long Course: Neuroendocrine Tumors of Lung, a Decade of Change!
In this third of four special episodes highlighting the USCAP 2021 Long Course on Pulmonary Pathology, our host discusses with Dr. Natasha Rekhtman of Memorial Sloan Kettering Cancer Center (MSKCC) her presentation on Neuroendocrine tumors. Dr. Rekhtman offers her perspective on the current status of the classification of pulmonary NE tumors and the “grey zones” that remain to be tackled.
Episode 17: USCAP 2021 Long Course: “Pulmonary Pathology: Practical Problems and Solutions”. HP, FHP, CTILD, UIP/IFP and more!
In this second of four special episodes highlighting the USCAP 2021 Long Course on Pulmonary Pathology, our host is joined by two distinguished faculty: Dr. Andrew Churg of the University of British Colombia and Dr. Maxwell Smith from the Mayo Clinic Arizona. The two international experts on interstitial lung disease (ILD) share their valuable perspective on “where we are and where we need to go” in our approach to the diagnosis and classification of hypersensitivity pneumonitis (HP) and usual interstitial pneumonitis (UIP).
Episode 16: USCAP 2021 Long Course: “Pulmonary Pathology: Practical Problems and Solutions”. Meet the Directors!
In this special episode, Dr. Sanja Dacic and Dr. Mary Beth Beasley highlight the topics of the upcoming Long Course on Pulmonary Pathology, that will air on March 13th during the USCAP 2021 annual meeting. As international experts and thought leaders on thoracic tumors, they have been heavily involved with developing guidelines for molecular biomarkers of mesotheliomas and Lung cancers. Tremendous advances have taken place in pulmonary pathology. The guests discuss their take on these exciting advancements and share their future vision.
Episode 15: MHC class I loss in endometrial carcinoma
MHC class I loss by tumor cells decreases tumor neoantigen presentation to the immune system and therefore represents a possible mechanism of immunotherapeutic resistance in cancers that otherwise could be good candidates for checkpoint inhibition (e.g. mismatch repair (MMR)-deficient and PD-L1-positive tumors). In this episode our guest, Dr. Anne Mills discusses her recent Modern Pathology publication on loss of MHC class 1 expression in some endometrial cancers. Study by Friedman et al, MHC class I loss in endometrial carcinoma: a potential resistance mechanism to immune checkpoint inhibition. Modern Pathology, 34, 627-636, 2021.
https://modernpathology.org/audio-do/episode-15-mhc-class-i-loss-endometrial-carcinoma
Episode 14: Predictors of metastases in non-seminomatous TGCT: The rationale for evolution of the pathologic staging system?
Pathological risk factors for metastatic disease in patients with testicular non-seminomatous germ cell tumors are debated. The tumor-node-metastasis (TNM) classification eighth edition for testicular cancers includes divergent versions, by the International Union Against Cancer (UICC) and by the American Joint Committee for Cancer (AJCC). In this episode we discuss with Dr. Daniel Berney his recent study on the topic. Study by Scandura et al, Pathological predictors of metastatic disease in testicular non-seminomatous germ cell tumors: which tumor-node-metastasis staging system? Modern Pathology, 2020.
Episode 13: Composite Nuclear Grading System to Predict Survival in Epithelioid Peritoneal Mesothelioma
This episode’s guest, Dr. David Chapel, was the recipient of the 2020 USCAP Stephen Vogel Award for his research as a trainee in the University of Chicago! Here, he discusses his recent report on a multi-institutional cohort of 225 malignant peritoneal mesotheliomas, assessed for 21 clinical, morphologic, and immunohistochemical potential prognostic parameters. The exemplary study, published in Modern Pathology, clarifies the complex interaction of clinical and pathologic features in peritoneal mesothelioma and validates the prognostic significance of a standardized nuclear grading system. Study by Chapel et al, Malignant peritoneal mesothelioma: prognostic significance of clinical and pathologic parameters and validation of a nuclear-grading system in a multi-institutional series of 225 cases. Modern Pathology, 34, 380-395, 2021.
Episode 12: APOBEC, the enemy within us!
APOBEC3B (A3B) is a newly recognized endogenous source of mutations in a range of human cancers by inflicting C-to-T or C-to-G base substitutions in 5′-TCA/T trinucleotide motifs. In this episode, Drs. Harris and Argyris discuss the impact of their recent findings on the role of APOBEC3A in Head and Neck Squamous Cancer. Study by Argyris et al, Endogenous APOBEC3B overexpression characterizes HPV-positive and HPV-negative oral epithelial dysplasias and head and neck cancers. Modern Pathology, 34, 280-290, 2020.
https://podcasts.apple.com/us/podcast/apobec-the-enemy-within-us/id1530197705?i=1000618779787
https://modernpathology.org/audio-do/episode-12-apobec-enemy-within-us
Episode 11: Serous Carcinoma of The Uterine Cervix: A Vanishing Entity
The Host discusses with Dr. Philip IP (Li Ka Shing Faculty of Medicine, University of Hong Kong) his recent study re-assessing Cervical adenocarcinoma with Serous-Like morphology in light of the recent changes in the Classification of cervical adenocarcinomas. Study by Wong et al, Cervical carcinomas with serous-like papillary and micropapillary components: illustrating the heterogeneity of primary cervical carcinomas. Modern Pathology, 2020.
https://modernpathology.org/audio-do/episode-11-serous-carcinoma-uterine-cervix-vanishing-entity
Episode 10: Top 20 of 2020, The Year in Review
Dr. Netto reflects on the topics of the most cited manuscripts published in Modern Pathology in 2020. A brief discussion of five selected studies involving COVID-19, DICER1, NTRK, Precursor lesions of HPV-Independent Vulvar Squamous Cell Carcinoma and Applications of Computational Pathology and Artificial Intelligence in Pathology.
https://podcasts.apple.com/us/podcast/top-20-of-2020-the-year-in-review/id1530197705?i=1000618779790
https://modernpathology.org/audio-do/episode-10-top-20-2020-year-review
Episode 9: Machine Learning-Based Algorithm to Predict Death from COVID-19
Dr. Netto discusses with his two guests, Dr. Peter MCaffrey from the UTMB in Galveston and Dr. Adam Booth, their publication on developing a machine learning model using 5 serum chemistry laboratory parameters for the prediction of death from COVID-19. The discussion is followed by a conversation on the exciting role of AI and social media in Pathology given the unique expertise of the guests. Study by Booth et al, Development of a prognostic model for mortality in COVID-19 infection using machine learning. Modern Pathology, 2020.
Episode 8: Kinase Fusion Related Thyroid Cancers
Dr. Peter Sadow, Director of Head and Neck Pathology at MGH discusses with Modern Pathology Editor Dr. George Netto his recent work defining morphologic correlates of the expanding list of Kinase Fusions driving thyroid cancers. A triage testing algorithm and therapeutic implications are highlighted in the discussion. Study by Chu et al, Clinicopathologic features of kinase fusion-related thyroid carcinomas: an integrative analysis with molecular characterization. Modern Pathology 33, 2458-2472, 2020.
https://modernpathology.org/audio-do/episode-8-kinase-fusion-related-thyroid-cancers
Episode 7: Pancreatic Cancer Genetics 2020
The recent publication of the “Pan-Cancer Atlas” by the Pan-Cancer Analysis of Whole Genomes Consortium provided a great opportunity for Dr. Ralph Hruban and his team to reflect on where we stand in our understanding of the genetics of pancreatic cancer. From germline variants that predispose to the development of the disease, to somatic mutations that are therapeutically targetable, genetics is now providing hope, where there once was no hope, for those diagnosed with pancreatic cancer. Study by Thompson et al, The genetics of ductal adenocarcinoma of the pancreas in the year 2020: dramatic progress, but far to go. Modern Pathology 33, 2544-2563, 2020.
https://podcasts.apple.com/us/podcast/pancreatic-cancer-genetics-2020/id1530197705?i=1000618779869
https://modernpathology.org/audio-do/episode-7-pancreatic-cancer-genetics-2020
Episode 6: ALK rearranged renal cell carcinoma (ALK-RCC)
The host discusses with Professor Ondrej Hes, from the Charles University in the Czech Republic, his recent multi-institutional study that further defines ALK-RCC as a genetically distinct renal cancer type showing a heterogeneous histomorphology. The authors advocate a routine ALK IHC screening for “unclassifiable RCCs” with heterogeneous features. Study by Kuroda et al, ALK rearranged renal cell carcinoma (ALK-RCC): a multi-institutional study of twelve cases with identification of novel partner genes CLIP1, KIF5B and KIAA1217. Modern Pathology 2020.
https://modernpathology.org/audio-do/episode-6-alk-rearranged-renal-cell-carcinoma
Episode 5: Xanthogranulomatous epithelial tumor
Dr Netto discusses with Dr. Andrew Folpe a novel tumor of soft tissue and bone with a predilection for young females. The newly discovered lesion is provisionally termed “xanthogranulomatous epithelial tumor”. Clues to the diagnosis of this tumor type are presented by Dr. Folpe with a practical guide to navigating the challenging differential diagnosis of epithelial expression in mesenchymal neoplasms. Study by Fritchie et al, Xanthogranulomatous epithelial tumor: report of 6 cases of a novel, potentially deceptive lesion with a predilection for young women. Modern Pathology, 33, 1889-1895. 2020.
https://modernpathology.org/audio-do/episode-5-xanthogranulomatous-epithelial-tumor
Episode 4: COVID-19 pulmonary pathology in cross Atlantic pandemic epicenters
A discussion with Dr. Borczuk of New York Presbyterian Hospital- Weill Cornell Medicine on his team findings in sixty eight COVID-19 autopsies, performed early on during the pandemic, at 3 institutions in heavily hit areas (2 USA, 1 Italy). While a heterogeneous disease, COVID-19 pneumonia displayed consistent features in all three centers. Study by Borczuk et al, COVID-19 pulmonary pathology: a multi-institutional autopsy cohort from Italy and New York City. Modern Pathology, 2020.
Episode 3: Quantitative assessment of residual pancreatic intraductal carcinoma following neoadjuvant chemotherapy
Modern Pathology Editor in Chief discusses with Laura Wood MD PhD her recent study on quantitative assessment of residual pancreatic intraductal carcinoma following neoadjuvant chemotherapy. The implications of finding that the intraductal component of pancreatic cancer is more resistant to chemotherapy are highlighted. Study by Fujikura et al, Intraductal pancreatic cancer is less responsive than cancer in the stroma to neoadjuvant chemotherapy. Modern Pathology, 2020.
Episode 1: Using “ONEST” algorithm to improve reproducibility of PD-L1 assessment by pathologists
A conversation with David Rimm, the author of a recent study on Triple negative breast cancer, on using a novel statistical algorithm (ONEST) to improve reproducibility of PD-L1 assessment by pathologists. Study by Reisenbichler et al, Prospective multi-institutional evaluation of pathologist assessment of PD-L1 assays for patient selection in triple negative breast cancer. Modern Pathology, 2020.