Spatially restricted drivers and transitional cell populations cooperate with the microenvironment in untreated and chemo-resistant pancreatic cancer

Pancreatic ductal adenocarcinoma is a lethal disease with limited treatment options and poor survival. We studied 83 spatial samples from 31 patients (11 treatment-naïve and 20 treated) using single-cell/nucleus RNA sequencing, bulk-proteogenomics, spatial transcriptomics and cellular imaging. Subpopulations of tumor cells exhibited signatures of proliferation, KRAS signaling, cell stress and epithelial-to-mesenchymal transition. Mapping mutations and copy number events distinguished tumor populations from normal and transitional cells, including acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia. Pathology-assisted deconvolution of spatial transcriptomic data identified tumor and transitional subpopulations with distinct histological features. We showed coordinated expression of TIGIT in exhausted and regulatory T cells and Nectin in tumor cells. Chemo-resistant samples contain a threefold enrichment of inflammatory cancer-associated fibroblasts that upregulate metallothioneins. Our study reveals a deeper understanding of the intricate substructure of pancreatic ductal adenocarcinoma tumors that could help improve therapy for patients with this disease

Critical histopathological analysis of 25 dedifferentiated liposarcomas, including uncommon variants, reviewed at a Tertiary Cancer Referral Center

Background: De-differentiated liposarcomas (DDLSs) are uncommon tumors with a wide histopathological spectrum. Materials and Methods: Over an 8-year period (2003-2011), 25 DDLSs, after review, were critically analyzed for histopathological features. Results: Twenty-five tumors, in 14 men and 11 women (M: F = 1.2:1), with age range of 22-88 years (mean, 53.9), occurred in retroperitoneum (14) (56%), thigh (3) (12%), paratesticular region (3) (12%), chest wall (2) (8%), leg (1) (4%), shoulder (1) (4%), and groin (1) (4%). Tumor size (21 tumors) varied from 7.5 to 25 cm (mean, 17.5). Histopathologically, DD component was high grade in 19 (76%) and low grade in 6 (24%) tumors. Whereas the most common WD component was adipocytic type; the most common DD component was pleomorphic sarcomatous (13) (52%), followed by myxofibrosarcomatous (MFS)-type (6) (24%). Low-grade DD components included MFS (2), fibrosarcoma (2), myogenic/myofibroblastic type (1), and IMFT-type (1). Three tumors displayed meningothelial-like whorls and metaplastic bone formation. Heterologous elements, noted in 11 (44%) tumors, included bone (8) and rhabdomyoblastic differentiation (2). Two tumors displayed homologous differentiation, reinforced with MDM2 staining. S100-P was diffusely positive in WD components (5/7) and focally in DD components (2/9). All patients were treated with surgery, including 10, who underwent adjuvant radiotherapy. Outcomes (16 patients, 64%), over 1-48 months included 10 patients free of disease, 4 died of disease, and 2 patients alive with disease. Conclusions: This study forms the largest documentation of DDLSs, including its wide histopathological spectrum, from our country. Rare cases overlap with pleomorphic liposarcoma. S100-P and MDM2 are useful in substantiating adipocytic differentiation, especially in selected cases. Analysis of adequate tumor sections is vital for correct identification of a DDLS. Surgical excision with adjuvant RT forms optimal treatment

Peripheral nodular enhancement in adrenal and renal hematomas: A report of 3 cases

There are a wide range of benign and malignant pathologies that the radiologist may encounter in the adrenal glands and kidneys, often incidentally when imaging is performed for other indications. Many imaging modalities including CT, MR, and US are often used in an attempt to characterize these lesions. A definitive radiological diagnosis, however, is not always possible. This is at times due to atypical presentations of typical lesions which may be mistaken for more aggressive or concerning pathologic conditions. Adrenal lesions that do not demonstrate characteristic benign imaging features might require surgical excision. Similarly, cystic renal lesions that demonstrate nodular enhancement are concerning for Bosniak IV lesions and require surgical management. We report 3 cases in 3 different patients of incidentally discovered hematomas with peripheral enhancement, 2 involving the adrenal gland and 1 involving the kidney. All 3 of these histologically proven hematomas demonstrated similar radiological manifestations of peripheral nodular progressive enhancement, mimicking neoplastic conditions, and necessitating surgical removal

Histo-molecular characterization of pancreatic cancer with microsatellite instability: intra-tumor heterogeneity, B2M inactivation, and the importance of metastatic sites

Pancreatic ductal adenocarcinoma (PDAC) with microsatellite instability (MSI)/defective mismatch repair (dMMR) is the only subtype of pancreatic cancer with potential response to immunotherapy. Here, we report the histo-molecular characterization of MSI/dMMR PDAC with immunohistochemistry, MSI-based PCR, and next-generation sequencing. Five paradigmatic cases have been identified. The main results include the first report in pancreatic cancer of MSI/dMMR intra-tumor heterogeneity, the presence of microsatellite-stable metastases from MSI/dMMR primary and recurrent B2M gene inactivation, which may confer resistance to immunotherapy. In addition to the classic PDAC drivers, ARID1A was the most common mutated gene in the cohort. Intra-tumor heterogeneity, B2M inactivation, and metastatic sites should be carefully considered in MSI/dMMR PDAC, which should also be investigated in routine diagnostic practice with specific molecular analysis. The chromatin remodeler ARID1A represents another potential driver gene in this context

Nestin as a diagnostic and prognostic marker for combined hepatocellular-cholangiocarcinoma

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