Perineural Growth Research Articles

Association of Tumor Microenvironment with Biological and Chronological Age in Head and Neck Cancer.

There is often a mismatch between the chronological and biological age of head and neck squamous cell carcinoma (HNSCC) patients. Treatment is based on chronological age, while biological age seems to be a better prognosticator for treatment toleration. This study investigated whether tumor characteristics are associated with chronological and biological age. The relation with survival was also assessed. Prospectively collected data from 164 newly diagnosed HNSCC patients enrolled in the OncoLifeS database were analyzed. Biological age was assessed by a multidomain geriatric assessment. Several immunological markers were tested by immunohistochemistry on tissue microarray sections from the tumor. Disease-free survival (DFS), adjusted for chronological- and biological age, was assessed by univariable and bivariable analyses. In biologically old patients, a lower infiltration of CD163+ macrophages (p = 0.036) as well as CD4+ (p = 0.019) and CD8+ (p = 0.026) lymphocytes was found in the tumor microenvironment. Chronological older patients showed significantly lower PD-L1 combined positive scores (p = 0.030). Advanced tumor stage and perineural growth were related to a worse DFS. None of the immunological markers showed a significant association with DFS. Biological age might have a stronger influence on tumor microenvironment than chronological age. These findings should initiate clinical studies investigating the response to specific treatment regimens (e.g., immunotherapy) according to the biological age.

Head and Neck Squamous Cell Carcinoma Presenting With Leptomeningeal Carcinomatosis and Myeloradiculopathy via Perineural Growth

San Luis, Carmela V. MD*; Breaux, Sarah MD*; Sotoudeh, Houman MD†; Fallon, Kenneth MD‡; Nozaki, Kenkichi MD, PhD* Author Information

The Effect of Tumor Characteristics and Location on the Extent of Lymph Node Metastases of Head and Neck Cutaneous Squamous Cell Carcinoma.

BackgroundThe extent of a neck dissection for patients with metastasis of cutaneous squamous cell carcinoma of the head and neck (HNcSCC) is still subject to debate and clear guidelines are lacking. Tumor characteristics like size, differentiation and tumor location are known risk factors for lymph node metastasis (LNM). There is some evidence that, depending on tumor location, LNM follows a specific pattern. This study aims to identify which tumor characteristics can predict the pattern and extent of LNM.MethodIn this cohort study 80 patients were included, who underwent a primary neck dissection for LNM of HNcSCC between 2003 and 2018 at the University Medical Center Groningen, the Netherlands. Retrospective data was collected for primary tumor characteristics and LNM and included surgical and follow-up data. Influence of tumor characteristics on the extent of LNM was analyzed using non-parametric tests. Logistic regression analysis were used to identify a metastasis pattern based on the primary tumor location.ResultsOnly primary tumor location was associated with the pattern of LNM. HNcSCC of the ear metastasized to level II (OR = 2.6) and the parotid gland (OR = 3.6). Cutaneous lip carcinoma metastasized to ipsilateral and contralateral level I (OR = 5.3). Posterior scalp tumors showed a metastasis pattern to level II (OR = 5.6); level III (OR = 11.2), level IV (OR = 4.7) and the parotid gland (OR = 10.8). Ear canal tumors showed a low risk of LNM for all levels. The extent of LNM was not related to age or any tumor characteristics i.e. tumor diameter, infiltration depth, differentiation grade, perineural growth and vascular invasion.ConclusionPrimary tumor location determines the LNM pattern. Whereas known unfavorable tumor characteristics did not relate to the extent of LNM. Location guided limited neck dissection combined with parotidectomy will treat most patients adequately.

Parasympathetic Nerve Fibers in the Tumor Microenvironment as a Novel Biomarker Predicting Oncological Outcome in Perihilar Cholangiocarcinoma

Introduction: Perineural growth defined by the invasion of cancers cells to nerves and nerve fibers is a characteristic biological feature in perihilar cholangiocarcinoma (pCCA). Recently, nerve fiber density (NFD) was linked to oncological outcomes in various malignancies, however, its prognostic role in pCCA remains to be elucidated. Method: Data of 101 pCCA patients who underwent curative intent surgery between 2010 and 2019 were included in this study. Extensive group comparisons and univariate and multivariable cox regression models were carried out to determine the association of cancer-specific survival (CSS), recurrence-free survival (RFS) with NFD and other clinico-pathological characteristics. Results: Patients with high NFD showed a median CSS of 90 months (95% CI: 48-132, 3-year-CSS=77%, 5-year-CSS=72%) compared to 33 months (95% CI: 19-47, 3-year-CSS=46%, 5-year-CSS=32%) in patients with low NFD (p=0.006 log rank). Further, N1 category (HR=2.84, p=0.001) and high NFD (HR=0.41, p=0.024) were identified as independent predictors of CSS in multivariable analysis. Patients with high NFD and negative lymph nodes, showed a median CSS of 90 months (3-year-CSS=88%, 5-year-CSS=80%), while patients either positive lymph nodes or low NFD displayed a median CSS of 51 months (3-year-CSS=59%, 5-year-CSS=45%) and patients with both positive lymph nodes and low NFD a median CSS of 24 months (3-year-CSS=26%, 5-year-CSS=16%, p=0.001 log rank). Conclusions: This study identifies NFD as an important novel prognostic biomarker in pCCA patients. NFD alone and in combination with nodal status in particular, allow to stratify patients based on their oncological risk after curative-intent surgery.

Differentiation of Benign From Malignant Sinonasal Masses Using Diffusion Weighted Imaging and Dynamic Contrast Enhanced Magnetic Resonance Imaging.

The sinonasal region is affected by a variety of neoplasms. A differentiation between benign and malignant masses is essential both for management and prognostication. Morphological analysis often does not allow this differentiation. This article aims to assess the value of advanced MRI (diffusion [DWI] and dynamic contrast enhanced MRI [DCE-MRI]) in differentiation of benign and malignant sinonasal masses. This prospective study included 40 patients with sinonasal masses who underwent advanced MR on 3T MR scanner. The lesions were analyzed based on morphological characteristics, qualitative, quantitative diffusion parameters, and time signal intensity curves. Apparent diffusion coefficient (ADC) values were acquired using b values of 50 and 1000 s/mm2. The accuracy of DWI, DCE-MRI, and combined DWI/DCE-MRI in differentiating benign from malignant sinonasal masses were analyzed. Perineural extension and growth pattern of the tumor were the best morphological discriminators. Mean ADC values for benign and malignant lesions were 1.675 ± 0.561 and 0.903 ± 0.405 × 10-3 mm2/sec, ,respectively. ROC revealed that ADC cutoff value of 1.005 × 10-3 mm2/sec provided an accuracy of 92.5% in differentiating benign from malignant masses (P value <.01). On excluding the benign vascular masses (Juvenile Nasopharyngeal Angiofibroma and hemangioma), the time signal intensity curve showed 78% accuracy (P value <.001). The highest diagnostic performance was achieved by combining DWI and DCE-MRI (95% accuracy). DWI has higher accuracy than DCE-MRI. Quantitative DWI is preferable over qualitative DWI. Accuracy of DCE-MRI can be increased by excluding vascular masses with characteristic imaging features. DWI and DCE-MRI have the highest accuracy when used in combination than either of them alone in differentiating benign from malignant sinonasal masses.

Nerve Fibers in the Tumor Microenvironment as a Novel Biomarker for Oncological Outcome in Patients Undergoing Surgery for Perihilar Cholangiocarcinoma

Introduction: Perihilar cholangiocarcinoma (pCCA) is a biliary tract cancer with a dismal prognosis, with surgery being the only chance of cure. A characteristic aggressive biological feature of pCCA is perineural growth which is defined by the invasion of cancer cells to nerves and nerve fibers. Recently, nerve fiber density (NFD) was linked to oncological outcomes in various malignancies; however, its prognostic role in pCCA remains to be elucidated. Materials and Methods: Data of 101 pCCA patients who underwent curative-intent surgery between 2010 and 2019 were included in this study. Extensive group comparisons between patients with high and low NFD were carried out, and the association of cancer-specific survival (CSS) and recurrence-free survival with NFD and other clinicopathological characteristics was assessed using univariate and multivariable cox regression models. Results: Patients with high NFD showed a median CSS of 90 months (95% CI: 48–132, 3-year CSS = 77%, 5-year CSS = 72%) compared to 33 months (95% CI: 19–47, 3-year CSS = 46%, 5-year CSS = 32%) in patients with low NFD (p = 0.006 log rank). Further, N1 category (HR = 2.84, p = 0.001) and high NFD (HR = 0.41, p = 0.024) were identified as independent predictors of CSS in multivariable analysis. Patients with high NFD and negative lymph nodes showed a median CSS of 90 months (3-year CSS = 88%, 5-year CSS = 80%), while patients with either positive lymph nodes or low NFD displayed a median CSS of 51 months (3-year CSS = 59%, 5-year CSS = 45%) and patients with both positive lymph nodes and low NFD a median CSS of 24 months (3-year CSS = 26%, 5-year CSS = 16%, p = 0.001 log rank). Conclusion: NFD has been identified as an important novel prognostic biomarker in pCCA patients. NFD alone and in combination with nodal status in particular allows to stratify pCCA patients based on their risk for inferior oncological outcomes after curative-intent surgery.

Validated Prognostic Nomograms for Patients With Parotid Carcinoma Predicting 2- and 5-Year Tumor Recurrence-Free Interval Probability.

Introduction: Salivary gland malignancies are rare tumors with a heterogenous histological and clinical appearance. Previously, we identified multiple prognostic factors in patients with parotid cancer and developed prognostic indices which have repeatedly been validated internationally, demonstrating their general applicability and lasting relevance. Recently, nomograms gained popularity as a prognostic tool. Thus, in this research we aimed to construct nomograms based on our previous validated prognostic models.Material and Methods: Nomograms were constructed using the previously reported dataset of 168 patients with parotid cancer which was used to develop pre- and postoperative prognostic scores, PS1 and PS2, respectively. Concordance indices for PS1 and PS2 were previously estimated at 0.74 and 0.71, respectively, and are in line with other, widely accepted oncological nomograms.Results: Pre- and postoperative nomograms predicting 2- and 5-year tumor recurrence-free survival probability are presented. All previously multivariately identified and validated prognostic factors, are incorporated (T size, N classification, pain, age at diagnosis, skin invasion, facial nerve dysfunction, perineural growth, and positive surgical margins). Examples of clinical application and interpretation are given.Conclusions: The presented prognostic nomograms for predicting 2- and 5-year tumor recurrence-free probability in patients with parotid cancer are powerful, user-friendly, visual tools and are based on internationally validated prognostic indices. They allow for a reliable prognostic assessment and result in a more individualized estimate of the risk for recurrence than the prognostic grouping based on PS1 and PS2. This facilitates assigning trial-patients to risk groups, and may assist in therapeutic decision making and determining appropriate follow-up intervals in clinical practice.

Postcolonoscopy Colorectal Cancer in Sweden From 2003 to 2012: Survival, Tumor Characteristics, and Risk Factors

The rate of postcolonoscopy colorectal cancer (PCCRC) is a measure of colonoscopy quality, but there are conflicting results from studies of survival times of patients with PCCRC. We assessed survival times of patients with PCCRC and characterized the microscopic and macroscopic features of postcolonoscopy colorectal tumors. We performed a population-based cohort study using data from a database in Sweden, on 458,937 colonoscopies (54.0% women) performed from 2003 through 2012. Rates of colorectal cancer within 3 years of a colonoscopy were calculated based on the World Endoscopy Organization guidelines. Risk factors were evaluated using Poisson regression analysis. We used Cox regression models and Kaplan-Meier analyses, stratified by sex, to assess conditional survival. Logistic regression models were used to evaluate features of postcolonoscopy colorectal tumors, including stage location (right, left, or rectum) differentiation grade (high or low), synchronous tumors, perineural growth, resection margins, and mucinous and vessel characteristics. Within 36 months after a colonoscopy, there were 19,184 individuals who had received a diagnosis of CRC; 1384 of these were PCCRCs (7.2%). The proportion of individuals with PCCRC decreased from 9.4% in 2003 to 6.1% in 2012. The largest risk factors for PCCRC were a prior diagnosis of CRC (relative risk [RR], 3.31; 95% CI, 2.71-4.04), ulcerative colitis (RR, 5.44; 95% CI, 4.75-6.23), Crohn's disease (RR, 3.81; 95% CI, 2.98-4.87), and prior polypectomy (RR, 2.32; 95% CI, 1.97-2.72). Individuals with PCCRCs had shorter survival times than individuals with CRCs detected during the index colonoscopy. Multivariate hazard ratios for PCCRC were 2.75 for men (95% CI, 2.21-3.42) and 2.00 for women (95% CI, 1.59-2.52), respectively. Individuals with left-side PCCRC had shorter survival times than patients with CRC detected during the index colonoscopy. Postcolonoscopy colorectal tumors had increased odds of low differentiation grade (odds ratio, 1.27; 95% CI, 1.09-1.49) compared with colorectal tumors detected during the index colonoscopy. In an analysis of colonoscopies in Sweden, the rate of PCCRCs decreased from 9.4% in 2003 to 6.1% in 2012. Diseases that require surveillance (such as prior colorectal neoplasms and inflammatory bowel diseases) are the largest risk factors for PCCRC. Patients with PCCRC have shorter survival times than patients with CRC detected during their initial colonoscopy-especially women and patients with left-side tumors.

Intramedullary Metastasis to the Cervical Spinal Cord from Malignant Pleural Mesothelioma: Review of the Literature and Case Reports.

Context:Malignant mesothelioma is an aggressive tumor; median survival of patients following diagnosis is 12 months.Aims:Pleural malignant mesothelioma tends to spread along preexisting tissue planes and has the rare ability to spread along the nerve root into the spinal cord. In our case, there is an evidence of exceptional direct hematogenous spread to the spinal cord by the spinal branch of the intercostal arteries or the veins of Batson's plexus.Settings and Design:The authors report a case of intramedullary hematogenous metastasis to the cervical spinal cord from malignant mesothelioma, with a review of the literature.Materials and Methods:A 68-year-old male was admitted to our department because of a slowly progressive mild weakness of both low extremities, more pronounced on the left side. The patient has been treated for a malignant mesothelioma with left thoracotomy and subsequently underwent radiotherapy. Magnetic resonance imaging of the cervical-thoracic spine revealed a contrast-enhancing intramedullary expansive lesion of the left half of the spinal cord at the C6–C7 level.Results:The patient underwent surgical treatment through a C6–C7 laminectomy. Through a median posterior spinal cord incision, an intramedullary grayish lesion was completely removed. The paraparesis progressively improved and 20 days after surgery, the patient had regained normal lower extremity function.Conclusions:Malignant mesothelioma can spread to the spinal canal by the direct extension through the intervertebral foramina, by hematogenous spread to the spinal meninges, and by perineural growth along a single nerve root. The cleavage plane of the tissue may determine whether a successful gross total resection can be achieved with a good outcome for the patient.

High CXCR4 expression in adenoid cystic carcinoma of the head and neck is associated with increased risk of locoregional recurrence

AimTreatment options for head and neck adenoid cystic carcinoma (AdCC) are limited in advanced disease. Chemokine receptor type 4 (CXCR4) is present in various tumour types, including AdCC. Upregulation is...

Lost in translation: confusion on resection and dissection planes hampers the interpretation of pathology reports for perihilar cholangiocarcinoma

Background: In perihilar cholangiocarcinoma (PHC) interpretation of the resection specimen is challenging for pathologists and clinicians alike. Thorough and correct reporting is necessary for reliable interpretation of residual disease status. The aim of this study is to assess completeness of PHC pathology reports in a single center and assess what hampers interpretation of pathology reports by clinicians. Material and Methods: Pathology reports of patients resected for PHC at a single expert tertiary center drafted between 2000 and 2018 were assessed. Reports were assessed regarding completeness, according to the guideline of the International Collaboration on Cancer Reporting (ICCR). Results: A total of 146 reports were assessed. Prognostic tumor characteristics as vasoinvasive growth and perineural growth, were missing in 30/146 (34%) and 22/146 (15%), respectively. One or more planes were missing in 94/146 (64%) of the reports, with the periductal dissection plane missing in 51/145 (35%) (Figure 1). Residual disease could be re-classified from R0 to R1 in 22 patients(15%). Reasons for R1 in these patients were the presence of a positive periductal dissection plane (n = 2), < 1 mm margin at the periductal dissection plane (n = 11) or liver parenchyma (n = 9). Completeness of reports improved significantly when drafted by an expert HPB pathologist. Conclusion: This study demonstrates that pathology reporting of PHC is challenging. Reports are frequently incomplete and often do not incorporate assessment of all resection planes and the dissection plane. The periductal dissection plane is frequently overlooked, but is a major cause of residual disease.

Roles of Proteoglycans in the Tumourigenesis and Development of Adenoid Cystic Carcinoma and Pleomorphic Adenoma of the Salivary Gland: A Systematic Review.

Salivary adenoid cystic carcinoma (ACC) and pleomorphic adenoma (PA) are the most common types of salivary gland tumours; the former is malignant and the latter is benign but with features of a border tumour. Proteoglycans (PGs) produced by neoplastic myoepithelial cells are ubiquitous in both types of tumours. However, normal myoepithelial cells of salivary glands do not have the ability to secrete PGs. When the synthesis of PGs is blocked, the pulmonary metastasis and perineural growth of salivary ACC as well as the implanting growth of salivary PA are inhibited, highlighting the important functions of PGs in the tumourigenesis and development of these two tumours. In this review, we summarise literature from the past 40 years, including more recent findings from our laboratory, to clarify the pivotal roles of PGs produced by neoplastic myoepithelial cells in both the histogenesis and biological behaviours of ACC and PA.

Lost in translation: confusion on resection and dissection planes hampers the interpretation of pathology reports for perihilar cholangiocarcinoma

In perihilar cholangiocarcinoma (PHC), interpretation of the resection specimen is challenging for pathologists and clinicians alike. Thorough and correct reporting is necessary for reliable interpretation of residual disease status. The aim of this study is to assess completeness of PHC pathology reports in a single center and assess what hampers interpretation of pathology reports by clinicians. Pathology reports of patients resected for PHC at a single expert tertiary center drafted between 2000 and 2018 were assessed. Reports were assessed regarding completeness, according to the guideline of the International Collaboration on Cancer Reporting (ICCR). A total of 146 reports were assessed. Prognostic tumor characteristics such as vasoinvasive growth and perineural growth were missing in 30/146 (34%) and 22/146 (15%), respectively. One or more planes were missing in 94/146 (64%) of the reports, with the periductal dissection plane missing in 51/145 (35%). Residual disease could be re-classified from R0 to R1 in 22 patients (15%). Reasons for R1 in these patients were the presence of a positive periductal dissection plane (n = 2), < 1-mm margin at the periductal dissection plane (n = 11), or liver parenchyma (n = 9). Completeness of reports improved significantly when drafted by an expert HPB pathologist. This study demonstrates that pathology reporting of PHC is challenging. Reports are frequently incomplete and often do not incorporate assessment of all resection planes and the dissection plane. The periductal dissection plane is frequently overlooked, but is a major cause of residual disease.

High podoplanin and low E-cadherin levels correlate with better prognosis in adenoid cystic carcinoma.

ObjectivesAs tumour spread is a complicating event for malignant salivary gland tumours, we decided to study factors related to cell adhesion and lymph vessel formation in two of the three most common malignant salivary gland tumours, mucoepidermoid carcinoma (MEC) and adenoid cystic carcinoma (ACC), to clarify the clinical relevance and potential usefulness of these factors. We also included a group of polymorphous adenocarcinoma (PAC) as this tumour, in common with ACC often shows perineural growth, but in contrast to ACC has an overall good prognosis.Material and methodsEighteen patients with ACC, 15 with MEC, and six with PAC were included. Protein expression of podoplanin and E‐cadherin was evaluated as percentage of cells expressing the protein and intensity of expression. Ki‐67 expression was included in the study as a marker of proliferative activity.ResultsLooking at podoplanin, significantly more ACCs were high expressing compared with both MECs (P = .001) and PACs (P = .028). Also when looking at Ki‐67 expression, significantly more ACCs were high expressing compared with MECs (P = .003). Significantly better survival was also seen for ACCs with high podoplanin (P = .022) and low E‐cadherin expression (P = .021), respectively.ConclusionsOur findings show that ACCs express significantly higher levels of podoplanin compared with both MECs and PACs and that high levels are correlated to better survival. Even though the group of PACs analysed was small, these tumours, despite their tendency to perineural spread, which they have in common with ACC, differ from ACCs concerning expression of factors with a known connection to tumour spread.

The prognostic value of sentinel lymph nodes on distant metastasis–free survival in patients with high-risk squamous cell carcinoma

BackgroundCutaneous squamous cell carcinoma (cSCC) is the second most common cutaneous cancer worldwide. Several tumour characteristics are considered to pose an elevated risk for systemic spread of carcinoma cells (‘high-risk’ features). Early detection of subclinical metastases could permit early treatment and improve overall survival. To detect occult metastases and evaluate risk of future distant metastases, diagnostic extirpation of the sentinel lymph node (SLNE) is routinely performed in cutaneous melanoma and can be offered in high-risk cutaneous squamous cell carcinoma (hrcSCC). However, the clinical utility of SLNE in patients with hrcSCC remains unknown. Material and methodsAn ambidirectional cohort study with prospective patient recruitment was performed. Between July 2008 and April 2017, of 139 eligible patients, SLNE was performed in 114 cases (25 patients refused). Median follow-up was 23.7 months. ResultsWe analysed the characteristics of 114 patients with hrcSCC who underwent SLNE. Eighty-nine patients (78.1%) were men, and 25 patients (21.9%) were women (median age 72.2 years). In multivariable analyses, histopathological detection of ulceration (hazard ratio, HR 2.9 [95% confidence interval, CI 0.7–12.2]), perineural growth (HR 3.0 [95% CI 0.6–14.6]) and clinically occult SLN metastases (HR 10.7 [95% CI 1.9–60.6]) were strongly associated with future occurrence of distant metastases. A positive predictive value of 50% was noted for patients where SLN metastasis was detected to develop distant metastases. However, distant metastases also occurred in seven patients when histopathological SLN evaluation had shown no evidence of metastases. ConclusionsOur data suggest SLNE is not a reliable diagnostic approach to evaluate the risk of future systemic carcinoma spread and development of distant metastases in patients with hrcSCC.

Treatment-induced changes of lymphocyte subsets in patients with adenoid cystic carcinoma of the head and neck.

Adenoid cystic carcinoma (ACC) of the head and neck is a rare and highly malignant tumor, characterized by perineural growth and early distant metastases. The composition of immune cells in the peripheral blood and the tumor microenvironment is critical to tumor growth and control. However, little is known about the frequency and function of the relevant immune cell subsets in this entity. In ACC patients (n = 11) and matched healthy donors (n = 11), the frequency of peripheral blood T and B cells was measured by flow cytometry at different treatment stages of disease (24 samples). Cells were further characterized by their expression of CCR7, PD-1, CD39 and CD73. Tumor-infiltrating lymphocytes (TIL) were analyzed by immunohistochemistry for ten patients and for three patients by flow cytometry. CD4+ T cells had significantly lower frequency after radiotherapy (RT). All other cell frequencies, including Treg, were stable through course of the disease. In B cells, CD73 was reduced after RT. CCR7 expression on T and B cells in patients with relapse/metastases (R/M) differed significantly from patients with active disease. PD-1 remained stable. Treg were more present in TIL compared to peripheral blood. Composition of lymphocyte subgroups behaves similar to squamous cell carcinoma in the head and neck, except for Treg, which remained stable. Nevertheless, the CD4+/Treg ratio was lower after RT, which could stand for an immunosuppressive effect in these patients. Therefore, it could be beneficial treating ACC with combined RT and immunomodulatory drugs.

Abstract B13: Perineural invasion in Ewing sarcoma—a novel mechanism and new therapeutic opportunities

Abstract Tumor dissemination and relapse are the major problems in Ewing sarcoma (ES) treatment, yet the mechanisms driving these processes are unknown. To elucidate the routes of ES metastatic spread, we used an orthotopic xenograft model. ES cells were injected into the gastrocnemius muscles of SCID/beige mice. Once the primary tumors reached the desired volume, they were excised by limb amputation. Subsequently, tumor dissemination was monitored by MRI and confirmed by histopathologic analysis. Interestingly, aside from typical hematogenous metastases, such as bone and lung lesions, we have also observed frequent perineural tumor dissemination manifested by the presence of migratory ES cells along the nerves adjacent to the primary tumors. This phenomenon was associated with formation of recurrent tumors at the amputation sites, as well as pelvic tumors with spine involvement. Interestingly, the level of perineural invasion (PNI) was dependent on the expression of neuropeptide Y (NPY) in ES cells. NPY is a neuronal protein released from peripheral sympathetic neurons, but also highly expressed in ES cells along with its receptors. The xenografts derived from ES cell lines not releasing endogenous NPY (TC71, TC32) exhibited frequent PNI in tumor-bearing limbs, as well as a high number of recurrent tumors at the surgery site and spine metastases (70% and 100% of mice with evidence of PNI for TC71 and TC32 xenografts, respectively). This phenomenon was less common in ES xenografts derived from NPY-rich SK-ES1 cells (17% of mice with signs of PNI). In line with these observations, NPY knockdown in SK-ES1 xenografts drastically accelerated formation of spinal tumors (60% of mice). Notably, in 40% of mice bearing SK-ES1/NPY shRNA xenografts the spinal tumors developed before the primary tumor growth was detectable at the site of ES cell injection. Thus, our in vivo experiments suggested that a lack of endogenous NPY in ES cells expressing high levels of its receptors triggers chemotactic effects of this peptide released from neighboring peripheral nerves, facilitating PNI. Indeed, in a transwell migration assay, NPY exerted significant chemotactic activity in SK-ES1/NPY shRNA cells, but not in the original SK-ES1 cell line. An even more profound chemotactic effect specific to the SK-ES1/NPY shRNA cells was observed with NPY-rich conditioned media obtained from neuroblastoma cells, which can serve as a model of peripheral sympathetic neurons. Further studies are required to determine which NPY receptors are responsible for its chemotactic properties. If the presence of perineural tumor growth is confirmed in human tumors, factors responsible for PNI in ES, e.g., NPY receptors, may become targets for novel therapies preventing disease dissemination and recurrence. Citation Format: Susana Galli, Sung-Hyeok Hong, Jason U. Tilan, Mina Adnani, Shiya Zhu, Yassi Fallah, Yi-Chien Lee, Olga Rodriguez, Chris Albanese, Ewa Izycka-Swieszewska, Joanna Kitlinska. Perineural invasion in Ewing sarcoma—a novel mechanism and new therapeutic opportunities [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr B13.

The value of histological grading of biopsy and resection specimens in early stage oral squamous cell carcinomas

IntroductionIn oral squamous cell carcinoma (OSCC) the differentiation grade of the tumor is determined on the biopsy and the resection specimen. The relation between tumor grade, nodal metastasis and survival is debatable. The aims of this study were to determine the correlation between differentiation grade of the biopsy and the resection specimen. Furthermore, we wanted to correlate tumor differentiation grade with nodal stage and survival. Patients and methodsOne-hundred and forty-five patients with OSCC staged as T1-2, N0 of the tongue, floor of mouth or cheek with primary resection of the tumor were examined. Biopsy and resection specimen were histologically re-assessed with regard to differentiation grade, as well as infiltrative, peri-neural and vascular invasive growth. ResultsThis study showed a poor correlation between differentiation grade in the incisional biopsy and the resection specimen of the same tumor. No significant relation between differentiation grade of the resection specimen and nodal involvement, as well as overall and disease-specific survival was found. ConclusionIn early OSCC the differentiation grade determined by biopsy is of little predictive value for the grading of the resection specimen. Poor differentiation grade could not be related to the presence of nodal metastasis or survival and seems not to have any prognostic value concerning outcome. Treatment planning must be related to these findings.

Prevalence and Prognostic Significance of Extramural Venous Invasion in Patients with Locally Advanced Esophageal Cancer

BackgroundExtramural venous invasion (EMVI) is a known adverse prognostic factor in patients with colorectal carcinoma. The prevalence and significance of EMVI in esophageal cancer (EC) patients is still unclear.MethodsFrom a prospectively maintained database, we retrospectively reviewed the resection specimens of patients with pathologic locally advanced (pT3/T4/N0-3) EC who were treated with curative intent between 2000 and 2015. Patients with previous malignancies and gastroesophageal junction (type II/III) tumors were excluded. Included were 81 patients who underwent surgery alone and 37 patients who underwent neoadjuvant chemoradiotherapy (nCRT). EMVI was assessed on hematoxylin and eosin slides and confirmed or excluded by additional Elastica van Gieson staining. Survival was analyzed using a multivariable Cox regression.ResultsEMVI was present in 23.5% (n = 19) of patients in the surgery-alone group and 21.6% (n = 8) of patients in the nCRT group. The prevalence of EMVI after surgery alone was significantly high in squamous cell carcinomas and among tumors located in the mid-esophagus, as well as those with lymphovascular invasion (p < 0.05). After nCRT, the presence of EMVI was significantly high in tumors with lymphovascular and perineural tumor growth (p = 0.034). EMVI status was an independent adverse prognostic factor for disease-free survival [hazard ratio (HR) 7.0, 95% confidence interval (CI) 2.3–21.8; p =0.001] and overall survival (HR 6.5, 95% CI 2.2–19.1; p = 0.001) in the surgery-alone group for node-positive tumors.ConclusionsIn this study of locally advanced > pT3/N0-3 EC patients, EMVI was present in 23.5% of patients in the surgery-alone group and in 21.6% of patients after nCRT. EMVI was an independent adverse prognostic factor in patients after surgery alone.

Salivary duct carcinoma.

The review puts new information on geno- and phenotype of salivary duct carcinoma (SDC) in the perspective of the updated 2017 WHO classification. The proportion of SDC is increasing. This may be because of a true rise in incidence, but certainly to better diagnostic tests and changed WHO definitions. In this light, a substantial proportion of carcinoma expleomorphic adenoma is now attributed to the category of SDC. 'Low-grade SDC' and 'SDC in-situ' of the former WHO classification, are now named low-grade and high-grade intraductal carcinoma (IDC), respectively. Recent series quantify biologic aggressiveness: perineural growth, vascular invasion, and extracapsular extension in lymph node metastasis are each observed in two out of three patients with SDC. Most patients die within 3 years, but once 5-year disease-free survival is reached, further disease activity is exceptional. The typical molecular biological profile with high human epidermal growth factor receptor 2 and androgen receptor expression is increasingly successfully exploited in clinical trials for advanced SDC. The aggressive SDC is increasingly diagnosed. Despite intensive combined surgery and radiation therapy, many patients recur, for whom new bullets, targeting the molecular biological mechanisms, are the subject of ongoing clinical trials.