Episodes
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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.
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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.
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Missing episodes?
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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)
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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.
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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.
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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.
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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)
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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.
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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.
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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.
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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.
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Professor Gregory Lauwers from Moffitt Cancer Center discusses his team’s recent study comparing index and metachronous gastric cancers in 42 Korean patients. Gastric adenocarcinomas were classified into 5 subtypes: EBV-associated, MMR deficient (MMRD), E cadherin aberrant, p53-aberrant [p53(+)], and p53 non-aberrant [p53(neg)]. Although no significant difference in the frequency of most molecular subtypes was found between index and metachronous lesions, the number of MMRD gastric cancers more than doubled in the latter group. Half of the metachronous cancers had a divergent molecular subtype. The later divergence could indicate a shift in the carcinogenic mechanism affecting residual mucosa possibly related to Helicobacter pylori eradication. Study by Lauwers et al, Comparative molecular subtypes of index and metachronous gastric adenocarcinomas: a study of 42 Korean patients. Modern Pathology, 34, 1728–1737 (2021).
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