Pattern Of Tumor Invasion Research Articles

ACANTHOLYTIC SQUAMOUS CELL CARCINOMA MIMICKING PERIAPICAL LESION: AN UNUSUAL CASE

Acantholytic squamous cell carcinoma (aSCC) is a rare and distinctive histologic subtype of squamous cell carcinoma characterized by acantholysis in the cancer nests leading to a pseudoglandular appearance. We describe the case of a 28-year-old female patient with symptomatic swelling in left maxilla. Radiographically, a poorly defined, multilocular, radiolucent lesion was found in the periapical region of teeth 24 and 25. Clinical diagnosis was periapical cyst, and the patient was submitted to incisional biopsy. Histologic feature of the incisional biopsy led to the diagnosis of adenocarcinoma not otherwise specified. The patient was referred to the public oncology center, tumor resection was performed, and the diagnosis of aSCC was established after analysis of the surgical specimen. Because of the high-grade features, poor differentiation, and tumor invasion pattern, the patient died after approximately 3 months from initial diagnosis; aSCC is recognized for its aggressive nature and poor prognosis, especially when it occurs in the oral cavity.

Genomic and Phenotypic Characterization of a Broad Panel of Patient-Derived Xenografts Reflects the Diversity of Glioblastoma.

Glioblastoma is the most frequent and lethal primary brain tumor. Development of novel therapies relies on the availability of relevant preclinical models. We have established a panel of 96 glioblastoma patient-derived xenografts (PDX) and undertaken its genomic and phenotypic characterization. PDXs were established from glioblastoma, IDH-wildtype (n = 93), glioblastoma, IDH-mutant (n = 2), diffuse midline glioma, H3 K27M-mutant (n = 1), and both primary (n = 60) and recurrent (n = 34) tumors. Tumor growth rates, histopathology, and treatment response were characterized. Integrated molecular profiling was performed by whole-exome sequencing (WES, n = 83), RNA-sequencing (n = 68), and genome-wide methylation profiling (n = 76). WES data from 24 patient tumors was compared with derivative models. PDXs recapitulate many key phenotypic and molecular features of patient tumors. Orthotopic PDXs show characteristic tumor morphology and invasion patterns, but largely lack microvascular proliferation and necrosis. PDXs capture common and rare molecular drivers, including alterations of TERT, EGFR, PTEN, TP53, BRAF, and IDH1, most at frequencies comparable with human glioblastoma. However, PDGFRA amplification was absent. RNA-sequencing and genome-wide methylation profiling demonstrated broad representation of glioblastoma molecular subtypes. MGMT promoter methylation correlated with increased survival in response to temozolomide. WES of 24 matched patient tumors showed preservation of most genetic driver alterations, including EGFR amplification. However, in four patient-PDX pairs, driver alterations were gained or lost on engraftment, consistent with clonal selection. Our PDX panel captures the molecular heterogeneity of glioblastoma and recapitulates many salient genetic and phenotypic features. All models and genomic data are openly available to investigators.

Evaluation and Prognostic Significance of Galectin-3 Expression in Oral Squamous Cell Carcinoma.

In squamous cell carcinomas of the oral cavity, factors that can predict prognosis are being studied. However, new prognostic factors are needed to provide information on the biological properties of tumors. Galectin-3 is known to be involved in many biological events such as cell adhesion and differentiation, angiogenesis, apoptosis, tumorigenesis, and metastasis. In our study, the prognostic role of galectin-3 expression in squamous cell carcinomas of the oral cavity was investigated. The study included 60 patients with a diagnosis of squamous cell carcinoma of the oral cavity. The demographic characteristics of the patients were compiled from the patient files. Galectin-3 expression was studied immunohistochemically. Cytoplasmic and nuclear expressions of galectin-3 were evaluated separately. In addition, the total expression score was calculated by multiplying the percentage and intensity scores for each cases. The critical expression score was determined according to the median value of the total scores. Among 60 cases, 28 tumors were located on the lip, 21 on the tongue, 4 on the floor of the mouth, 3 on the orobuccal mucosa, 3 on the retromolar trigone, and 1 on the gingivobuccal junction. There was no statistically significant relationship between prognosis and nuclear or cytoplasmic galectin-3 expression. Tumor grade and invasion pattern were found to be associated with the galectin-3 total expression score. Although galectin-3 total expression score was correlated with the tumor grade and invasion pattern, it is not associated with overall survival or recurrence rates. However, there is a need for a large series of cases in which methods are standardized in order to clarify the prognostic role of galectin-3 expression in oral squamous cell carcinomas.

Prognostic Value of c-Myc Immunohistochemical Expression in Muscle Invasive Urothelial Carcinoma of the Urinary Bladder: A Retrospective Study.

Objective:This study aimed to investigate the immunohistochemical expression of c-Myc in muscle invasive urothelial carcinoma (MIUC) of the urinary bladder and to evaluate the correlation of c-Myc expression with different clinicopathological parameters and outcome, including a relatively new histopathological tumor characteristic that is the growth pattern of tumor invasion. Methods:A total of 66 formalin-fixed and paraffin-embedded sections of MIUC obtained from radical cystectomy specimens were enrolled. The sections were stained with c-Myc antibody using immunohistochemistry technique. Results:Tumor cells showed variability in nuclear c-Myc expression according to the growth pattern of invasion. The median H-score of nuclear expression of infiltrative pattern was significantly higher than that of non-infiltrative pattern (p<0.001). Nuclear expression of c-Myc in tumor tissue had a significant association with poor prognostic factors (sarcomatoid variant (p<0.001), perineural invasion (p=0.037), lymphovascular invasion (p<0.001), lymph node metastasis (p<0.001), distant metastasis (p=0.042) and advanced stage grouping (p=0.001). Kaplan Meier survival analysis demonstrated that c-Myc expression could not be significantly correlated with overall survival or disease free survival rates. Conclusion:Nuclear c-Myc seems to have a prominent role in epithelial to mesenchymal transition with consequential in tumor progression and metastasis, while it is not as much useful to predict the clinical behavior of patients with MIUC.

Is Not It the Time to Change the Treatment of Intermediate-Risk Patients Suffering From Gestational Trophoblastic Neoplasia?

Objectives: The present study attempted to provide a clear view of gestational trophoblastic neoplasia (GTN) with the focus on resistance to treatment approaches in Iran. Materials and Methods: This retrospective cohort study reviewed the medical records of 272 patients with the definitive diagnosis of GTN referring to Imam Khomeini hospital in Tehran during 2007-2017. Results: The mean age of participants was 29.19 ± 7.46 years. The abnormal uterine bleeding (AUB) was the most common clinical manifestation in 64.3% of patients. Regarding the risk scoring condition according to the World Health Organization criteria, 77.6%, 9.1%, and 13.3% were categorized as low-, intermediate-, and high-risk cases. Single therapy with methotrexate was used in 22.8% of patients and actinomycin-D was planned for 42.3% whereas 11.0% and 1.5% were considered for treatment with the EMA-CO (Etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine) and EMA-EP (Etoposide methotrexate and actinomycin-D/ etoposide and cisplatin) regimens, respectively. Good response to methotrexate was 66.7% but it was 83.6% in the ACT group (P = 0.001). The resistance to single-agent chemotherapy in low- and intermediate-risk groups was 16% and 92%, respectively. In addition, 20.2% of patients in stage one had tumor invasion pattern in the uterus in pretreatment Doppler ultrasonography, but 52% and 30% had resistance to chemotherapy treatment in invasive and noninvasive groups, respectively (P = 0.008). Conclusions: In general, due to the high resistance of the intermediate-risk subgroup to a single therapy, a combination therapy may be more useful to treat this disorder. The close association between tumor invasion pattern in the uterus in Doppler ultrasonography and drug resistance can be considered as a new criterion for tumor risk scoring.

Predictive factors for late cervical metastasis in stage I and II squamous cell carcinoma of the lip.

Many authors have described clinicopathologic parameters as factors related to cervical lymph node metastasis development in CN0 stage lip cancer. However, predictive factors for occult lymph node metastasis and criteria for elective neck dissection, especially for early tumour, remain undefined. A multi-institutional study with 193 consecutive patients with early lip SCC treated from January 1990 to March 2006 was carried out retrospectively to determine factors predicting occult metastasis. The overall late LNM rate was 13% (25/193). In the multivariate logistic regression study, tumour size and pattern of tumour invasion were factors related to the occurrence of late LNM with rates of sensitivity, specifity and accuracy for occult LNM prediction of 50%, 89.5% and 87%, respectively. Our results indicate that patients with stage I and II SCC of the lip with tumour size greater than 18mm and more aggressive pattern of invasion must be considered a high-risk group for LNM and an END should be performed.

Patterns of Invasive Growth in Malignant Gliomas—The Hippocampus Emerges as an Invasion-Spared Brain Region

BACKGROUND: Widespread infiltration of tumor cells into surrounding brain parenchyma is a hallmark of malignant gliomas, but little data exist on the overall invasion pattern of tumor cells throughout the brain. METHODS: We have studied the invasive phenotype of malignant gliomas in two invasive mouse models and patients. Tumor invasion patterns were characterized in a patient-derived xenograft mouse model using brain-wide histological analysis and magnetic resonance (MR) imaging. Findings were histologically validated in a cdkn2a−/− PDGF-β lentivirus-induced mouse glioblastoma model. Clinical verification of the results was obtained by analysis of MR images of malignant gliomas. RESULTS: Histological analysis using human-specific cellular markers revealed invasive tumors with a non-radial invasion pattern. Tumors cells accumulated in structures located far from the transplant site, such as the optic white matter and pons, whereas certain adjacent regions were spared. As such, the hippocampus was remarkably free of infiltrating tumor cells despite the extensive invasion of surrounding regions. Similarly, MR images of xenografted mouse brains displayed tumors with bihemispheric pathology, while the hippocampi appeared relatively normal. In patients, most malignant temporal lobe gliomas were located lateral to the collateral sulcus. Despite widespread pathological fluid-attenuated inversion recovery signal in the temporal lobe, 74% of the “lateral tumors” did not show signs of involvement of the amygdalo-hippocampal complex. CONCLUSIONS: Our data provide clear evidence for a compartmental pattern of invasive growth in malignant gliomas. The observed invasion patterns suggest the presence of preferred migratory paths, as well as intra-parenchymal boundaries that may be difficult for glioma cells to traverse supporting the notion of compartmental growth. In both mice and human patients, the hippocampus appears to be a brain region that is less prone to tumor invasion.

Apolipoprotein E Promotes Invasion in Oral Squamous Cell Carcinoma

Oral squamous cell carcinoma (OSCC) patients generally have a poor prognosis, because of the invasive nature of these tumors. In comparing transcription profiles between OSCC tumors with a more invasive (worst pattern of tumor invasion 5) versus a less invasive (worst pattern of tumor invasion 3) pattern of invasion, we identified a total of 97 genes that were overexpressed at least 1.5-fold in the more invasive tumor subtype. The most functionally relevant genes were assessed using invitro invasion assays with an OSCC cell line (UM-SCC-1). Individual siRNA knockdown of 15 of these 45 genes resulted in significant reductions in tumor cell invasion compared to a nontargeting siRNA control. One gene whose knockdown had a strong effect on invasion corresponded to apolipoprotein E (APOE). Both matrix degradation and the number of mature invadopodia were significantly decreased with APOE knockdown. APOE knockdown also resulted in increased cellular cholesterol, consistent with APOE's role in regulating cholesterol efflux. APOE knockdown resulted in decreased levels of phospho-extracellular signal-regulated kinase 1/2, phospho-c-Jun N-terminal kinase, and phospho-cJun, as well as decreased activator protein 1 (AP-1) activity. Expression of matrix metalloproteinase 7 (MMP7), an AP-1 target, was also significantly decreased. Our findings suggest that APOE protein plays a significant role in OSCC tumor invasion because of its effects on cellular cholesterol and subsequent effects on cell signaling and AP-1 activity, leading to changes in the expression of invasion-related proteins, including MMP7.

Evaluation and influencing factors of surgical margin status of oral squamous cell carcinoma

Surgical resection with adequate margins is an essential component of the treatment for patients with oral squamous cell carcinoma (OSCC). A distance of 5 mm or more between healthy tissue to the tumor front is generally accepted as a safe margin. It is very important for surgeons to precisely evaluate the resection area of tumor both pre- and intra-operatively and try to achieve a safe margin, which will result in a decreased risk of local recurrence. The relationship of surgical margin status to patients' prognosis, and factors which will affect surgical margin distance demand are discussed in this paper. We recommend that adequate margins evaluation should take consideration of many factors such as anatomical location, depth of tumor invasion, pattern of tumor invasion, mucosal dysplasia grade and so on. With the development of molecular biology, surgical margin study at molecular level can give us a new strategy to evaluate its adequacy.

Evaluation of the pattern and mechanism of bony invasion in gingivobuccal sulcus and gingival squamous cell carcinoma and its correlation with the regional lymph node metastasis: A histopathological study

ObjectiveThe purpose of this study was to assess the frequency of bony invasion and to evaluate the pattern and mechanism of tumor invasion into the bone and its correlation with the regional lymph node metastasis in gingivobuccal sulcus (GBS) and gingival squamous cell carcinoma. Study designA prospective study in which 25 resected specimens of the jaws along with the associated lymph nodes of patients treated for GBS and gingival squamous cell carcinomas were evaluated for the frequency, pattern and mechanism of tumor invasion into the bone and the regional lymph node metastasis, using a light microscope. Results8 of the 25 cases showed bony invasion, among which 5 (20%) showed invasive pattern of tumor invasion while 3 (12%) showed the erosive pattern into the bone. The main mechanism of bony invasion was via the cortical plate (20%) than the periodontal ligament (12%). Regional lymph node metastasis was seen in 6 of the 8 cases showing bony invasion. No significant correlation was found between any of the above parameters. ConclusionIn our attempt to study the tumor invasion into the bone, we found no significant correlation between the pattern and mechanism of invasion and the regional lymph node metastasis. A possible treatment guide through our study to the surgeon from our side is to prevent aggressive resections and to preserve the integrity of the jaw and thus, to provide the maximum probability of cure and maintain the quality of life.

WHO 1973 grade 3 and infiltrative growth pattern proved, aberrant E-cadherin expression tends to be of predictive value for progression in a series of stage T1 high-grade bladder cancer after organ-sparing approach.

Stage pT1 urothelial bladder cancer (UBC) is characterized as a challenging subentity of urothelial carcinoma with an unforeseeable clinical course. In addition to more or less established clinical and histopathological features, we evaluated the role of epithelial-mesenchymal transition (EMT) marker E-cadherin, shown to be of prognostic value in muscle-invasive disease, regarding the prognosis of stage pT1 high-grade (hg) UBC. Tissue of 226 stage pT1 hg UBC patients from transurethral resection could be immunostained for E-cadherin. Kaplan-Meier analysis and univariate and multivariate Cox regression analyses regarding progression-free (PFS) and cancer-specific survival (CSS) were performed. Aberrant expression of E-cadherin was recognized in 74% of patients. Kaplan-Meier analysis showed that aberrant E-cadherin expression was associated with worse 10-year PFS (62 vs. 90%, p=0.045). In univariate analysis, aberrant E-cadherin staining, associated carcinoma in situ, grading 3 after WHO classification 1973 and infiltrative growth pattern at the invasion front were the statistically significant predictive factors for worse PFS, only infiltrative growth pattern for CSS. With regard to progression, grading 3 after WHO classification of 1973 (HR 6.49; CI 1.54-27.28, p=0.011) and infiltrative tumor invasion pattern (HR 2.06; CI 1.10-3.86, p=0.024) revealed as independent factors for PFS, and there was a trend also for E-cadherin expression (HR 0.45; CI 0.19-1.06; p=0.068). Regarding CSS, infiltrative tumor growth pattern (HR 3.79; CI 1.67-8.60, p=0.001) was the only statistically significantly independent predictive factor in multivariate Cox regression analysis. Beside invasion growth pattern and WHO grading 1973 that achieved to be independent prognostic factors, there was a trend for the parameter E-cadherin expression to be of predictive value for PFS in stage pT1 hg urothelial bladder carcinoma after organ-sparing approach. Further studies on genetic level are warranted to define the distinct role of EMT in early-invasive UBC.

Identification of Anatomic Correlates of Failure in Patients With T4a Larynx Cancer

To identify whether anatomic patterns of primary tumor invasion in T4a laryngeal squamous cell carcinoma predict local control (LC) in patients treated with non-surgical larynx preservation (LP) approaches versus patients treated with total laryngectomy (followed by post-operative radiation therapy (TL-PORT)). We retrospectively reviewed the medical records of patients with T4a (AJCC 7th) squamous cell laryngeal cancer treated between 1983 to 2011 at a single institution Anatomic invasion by primary tumor of any combination of cartilage (cricoid or thyroid), muscles, or soft tissue (thyroid gland or esophagus) was recorded. Areas of invasion were then categorized by number of structures multiplicity such as single cartilage, muscle, or soft tissue versus multiple (e.g. cartilage and muscle/soft tissue), then grouped into a binary of single (SIP) or multiple invasion pattern (MIP). Kaplan-Meier and log-rank tests were used to evaluate LC. Cox regression multivariate analysis was performed. 220 patients with a median follow-up of 68 months were analyzed. 60 (27%) received LP with RT (85% of whom also received chemotherapy), and160 patients (73%) received TL-PORT, 80% of patients in LP group had SIP and 20% had MIP. In comparison, 62% of TL-PORT patients had SIP while 38% had MIP. The 5-year LC was significantly better in LP patients with SIP compared to MIP (88% vs. 0%, P<.0001). However, the 5-year LC was not statistically different in patients with SIP compared to MIP in TL-PORT group (86% vs. 97%, P = 0.4). On multivariate analysis, MIP in LP cohort was the only independent predictor of LC (HR 19.4; 95% CI 5.5-80.3, P<.0001) but in TL-PORT group none of the studied variables (age, sex, ethnicity, larynx subsite of origin, performance status, nodal stage, radiation dose, chemotherapy use) was predictive of LC. LC for T4a laryngeal cancer patients with SIP and MIP is favorable in TL-PORT group, while LP should be eschewed for even minimal multi-anatomic site involvement but remains an option for selected cases with SIP.

Patterns of Primary Tumor Invasion and Regional Lymph Node Spread Based on Magnetic Resonance Imaging in Early-Stage Nasal NK/T-cell Lymphoma: Implications for Clinical Target Volume Definition and Prognostic Significance

This study aimed to determine the pathways of primary tumor invasion (PTI) and regional lymph node (LN) spread based on magnetic resonance imaging (MRI) in early-stage nasal NK/T-cell lymphoma (NKTCL), to improve clinical target volume (CTV) delineation and evaluate the prognostic value of locoregional extension patterns. A total of 105 patients with newly diagnosed early-stage nasal NKTCL who underwent pretreatment MRI were retrospectively reviewed. All patients received radiation therapy with or without chemotherapy. The incidences of PTI and regional LN involvement were 64.7% and 25.7%, respectively. Based on the incidence of PTI, involved sites surrounding the nasal cavity were classified into 3 risk subgroups: high-risk (>20%), intermediate-risk (5%-20%), and low-risk (<5%). The most frequently involved site was the nasopharynx (35.2%), followed by the maxillary (21.9%) and ethmoid (21.9%) sinuses. Local disease and regional LN spread followed an orderly pattern without LN skipping. The retropharyngeal nodes (RPNs) were most frequently involved (19.0%), followed by level II (11.4%). The 5-year overall survival (OS), progression-free survival (PFS), and locoregional control (LRC) rates for all patients were 72.8%, 65.2%, and 90.0%, respectively. The presence of PTI and regional LN involvement based on MRI significantly and negatively affected PFS and OS. Early-stage nasal NKTCL presents with a high incidence of PTI but a relatively low incidence of regional LN spread. Locoregional spread followed an orderly pattern, and PTI and regional LN spread are powerful prognostic factors for poorer survival outcomes. CTV reduction may be feasible for selected patients.

Can the inferior alveolar nerve be used as a marker in frozen section for free margin control after segmental mandibulectomy in tumour ablation?

This study critically assessed the possibility of tumour spread along the inferior alveolar nerve (IAN) and its sensitivity as an intraoperative marker for clear bony margin control in frozen section during segmental mandibulectomy. Fifteen patients with oral squamous cell carcinoma (OSCC) involving the mandible and requiring a segmental mandibulectomy were included in this prospective trial. The ends of the IAN were analyzed using quick section analysis and the results compared with those of the definite pathological report. Nerve tissue could be identified in 25 of the 27 specimens collected. No specimen revealed tumour invasion. All histological diagnoses were finally confirmed. Three positive bony margins with microscopic carcinoma infiltrates were found, whereas corresponding nerve tissue did not confirm tumour invasion. This study supports the assumption that the pattern of tumour invasion is rarely primarily along the IAN in OSCC involving the mandible. Quick section analysis of the nerve tissue alone is therefore not a valid marker for intraoperative bony margin control. However, it can be used as an additional intraoperative diagnostic tool combined with other methods in rare cases of primary tumour spread along the IAN. A review of current knowledge regarding bony margin control published in the literature is provided.

A radiomic signature based on advanced tumor shape parameters (Spiculated-ness) to predict the outcome of locally advanced (LA) HNSCC patients.

11571Background: Tumor invasion patterns are known to be associated with HNSCC pts outcome. Radiomics is a rapidly-emerging field involving the extraction of quantitative imaging features from stan...

Abstract B87: Cell lines generated from PDAC transgenic mice reveal integrin αvβ6 modifies the invasive phenotype of pancreatic cancer

Abstract Pancreatic adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in the UK. Five-year survival rates are less than 3% and haven’t improved over the last 40 years. Thus novel approaches are required urgently. We have found that high expression of the integrin β6 subunit gene (ITGB6) correlates with a significant reduction (Hazard Ratio 1.74; Logrank p=6x10-4) in overall survival from PDAC. Thus we have begun to examine the biological functions mediated by αvβ6 in a transgenic model of PDAC. A panel of cell lines were generated from PDAC tumors of a novel transgenic mouse and characterized for markers of tissue identity, integrin expression and ability to invade using 3D-organotypic assays. Cell populations appeared to contain both epithelial (E-cadherin positive) and mesenchymal (vimentin positive) characteristics, highlighting their polyclonality. In addition, two cell populations, KVC1 and KPCD3, expressed low levels of αvβ6 and were studied further. KVC1 and KPCD3 cells were labeled with 10D5 (anti-αvβ6) and sorted by FACS to obtain high-αvβ6 expressing monoclonal cell lines. The resulting cell lines after four rounds of sorting (S4) demonstrated mean MFI values of approximately 4.5-fold (KVC1 vs. KVC1 S4 A+) and approximately 3-fold (KPCD3 vs. KPCD3 S4 E+) higher than their parental counterparts. To compare the invasion profile of the parental populations and S4 monoclonal cell lines, cells were placed in 3D organotypic assays with mouse embryonic fibroblasts (MEFs) for 14 days before gels were fixed and processed to paraffin. H&amp;E stained sections revealed that parental populations KVC1 and KPCD3 formed invasive, single-cell walled ductal structures that had penetrated into the matrigel-collagen mix, but only in the presence of MEFs. In contrast, αvβ6-positive S4 populations, KVC1 S4 A+ and KPCD3 S4 E+, also demonstrated strong invasion but the invasive ductal phenotype was lost, the cells invading as small cohesive groups and individual cells. These data suggest that the pattern of PDAC tumour invasion may be modulated by expression of the integrin αvβ6. Current studies explore the mechanisms by which these phenotypic changes are generated. Citation Format: Claire S. Reader, Sabari Vallath, Jennifer Morton, Colin Steele, Hemant M. Kocher, Stephen M. Keyse, Owen Sansom, John F. Marshall. Cell lines generated from PDAC transgenic mice reveal integrin αvβ6 modifies the invasive phenotype of pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B87.

Retrospective cohort study of prognostic factors in patients with oral cavity and oropharyngeal squamous cell carcinoma.

Prognostic factors in oral cavity and oropharyngeal squamous cell carcinoma (SCC) are debated. The purpose of this study was to investigate the association of prognostic factors with oncologic outcomes. Patients with oral cavity and oropharyngeal SCC treated from 1997 to 2012 were included in this retrospective cohort study. Associations of prognostic factors with locoregional recurrence (LRR) or overall survival (OS) were analyzed using the logistic regression and the Cox models. Six hundred thirty-four patients were included in this study; tumor size, surgical margins, and N classification were associated with LRR (p < .0001); considering histopathology: perineural invasion, lymphocytic infiltration, infiltrative borders, and N classification were significant determinants of LRR. Tumor size, N classification, alcoholism, and surgical margins were associated with OS (p < .0001); considering pathologic prognostic factors, perivascular invasion, islands borders, and surgical margins were independently associated with OS (p < .0001). Surgical margins, perineural and perivascular invasion, lymphocytic infiltration, and infiltrative patterns of tumor invasion are significant prognostic factors in oral cavity and oropharyngeal SCC.

Microscopic Invasion Patterns and Epithelial Cell-phenotypes in Early Gastric Cancer with Submucosal Invasion

Background and study aims: Early gastric cancers show gastric and/or intestinal phenotypes with specific mucin production profiles, and the phenotypes can vary with tumor progression. The aim of this study was to evaluate the correlation between tumor invasion patterns and phenotypes in the mucosa and submucosa of early gastric cancers. Methods: Phenotypic expressions of 44 endoscopically resected gastric cancers with submucosal invasion were evaluated immunohistochemically using MUC5AC and MUC6 as gastric and MUC2 and CD10 as intestinal phenotypic markers. Results: Cancers were classified into two patterns by invasion pattern: 19 collapsing pattern (C-pattern) tumors had cancer cells that invaded to the submucosa with expansive destruction of the muscularis mucosae, while 25 passing-through pattern (P-pattern) tumors formed focal cancer cell aggregations in the submucosa without massive destruction of the muscularis mucosae. Cancers with C-pattern invasion were likely to show similar phenotypes between the mucosa and submucosa, while phenotypes of cancers with P-pattern invasion were likely to differ between the two layers (rate of the same phenotypes: C-pattern 68% vs. P-pattern 28%, p = 0.008). Of 22 cancers with P-pattern invasion that included the intestinal phenotype component in the mucosa, 13 (59%) expressed the gastric phenotype alone in the submucosa. Conclusions: Phenotype presentation in the mucosa and submucosa differ by the invasion pattern in early gastric cancer. Tumors with P-pattern invasion are likely to express the gastric phenotype in the submucosa, regardless of phenotype in the mucosa, suggesting that such cancers might achieve submucosal invasion prior to intestinalization occurring in the mucosa.

Extragastrointestinal stromal tumors: Computed tomography and magnetic resonance imaging findings

Extragastrointestinal stromal tumors (EGISTs) are rare mesenchymal tumors that originate outside the gastrointestinal tract. The aim of the present study was to investigate the computed tomography (CT) and magnetic resonance imaging (MRI) features of EGISTs and analyze the correlations between radiological findings and pathological features. CT and MRI images of 24 patients with EGISTs were reviewed retrospectively. Patient demographics and tumor characteristics, including localization, size, contours, borders, cystic-necrotic components, calcification, hemorrhage, tumor vessels, attenuation and intensity, degree and pattern of enhancement, ascites, tumor invasion, lymphadenopathy and distant metastasis were recorded. Statistical analyses to compare the radiological characteristics of low- and high-grade EGISTs were performed with χ2 or Fisher’s exact tests. The mean patient age at the time of presentation was 53 years. A total of 24 EGISTs were detected, originating in the omentum (n=4), mesentery (n=19) and retroperitoneum (n=1), respectively. The EGISTs displayed a predominantly spindle cell subtype (87.5%; 21/24). The majority of the EGISTs appeared as large (>10 cm; 70.8%; 17/24), round or oval (66.7%; 16/24), cystic-solid (87.5%; 21/24) and ill-defined (66.7%; 16/24) soft-tissue masses. The EGISTs were hypodense (69.6%; 16/23) or isodense (30.4%; 7/23) on CT images, hypointense (50%; 3/6), isointense (33.3%; 2/6) or hyperintense (16.7%; 1/6) on T1-weighted imaging (T1WI), and hyperintense on T2WI (100%; 6/6) and diffusion-WI (DWI; 100%; 6/6). A total of 54.2% (13/24) of the EGISTs displayed tumor vessels. Overall, 95.8% (23/24) of the masses showed marked enhancement and 87.5% (21/24) demonstrated heterogeneous enhancement. Calcification, hemorrhage, ascites and lymphadenopathy were rare characteristics in the EGISTs. Distant metastases were present in 10 patients (41.7%). The size, borders, tumor vessels and distant metastasis correlated with high-grade EGISTs [>5 mitoses/50 high-power fields (HPFs)] (P<0.05). The results of the present study indicated that clinical and radiological features, including advanced age, a large tumor size, cystic-necrotic components, rare lymphadenopathy, a heterogeneous enhancement pattern and hepatic metastasis may aid in the diagnosis of EGISTs. Radiological characteristics, such as a large size (>10 cm), ill-defined borders, tumor vessels and distant metastasis, can provide useful information in identifying the malignant behavior of EGISTs.

AI-04 * MECHANISMS OF GLIOMA FORMATION: PERIVASCULAR GLIOMA INVASION IS A VEGF-INDEPENDENT MECHANISM OF TUMOR VASCULARIZATION

Malignant glioma cells associate with various microanatomical brain structures such as blood vessels, white matter tracts, and brain parenchyma as they spread throughout the brain. However, how these distinct brain tumor invasion patterns coordinate tumor growth and influence clinical outcomes remains unknown. We have investigated how perivascular growth affects glioma growth patterning and response to anti-angiogenic therapy within the highly vascularized brain. We show that orthotopically implanted rodent and human malignant glioma cells, as well as de-novo generated endogenous mouse brain tumors, biopsies of primary human glioblastoma, and peripheral cancer metastasis to the human brain each use brain perivascular space as a means for tissue invasion. Perivascularly invading brain tumors become vascularized by normal brain microvessels as individual gliomas cells use perivascular space as a conduit for tumor invasion. We generated an agent-based computational model, which recapitulated biologically observed perivascular glioma growth without the need for neoangiogenesis. This in-silico result prompted us to test whether neoangiogenesis is indeed required for tumor progression in perivascularly invading glioma by treating tumor-bearing animals with angiogenesis inhibitors bevacizumab and DC101. These inhibitors induced the expected vessel-normalization, yet failed to reduce tumor growth or improve survival of mice implanted orthotopically with gliomas from mouse or human origin, or mice subjected to sleeping-beauty generated endogenous gliomas; in all models tested anti-angiogenics exacerbated brain tumor invasion. Our results provide compelling experimental evidence for the recently described failure of clinically used anti-angiogenics to extend the survival of human glioma patients. Given that anti-angiogenics may be beneficial in some patients suffering from certain genetically identifiable glioma subtypes, whether there are mouse or human glioma cells whose growth in-vitro can be reduced by anti-angiogenic approaches remains to be determined.