Summary We report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCC/PGLs), a rare tumor type. Multi-platform integration revealed that PCC/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically-mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, NF1). We also discovered fusion genes in PCC/PGL, involving MAML3, BRAF, NGFR and NF1. Integrated analysis classified PCC/PGLs into four molecularly-defined groups: a kinase signaling subtype, a pseudohypoxia subtype, a Wnt-altered subtype, driven by MAML3 and CSDE1, and a cortical admixture subtype. Correlates of metastatic PCC/PGL included the MAML3 fusion gene. This integrated molecular characterization provides a comprehensive foundation for developing PCC/PGL precision medicine.
BackgroundPatient-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.MethodsWe 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.ResultsWe 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.ConclusionsThese 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.
Context.— 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. Objective.— 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. Data Sources.— The review and analysis of the latest literature describing pancreatic cystic lesions. Conclusions.— 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.
Historically, heart, liver, and kidney biopsies were performed to demonstrate amyloid deposits in amyloidosis. Since the clinical presentation of this disease is so variable and non-specific, the associated risks of these biopsies are too great for the diagnostic yield. Other sites that have a lower biopsy risk, such as skin or gingival, are also relatively invasive and expensive. In addition, these biopsies may not always have sufficient amyloid deposits to establish a diagnosis. Fat pad aspiration has demonstrated good clinical correlation with low cost and minimal morbidity. However, there are no standardized protocols for performing this procedure or processing the aspirated specimen, which leads to variable and nonreproducible results. The most frequently utilized modality for detecting amyloid in tissue is an apple-green birefringence on Congo red stained sections using a polarizing microscope. This technique requires cell block preparation of aspirated material. Unfortunately, patients presenting in early stage of amyloidosis have minimal amounts of amyloid which greatly reduces the sensitivity of Congo red stained cell block sections of fat pad aspirates. Therefore, ultrastructural evaluation of fat pad aspirates by electron microscopy should be utilized, given its increased sensitivity for amyloid detection. This article demonstrates a simple and reproducible procedure for performing anterior fat pad aspiration for the detection of amyloid utilizing both Congo red staining of cell block sections and electron microscopy for ultrastructural identification.
Among patients with localized PC who received neoadjuvant therapy and surgery, the benefit of adjuvant therapy was limited to those with node-positive disease.
Background:p16 INK4a (p16) is a well-recognized surrogate molecular marker for human papilloma virus (HPV) related squamous dysplasia. Our hypothesis is that the invasive interventions and related morbidities could be avoided by objective stratification of positive cytologic interpretations by p16 immunostaining of cell block sections of cytology specimens.Materials and Methods:Nuclear immunoreactivity for p16 was evaluated in cell block sections in 133 adequate cases [20 negative for intraepithelial lesion or malignancy, 28 high-grade squamous intraepithelial lesion (HSIL), 50 low-grade squamous intraepithelial lesion (LSIL), 21 atypical squamous cells, cannot exclude HSIL (ASC-H), and 14 atypical squamous cells of undetermined significance (ASCUS)] and analyzed with cervical biopsy results.Results:(a) HSIL cytology (28): 21 (75%) were p16 positive (11 biopsies available — 92% were positive for cervical intraepithelial neoplasia (CIN) 1 and above) and 7 (25%) were p16 negative (3 biopsies available — all showed only HPV with small atypical parakeratotic cells). (b) LSIL cytology (50): 13 (26%) cases were p16 positive (12 biopsies available — all were CIN1 or above) and 37 (74%) were p16 negative (12 biopsies available — all negative for dysplasia. However, 9 (75%) of these biopsies showed HPV). (c) ASC-H cytology (21): 14 (67%) were p16 positive (6 biopsies available — 5 showed CIN 3/Carcinoma in situ/Ca and 1 showed CIN 1 with possibility of under-sampling. Cytomorphologic re-review favored HSIL) and 7 (33%) were p16 negative (5 biopsies available — 3 negative for dysplasia. Remaining 2 cases — 1 positive for CIN 3 and 1 showed CIN 1 with scant ASC-H cells on cytomorphologic re-review with possibility under-sampling in cytology specimen). (d) ASCUS cytology (14): All (100%) were p16 negative on cell block sections of cervical cytology specimen. HPV testing performed in last 6 months in 7 cases was positive in 3 (43%) cases.Conclusion:p16 immunostaining on cell block sections of cervical cytology specimens showed distinct correlation patterns with biopsy results. Reflex p16 immunostaining of cell blocks based on the algorithmic approach to be evaluated by a multiinstitutional comprehensive prospective study is proposed.
Purpose: There is an imperfect correlation between the histology and behavior of solitary fibrous tumor (SFT). In addition, recurrence is common, and dedifferentiation may occur over time. Preferred primary treatment is intact excision, but friable pseudocapsules and tenacious attachments can thwart this goal in the crowded, visually sensitive orbit. This study addresses the fate and appropriate management of incompletely excised orbital SFT. Methods: Among a single surgeon’s 7-case experience with orbital SFT, 3 cases involved incomplete primary excision, either before (2 cases) or after (1 case) referral. We reviewed the clinicopathologic data in these 3 cases, with follow-up intervals of 18, 21, and 52 years after initial presentation. We reviewed the English-language literature on SFT, with special attention to evolving nomenclature, orbital involvement, recurrence, malignant transformation, and management options. Results: Benign versus malignant designations of SFT vary with histological and behavioral criteria. Approximately 150 orbital cases have been reported. Published rates of primary malignancy and recurrence across all histologic categories are 6% to 12% and 30% to 37%, respectively. We identified 43 well-documented recurrences (range, 6 months–33 years; median, 3 years) and 10 cases of histological dedifferentiation (range, 14 months–33 years). Because of SFT’s rarity and needed follow-up intervals, the value of adjuvant therapy is not yet proven. In follow up of 18, 21, and 52 years after initial presentation, our 3 cases with incomplete excision showed either no recurrence (Case 1) or no morphological dedifferentiation (Cases 2, 3). Conclusion: A treatment algorithm is predicated on the completeness of surgical excision and histological features. However, we recommend case-by-case multidisciplinary decisions in a tumor-board setting.
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