Stromal Reaction Research Articles

Histopathological categorization of desmoplastic reaction in gallbladder carcinoma: its relation to cancer invasiveness and prognostic utility

BackgroundDesmoplastic changes in a tumor have been observed to affect the tumor microenvironment, leading to both the facilitation and prevention of tumor invasiveness.MethodsBetween 2016 and 2020, a total of 120 patients were diagnosed with gallbladder carcinoma. The cases were reviewed for the type of desmoplastic reaction, tumor grade, and stage. The type of desmoplastic reaction was classified as mature, intermediate, and immature, and they were correlated with tumor grade and stage.ResultsOut of the total number of cases, 21.67%, 48.33%, 25%, and 5% belonged to stages 1, 2, 3, and 4, respectively. A total of 79.2% of these cases showed desmoplastic stromal reaction, and there was a significant correlation (p < 0.05) between the type of desmoplasia and tumor grade and stage. The occurrence of immature stroma was correlated with increasing tumor grade and stage, and occurrence of mature stroma was negatively correlated with increasing tumor grade and stage.ConclusionThe assessment of the type of stromal desmoplastic reaction in primary gallbladder carcinoma can predict the tumor invasiveness.

Abstract 5447: Artificial intelligence (AI)-based classification of stromal subtypes reveals associations between stromal composition and prognosis in NSCLC

Abstract Background: Many cancers are known to involve a desmoplastic stromal reaction. While cancer-associated stroma (CAS) has long been appreciated histologically, single-cell molecular analyses have revealed its heterogeneity, and the cellular composition of CAS has been linked to prognosis in several cancer types, including NSCLC. While pathologists have sought to manually classify CAS based on collagen architecture or nuclear density, this approach has not sufficiently captured the heterogeneity of CAS. To this end, we have developed an artificial intelligence (AI)-based model to predict stromal composition in NSCLC from hematoxylin and eosin (H&amp;E)-stained tissue Methods: We developed a convolutional neural network-based model to classify CAS as immature, mature, densely inflamed, densely fibroblastic, or elastosis. This model was trained using manual pathologist-derived annotations (N=3019) of H&amp;E-stained whole slide images (WSIs) of PDAC obtained from the TCGA (N=126). This stromal subdivision model was deployed on H&amp;E-stained LUAD (N=468) and LUSC (N=430) WSIs. Model performance was assessed by qualitative review by expert pathologists. Human interpretable features (HIFs) were extracted from the stromal subdivision model (e.g., proportional area of mature relative to total stroma) and were assessed to identify associations with overall survival (OS) using univariate Cox regression analysis after adjusting for age, sex, and tumor stage. Results: The stromal subdivision model successfully predicted areas of immature, mature, densely inflammatory, and densely fibrotic stroma, as well as elastosis, in LUAD and LUSC. In LUAD, higher combined proportional areas of mature and fibroblastic stroma relative to total cancer stroma was associated with poor OS (p=0.007), while higher combined proportional areas of densely inflamed stroma and elastosis relative to total cancer stroma was associated with improved OS (p=0.007). These findings were validated by stratified tertile analysis based on the corresponding risk direction. Notably, while the average stromal compositions did not differ significantly between NSCLC subtypes, the stromal HIFs were only prognostic in LUAD but not in LUSC. Conclusions: We developed a first of its kind model to characterize CAS subtypes in NSCLC tissue. Features extracted from this model are related to prognosis in LUAD, but not in LUSC, further confirming the importance of CAS to tumor biology and the importance of considering histologic subtypes. Work is ongoing to identify relationships between stromal HIFs and treatment response in NSCLC as well as other cancer indications. Citation Format: Fedaa Najdawi, Sandhya Srinivasan, Neel Patel, Michael G. Drage, Christian Kirkup, Chintan Parmar, Jacqueline Brosnan-Cashman, Michael Montalto, Andrew H. Beck, Archit Khosla, Ilan Wapinski, Ben Glass, Murray Resnick, Matthew Bronnimann. Artificial intelligence (AI)-based classification of stromal subtypes reveals associations between stromal composition and prognosis in NSCLC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5447.

Peritumoral and Intratumoral Lymphocytic Infiltration and Stromal Reaction in High-Risk Endometrioid Carcinomas

Peritumoral and Intratumoral Lymphocytic Infiltration and Stromal Reaction in High-Risk Endometrioid Carcinomas

Basaloid Squamous Cell Carcinoma of Cervix – A Rare Case Report

Basaloid squamous carcinoma of the uterine cervix is a rare tumor type characterized by an ulcerated, infiltrating growth pattern; nests or cords of small basaloid cells; prominent peripheral palisading of cells in the tumor cell nests; and the absence of significant stromal reaction. The characteristic microscopic features are nests, lobules, trabeculae and groups of round to oval basaloid tumor cells. These tumor cells are small with high nuclear cytoplasmic ratio and shows peripheral palisading. There may be areas of comedo type necrosis and areas showing typical squamous cell carcinoma differentiation.

Immunosuppressive microenvironment improvement and treatment of aggressive malignancy pancreatic ductal adenocarcinoma based on local administration of injectable hydrogel

Pancreatic cancer, particularly pancreatic ductal adenocarcinoma (PDAC), is among the most devastating solid malignancies globally owing to the lack of effective therapies, which is characterized by a profuse fibrotic stromal reaction, hypoxia, and an immunosuppressive microenvironment. Although immunotherapy shows tremendous clinical benefits for the management of solid tumors, to date, immunotherapy has largely failed to produce significant improvements in PDAC survival. Thus, the strategy that specifically targets the complicated immunosuppressive tumor microenvironment (TME) and immune-related therapeutic resistance in PDAC is an urgent need. Photothermal immunotherapy, which combines “local tumor hyperthermia” with “immune remodeling”, is an effective modality for PDAC treatment. This study develops an injectable peptide-based hydrogel for integration with near-infrared photothermal pigment (biliverdin, (BV)) and a clinically approved immunomodulatory peptide (thymopentin, (TP5)) for local PDAC administration and treatment. The tumors are efficiently ablated using local photothermal therapy. Moreover, the immune response in vivo is correspondingly activated to transform “cold” TME into “hot” TME by improving T-cell infiltration and alleviating tumor hypoxia, thus effectively inhibiting tumor recurrence and metastasis. The strategy developed in this study provides a potent method for the treatment of relapsed and refractory pancreatic malignancies with a poor immune response.

Biliary Atresia Remnants Revisited: Myogenesis, Hepatic Duct-Like Structures, and Fate of Peribiliary Glands.

Proximal levels of excised remnants from youngest infants may reveal early features of biliary atresia (BA). A targeted IHC survey was applied to 34 most proximal 2 levels in 17 BA remnants excised at age 10-74 days including 7 = <30 days old and 6 control hepatic ducts (HD). Severity of inflammation and extent of active fibroplasia do not distinguish proximal remnants in younger (n = 7) and older (n = 10) infants. In 27/34 levels of 14/17 remnants, reactive stroma is focally SM-MHC-2 (+), marking smooth muscle myosin, termed reactive myogenesis (RM), that is absent in controls. RM facilitates identification of 3 novel hepatic duct remnants (HDR): an HD-like collagen collar lined by degenerating cholangiocytes (n = 5); erosion defects in loose reactive stroma (n = 14); solitary foci of hyperplastic squamoid epithelium (n = 4). Peribiliary glands are either hyperplastic or atretic and typically lack RM. Minimally inflammed end-stage lesions in BA remnants occur at youngest ages favoring prenatal onset. Three novel HDR are defined. RM, a useful surrogate for HDR, is a prevalent inappropriate stromal reaction in proximal remnants of uncertain biological significance. RM is the source of mature smooth muscle in BA remnants.

Does the Expression of Vascular Endothelial Growth Factor (VEGF) and Bcl-2 Have a Prognostic Significance in Advanced Non-Small Cell Lung Cancer?

Lung cancer is the most common cause of mortality from malignant tumors worldwide. The five-year survival rate for people with advanced stages varies considerably, from 35.4% to 6.9%. The angiogenic potential of bcl2 is not well known, nor is the way in which tumor cells with excessive bcl2 expression affect VEGF production. Hypothetically, given that tumor growth, progression and metastasis are dependent on angiogenesis, the antiapoptotic effect is expected to form a link between these two molecules. The aim of this study was to evaluate the relationship between bcl-2 and VEGF expression, clinicopathological features and survival in 216 patients with advanced NSCLC. Archival tumor tissues were examined by immunohistochemistry for the expression of bcl-2 and VEGF. Immunoreactivity for bcl-2 was observed in 41.4% of NSCLCs, 51% of squamous and 34.8% of adenocarcinomas-expressed Bcl-2. There was an inverse correlation of mononuclear stromal reaction and bcl-2 expression in adenocarcinoma (p < 0.0005). A total of 71.8% NSCLCs were VEGF positive, 56% of squamous and 82.2% of adenocarcinomas. High level of VEGF expression was significantly associated with histology type (p = 0.043), low histology grade (p = 0.014), clinical stage IV (p = 0.018), smoking history (p = 0.008) and EGFR mutations (p = 0.026). There was an inverse correlation in the expression of Bcl-2 and VEGF in NSCLC patients (p = 0.039, r = -0.163). Two-year survival of patients with unresectable NSCLC was 39.3%, and 50% of patients were alive at 17 months. Our results demonstrated no difference in survival for patients in advanced NSCLC grouped by bcl-2 and VEGF status. Additionally, we observed an inverse correlation in the expression of Bcl-2 and VEGF in NSCLC and mononuclear reaction and bcl-2 expression in adenocarcinomas.

Intratumour Fusobacterium nucleatum and immune response to oesophageal cancer.

Experimental evidence suggests a role of intratumour Fusobacterium nucleatum in the aggressive behaviour of gastrointestinal cancer through downregulating anti-tumour immunity. We investigated the relationship between intratumour F. nucleatum and immune response to oesophageal cancer. Utilising an unbiased database of 300 resected oesophageal cancers, we measured F. nucleatum DNA in tumour tissue using a quantitative polymerase chain reaction assay, and evaluated the relationship between the abundance of F. nucleatum and the densities of T cells (CD8 + , FOXP3 + and PDCD1 + ), as well as lymphocytic reaction patterns (follicle lymphocytic reaction, peritumoural lymphocytic reaction, stromal lymphocytic reaction and tumour-infiltrating lymphocytes) in oesophageal carcinoma tissue. F. nucleatum was significantly and inversely associated only with the peritumoural lymphocytic reaction (P = 0.0002). Compared with the F. nucleatum-absent group, the F. nucleatum-high group showed a much lower level of the peritumoural lymphocytic reaction (univariable odds ratio, 0.33; 95% confidence interval, 0.16-0.65; P = 0.0004). A multivariable model yielded a similar finding (multivariable odds ratio, 0.34; 95% confidence interval 0.16-0.69; P = 0.002). Intratumour F. nucleatum is associated with a diminished peritumoural lymphocytic reaction, providing a platform for further investigations on the potential interactive roles between intratumour F. nucleatum and host immunity.

The Token Transition-Minimal Deviation AdenocarcinomaUterine Cervix

Gastric type adenocarcinoma is a high grade, frequently discerned mucinous adenocarcinoma with gastric differentiation incriminating the endocervical canal. Of obscure aetiology, neoplasm depicts STK11 genetic mutations with chromosome 3q gain and chromosome 1p loss. Tumefaction exhibits cytological and histological features of gastric differentiation as tumour cells incorporated with voluminous, clear or pale, foamy, eosinophilic cytoplasm, tall, abundant, apical mucin, miniature, spherical, elliptical or enlarged, basal nuclei, irregular, vesicular chromatin and prominent nucleoli. The well differentiated neoplasm is comprised of well defined glandular articulations and minimal to absent stromal desmoplastic reaction. Neoplastic glands of variable outline, magnitude and irregular or claw-like glandular contour are observed. Tumour cells appear immune reactive to HIK1083, MUC6, p53, carcinoembryonic antigen (CEA) or mCEA, CK7, PAX8, CAIX or HNF-1B. Minimal deviation adenocarcinoma requires segregation from neoplasms such as human papillomavirus (HPV) associated endocervical adenocarcinoma, human papillomavirus (HPV) associated endocervical adenocarcinomas intestinal(goblet cell) type, clear cell adenocarcinoma, invasive stratified mucin producing adenocarcinoma, metastatic gastric or pancreaticobiliary carcinoma, lobular endocervical glandular hyperplasia, atypical lobular endocervical glandular hyperplasia, diffuse laminar endocervical glandular hyperplasia, tunnel clusters, florid deep glands, microglandular hyperplasia, pseudo-infiltrative tubal metaplasia, endocervicosis, endosalpingosis or endocervical type adenomyoma. Minimal deviation adenocarcinoma can be adequately categorized upon histological examination of tissue obtained with surgical sampling. Stage I tumours may be managed with surgical procedures as trachelectomy or radical hysterectomy and regional lymphadenectomy upon initial disease representation

ROLE OF STROMAL MICROENVIRONMENT IN THE FORMATION OF INVASIVE, ANGIOGENIC, AND METASTATIC POTENTIAL OF ENDOMETRIOID CARCINOMA OF ENDOMETRIUM.

Histological preparations of ECE samples (n = 51) were analyzed. Expression of CXCL2 and CXCR4 antigens in tumor cells, the content of CXCL12+ fibroblasts and CD163+ macrophages, and the density of microvessels were determined by the immunohistochemical method. Groups of ECE with desmoplastic and inflammatory stromal reactions were delineated. The majority (80.0%) of tumors with desmoplasia were of low differentiation grade, deeply invading the myometrium; 65.0% of patients with these tumors were at stage III of the disease. In ECE cases of stages I-II, 77.4% of ECE showed an inflammatory type of stroma. The high angiogenic and invasive potential of EC of stages I-II was associated with an inflammatory stromal type, high counts of CD163+ macrophages and CXCL12+ fibroblasts in the tumor microenvironment, high expression of the chemokine receptor CXCR4, and reduced expression of its ligand CXCL12 in tumor cells. In the majority of EC of stage III, the increase in angiogenic, invasive, and metastatic potential was accompanied by the presence of desmoplastic stroma, increased expression of CXCR4 in tumor cells, and a high count of CXCL12+ fibroblasts. The obtained results showed that the morphological architecture of the stromal ECE component is related to the molecular features of its constituents and tumor cells. Their interaction modulates the phenotypic characteristics of ECE associated with the degree of malignancy.

Nested Subtype of Urothelial Carcinoma in the Upper Urinary Tract: A Series of 15 Cases.

Nested subtype of urothelial carcinoma (NVUC) of the upper urinary tract is rare. While this subtype has an aggressive behavior in the urinary bladder, little is known about this subtype in the renal pelvis and ureter. In addition, due to NVUC's bland morphology and resemblance to von Brunn nests proliferation, which can be florid in the renal pelvis and ureter, establishing a diagnosis of NVUC in these sites can be difficult, especially on small biopsies. Nineteen cases of NVUC of the renal pelvis and the ureter were identified. One was in-house and 18 cases were sent to the genitourinary pathology consult service. Four cases were excluded due to difficulty in obtaining the slides from other institutions. In all, 8/15 (53.33%) cases showed large nested morphology, 4/15 (26.66%) cases showed mixed large and small nested morphology, and only 3/15 (20%) cases showed predominantly small nested morphology. In all cases, the invasive component was pure nested subtype, and tumors were all unifocal. In 8/15 cases, there was the presence of an overlying low-grade papillary urothelial carcinoma. An associated desmoplastic stromal reaction was none/minimal in 12/15 (80%) cases, with a prominent reaction in the remaining 3/15 (20%) cases. Pathologic stages for the resections were pT1 (n=1), pT2 (n=3), pT3 (n=8), and pT4 (n=1). There was only 1 case with a lymph node metastasis at the time of resection who had pT4 disease. Follow-up was available in 10/15 cases, 7/10 cases showed no recurrences or metastases, and the remaining 3/10 cases later developed urothelial carcinoma of the bladder. In 5/15 cases, follow-up could not be obtained. Similar to NVUC in the urinary bladder, NVUC in the upper tract typically lacks an associated desmoplastic reaction and has by definition bland cytology. In contrast to NVUC of the urinary bladder, NVUC in the upper urothelial tract is: (1) more frequently associated with an overlying papillary urothelial carcinoma; (2) more commonly has a large nested pattern; and (3) appears to behave less aggressively.

Uncoupling protein 2 deficiency of non-cancerous tissues inhibits the progression of pancreatic cancer in mice

BackgroundPancreatic ductal adenocarcinoma (PDAC) is a disease of the elderly mostly because its development from preneoplastic lesions depends on the accumulation of gene mutations and epigenetic alterations over time. How aging of non-cancerous tissues of the host affects tumor progression, however, remains largely unknown. MethodsWe took advantage of a model of accelerated aging, uncoupling protein 2-deficient (Ucp2 knockout, Ucp2 KO) mice, to investigate the growth of orthotopically transplanted Ucp2 wild-type (WT) PDAC cells (cell lines Panc02 and 6606PDA) in vivo and to study strain-dependent differences of the PDAC microenvironment. ResultsMeasurements of tumor weights and quantification of proliferating cells indicated a significant growth advantage of Panc02 and 6606PDA cells in WT mice compared to Ucp2 KO mice. In tumors in the knockout strain, higher levels of interferon-γ mRNA despite similar numbers of tumor-infiltrating T cells were observed. 6606PDA cells triggered a stronger stromal reaction in Ucp2 KO mice than in WT animals. Accordingly, pancreatic stellate cells from Ucp2 KO mice proliferated at a higher rate than cells of the WT strain when they were incubated with conditioned media from PDAC cells. ConclusionsUcp2 modulates PDAC microenvironment in a way that favors tumor progression and implicates an altered stromal response as one of the underlying mechanisms.

Cancer-Associated Fibroblasts Induce Proliferation and Therapeutic Resistance to Everolimus in Neuroendocrine Tumors through STAT3 Activation

Introduction: Cancer-associated fibroblasts (CAF) have been identified as relevant contributors to cancer progression and drug resistance in many tumors. Although neuroendocrine tumors (NET) are often associated with a strong stromal reaction, no study has addressed whether CAF are involved in progression and therapeutic resistance in NET. The aim of this study was to characterize the role of CAF in NET. Methods: We established primary CAF cultures derived from NET liver metastases to study the effect on NET cell lines NT-3 and BON. Immunohistochemistry was performed on tissue sections of primary and metastatic NET tissue. Results: Immunohistochemistry identified CAF dispersed in between tumor cells and within fibrotic bands separating tumor cell clusters in NET. Stimulating NET cells with CAF decreased expression of SSTR2 and chromogranin A and induced expression of CXCR4. CAF induced a 2.3-fold increase in proliferation and completely reversed the response to everolimus in NT-3 cells. We identified STAT3 as the main signaling pathway induced by CAF. STAT3 targeting by small interfering RNA knockdown and inhibitors prevented CAF-induced proliferation and restored everolimus responsiveness. STAT3 activation in NET tissue was associated with decreased chromogranin A expression, increased Ki-67 index, and decreased 5-year overall and progression-free survival. CAF directly influence proliferation and therapeutic response in NET cells. Conclusion: Identifying STAT3 as the contributing pathway of this so far neglected tumor-stroma interaction has the potential to become a new therapeutic target to halt tumor growth and to restore therapeutic responsiveness in NET.

Prognostic value of desmoplastic stromal reaction, tumor budding and tumor-stroma ratio in stage II colorectal cancer

Existing high-risk factors are insufficient to accurately predict the postoperative recurrence risk of stage II colorectal cancer (CRC). The discovery of additional prognostic markers may be the key to improving the current status of stage II CRC treatment. The present study aimed to evaluate the relationship among desmoplastic reaction (DR), tumor budding (TBd), the tumor-stroma ratio (TSR) and their prognostic value for relapse-free survival (RFS). In this study, 207 patients with histologically confirmed stage II CRC from January 2012 to August 2018 were retrospectively reviewed from a single center; the cohort was divided into subgroups based on low or high TSR, and low, intermediate or high DR and TBd. Kaplan-Meier curve analysis and log-rank test were applied to examine RFS among subgroups. Univariate and multivariate Cox proportional hazards analyses were used to identify independent factors associated with RFS, and a nomogram was subsequently developed. Abnormal CA242, CEA, T4 stage, presence of hypertension, internal obstruction or perforation (IOP), lymphovascular or/and perineural invasion (PNI), number of nodes examined less than 12, low-frequency microsatellite instability (MSI-L), higher Ki-67 and immature DR were associated with a lower RFS. In multivariable analysis, DR (HR =2.111; 95% CI: 1.184-3.766; P=0.011), LVI (HR =1.919; 95% CI: 1.004-3.669; P=0.049) and PNI (HR =2.724; 95% CI: 1.362-5.448; P=0.005) were prognostic factors for RFS. On this basis, a nomogram that integrated DR and clinicopathologic predictors for predicting RFS passed the calibration and had an area under the curve of 0.826. The prognostic significance of DR outperformed TBd and TSR, therefore, we recommend adding DR as a biomarker in routine pathological reports. The novel nomogram combining these factors may be used as a reliable and effective tool for the prediction of RFS in stage II CRC, thus helping optimize therapeutic regimens under cooperation of oncologists and surgeons. Further multicentric studies are required for validation of this novel, simple and cost-effective prognostic model.

Abstract C064: Prognostic impact of an immunomorphological signature integrating immune, fibroblast and tumor markers in a series of 217 patients operated on for pancreatic adenocarcinoma

Abstract An integrative approach taking into consideration the tumor microenvironment, in particular cancer-associated fibroblasts (CAFs) and tumor-infiltrating lymphocytes (TILs) and its interaction with tumor cells offers a more precise reflect of pancreatic ductal adenocarcinomas (PDACs) biology. In this setting, an immunomorphological signature established from bioinformatics data could thus represent an attractive approach. Moreover to molecular signatures, on which there is still no consensus. This study aimed to evaluate the prognostic value of a panel of morphological and immunohistochemical (IHC) markers on the immune, fibroblastic and epithelial contingents of PDACs for overall (OS) and relapse-free (RFS) survival. Two hundred and seventeen patients operated for PDAC between 2000 and 2017 were included for a tissue microarray (TMA) analysis. A panel of antibodies and special stains was selected based on a previous bioinformatics study (under review) literature data. Slides were digitized and lymphocytes expressing CD3, CD8 and CD20 were quantified. A pixel classifier was used to assess the percentage of collagen and fibroblasts expressing anti-LRRC15, HSP47, α-SMA and FAP antibodies involved in the stroma reaction. Due to the co-marking of stromal and epithelial cells of PTK7 and β-catenin, respectively implicated in embryogenesis and the canonical Wnt pathway, these markers were interpreted semi-quantitatively in a double-blind fashion. After dichotomization using the maximized log-rank method, the association of these parameters with OS and RFS was assessed by univariate and multivariate Cox models. Five years after surgical resection, 26 patients (12.0%) were free of recurrence and 56 (25.8%) were alive. In multivariate analysis, the following parameters were associated with reduced OS and RFS: poor differentiation, lymph node ratio greater than 0.2, loss of tumor β-catenin on tumor cells, a low density of tumor-infiltrating CD3 T lymphocytes and a high percentage of HSP47 fibroblasts. Reduced OS was also associated with an age greater than 65 years at the time of surgery and the absence of adjuvant treatment. In order to evaluate the joint effects of the three tumor compartments markers independentely related to OS and RFS (β-catenin, HSP47, CD3), we grouped them into 3 classes (0/1+, 2+, 3+) according to the number of good prognosis criteria (class 3+ with the greatest number of good prognosis criteria). The multivariate analysis shows an additive effect of these parameters in OS and RFS compared to class 3+ patients. These data underline the interest of simultaneously characterizing the three epithelial, immune and fibroblastic compartments in PDAC. Furthermore, we highlight for the first time the prognostic impact of HSP47 by immunohistochemistry and confirm the β-catenin one. This tissue approach with an IHC panel studied on an operating specimen could be a first step towards applicability on biopsies and lead to a better patient stratification in a therapeutic setting. Citation Format: Franck Monnien, Chloé Molimard, Marine Abad, Marie-Paule Algros, Sophie Félix, Nikolaus Zirganos, Bruno Heyd, Angélique Vienot, Christophe Borg, Frédéric Bibeau. Prognostic impact of an immunomorphological signature integrating immune, fibroblast and tumor markers in a series of 217 patients operated on for pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C064.

Abstract IA019: Stromal-epithelial co-evolution and complicity in pancreas cancer

Abstract The robust desmoplasia of PDA is its distinguishing feature and non-malignant components constitute the bulk of the tumor mass. This stromal reaction includes myofibroblasts, inflammatory fibroblasts, endothelial cells, pericytes, and various immune-cell subsets, all embedded within a dense and complex extracellular matrix (ECM). Dominated by non-malignant cells, the mutated epithelium must therefore combat, cooperate with, or coopt the surrounding cells and signaling processes in its microenvironment. It is proposed that an invasive PDA represents the coordinated evolution of malignant and non-malignant cells and mechanisms that subvert and repurpose the dictums of normal tissue composition, architecture, and physiology to foster tumorigenesis. The detailed kinetics and stepwise construction of the pancreas cancer neo-organ suggest that it is governed by a discrete set of organizing rules and principles – and repeated attempts to target its specific components reveal self-regulating mechanisms of resistance. Indeed, many of these cells arise and operate at the behest of oncogenic KRAS, the signature genetic mutation in PDA. These cells, in turn, support and shape the evolving malignancy. It is frequently debated in pancreas and other cancers whether the stroma is “good” or “bad”, tumor-constraining or tumor-promoting. However, because the stroma is neither static nor monolithic, the question is misguided. The stroma is more nuanced: some elements overtly accelerate, and others attenuate, disease progression but most of the cells and processes found in an evolving pancreas cancer are adaptive at some point during its development. In the end, these elements collectively conspire to create a drug- and immune-privileged sanctuary for PDA progression. To fully overcome the extraordinary resistance of this formidable cancer will require parsing the myriad interactions and interdependencies among the various stromal elements and the epithelial PDA cell. Understanding how to combine strategies against these distinct components and processes – which ones to target, in what order and for how long – will be critical, and perhaps necessary, for success and to avoid making matters worse. Citation Format: Sunil R. Hingorani. Stromal-epithelial co-evolution and complicity in pancreas cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr IA019.

The heterogeneity of cancer-associated fibroblast subpopulations: Their origins, biomarkers, and roles in the tumor microenvironment.

The prognosis for patients with cancers known for a highly activated stromal reaction, including diffuse-type (scirrhous) gastric cancer, consensus molecular subtype 4 (CMS4) colorectal cancer, and pancreatic ductal adenocarcinoma, is extremely poor. To explore the resistance of conventional therapy for those refractory cancers, detailed classification and investigation of the different subsets of cancer-associated fibroblasts (CAFs) involved are needed. Recent studies with a single-cell transcriptomics strategy (single-cell RNA-seq) have demonstrated that CAF subpopulations contain different origins and marker proteins with the capacity to either promote or suppress cancer progression. Through multiple signaling pathways, CAFs can promote tumor growth, metastasis, and angiogenesis with extracellular matrix (ECM) remodeling; they can also interact with tumor-infiltrating immune cells and modulate the antitumor immunological state in the tumor microenvironment (TME). Here, we review the recent literature on the various subpopulations of CAFs to improve our understanding of the cell-cell interactions in the TME and highlight future avenues for CAF-targeted therapy.

Expression Pattern of Tenascin-C, Matrilin-2, and Aggrecan in Diseases Affecting the Corneal Endothelium.

Purpose: The aim of this study was to examine the expression pattern of tenascin-C, matrilin-2, and aggrecan in irreversible corneal endothelial pathology such as pseudophakic bullous keratopathy (PBK) and Fuchs’ endothelial corneal dystrophy (FECD), which most frequently require corneal transplantation. Materials and methods: Histological specimens of corneal buttons removed during keratoplasty were investigated in PBK (n = 20) and FECD (n = 9) and compared to healthy control corneas (n = 10). The sections were studied by chromogenic immunohistochemistry (CHR-IHC) and submitted for evaluation by two investigators. Semiquantitative scoring (0 to 3+) was applied according to standardized methods at high magnification (400x). Each layer of the cornea was investigated; in addition, the stroma was subdivided into anterior, middle, and posterior parts for more precise analysis. In case of non-parametric distribution Mann–Whitney test was applied to compare two groups. Kruskal–Wallis and Dunn’s multiple comparisons tests have been applied for comparison of the chromogenic IHC signal intensity among corneal layers within the control and patient groups. Differences of p < 0.05 were considered as significant. Results: Significantly elevated tenascin-C immunopositivity was present in the epithelium and every layer of the stroma in both pathologic conditions as compared to normal controls. In addition, also significantly stronger matrilin-2 positivity was detected in the epithelium; however, weaker reaction was present in the endothelium in PBK cases. Minimal, but significantly elevated immunopositivity could be observed in the anterior and posterior stroma in the FECD group. Additionally, minimally, but significantly higher aggrecan immunoreaction was present in the anterior stroma in PBK and in the posterior stroma in both endothelial disorders. All three antibodies disclosed the strongest reaction in the posterior stroma either in PBK or in FECD cases. Conclusions: These extracellular matrix molecules disclosed up to moderate immunopositivity in the corneal layers in varying extents. Through their networking, bridging, and adhesive abilities these proteins are involved in corneal regeneration and tissue reorganization in endothelial dysfunction.

Proliferative lesions with mesonephric features in the gynecologic tract: a clinicopathological analysis of sixteen cases

Objective: To investigate the clinicopathological features of proliferations with mesonephric features (PMF) of the gynecologic tract. Methods: A retrospective analysis was performed on the clinical and pathological data of 16 cases with PMF that were diagnosed from October 2016 to January 2022 at a single institution. The relevant literature was reviewed. Results: Among the 16 cases, with an average of 53 years (31-68 years), there were 5 cases of mesonephric hyperplasia, 4 cases of mesonephric adenocarcinoma and 7 cases of mesonephric-like adenocarcinoma. The five cases of mesonephric hyperplasia were located in the lateral wall of the cervix and composed of simple tubules with growth patterns of diffuse or lobular clusters, without obvious stromal reaction. Four cases of mesonephric adenocarcinoma consisted of a mixture of papillary, cribriform, solid and other architectures, the nuclei resembling these of papillary thyroid carcinoma, and strong fibroproliferative reaction. They were located deep in the cervical and vaginal stroma. One of the tumors showed atypical mesonephric hyperplasia adjacent to the tumor. Five uterine and two ovarian mesonephric-like adenocarcinoma cases had similar histological morphology with mesonephric adenocarcinoma, but no mesonephric remnants/mesonephric hyperplasia were found near the tumors. In addition, four (4/5) uterine mesonephric-like adenocarcinoma cases originated from the endometrium with secondary involvement of myometrium, including one case with clear demarcation between the normal endometrium and the neoplastic glands. One (1/5) uterine mesonephric-like adenocarcinoma case was mainly located in the deep myometrium, along with adenomyosis around the tumor, without mesonephric remnants. Two ovarian mesonephric-like adenocarcinoma cases were associated with endometriotic cyst/endometrioid cystadenoma, including one case with an abrupt transition between normal epithelium and atypical mesonephric cells within the single individual cyst directly adjacent to tumor. All mesonephric hyperplasia and mesonephric adenocarcinoma cases were positive for GATA3, PAX8 and CD10 in a varying degree, and negative for ER, PR and TTF1. Although mesonephric-like adenocarcinoma showed a considerable overlap of immunohistochemical expression with mesonephric adenocarcinoma, seven mesonephric-like adenocarcinoma cases were positive for TTF1 and negative for GATA3. Conclusions: PMF is a class of rare proliferative lesions with morphological and immunophenotypic characteristics of mesonephric duct. Its commonly involved site, microscopic morphology, associated benign and/or atypical lesions, and immunophenotype may contribute to its diagnosis and differential diagnosis.

Post therapeutic changes in various malignancies

Background: Neo adjuvant Radiotherapy and chemotherapy can cause significant changes in the gross and microscopic appearance of malignant tissues and normal surrounding tissues. Since radiotherapy is now offered to a large number of cancer patients, pathologists are more frequently presented with such changes. Both epithelial and stromal changes can be present. Epithelial changes in the form of atrophy, apoptosis, necrosis, dysplasia and neoplasia, while stromal changes the form of fibrosis, exudates, necrosis, pattern of invasion and vessel wall thickness. These changes may interfere with recognition of microscopic residual tumor if present. With increasing use of radiation therapy in cancer treatment and longer survival of patients, assessment of radiation-associated changes in tissues and tumours has become an important issue in modern pathology.Materials and Methods: The present study was carried out on 50 patients. Type of samples includes cytological smears and histopathological specimens received in respective cytopathology and histopathology section of the pathology department after any chemotherapy or radiotherapy.Objective1.To study cyto-morphological changes after chemotherapy and/or radiotherapy. 2.To differentiate secondary malignancy from radiation damage.Results: The present study was carried out on 50 patients including 13 patients with lymph node metastasis,12 cases with head & neck region, 2 scrap smear, 9 anterior chest wall swelling, 3 cases of liver, 5 cases of lung,1 plural fluid and 5 cases of breast. The effects have been divided mainly into two, as pathological changes in tumor cells and changes in the stroma.Conclusion: It is concluded from the findings of present study that various nuclear abnormalities reveal a statistically significantly increases with increasing chemoradiation doses and time interval. Post neoadjuvant chemotherapy, specimens revealed nuclear enlargement, nuclear shrinkage, necrosis, vacuolation of nucleus, vacuolation of cytoplasm, dyscohesion, and shrinkage of tumor cells with nuclear changes of nonviability like karyorrhexis, karyolysis, and pyknosis. Stromal reactions manifested as fibrosis, elastosis, collagenization, hyalinization, microcalcification, and neovascularization. Areas of necrosis included both vascular and avascular pattern. The stroma also revealed fibrinoid necrosis and mucinous change. Hyalinization of the blood vessel wall was a common finding.