Absence Of Perineural Invasion Research Articles

Prognostic Implications of Modified Gleason Score and Gleason Grade Group in Histopathologic Study of Prostatic Adenocarcinoma: A Cross-sectional Study

Introduction: The Gleason Score (GS) is the most powerful prognostic indicator in prostatic carcinoma. The assignment of the GS is based on the histopathologic patterns of prostatic adenocarcinoma, which are classified according to the Gleason Pattern (GP). Periodic revisions in the definitions of the GP Score are attempted by the International Society of Urologic Pathology (ISUP), followed by the introduction of the Gleason Grade Group (GG) System, which aims to improve prognostication in prostate cancer. Aim: To determine whether the ISUP 2014 GG group system is a better prognostic indicator compared to the ISUP 2005 Modified GS. Materials and Methods: This cross-sectional study was conducted over four years, from January 2016 to December 2019, at the Department of Pathology, SDM College of Medical Sciences and Hospital, Shri Dharmasthala Manjunatheshawara University, Sattur, Dharwad, Karnataka, India. Core biopsies and transurethral resection biopsies of the prostate with a diagnosis of prostatic carcinoma were included in the study. Demographic details, Prostate-specific Antigen (PSA) levels and follow-up data were retrieved from the case files. Histopathology slides from all patients were examined and assigned GS scores from 6 to 10 and GG scores from 1 to 5. The slides were also analysed for the presence or absence of Perineural Invasion (PNI) and Cribriform Pattern (CFP). The percentage of tumour involvement was documented. Patients were followed-up for a period of two to five years for evidence of metastasis and/or death due to prostatic carcinoma. Categorical variables were analysed using descriptive statistics. Results: The mean age of presentation was 70.21 years. A total of 52 cases were included in the study, with a histopathological diagnosis of adenocarcinoma in all cases. Three special variants were encountered, including one case each of Signet Ring Cell Carcinoma (SRCC), pseudo hyperplastic adenocarcinoma and intraductal foamy gland carcinoma. The distribution of GG scores was as follows: 7 (13.46%) for GG 1, 5 (9%) for GG 2, 6 (11.5%) for GG 3, 8 (15.38%) for GG 4 and 26 (50%) for GG 5. There were 23 cases with metastasis, with most belonging to GG 5 and GG 4. PNI and CFP were noted in 34 (65.38%) and 25 (48.07%) cases, respectively. Tissue cores with greater than 50% tumour involvement were observed in 32 cases (61.53%). Conclusion: The current study underscores the prognostic importance of the ISUP 2014 GG system over the ISUP 2005 GS system. Histomorphological parameters such as PNI, CFP and a percentage of tumour involvement greater than 50% significantly influence prostate cancer prognosis. These factors may provide valuable information for optimal clinical management.

High Expression of the Tumor Suppressor Protein ITIH5 in Cholangiocarcinomas Correlates with a Favorable Prognosis.

Background: Cholangiocarcinoma (CCA) are aggressive bile duct cancers with a poor prognosis for which there are only few established prognostic biomarkers and molecular targets available. The gene ITIH5, a known class II tumor suppressor gene (C2TSG), encodes a secreted protein of the extracellular matrix mediating tumor suppressive properties. Recently, it was surprisingly found that the ITIH5 protein is specifically upregulated in CCAs and that ITIH5 detection in blood could be an excellent liquid biopsy marker for indicating the presence of a CCA tumor in a patient. We therefore investigated whether patients with CCAs with abundant versus low ITIH5 protein expression also differ in their prognosis. Methods: To clarify this question, a large CCA cohort (n = 175) was examined using immunohistochemistry on a tissue microarray (TMA). Results: Abundant ITIH5 expression in CCA was associated with favorable survival, a low UICC stage and the absence of perineural invasion (PNI). Conclusions: ITIH5 has biomarker potential not only for the early detection of CCA from blood-based liquid biopsies but also as a prognostic tissue biomarker for risk stratification. Our results suggest that the upregulation of ITIH5 is particularly abundant in intrahepatic CCAs (iCCA). The mechanisms mediating the strong initial upregulation of ITIH5 during the oncogenic transformation of bile duct cells are still unclear.

Vascular Resection for Pancreas Cancer - 10-year Experience from a Single High Volume-center.

Combined pancreatic and vascular resections are increasingly performed for pancreatic ductal adenocarcinoma (PDAC). We evaluated the outcomes after pancreatectomy with non-vascular resection (NVR), venous resection (VR), and arterial resection (AR). Retrospective review (2011-2023) of 715 PDAC patients treated with curative-intent surgery. Associations among clinicopathological data, perioperative therapy, time to recurrence (TTR), and overall survival (OS) were evaluated. Initial staging revealed 533 resectable, 98 borderline, and 84 locally advanced PDAC cases. Pancreaticoduodenectomy was the most common procedure (n=467). NVR was performed in 351 (58.2%) patients, VR in 181 (30.0%), and AR in 70 (11.8%). The median TTR and OS did not significantly differ according to the initial staging or type of pancreas resection. Median TTR and OS were significantly shorter for VR (14.5 and 22.7mo) compared to NVR (18.6 and 30.5mo, P<0.001) and AR (20.6 and 30.9mo, P=0.004 and P=0.017). Chemotherapy or chemoradiation significantly prolonged TTR (20.1 vs. 10.2mo, P<0.001 and 25.3 vs. 16.4mo, P<0.001) and OS (31.5 vs. 17.2mo, P<0.001 and 35.5 vs. 27.5mo, P=0.030). AR was associated with higher 90-day mortality rates. In the multivariable analysis, vascular resection was not associated with OS. Perioperative therapy, pathological N0 status, and absence of perineural invasion were the key predictors of longer TTR and OS. Pancreatectomy with AR was not associated with worse oncological outcomes when controlling for perioperative therapy. However, AR was associated with higher 90-day mortality rates. Patient selection is crucial when performing AR in patients with PDAC.

Vascular resection for pancreas cancer: Ten-year real-world experience from a single high-volume center.

638 Background: In pancreatic ductal adenocarcinoma (PDAC), to identify prognostic factors for surgically treated patients, including vascular resections. Methods: Retrospective review (2011 – 2023) of pathologically proven PDAC treated with curative-intent surgery (n = 715) at a high-volume cancer center. We tested associations between clinicopathological and radiological data, perioperative therapy, time to recurrence (TTR) and overall survival (OS). Results: Demographic and clinicopathological variables were comparable to published surgical cohorts. Initial NCCN radiological staging was 533 (74.5%) resectable, 98 (13.7%) borderline, and 84 (11.7%) locally advanced PDAC. There were 467(65.3%) pancreaticoduodenectomies, 104 (14.5%) distal pancreatectomies, 31 (4.3%) total pancreatectomies and 112 (15.7%) aborted procedures, mostly due to metastatic disease (82.1%). Of the 603 resected cases, 351 (58.2%) were non-vascular resections (NVR), 181 (30.0%) venous-only resections (VR), and 70 (11.8%) were arterial ± venous resections (AR). Median length of stay was 8 days, ICU admission rate was 6.1% (n = 37), readmissions occurred in 114 (18.9%) cases and reoperations in 47 (7.8%) cases. The 90-day mortality rate was 3.2% (n = 19) and the 5-year OS was 20.7%. Perioperative chemotherapy was given to 258 (78.4%) NVR, 129 (75.9%) VR and 60 (93.8%) AR. Perioperative chemoradiation was given to 20 (6.8%) NVR, 34 (21.0%) VR and 43 (66.1%) AR. Median TTR and OS did not significantly differ by initial NCCN staging or type of pancreas resection. Median TTR and OS were significantly shorter for VR (14.5 and 22.7 months) compared to NVR (18.6 and 30.5 months, p&lt;0.001) and AR (20.6 months, p = 0.004 and 30.9 months, p = 0.017). Patients who received chemotherapy or chemoradiation had significantly longer TTR (20.1 vs. 10.2 months, p&lt;0.001 and 25.3 vs. 16.4 months, p&lt;0.001) and OS (31.5 vs. 17.2 months, p&lt;0.001 and 35.5 vs. 27.5 months, p=0.030) compared to patients not receiving any therapy. In multivariate analysis, when controlling for perioperative therapy and usual clinicopathological factors, vascular resection was not associated with TTR and OS. Perioperative chemotherapy, chemoradiation, pathological N0 status, and absence of perineural invasion were significant independent predictors of longer TTR and OS. For VR specifically, patients who received chemotherapy and chemoradiation had significantly longer median TTR and OS (41.9 and 35.3 months) compared to patients receiving chemotherapy alone (14.3 and 24.6 months, p&lt;0.001 and p=0.017) or receiving no perioperative therapy (9.5 and 12.8 months, p &lt;0.001 and p = 0.004). Conclusions: In this cohort of patients with PDAC treated with surgical resection at a high-volume cancer center, vascular resection was not associated with oncological outcomes when controlling for administration of perioperative therapy.

Mutation Profile via Next-Generation Sequencing in Patients with Colorectal Adenocarcinoma and Its Clinicopathological Correlation.

Recent studies that reveal the molecular profiles of colorectal carcinomas have demonstrated tumor heterogeneity. Characterization of colorectal carcinoma-specific genomic alterations is essential for developing more successful and targeted treat- ment protocols. Moreover, it is vital in elucidating the pathogenesis and mechanisms of resistance against treatment and predicting prognosis. The study included 73 cases diagnosed with colorectal carcinomas and subjected to molecular analysis by the next-generation sequencing. The association between the clinicopathologic parameters and pathogenic mutations detected in 32 genes was evaluated. Pathogenic mutations were determined in a total of 24 genes. The Cell Division Cycle 27 (CDC27), Kirsten rat sarcoma viral proto-oncogene (KRAS), serine/threonine protein kinase B-raf (BRAF), phosphatase and tensin homolog, breast cancer 2 (BRCA2), and phosphotidylinositol-4,5-biphosphate 3-kinase (PIK3CA) mutations were determined at higher rates, with the adenomatous polypo- sis coli mutation determined at a lower rate than in the literature. There were significant positive correlations between CDC27 and phosphatase and tensin homolog (PTEN), PTEN and BRCA2, and PTEN and adenomatous polyposis coli (APC) concomitant muta- tions, whereas negative correlations were present between BRAF and KRAS. Statistically significant relationships were present between KRAS exon 2 and mucinous morphology, PIK3CA and absence of perineural invasion, BRAF and tumor differentiation/localization, MutS homolog 3 (MSH3) and tumor diameter, and BRCA2 and absence of lymph node metastasis. It is necessary to have a comprehensive database of genomic alterations of colorectal carcinomas to interpret mutations more accurately clinically. There are no studies on the frequency of mutations in colorectal carcinomas in the Turkish population; thus, follow-up and treatment protocols are organized following the European and American databases and guidelines. A comprehensive study of the colorectal carcinoma patients' mutation profile in the Turkish patient cohort by the next-generation sequencing method will help to provide significant therapeutic, prognostic, and predictive data and design more successful treatment and follow-up strategies.

SJLA_2024_A8: Clinical and Survival Patterns of Pulmonary Metastases in Colorectal Cancer Patients

Background: Pulmonary metastasis (PM) from colorectal cancer (CRC) is a rare and incompletely understood entity which affects 10% of CRC patients. The 5-year overall survival (OS) of Stage IV CRC is 11.3% and in pulmonary metastatectomy range from 40% to 69.7%. This study aims to evaluate the overall 5-year survival of PM from CRC and identify potential independent risk factors affecting the OS. Methods: A retrospective study was conducted in a tertiary care center (Royal Hospital). The study included all patients diagnosed with Stage IV CRC with PM aged &gt;18 years between 2008 and 2015. Patients with no follow-up and missed data were excluded. Data were retrieved from the electronic record system (Al-Shifaa) and analyzed using SPSS software. Results: The prevalence of PM in the overall CRC cases was 15.2% (84/554 patients). Seventy-one patients were included in this study after the application of exclusion criteria with the mean age of patients was 60.35 ± 16.4 years; majority male gender 64.8% (46) and most of them with no comorbidities 57.7% (42). The most common location of primary tumor is sigmoid 31% (22) and diagnosed with T3 40.8% (29) status and N2 32.4% (23) status with high CEA &gt; 5 at presentation and diagnosis. The majority of cases presented with synchronous PM 74.6% (53) and following metastasis features bilateral lung side 69.0% (49), =&gt;10 nodules 42.3% (30), &lt;1 cm size 66.2% (47), and no lymph involvement 57.7% (41). Five-year OS rate is 15.3%, and the median OS time is 15 months. There was a statistically significant difference in the OS distribution between those who received surgery and those who did not receive surgery (Log-rank test, P = 0.004) and 5-year OS rate in the surgical group is 55.6% versus 8.3% in nonsurgical. Median survival time was 71 months versus 13 months, respectively. Several factors were found to be associated with a favorable OS, which include the middle age group (P = 0.007), absence of perineural invasion (P = 0.015), and isolated PM (P = 0.003). In addition, multivariate Cox regression showed OS relatively poor in females (P0.001), metachronous (0.003), T4 (0.005), and normal CEA at diagnosis (0.011). Conclusion: The present study showed 5-year OS rate is 15.3%, and the median OS time is 15 months for Stage IV CRC with pulmonary metastasis. Surgical management, middle age group (40–59 years), absence of perineural invasion, and isolated pulmonary metastasis at diagnosis may be associated with improved survival. Female gender, tumor status T4, Carcinoembryonic &lt;=5 at diagnosis, and metachronous lung mts were associated with poorer survival outcomes. Despite the study’s limitations of retrospective design with a small sample size, the results can be considered as part of MDT-based decision-making. These findings will require future large multicenter studies.

Human papilloma virus-related oral and oropharyngeal squamous cell carcinoma: An assessment of histomorphological features

ABSTRACT Background: Human papillomavirus (HPV) has emerged as an important cause of oral and oropharyngeal squamous cell carcinomas (OSCC and OPSCC). Cancers with HPV as a causative agent are seen to exhibit certain specific histomorphological features. Aim: This study aims to describe the histomorphology of oral and oropharyngeal cancers and discuss their association with HPV. Material and Methods: Hospital-based prospective study done over 31 months (December 2018–April 2021), including a total of 90 cases of OSCC and OPSCC. They were subjected to detailed histopathological evaluation, DNA polymerase chain reaction testing for testing of HPV association, followed by the analysis of data by statistical methods. Results: Out of a total of 90, 73 cases were OSCC and 17, OPSCC. A total of 15 cases were HPV positive. HPV status was found to be significantly associated with purely nonkeratinizing tumors and hybrid/mixed squamous cell carcinomas, pushing the pattern of invasion, absence of perineural invasion, presence of tumor infiltrating lymphocytes, moderate-to-dense host lymphocyte response, loose stromal response, absence of tumor budding, and high mitotic rate (&gt;20/10 hpf). Conclusion: HPV-positive OSCC and OPSCC have distinct histomorphological features and careful analysis of the same can assist in identifying these types of cancers better and thus help in prognostication and treatment.

Side specific differences of tumor budding on non-metastatic colon cancer.

Recent literature suggests that tumor budding (TB) may have a significant clinical impact on colorectal cancers. Our study aims to reveal the effect of TB on the long-term outcomes of patients and to reveal whether there is a difference in tumor location and TB in colonic cancer. A cohort of 100 patients with non-metastatic colon cancer was included in the study. The clinicopathological information of the patients was reviewed. Patients' preparations were re-evaluated to identify TB as: low, medium, and high and represent 0-4 buds, 5-9 buds, and 10 or more buds per 0.785 mm2, respectively. Long-term oncological outcomes of patients were analyzed. The recurrence, metastasis, and final status of the patients were determined during the follow-up period. Low TN was associated with <65 year (p = 0.048), absence of lymphatic metastasis (p = 0.003), and absence of perineural invasion (p = 0.023). High TB was associated with higher pT stage (p = 0.017) and tumor stage (p = 0.005). Additionally, right-sided tumors had a high TB score than left side (82.3% vs. 23.6%, p = 0.011). Patients with high TB had lower overall survival, but these were not statically significant. According to multiple regression analysis, mortality risk was associated with age (p = 0.046), pN status (p = 0.003) and TB (p = 0.040). High TB is associated with mortality in colon cancer and is more common in right colonic carcinoma.

PLK2 Single Nucleotide Variant in Gastric Cancer Patients Affects miR-23b-5p Binding.

Chromosomal instability is a hallmark of gastric cancer (GC). It can be driven by single nucleotide variants (SNVs) in cell cycle genes. We investigated the associations between SNVs in candidate genes, PLK2, PLK3, and ATM, and GC risk and clinicopathological features. The genotyping study included 542 patients with GC and healthy controls. Generalized linear models were used for the risk and clinicopathological association analyses. Survival analysis was performed using the Kaplan-Meier method. The binding of candidate miRs was analyzed using a luciferase reporter assay. The PLK2 Crs15009-Crs963615 haplotype was under-represented in the GC group compared to that in the control group (Pcorr=0.050). Male patients with the PLK2 rs963615 CT genotype had a lower risk of GC, whereas female patients had a higher risk (P=0.023; P=0.026). The PLK2 rs963615 CT genotype was associated with the absence of vascular invasion (P=0.012). The PLK3 rs12404160 AA genotype was associated with a higher risk of GC in the male population (P=0.015). The ATM Trs228589-Ars189037-Grs4585 haplotype was associated with a higher risk of GC (P<0.001). The ATM rs228589, rs189037, and rs4585 genotypes TA+AA, AG+GG, and TG+GG were associated with the absence of perineural invasion (P=0.034). In vitro analysis showed that the cancer-associated miR-23b-5p mimic specifically bound to the PLK2 rs15009 G allele (P=0.0097). Moreover, low miR-23b expression predicted longer 10-year survival (P=0.0066) in patients with GC. PLK2, PLK3, and ATM SNVs could potentially be helpful for the prediction of GC risk and clinicopathological features. PLK2 rs15009 affects the binding of miR-23b-5p. MiR-23b-5p expression status could serve as a prognostic marker for survival in patients with GC.

Long-Term Survivors after Upfront Resection for Pancreatic Ductal Adenocarcinoma: An Actual 5-Year Analysis of Disease-Specific and Post-Recurrence Survival.

Data on long-term actual survival in patients with surgically resected pancreatic ductal adenocarcinoma (PDAC) are limited. The aim of this study was to evaluate the actual 5-year disease-specific survival (DSS) and post-recurrence survival (PRS) in patients who underwent pancreatectomy for PDAC. Data from patients who underwent upfront surgical resection for PDAC between 2009 and 2014 were analyzed. Exclusion criteria included PDAC arising in the background of an intraductal papillary mucinous neoplasm and patients undergoing neoadjuvant therapy. All alive patients had a minimum follow-up of 60 months. Independent predictors of PRS, DSS, and survival >5 years were searched. Of the 176 patients included in this study, 48 (27%) were alive at 5years, but only 20 (11%) had no recurrence. Median PRS was 12months. In the 154 patients after disease recurrence, independent predictors of shorter PRS were total pancreatectomy, G3 tumors, early recurrence (<12months from surgery), and no treatment at recurrence. Median DSS was 36 months. Independent predictors of DSS were CA19-9 at diagnosis >200U/mL, total pancreatectomy, N+ status, G3 tumors and perineural invasion. Only the absence of perineural invasion was a favorable independent predictor of survival >5years. More than one-quarter of patients who underwent upfront surgery for PDAC were alive after 5years, although only 11% of the initial cohort were cancer-free. Long-term survival can also be achieved in tumors with more favorable biology in an upfront setting followed by adjuvant chemotherapy.

Prognostic effect of perineural invasion in successive years in patients with locally advanced gastric cancer.

The present study evaluates the prognostic significance of perineural invasion (PNI) on 2-year, 5-year, and overall survival in patients undergoing gastrectomy and D2 lymphadenectomy due to locally advanced gastric cancer. Included in the study were 231 patients who underwent surgery between November 2006 and October 2018 due to stage 1B and over locally advanced gastric cancer, whose records were reviewed retrospectively. The variables in the presence or absence of PNI were compared between the two groups with a Chi-square test, a Fisher's exact test, a likelihood ratio, and a Mann-Whitney U test. Overall survival data were evaluated with a Kaplan-Meier test. Prognostic factors were evaluated with a stepwise Cox regression analysis. PNI was identified in 167 (72.3%) of the patients. The 2-year, 5-year, and overall survival rates at the end of the follow-up period were 85.9%, 70.3%, and 64.1% in those without PNI, and 52.7%, 38.3%, and 36.5% in those with PNI, respectively. In a multivariate analysis, PNI appeared to be a significant prognostic factor for 2-year survival (P = 0.04) but had no effect on 5-year and overall survival. Survival was shorter in patients with PNI than in patients without PNI, and PNI had no effect on overall survival, although it was found to be of prognostic significance for 2-year survival.

Perineural invasion in prostate needle biopsy: Prognostic value on radical prostatectomy and active surveillance.

The aim of this study was to evaluate the clinical impact of perineural invasion (PNI) in prostate biopsy in patients submitted to radical prostatectomy and on active surveillance (AS). We performed a single center, retrospective, cohort study on patients diagnosed with clinically localized prostate cancer and submitted to radical prostatectomy between January 2010 and December 2016. We evaluated clinical and anatomopathological characteristics from the biopsy and radical prostatectomy specimen and correlated with biochemical recurrence (BCR) using a survival analysis. We also evaluated the impact of PNI in patients with criteria for active surveillance. The cohort analyzed consists of 107 patients, with a mean age of 63.1 years and a mean PSA prior to biopsy of 7.8 ng/ml. In prostate biopsy, 66.4% of the patients had a Gleason score of 6, 30.9% had a Gleason score of 7, and 2.7% had a Gleason score of 8 or higher, with PNI being detected in 57 (53.3%) of the patients. Regarding the anatomopathological characteristics of the surgical specimen, invasion of the seminal vesicles was observed in 6.5%, lymph nodes involvement in 9.3% and positive surgical margins in 27.1% of the cases. During follow-up, BCR was recorded in 24.3% of cases. Clinicopathological features were stratified according to the presence or absence of PNI, with statistical significance in relation to the Gleason Score (p = 0.001), pathologic T stage (p = 0.001), D'Amico risk (p = 0.002) and upstaging of the Gleason score (p = 0.045). The survival analysis revealed a relationship between PNI and BCR (hazard ratio = 2.98; 95% CI: 1.36-6.58; p = 0.007). Regarding the men potentially eligible for AS, the presence of PNI on the biopsy presented a significant relation with Gleason upgrade (p = 0.004) and extraprostatic extension (p = 0.017). The presence of PNI in prostate biopsy is related to adverse anatomopathological factors, being a potential predictor of BCR and have a possible role in the selection of patients for AS.

Perineural invasion is increased in patients receiving colonic stenting as a bridge to surgery: a systematic review and meta-analysis.

In recent years, there has been growing concern about the potential association of stent placement as a bridge to surgery in malignant colon obstruction and some anatomopathological findings that could lead to worsening long-term cancer outcomes, such as perineural, vascular and lymphatic invasion. The aim of the present review was to assess the pathological changes found in surgical specimens after stent placement for obstructing colon cancer vs. emergency surgery, and the impact of perineural invasion on survival rates METHODS: MEDLINE, Cochrane Library, Ovid and ISRCTN Registry were searched, with no restrictions. We performed four meta-analyses to estimate the pooled effect sizes using a random effect model. The outcomes were perineural, vascular and lymphatic invasion rates, and 5-year overall survival rate in patients with obstructive colon cancer, depending on the presence or absence of perineural invasion. Ten studies with a total of 1273 patients were included in the meta-analysis. We found that patients in the stent group had a significantly higher risk of perineural (OR 1.98, 95% CI 1.22-3.21; p = 0.006) and lymphatic invasion (OR 1.45, 95% CI 1.10-1.90; p = 0.008). Furthermore, patients with positive perineural invasion had almost twice the risk of dying compared to those with no perineural invasion (HR 1.92, 95% CI 1.22-3.02; p = 0.005). Stent placement as a bridge to surgery in colorectal cancer patients modifies the pathological characteristics such as perineural and lymphatic invasion, and this may worsen the long-term prognosis of patients. The presence of perineural infiltration in obstructed colon cancer decreases the long-term survival of patients.

Intraepithelial tumour infiltrating lymphocytes are associated with absence of tumour budding and immature/myxoid desmoplastic reaction, and with better recurrence-free survival in stages I-III colorectal cancer.

Tumour budding (TB), desmoplastic reaction (DR) and intraepithelial tumour infiltrating lymphocytes (iTILs) are recently recognised prognostic factors in colorectal cancer (CRC). In this study, we evaluated their significance and relationship to each other and their cumulative effect on survival. A total of 372 stages I-III CRC cases from 2013 to 2016 were included. Low TB was identified in 302 (81%) cases, immature/myxoid DR in 67 (18%) cases and iTILs in 130 (35.0%) cases. iTILs was associated with low budding (P=0.0247), non-myxoid DR (P=0.0004), poorly differentiated histology (P=0.0015), absence of perineural invasion (P=0.0367) and loss of mismatch repair proteins (P=0.0002). Absence of iTILs and presence of immature/myxoid DR were associated with a worse recurrence-free survival (RFS) [hazard ratio (HR)=2.191, 95% confidence interval (CI)=1.232-3.895; and HR=5.706, 95% CI=3.632-8.964, respectively]. A competing risk analysis showed statistically significant prognostic groups combining iTILs and TB (P<0.0001). Cases with iTILs and low TB were associated with better RFS compared to cases without iTILs and with intermediate/high TB (HR=0.214, 95% CI=0.109-0.421). Similarly, combining iTILs and DR revealed statistically significant prognostic groups (P<0.0001). Cases with iTILs and a non-myxoid DR had better RFS compared to cases without iTILs and immature/myxoid DR (HR =0.113, 95% CI=0.056-0.230). On multivariate cause-specific analysis, patients' age (P=0.0045), iTILs (P=0.0345), DR (P<0.0001) and pTNM prognostic groups (P<0.0001) were associated with RFS. Our study validates the association of iTILs and DR as independent prognostic finding in CRC, and propose a prognostic model using the combinations of iTILs with TB and stromal reaction in CRC.

Management of the positive pathologic circumferential resection margin in rectal cancer: A national cancer database (NCDB) study

BackgroundThe circumferential resection margin (CRM) is a primary predictor of local recurrence and survival in rectal cancer, and an important consideration in guiding treatment. CRM is usually predicted preoperatively, so optimal management of an unexpected pathologic positive CRM involvement is debatable. We aimed to investigate the postoperative management of T3N0 rectal cancers with a positive pathologic CRM, and the impact of each strategy on survival. MethodsThe NCDB was reviewed for pathological T3N0 rectal cancer cases from 2010 to 2015, that received neoadjuvant chemotherapy, had surgical resection with pathological clear margins, but a positive pathologic CRM(disease≤2 mm from radial margin). The main outcomes were the incidence, treatment modalities used, and impact of each modality on survival. Univariate analysis evaluated the demographic and provider characteristics across treatment groups. Kaplan-Meier and Cox regression analysis assessed survival and factors associated with overall survival (OS). ResultsOf 1607 cases with a positive CRM, 65% (1045) received no adjuvant treatment and 35% (n = 562) received adjuvant chemotherapy (AC). After matching, the 1-, 3-, and 5-year OS rates were 98.5%, 88.6% and 76.6% for AC and 96.9%, 84.6% and 68.4% for with no treatment (p = .027). Factors independently associated with improved OS were treatment at an academic/research facility (p = .009), minimally invasive approach (p = .005), well and moderately differentiated tumor (p < .001), absence of perineural invasion (p = .015) and AC administration (p = .047). ConclusionIn T3N0 rectal cancers resected with local clear margins but a positive pathologic CRM, AC improved OS. However, only a third received this option. Further study is needed to investigate the disparities in AC use in these patients with unexpected pathologic results.

Clinico-pathological correlates and survival outcomes in 214 resected ampullary adenocarcinomas – are outcomes different in intestinal and pancreatobiliary subtypes with adjuvant gemcitabine?

BackgroundEvidence suggests that intestinal type (IT) and pancreatobiliary (PB) subtypes of ampullary adenocarcinoma (AC) may have different outcomes. The current study evaluated differences in outcomes between these subtypes and the benefit of adjuvant chemotherapy (AT). MethodsA prospectively maintained database of patients who underwent upfront resection for AC from January 2012 to March 2016 was conducted. A dedicated pathologist reported differentiation between IT and PB subtypes. Results214 patients were included for analysis: 105 PB subtype and 109 IT subtype. With a median follow up of 46.3 months, estimated 4 year overall survival (OS) was 65.8%. In patients with stage II–III disease, lymph-node ratio (LNR) < 0.2 [Not reached (NR) vs. 30.72 months; p = 0.002], absence of perineural invasion (PNI) (NR vs. 31.61 months; p = 0.032) and AT (gemcitabine – 96.1%) (NR vs. 22.28 months) were prognostic for superior OS. There was no difference in OS between IT and PB subtypes, but both subtypes with stage II–III disease benefitted from AT statistically as compared to observation (IT: NR vs. 28.62 months; PB: 18.46 months vs. 58.09 months; p < 0.001). ConclusionsAC-IT and AC-PB did not have a different OS when treated with resection and adjuvant gemcitabine, though adjuvant therapy benefitted both subtypes individually.

Abstract 4249: Tumor-infiltrating B lymphocytes may serve as a prognostic biomarker for head and neck squamous carcinoma

Abstract B lymphocytes exert multifaceted functions to produce antibodies in humoral response, present antigen in cell-mediated immunity and suppress immunopathology via anti-inflammatory cytokines. Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancers in world. The development and progression of HNSCC is closely related to the dysregulation and evasion of immune system, which enables cancer cells to proliferate and metastasize. In HNSCC, high CD8+ T cell infiltration predicts better patient survival, and the suppressive T cells (Treg) correlates with tumor progression. Nevertheless, the precise role of tumor-infiltrating B lymphocytes (TIL-B) in HNSCC is poorly defined. With a recently published bioinformatics approach, Tumor Immune Estimation Resources (TIMER), comprehensive pan-Cancer analysis was performed on 25 cancer types using the publicly available TCGA database with both survival and RNA-Seq information. Univariate COX regression demonstrates that in lower grade glioma (Hazard Ratio (HR)=830, P=1.3E-06), diffuse large B-cell lymphoma (HR=130, P=0.01), and papillary renal cell carcinoma (HR=15, P=0.02), TIL-B levels are associated with poor survival. Whilst in HNSCC (HR=0.082, P=0.0015), breast invasive carcinoma (HR=0.12, P=0.042), uterine corpus endometrial carcinoma (HR=0.045, P=0.039), cervical carcinoma (HR=0.00049, P=0.022,) and thymoma (HR=1.6E-05, P=0.026), TIL-B levels are associated with better survival. Note that among these 5 cancer types, HNSCC has the lowest P-value, suggesting TIL-B level is likely a good prognostic biomarker for patient outcome in HNSCC. In other 17 cancer types, TIL-B are not related to patient survival (P=n.s.). In HNSCC, clinicopathological analysis shows that the extreme high TIL-B level (top 15% patients with the highest TIL-B level vs. the bottom 15%) is associated with living status (P=0.0047), early AJCC pathological T stage (P=2.71E-04), high differentiation grade (P=5.00E-05), and the absence of perineural invasion (P=8.52E-04). Furthermore, Kaplan-Meier survival curves based on TIL-B level indicate that patients with high TIL-B (top 15%) show longer survival compared with those with low level (bottom 15%; P=0.0005). The median overall survival time is 67.81 months in TIL-B high and 35.91 in TIL-B low group. In conclusion, this study reveals that TIL-B may serve as independent prognostic biomarker for overall survival of HNSCC patients. Acknowledgements: VWYL receives funding supports from the Research Grant Council, HK (General Research Fund: #1711484; #17121616; #14168571; Theme-based Research: T12-401/13-R), Health and Medical Research Fund (HMRF #15160691), the University-Industry Collaboration Program (UIM/329; Innovation and Technology Fund, HK), and the Hong Kong Cancer Fund, HK. YL receives funding (Postdoctoral Hub of UIM/329) from the Innovation and Technology Fund, HK government) This study also receives funding from Lee Hysan Foundation Research Grant &amp; Endowment Fund Research Grant Schemes 2018-2019. Citation Format: Yuchen LIU, Vivain W. Lui. Tumor-infiltrating B lymphocytes may serve as a prognostic biomarker for head and neck squamous carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4249.

ARID3A Positivity Correlated With Favorable Prognosis in Patients With Residual Rectal Cancer After Neoadjuvant Chemoradiotherapy.

Recent studies have shown a marked increase of AT-rich interactive domain 3A (ARID3A) in colon cancer tissue compared to normal colon mucosa. However, the role of ARID3A has not yet been determined in rectal cancer. We, therefore, investigated the clinical relevance of ARID3A expression in patients with residual rectal cancer after neoadjuvant chemoradiotherapy (NACRT). One hundred thirty-four patients who underwent surgical resection for residual rectal cancer after NACRT were analyzed. ARID3A expression was evaluated using immunohistochemistry on whole-tissue sections. KRAS exon 2 (codons 12 and 13) and BRAF V600E mutation status were determined using polymerase chain reaction. ARID3A positivity was found in 91 cases (64.5%), and it correlated with absence of perineural invasion (p=0.031), longer disease-free survival (DFS) (p=0.048) and cancer-specific survival (CSS) (p=0.006). However, ARID3A positivity was not correlated with KRAS (p=0.231) or BRAF mutation status (p=0.577). In multivariate analysis, ARID3A positivity was independently associated with a favorable CSS (p=0.035), but not DFS (p=0.051). ARID3A positivity can predict favorable prognosis in patients with residual rectal cancer after NACRT.

A systemic review and meta-analysis for prognostic values of pretreatment lymphocyte-to-monocyte ratio on gastric cancer

The systemic inflammation plays a crucial role in carcinogenesis and cancer progression. Pretreatment lymphocyte-to-monocyte ratio (LMR) has been suggested to be associated with clinical outcomes in various malignancies. To evaluate the prognostic significance of pretreatment LMR on gastric cancer, we conducted a comprehensive literature search in PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov (Prospero Registration No. CRD42018087263). This meta-analysis included all studies evaluating the prognostic significance of pretreatment LMR on gastric cancer. The main outcome measures included overall survival (OS), progression-free survival (PFS), and the relationship between LMR and clinicopathological features. In total, 11 studies (12 cohorts) enrolling 14,262 patients with gastric cancer were included. The pooled estimates showed that elevated pretreatment LMR was significantly associated with better OS (hazard ratio (HR): 0.71, 95% confidence interval (CI): 0.58–0.83) and better PFS (HR: 0.71, 95% CI: 0.44–0.99). The elevated LMR was also significantly associated with young patients, female, low level of carcinoembryonic antigen (CEA), low level of carbohydrate antigen 19-9 (CA19-9), stage I–II, small tumor size, absence of lymph node metastasis, absence of vascular invasion, and absence of perineural invasion. In conclusion, the elevated pretreatment LMR predicted the better clinical outcomes in patients with gastric cancer.

Impact of perineural invasion as a histopathological prognostic factor in ypStage II/III oesophageal squamous cell carcinoma†.

The 8th edition American Joint Committee on Cancer Tumour-Nodes-Metastasis (TNM) staging system distinguishes between the clinical (c), pathological (p) and post-neoadjuvant pathological (yp) stage groups. However, the ability to discriminate between ypStage II and ypStage III is poor. We aim to identify prognostic factors in patients with ypStage II/III oesophageal squamous cell carcinoma. The data of 150 patients with ypStage II/III oesophageal squamous cell carcinoma from 2 medical centres were retrospectively reviewed. The neoadjuvant treatments included chemotherapy with cisplatin and 5-fluorouracil, administered concurrently with external beam radiation. The determination of perineural invasion (PNI) was based on pathological reports. Survival curves were compared using the log-rank test, and multivariable survival analysis was performed with a Cox regression model. The 3-year/5-year overall survival rate/median survival in ypStages II, IIIa and IIIb were 35.3%/26.9%/21.9 [95% confidence interval (CI) 14.9-28.8] months, 33.8%/22.5%/22.4 (95% CI 20.1-24.7) months and 21.7%/14.0%/14.4 (95% CI 11.1-17.7) months, respectively (P = 0.07). The 3-year/5-year overall survival rate/median survival was 36.7%/26.4%/22.8 (95% CI 19.2-26.5) months in the absence of PNI and 6.9%/3.4%/9.1 (95% CI 8.9-9.4) months in the presence of PNI (P < 0.001). In the multivariable survival analysis, tumour location in the upper third of the thoracic oesophagus [hazard ratio (HR) 1.692, 95% CI 1.087-2.635; P = 0.020] and positive PNI (HR 3.316, 95% CI 2.005-4.905; P < 0.001) remained as independent prognostic factors. The existence of PNI after neoadjuvant treatment is closely associated with poor prognosis and could be incorporated into the TNM staging system for better discrimination between patients with ypStage II/III oesophageal squamous cell carcinoma.