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Background Patient-derived tumor models are the new standard for pre-clinical drug testing and biomarker discovery. However, the emerging technology of primary pancreatic cancer organoids has not yet been broadly implemented in research, and complex organotypic models using organoids in co-culture with stromal and immune cellular components of the tumor have yet to be established. In this study, our objective was to develop and characterize pancreatic cancer organoids and multi-cell type organotypic co-culture models to demonstrate their applicability to the study of pancreatic cancer. Methods We employed organoid culture methods and flow cytometric, cytologic, immunofluorescent and immunohistochemical methods to develop and characterize patient-derived pancreatic cancer organoids and multi-cell type organotypic co-culture models of the tumor microenvironment. Results We describe the culture and characterization of human pancreatic cancer organoids from resection, ascites and rapid autopsy sources and the derivation of adherent tumor cell monocultures and tumor-associated fibroblasts from these sources. Primary human organoids displayed tumor-like cellular morphology, tissue architecture and polarity in contrast to cell line spheroids, which formed homogenous, non-lumen forming spheres. Importantly, we demonstrate the construction of complex organotypic models of tumor, stromal and immune components of the tumor microenvironment. Activation of myofibroblast-like cancer associated fibroblasts and tumor-dependent lymphocyte infiltration were observed in these models. Conclusions These studies provide the first report of novel and disease-relevant 3D in-vitro models representing pancreatic tumor, stromal and immune components using primary organoid co-cultures representative of the tumor-microenvironment. These models promise to facilitate the study of tumor-stroma and tumor-immune interaction and may be valuable for the assessment of immunotherapeutics such as checkpoint inhibitors in the context of T-cell infiltration.

Pancreatic cystic lesions (PCLs) are very common, and their detection is increasing with the advances in imaging techniques. Because of the major implications for management, distinguishing between neoplastic and nonneoplastic PCLs is critical. Neoplastic cysts with potential to progress into cancer include mucinous PCLs (intraductal papillary mucinous neoplasms and mucinous cystic neoplasms) and nonmucinous cysts (solid pseudopapillary tumors, serous cystic neoplasms, and neuroendocrine tumors with cystic degeneration). Nonneoplastic cysts with no risk of malignant transformation include pseudocysts, retention cysts, lymphoepithelial cysts, cystic pancreatic lymphangioma, and duplication cyst/ciliated foregut cysts. The role of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) cytology with cyst fluid analysis in the diagnosis of PCLs has evolved during the last decade; however, a definitive diagnosis on cytologic specimens is hampered by the sparse cellularity and can be challenging. EUS-FNA can play an important role to differentiate low-risk from high-risk pancreatic cysts and to distinguish between patients with cysts who need clinical follow-up versus those who require surgery. To provide an integrative approach to diagnose pancreatic cystic lesions using EUS-FNA cytology and cyst fluid analysis, along with clinical, radiologic, histologic, genetic, and molecular characteristics. The review and analysis of the latest literature describing pancreatic cystic lesions. Accurate diagnosis of PCLs requires a multidisciplinary and multimodal team approach, including the integration of clinical findings, imaging, cytology, cyst fluid analysis, and molecular testing.

Abstract Objectives To determine outcomes following relocation of frozen section services (FSS) and the implementation of a dedicated gastrointestinal frozen service. Methods We reviewed our FSS 6 months prior to and following FSS relocation. Satisfaction surveys were sent to surgeons and pathologists. Survey feedback resulted in a pilot of gastrointestinal subspecialist frozen section coverage. Results There were 1,607 and 1,472 specimens from 667 and 602 patients pre- and post-FSS relocation, respectively. There was a decline in median specimen delivery time to pathology (12 vs 10 minutes, P < .001) and an increase in median time from receipt in pathology to intraoperative diagnosis (20 vs 22 minutes, P = .008) in cases with intrapathology consultation but no change without consultation (median, 19 minutes). Intrapathology consultation decreased from 19.7% (317/1,607) to 11.5% (169/1,472) (P < .001). Discordance rates between frozen section and permanent section remained low and similar (2.0% [33/1,607] vs 2.7% [40/1,472], P = .24). There was no significant change in discordance with dedicated gastrointestinal subspecialty frozen section interpretation. Conclusions Relocation of FSS and dedicated subspecialty interpretation may improve surgeon satisfaction but can also create workflow challenges. Pathology departments need to achieve a balance between satisfaction and adequacy to establish best frozen section coverage models.

Human Papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) remains a challenging malignancy, with radiotherapy, alone or combined with immune checkpoint inhibitors, often failing to achieve durable disease control. Here, by conducting longitudinal multi-omic analyses of pre- and post-radiation biopsies from patients receiving a pre-operative hypofractionated radiation regimen, we uncover that radiation rapidly depletes a subpopulation of tumor-infiltrating lymphocytes (TIL), characterized by a proliferative, cytotoxic, and tissue-resident gene signature (T Prolif_Tox ). We provide multi-dimensional evidence for tumor antigen-specificity of T Prolif_Tox clonotypes and show that post-radiation tumors are instead repopulated by regulatory and non-specific clones. Finally, TIL depletion correlates with radiorecurrent disease after conventional radiation, emphasizing the potential impact of radiation-induced TIL loss regardless of fractionation. Thus, this study provides key insights into radiotherapy-induced alterations in the immune microenvironment that drive immunologic radioresistance and proposes restoring tumor antigen-specific T cell clonotypes as a strategy to improve radioimmunotherapy responses in HNSCC. Combining radiation therapy (RT) with immunotherapy has had limited therapeutic benefits in the treatment of head and neck cancer (HNSCC). Here, the authors present a multi-omics analysis of patient biopsies pre- and post- hypofractionated RT and uncover RT-mediated depletion of tumor-reactive CD8+ T cells as the underlying cause of immunologic radioresistance in HNSCC.

Background Among patients with localized pancreatic cancer (PC), the benefit of adjuvant therapy after neoadjuvant therapy and surgery is unknown. Methods Patients with localized PC who completed all intended neoadjuvant therapy and surgery were categorized based on the receipt of adjuvant therapy and by pathologic lymph node status (LN − /LN + ). Results Data was available from 234 consecutive patients, 121 (52%) with resectable and 113 (48%) with borderline resectable PC. Of the 234 patients, 92 (39%) were LN + and 142 (61%) were LN − . The median overall survival (OS) for the 234 patients was 39 months, 42.3 months for patients who received any adjuvant therapy and 34.1 months for those who did not ( p  = 0.29). Of the 92 LN + patients, the median OS with and without adjuvant therapy was 29.5 and 23.2 months, respectively ( p  = 0.02). Of the142 LN − patients, the median OS was 45 months with or without adjuvant therapy ( p  = 0.86). In an adjusted hazard model, additional adjuvant therapy had a significant protective effect among LN + patients (HR 0.39; 95% CI 0.21–0.70; p  = 0.002) but not in LN − patients (HR 0.89; 95% CI 0.53–1.52; p  = 0.68). Conclusion Among patients with localized PC who received neoadjuvant therapy and surgery, the benefit of adjuvant therapy was limited to those with node-positive disease.

Stensen’s duct carcinoma (StDC) is an extremely rare neoplasm, with fewer than 40 cases reported in the literature. We report a unique case of primary StDC with papillary features and intestinal differentiation of a 74-year-old male. We discuss the radiologic and pathologic correlation along with the differential diagnosis of this rare entity.

Objectives: Although oropharyngeal neoplasia can often lead to dysphagia, salivary gland tumors rarely grow within the tongue base. We present the case of a 75-year-old man with adenoid cystic carcinoma of the base of the tongue causing profound dysphagia and weight loss, and provide a current literature review and update on the management of these rare tumors. Methods: We present a case report and a literature review. Results: Physical examination performed at the initial visit revealed a firm right base-of-tongue mass with no palpable lymphadenopathy. Flexible fiberoptic laryngoscopy confirmed a large submucosal mass at the right base of the tongue that obscured the right vallecula. Histopathologic analysis of the operative biopsy specimens revealed the classic features of adenoid cystic carcinoma. Treatment included radical pharyngotomy with wide local excision and primary closure, followed by postoperative radiation treatment. Conclusions: We demonstrate the clinical examination findings and histopathologic characteristics of this disease, and review the literature for clinical treatment recommendations for this rare cause of dysphagia.

Abstract Background Second opinion review of pathology cases can identify diagnostic errors that impact patient care. Objective We sought out to determine discrepancy rates and clinical impact of review of pathology cases to reassess our policy of review on all second opinion cases. Methods All second opinion pathology cases over 1 year (2018) were retrospectively reviewed for discrepancy, multiple pathologist review and clinicopathologic features via chart and slide review. Cases were categorized as no significant discordance, major discordance without management change and major discordance with management change. Results Among 4239 second opinion cases, 3.7% (156/4239) had major discordance with no change in management and 1% (42/4239) had major discordance with change in management. Discordance was significantly associated with multiple pathologist review at our institution (P < 0.001). Highest rates of discordance were observed for thyroid fine needle aspiration (15.3%, 26/170), tissue biopsy of bone/soft tissue (9.6%), endocrine (8.8%), genitourinary (6.7%), gynecologic (6.2%), hematopathology (4%), gastrointestinal/liver (3.7%) and thoracic (3%) sites. Conclusions Our study showed a 1% major discordance rate with resulting significant change in clinical management, spread across nearly all subspecialties. Thus, we support recommendations for review of relevant outside pathology material for all patients for which review has the potential to illicit management change such as instituting a major medical or surgical therapy.