Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy marked by late diagnosis, rapid progression, and poor prognosis, with a 5-year survival rate of 2–9%. Traditional tissue biopsy faces limitations in accessibility and real-time monitoring. Liquid biopsy—a minimally invasive technique analyzing tumor-derived materials such as circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), exosomes, tumor-educated platelets (TEPs), and cell-free RNAs (cfRNAs)—offers dynamic insights into PDAC biology. This review advances beyond the prior literature by offering a unified synthesis that bridges molecular mechanisms, biomarker dynamics, and clinical translation within the context of PDAC. It also summarizes key clinical trials evaluating liquid biopsy in PDAC, underscoring its growing impact on precision oncology.

Objectives: There is recently reported increased prevalence of Isospora organisms in cholecystectomy specimens from immunocompetent patients, especially in acalculous cholecystectomies. We performed an ultrastructural and molecular evaluation of these specimens. Methods: From 28 gallbladders with intraepithelial inclusions, two specimens with diffuse involvement of the gallbladder epithelium were analyzed by electron microscopy. Polymerase chain reaction was performed on five samples for the ITS2 region of C belli and eukaryotic 18S region. The 18S products were sequenced by next-generation sequencing. Results: Electron microscopic analysis showed cytoplasmic condensations leading to vacuole formation. In contrast with true C belli, there were no identifiable organelles or organization. None of these cases showed amplified products other than human on molecular analysis. Conclusions: Electron microscopic analysis demonstrates that the inclusions are condensed cytoplasmic material and not true organisms.

Transformation of primary prostate adenocarcinoma to squamous cell carcinoma after initial treatment with chemotherapy and hormonal therapy is extremely rare and typically results in rapid treatment-refractory disease progression and death. Here, we present a case of a 64-year-old man who was initially diagnosed with metastatic prostate adenocarcinoma (positive PSA and NKX3.1 stains, total PSA 747.2 ng/ml) to the thoracic spine (T8) in 2019. The patient received androgen deprivation therapy and chemotherapy with good response (PSA 2.53 ng/ml). In 2022, the patient had a tumor resection from the left humerus with a consequent fracture. Pathology showed pure squamous carcinoma without any adenocarcinoma component (PSA and NKX3.1 stains negative and weak p504s stain, PSA 19.82 ng/ml). Given the patient’s history of metastatic prostate adenocarcinoma and no history of any other malignancies, a diagnosis of squamous carcinoma transformed from prostate adenocarcinoma was rendered. The patient passed away in 2023. Molecular profiling identified the same TP53 mutation and two variants of uncertain significance in both specimens, suggesting the same primary. However, there was CCND3 amplification and absence of the TMPRSS2::ETV4 fusion in the 2022 specimen, which may be associated with squamous transformation and poor prognosis. A microarray might be beneficial to confirm loss of the TMPRSS2::ETV4 fusion. This case illustrates the rare occurrence of squamous transformation in prostate adenocarcinoma and the aggressive clinical course, and need for more therapy guidance and prognostic studies. It also highlights the importance of molecular profiling to provide insights into the pathogenesis of histologic transformation.

Dedifferentiated chondrosarcoma (DDCS) is a rare entity, constituting only 1-2% of all primary bone tumors, and has a dismal prognosis. Nearly two-thirds of the primary tumors of DDCSs are found in the appendicular skeleton, mostly involving the femur, humerus, and pelvis. DDCS of the small bones of the hand and foot are exceedingly rare with only four cases documented in the literature so far. In this report, we present a case of a 91-year-old woman with a rapidly growing bone tumor initially thought to be a trigger finger, which, on histologic examination of the amputation, turned out to be DDCS. On a follow-up CT scan, multiple pulmonary metastases were identified. Next-generation sequencing identified isocitrate dehydrogenase 2 (IDH2) (p.R172S, c.516G>T), TERT (c.-146C>T), and TP53 (c.559+1G>A) mutations. Microsatellite instability was equivocal and tumor mutation burden was low. Due to the advanced age of the patient, she was given palliative treatment and was alive at the six-month follow-up.

Context.—: Biomarker reporting has increasingly become a key component of pathology reporting, providing diagnostic, prognostic, and actionable therapeutic data for patient care. Objective.—: To expand and improve the College of American Pathologists (CAP) biomarker protocols. Design.—: We surveyed CAP members to better understand the limitations they experienced when reporting cancer biomarker results. A Biomarker Workgroup reviewed the survey results and developed a strategy to improve and standardize biomarker reporting. Drafts of new and revised biomarker protocols were reviewed in both print and electronic template formats during interactive webinars presented to the CAP House of Delegates. Feedback was collected, and appropriate revisions were made to finalize the protocols. Results.—: The first phase of the CAP Biomarker Workgroup saw the development of (1) a new stand-alone general Immunohistochemistry Biomarker Protocol that includes reporting for ER (estrogen receptor), PR (progesterone receptor), Ki-67, HER2 (human epidermal growth factor receptor 2), PD-L1 (programmed death ligand-1), and mismatch repair; (2) a new Head and Neck Biomarker Protocol that updates the prior 2017 paper-only version into an electronic template, adding new diagnostic and theranostic markers; (3) a major revision to the Lung Biomarker Protocol to streamline it and add in pan-cancer markers; and (4) a revision to the Colon and Rectum Biomarker Protocol to add HER2 reporting. Conclusions.—: We have taken a multipronged approach to improving biomarker reporting in the CAP cancer protocols. We continue to review current biomarker reporting protocols to reduce and eliminate unnecessary methodologic details and update with new markers as needed. The biomarker templates will serve as standardized modular units that can be inserted into cancer-reporting protocols.

Objectives: To examine the clinical, pathologic, and molecular features of mixed and mixed feature endometrial carcinomas and compare them to pure serous carcinoma and pure endometrioid carcinoma. Methods: The study analyzed the clinical characteristics, histologic composition, and molecular genetic profiles of mixed and mixed feature endometrial cancers, with a focus on shared and distinct mutations. Patient demographics, disease-free survival, and molecular alterations, including in TP53, PIK3CA, TERT, MAP2K1 genes, and ERBB2 gene amplifications, were assessed and compared to pure serous and pure endometrioid carcinomas. Results: Patients with mixed and mixed-feature carcinomas were older (median age: 73 years) and had worse disease-free survival (median: 23 months) than those with pure endometrioid carcinoma (median: 48 months). Mixed and mixed-feature carcinomas were histologically high-grade, most commonly comprising serous and endometrioid components. Molecular profiling supported a clonal origin of these tumors, with identical TP53 and PIK3CA gene mutations between the two histologic components in each case. There were additional gene mutations (e.g., TERT and MAP2K1) found in higher-grade components. ERBB2 amplifications were more frequent in the mixed carcinomas groups (33%) compared to pure serous (11%) and pure endometrioid carcinomas (0%). Some of the mixed and mixed-feature carcinomas also showed FBXW7 mutations, not seen in either the pure endometrioid or pure serous carcinomas. Conclusions: Mixed and mixed-feature carcinomas share origins with pure endometrial serous and endometrioid carcinoma subtypes but exhibit distinct molecular alterations. These findings highlight the importance of molecular subtyping for diagnosis and treatment planning. Future research could focus on larger cohorts and targeted sequencing to better understand the pathogenesis of mixed and mixed-feature carcinomas in order to refine therapeutic strategies.