Gold standard for immunohistochemical analyses is the manual assessment by two specialist pathologists. This process is time-consuming, highly dependent on the respective evaluator and often difficult to reproduce. The use of image analysis software, such as ImageJ, QuPath, or CellProfiler, which employ machine learning and/or deep learning mechanisms to perform biomarker analyses, offers a potential solution to these problems. The objective of our study is to evaluate whether digital assessment using the open-source software QuPath is comparable to manual evaluation and to examine the inter-evaluator variability between the two manual evaluators and two software-based evaluations. Six tissue microarrays (TMAs) were constructed for a cohort of 309 patients with primary oral squamous cell carcinoma (OSCC). The tumor tissue and corresponding non-lesional squamous epithelial mucosa specimen were immunohistochemically stained for the biomarkers Ki67, as a nuclear marker; the epidermal growth factor receptor (EGF-R), as a membranous marker; and the major histocompatibility complex class I (MHC-I) heavy chain (HC) expressed on the membrane and in the cytoplasm. The staining pattern was analyzed by two experienced, independent manual evaluators and by QuPath. The percentage of positive cells, for Ki67, and the histoscore (H-score) based on the percentage of positive cells and their staining intensity, for EGF-R and MHC-I, were determined as final values. The results yielded high to excellent spearman correlation coefficients for all three biomarkers (p<0.001) in lesional and non-lesional tissues. The Bland-Altman plots demonstrated a high degree of agreement between manual and software-based analysis, as well as inter-evaluator variability demonstrating a high comparability of the evaluation methods. However, a prerequisite for a proper software-based analysis is an accurate, time-consuming annotation of the single specimen, which requires users with a comprehensive understanding of histology and extensive training in QuPath. Once these requirements are met, the software-based analysis offers advantages for large-scale biomarker studies due to objective and reproducible comparability of the stainings leading to a greater accuracy as well as the reuse of established conditions across similar analyses without requiring further operator input.

ZusammenfassungKonkremente des Tränenapparates, sog. Dakryolithen, können an unterschiedlichen Lokalisationen auftreten und führen zu verschiedenen klinischen Zeichen. Gemeinsam ist das Auftreten chronischer Entzündungen, die akut exazerbieren können. Anhand einer Literaturrecherche sowie deskriptiver Vorstellung und Korrelation der Klinik mit histopathologischen Befunden sollen die wichtigsten Informationen zur Epidemiologie, Ätiopathogenese, Zusammensetzung, Histologie und Therapie gegeben werden. Weiterhin werden die bekannten Einflussfaktoren zur Lithogenese im Tränensack zusammengefasst. Konkremente der Tränendrüse zeigen eine Schwellung im Bereich des lateralen Kanthus. Die häufig nur mit leichten Schmerzen einhergehende Veränderung führt oft auch zu einer umschriebenen konjunktivalen Hyperämie. Histologisch ist das Gewebe der Tränendrüse von einer akut-erosiven bis chronischen Entzündungsreaktion gekennzeichnet. Die Konkremente bestehen aus amorphem Material. Das entzündliche Infiltrat ist von neutrophilen Granulozyten dominiert. Tränenröhrchensteine sind in hohem Maße mit dem klinischen Bild einer chronischen Kanalikulitis assoziiert. Klinisch liegen zumeist eine Epiphora und ein purulenter Sekretausfluss im Bereich des betroffenen Tränenröhrchens vor. Die Konkremente der Tränenröhrchen weisen typischerweise Actinomyces-Drusen auf. Das umgebende Gewebe reagiert mit einer plasmazellulären sowie granulozytären Infiltration. Dakryolithen (Konkremente des Tränensackes) manifestieren sich im Rahmen einer Dakryozystitis, wobei hier sowohl akute als auch chronische Entzündungen vorkommen. Sie werden in bis zu 18% der Dakryozystorhinostomien gefunden und stellen eine große diagnostische Herausforderung dar. Wiederkehrende episodenhafte Epiphora mit mukopurulenter Sekretion und akuter Dakryozystitis sind typisch. Zumeist besteht eine Spülbarkeit der ableitenden Tränenwege. Histologisch imponiert ein lymphozytäres Infiltrat mit submuköser Fibrose. Unmittelbar angrenzend zu den Konkrementen finden sich Zeichen einer akuten Entzündungsreaktion. Das therapeutische Mittel der Wahl ist die Extraktion der Konkremente und die Beseitigung der Tränenabflussstörung, da hierin ein wichtiger Faktor zur Entstehung gesehen wird.

Concrements of the lacrimal apparatus, known as dacryoliths, can occur at different localizations and can cause a variety of symptoms. A common clinical sign is chronic inflammation, possibly exhibiting acute exacerbation. Based on a literature review and descriptive clinical cases with histopathological correlations, this contribution summarises the most important information concerning epidemiology, aetiopathogenesis, composition, histology, and therapy of lacrimal concrements. Furthermore, factors known to affect lacrimal lithogenesis are addressed. Concrements of the lacrimal gland cause a swelling at the lateral canthus. With only mild pain, this manifests as circumscribed conjunctival hyperaemia. Histologically, the gland tissue is characterised by acute-erosive to chronic inflammation. The concrements consist of amorphic material. Inflammatory infiltration is dominated by neutrophil granulocytes. Canalicular concrements are highly correlated with chronic canaliculitis. Besides epiphora, patients present with purulent discharge at the affected canaliculus. Actinomyces are frequently found inside these deposits and form drusen-like formations. The surrounding tissue reacts with plasma-cellular and granulocytic inflammation. Dacryoliths (concrements of the lacrimal sac) are associated with dacryocystitis, whereby acute and chronic types are common. Stones can be found in up to 18% of patients undergoing dacryocystorhinostomy or dacryoendoscopy. Preoperative diagnostic testing is challenging, as many lacrimal sac stones cannot be reliably visualised by diagnostic procedures. Recurring episodes of epiphora, mucopurulent discharge, and dacryocystitis are common indicators of dacryoliths. Lacrimal syringing is often possible and shows that total blockage is not present. Histology of the lacrimal mucosa reveals lymphocytic infiltration and submucosal fibrosis. The immediate vicinity of the dacryoliths shows acute inflammation. Therapy consists of stone extraction and improving lacrimal drainage, as the latter is recognised as the main risk factor for dacryolith formation.

Lymphome werden in Hodgkin-Lymphome und Non-Hodgkin-Lymphome eingeteilt. Insgesamt gehören Lymphome mit einer Inzidenz von 2,5% im Kopf-Hals-Bereich zu den zweithäufigsten malignen Tumorgeschehen nach den Plattenepithelkarzinomen. In der Regel sind der Waldeyersche Rachenring, die Nasenhöhle/Nasennebenhöhlen, die Orbita oder die Speicheldrüsen betroffen. Eine Beteiligung des Schläfenbeins im Rahmen eines generalisierten Lymphoms wird beschrieben, wobei eine primäre Manifestation im Bereich des Schläfenbeins ohne eine systemische Beteiligung in der Literatur eine Seltenheit darstellt. Wir berichten über eine 73-jährige Patientin welche von auswärts in unsere Klinik verlegt wurde mit einem auf eine Otitis externa maligna verdächtigen Befund. Initial bestand eine ausgeprägte Schwellung im Bereich der linken Schläfe. Bildmorphologisch stellte sich zusätzlich eine ausgeprägte extrakranielle Weichteilschwellung temporal dar sowie ausgedehnte knöcherne Destruktionen im lateralen Anteil der Pars squamosa. Bei permeativem Muster der Osteolysen wurde der radiologische Verdacht auf ein Lymphom geäußert, sodass eine histologische Sicherung angestrebt wurde. Es erfolgte die Exzisionsbiopsie. Nach histopathologischer Aufarbeitung stellte sich eine diffuse Infiltration durch eine reife, hoch proliferationsaktive B-Zell-Neoplasie (CD20-positiv), im Speziellen eines diffus-großzelligen B-Zell-Lymphoms (DLBCL) dar. Im Rahmen einer Knochenmarkspunktion konnte keine beweisbare Manifestation erfolgen. In einer Positronenemissionstomographie zeigte sich neben dem Nachweis von aktivem Lymphomgewebe links temporal kein weiterer Befall, sodass eine Klassifikation nach Ann Arbor IV/E vorliegt bei primärer Infiltration des Mastoids und des äußeren Gehörgangs ohne systemische Beteiligung.

Lymphomas can be divided into Hodgkin lymphomas and non-Hodgkin lymphomas. Lymphomas are the second most frequent malignant tumors after squamous cell carcinomas, with an incidence of 2.5% in the head and neck region. It usually involves the Waldeyer's ring, the nasal cavity and/or paranasal sinuses, the orbit, or the salivary glands. Involvement of the temporal bone in the setting of generalized lymphoma has been described. Primary manifestation in the temporal bone only without systemic involvement is a rarity in the literature.

The extracellular matrix component biglycan (BGN) plays an essential role in various physiological and pathophysiological processes. A deficient BGN expression associated with reduced immunogenicity was found in HER-2/neu-overexpressing cells. To determine whether BGN is suppressed by oncogene-driven regulatory networks, the expression and function of BGN was analyzed in murine and human BGNlow/BGNhigh K-RASG12V-transformed model systems as well as in different patients' datasets of colorectal carcinoma (CRC) lesions. K-RAS-mutated CRC tissues expressed low BGN mRNA and protein levels when compared to normal colon epithelial cells, which was associated with a reduced patients' survival. Transfection of BGN in murine and human BGNlow K-RAS-expressing cells resulted in a reduced growth and migration of BGNhigh vs BGNlow K-RAS cells. In addition, increased MHC class I surface antigens as a consequence of an enhanced antigen processing machinery component expression was found upon restoration of BGN, which was confirmed by RNA-sequencing of BGNlow vs. BGNhigh K-RAS models. Furthermore, a reduced tumor formation of BGNhigh versus BGNlow K-RAS-transformed fibroblasts associated with an enhanced MHC class I expression and an increased frequency of tumor-infiltrating lymphocytes in tumor lesions was found. Our data provide for the first time an inverse link between BGN and K-RAS expression in murine and human K-RAS-overexpressing models and CRC lesions associated with altered growth properties, reduced immunogenicity and worse patients' outcome. Therefore, reversion of BGN might be a novel therapeutic option for K-RAS-associated malignancies.

Introduction. Tumor cells are influenced by their microenvironment, including immune infiltration. These tumor infiltrating lymphocytes (TILs) are considered to have prognostic and predictive value for patients with early breast cancer. The aim of this study was to evaluate the distribution of TILs and the association with survival in unselected sample of breast cancers. Patients and Methods. From a prospective, multicenter cohort of 1,270 breast cancer patients (PiA, Prognostic Assessment in routine application, NCT 01592825), 1,136 samples were evaluated for TIL infiltration inside the borders of the invasive tumor, following the recommendations of the international TILs working group. TILs were assigned to one of these three TILs groups: low TILs (<10%) intermediate (10-60%) and high TILs (>60%) and additionally scored as a continuous parameter per 10% increment. Primary objective was the distribution of TILs in different groups dependent on hormone receptor and HER2 status of the tumor (IHC group). Second objective was the association of TILs with recurrence free interval (RFI) and overall survival (OS) in univariate and multivariate analyses. The median observation time was 62 months (1-123). Results. Dependent on the IHC types a specific distribution of TILs was found: more than 60% TILs were detected in 1.5% (12 of 828) of hormone receptor (HR) positive and HER2 negative tumors, 9.7% (17 of 175) of HER2 positive tumors with any HR status and 18.8% (25 of 133) of triple negative breast cancer (TNBC). Patients with HR positive and HER2 negative tumors showed no impact of TILs with regard to RFI and OS. In the HER2 positive group with more than 60% TILs, no RFI event was detected, and with less than 60% TILs, 15% of the patients had an RFI event. The probability of OS was 94% (TILs >60%) and 81% (TILS ≤60%). For TNBC and the same TIL cut off, 88% had no RFI and OS event, compared to 70% with no event for RFI and 74% for OS. Applying 10% increments of TILs to the entire cohort, the multivariate analysis revealed a hazard ratio of 0.895 (95% CI 0.796-1.007) for RFI and a significant hazard ratio of 0.890 (95% CI 0.794-0.997) for OS. Considering the IHC groups, a 10% increment of TILs in HER2 positive tumors led to an increase of RFI (0.792, 95% CI 0.601-1.043) and OS (0.713, 95% CI 0.533-0.955, p<0.05) and in TNBC an increase of RFI (0.906, 95% CI 0.773-1.063) and OS (0.941, 95% CI. 0.795-1.115). There was no effect of TILs for patients with HR positive tumors. For the HER2 positive group the highest likelihood of a significant effect was determined for a cut-off of 20% (RFI: 2.467, 95% CI 0.903-6.735, p=0.078; OS: 4.565, 95% CI 1.583-13.159, p=0.005), for TNBC the highest likelihood was found at a cut-off of 5% (RFI: 1.440, 95% CI 0.627-3.308, p=0.390; OS: 2.035, 95% CI 0.906-4.571, p=0.085). Conclusion. Using data from our multicenter, consecutive enrolled cohort, TILs were ascertained as an independent even not significant prognostic factor for patients with HER2 positive and TN tumours. A 10% increment of TILs led to a 21% better disease specific survival (RFI) for patients with HER2-positive tumors and a 10% better RFI for patients with TNBC. Hence, for clinical implementation of prognostic assessment, we would suggest to use 20% as the cut-off for HER2 positive tumors and 5% for TN tumors. Citation Format: Kathleen Schüler, Daniel Bethmann, Tilmann Lantzsch, Christoph Uleer, Volker Hanf, Susanne Peschel, Jutta John, Marleen Pöhler, Joerg Buchmann, Karl-Friedrich Buerrig, Edith Weigert, Eva Johanna Kantelhardt, Christoph Thomssen, Martina Vetter. Tumor infiltrating lymphocytes as a prognostic factor [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-07-15.

Tumour-infiltrating lymphocytes (TILs) are considered to have prognostic and predictive value for patients with early breast cancer. We examined 1166 breast cancer patients from a prospective, multicentre cohort (Prognostic Assessment in Routine Application (PiA), n = 1270, NCT 01592825) following recommendations from the International TILs Working Group. TIL quantification was performed using predefined groups and as a continuous variable in 10% increments. The primary objective was the distribution of TILs in different breast cancer types. The second objective was the association with the recurrence-free interval (RFI) and overall survival (OS). Stromal infiltration with more than 60% TILs appeared in 2% of hormone receptor (HR)-positive and HER2-negative tumours, in 9.8% of HER2-positive tumours (any HR) and 19.4% of triple-negative breast cancers (TNBCs). Each 10% increment was associated with an improvement in the prognosis in HER2-positive samples (RFI, hazard ratio 0.773, 95% CI 0.587–1.017; OS, hazard ratio 0.700, 95% CI 0.523–0.937). When defining exploratory cut-offs for TILs, the use of a 30% threshold for the HR-positive and HER2-negative group, a 20% threshold for the HER2 group and a 60% threshold for the TNBC group appeared to be the most suitable. TILs bore prognostic value, especially in HER2-positive breast cancer. For clinical use, additional research on the components of immune infiltration might be reasonable.

BackgroundIntratympanic injections of glucocorticoids have become increasingly common in the treatment of idiopathic sudden sensorineural hearing loss (ISSHL). However, due to their fast elimination, sustained applications have been suggested for local drug delivery to the inner ear.Materials and methodsThe study is based on a retrospective chart review of patients treated for ISSHL at a single tertiary (university) referral center. We included patients who were treated with a solid, biodegradable, poly(D,L-lactic-co-glycolic acid) (PLGA)-based drug delivery system providing sustained delivery of dexamethasone extracochlear into the round window niche (n = 15) or intracochlear into scala tympani (n = 2) for tertiary therapy of ISSHL in patients without serviceable hearing after primary systemic and secondary intratympanic glucocorticoid therapy. We evaluated the feasibility and safety through clinical evaluation, histological examination, and functional tests [pure-tone threshold (PTA), word recognition scores (WRS)].ResultsWith adequate surgical preparation of the round window niche, implantation was feasible in all patients. Histologic examination of the material in the round window niche showed signs of resorption without relevant inflammation or foreign body reaction to the implant. In patients where the basal part of scala tympani was assessable during later cochlear implantation, no pathological findings were found. In the patients with extracochlear application, average preoperative PTA was 84.7 dB HL (SD: 20.0) and 76.7 dB HL (SD: 16.7) at follow-up (p = 0.08). The preoperative average maximum WRS was 14.6% (SD: 17.9) and 39.3% (SD: 30.7) at follow-up (p = 0.11). Six patients (40%), however, reached serviceable hearing. The two patients with intracochlear application did not improve.ConclusionThe extracochlear application of the controlled release system in the round window niche and – based on limited observations - intracochlear implantation into scala tympani appears feasible and safe. Due to the uncontrolled study design, conclusions about the efficacy of the treatment are limited. These observations, however, may encourage the initiation of prospective controlled studies using biodegradable controlled release implants as drug delivery systems for the treatment of inner ear diseases.

HER3 is highly expressed in luminal breast cancer subtypes. Its activation by NRG1 promotes activation of AKT and ERK1/2, contributing to tumour progression and therapy resistance. HER3-targeting agents that block this activation, are currently under phase 1/2 clinical studies, and although they have shown favorable tolerability, their activity as a single agent has proven to be limited. Here we show that phosphorylation and activation of HER3 in luminal breast cancer cells occurs in a paracrine manner and is mediated by NRG1 expressed by cancer-associated fibroblasts (CAFs). Moreover, we uncover a HER3-independent NRG1 signaling in CAFs that results in the induction of a strong migratory and pro-fibrotic phenotype, describing a subtype of CAFs with elevated expression of NRG1 and an associated transcriptomic profile that determines their functional properties. Finally, we identified Hyaluronan Synthase 2 (HAS2), a targetable molecule strongly correlated with NRG1, as an attractive player supporting NRG1 signaling in CAFs.

Introduction: Triple-negative breast cancer (TNBC) is considered the most aggressive type of breast cancer (BC) with limited options for therapy. TNBC is a heterogeneous disease and tumors have been classified into TNBC subtypes using gene expression profiling to distinguish basal-like 1, basal-like 2, immunomodulatory, mesenchymal, mesenchymal stem-like, luminal androgen receptor (LAR), and one nonclassifiable group (called unstable). Objectives: The aim of this study was to verify the clinical relevance of molecular subtyping of TNBCs to improve the individual indication of systemic therapy. Patients and Methods: Molecular subtyping was performed in 124 (82%) of 152 TNBC tumors that were obtained from a prospective, multicenter cohort including 1,270 histopathologically confirmed invasive, nonmetastatic BCs (NCT 01592825). Treatment was guideline-based. TNBC subtypes were correlated with recurrence-free interval (RFI) and overall survival (OS) after 5 years of observation. Results: Using PAM50 analysis, 87% of the tumors were typed as basal with an inferior clinical outcome compared to patients with nonbasal tumors. Using the TNBCtype-6 classifier, we identified 23 (15%) of TNBCs as LAR subtype. After standard adjuvant or neoadjuvant chemotherapy, patients with LAR subtype showed the most events for 5-year RFI (66.7 vs. 80.6%) and the poorest probability of 5-year OS (60.0 vs. 84.4%) compared to patients with non-LAR disease (RFI: adjusted hazard ratio [aHR] = 1.87, 95% confidence interval [CI] 0.69–5.05, p = 0.211; OS: aHR = 2.74, 95% CI 1.06–7.10, p = 0.037). Conclusion: Molecular analysis and subtyping of TNBC may be relevant to identify patients with LAR subtype. These cancers seem to be less sensitive to conventional chemotherapy, and new treatment options, including androgen receptor-blocking agents and immune checkpoint inhibitors, have to be explored.

Zusammenfassung Zielsetzung Es war das Ziel dieser Untersuchung, Daten zu epithelialen Speicheldrüsentumoren im Rahmen einer umfassenden monozentrischen und retrospektiven Analyse zu erheben. Material und Methoden Analysiert wurden Patienten mit einer epithelialen Speicheldrüsenneoplasie, welche zwischen 1993 und 2017 entweder die Klinik für Mund-, Kiefer- und Gesichtschirurgie (MKG) des Universitätsklinikums Halle (UKH) aufsuchten oder/und am Institut für Pathologie (IPA) des UKH diese Diagnose erhielten oder/und deren Diagnose zwischen 2000 und 2017 dem Statistischen Landesamt Sachsen-Anhalt gemeldet wurde. Folgende Parameter wurden erhoben: demografische Daten, Tumorlokalisation, Tumorentität, Klinik, Therapieverfahren und Verlauf. Die Daten wurden in einer Datenbank im Format SPSS 21.5 erfasst und statistisch analysiert. Ergebnisse Im Beobachtungszeitraum wurden unter Verwendung der Datenbanken der MKG sowie des IPA des UKH 382 Patienten mit einer epithelialen Speicheldrüsenneoplasie registriert. Die häufigste Tumorlokalisation entfiel auf die Gl. parotis mit 71 % (n = 271), während 15 % der Tumoren in den kleinen Speicheldrüsen auftraten (n = 57). Der Anteil benigner Speicheldrüsentumoren betrug 80 % (n = 307). Im genannten Zeitraum waren in Sachsen-Anhalt 5586 Patienten mit epithelialen Speicheldrüsentumoren gemeldet worden. Schlussfolgerung Unserer Kenntnis nach ist dies die erste epidemiologische Analyse zur Evaluation von Häufigkeit, Dignität und Therapie von epithelialen Speicheldrüsenneoplasien in Sachsen-Anhalt. Das pleomorphe Adenom mit der Vorzugslokalisation Ohrspeicheldrüse ist in unserer Analyse die häufigste Entität. Unter den malignen Pathologien dominiert das adenoid-zystische Karzinom, welches in der Regel von den kleinen Speicheldrüsen seinen Ausgang nimmt.

Progression of oral squamous cell carcinoma (OSCC) has been associated with an escape of tumor cells from the host immune surveillance due to an increased knowledge of its underlying molecular mechanisms and its modulation by the tumor microenvironment and immune cell repertoire. In this study, the expression of HLA class I (HLA-I) antigens and of components of the antigen processing machinery (APM) was analyzed in 160 pathologically classified human papilloma virus (HPV)-negative OSCC lesions and correlated to the intra-tumoral immune cell response, IFN-γ signaling and to the patient’s outcome. A heterogeneous but predominantly lower constitutive protein expression of HLA-I APM components was found in OSCC sections when compared to non-neoplastic cells. Tumoral HLA-I APM component expression was further categorized into the three major phenotypes HLA-Ihigh/APMhigh, HLA-Ilow/APMlow and HLA-Idiscordant high/low/APMhigh. In the HLA-Ihigh/APMhigh group, the highest frequency of intra-tumoral CD8+ T cells and lowest number of CD8+ T cells close to FoxP3+ cells were found. Patients within this group presented the most unfavorable survival, which was significantly evident in stage T2 tumors. Despite a correlation with the number of intra-tumoral CD8+ T cells, tumoral JAK1 expression as a surrogate marker for IFN-γ signaling was not associated with HLA-I/APM expression. Thus, the presented findings strongly indicate the presence of additional factors involved in the immunomodulatory process of HPV-negative OSCC with a possible tumor-burden-dependent complex network of immune escape mechanisms beyond HLA-I/APM components and T cell infiltration in this tumor entity.

Background This study aimed to analyze margin status and the impact of the immune elements on recurrence in patients with oral squamous cell carcinoma (OSCC), employing a prognostic biomarker, cumulative suppressive index (CSI), which reflects FoxP3+, PD-L1+, and CD8+ cell spatial relationships in the tumor microenvironment. Methods Cox proportional hazards regression was used to evaluate the interactive effect of the margin by CSI discrepancy (high, 3-4 vs low, 0-2) on recurrence free survival (RFS) and overall survival (OS) in 119 patients with stage I to IVA OSCC. Results In cases with negative margins, multivariable analysis showed high CSI was significantly associated with worse RFS (HR = 2.59, 95% CI [1.03, 6.49],P= .04) and OS (HR = 5.49, 95% CI [1.48, 20.35],P= .01) compared to low CSI. However, high CSI was not significantly associated with recurrence in cases with positive margins. Conclusions Immune architecture analysis can augment our current histopathological risk assessment of margin status.

Objective The purpose of this research was to analyze all epithelial salivary gland tumors in this region in a comprehensive monocentric, retrospective study. Material and methods In the period from 1993 to 2017, all patients with the diagnosis of epithelial salivary gland tumors either treated at the Department of Oral and Maxillofacial Plastic Surgery of the Martin Luther University, Halle-Wittenberg (MLU), University hospital and/ or processed at the Institute of Pathology of the MLU, University hospital and/or registered between 2000 and 2017 by the "Statistisches Landesamt" Sachsen-Anhalt were analyzed. The following parameters were summarized and statistically analyzed in a database using SPSS 21.5: demographic data, tumor localization, entity, therapy and disease course. Results 382 patients with the diagnosis of epithelial salivary gland neoplasia were identified. With 71 % the most frequent tumor localization was the glandula parotis [n = 271]. 15 % of the tumors originated from minor salivary glands [n = 57]. Most tumors were benign at over 80 % [n = 307]. In SaxonyAnhalt, 5586 patients with epithelial salivary gland tumors were reported in the mentioned period. Conclusion To the best of our knowledge this is the first epidemiologic analysis of frequency, valency and therapy of salivary gland tumors in Saxony- Anhalt. The results confirm the predominance of benign epithelial salivary gland tumors, most of all pleomorphic adenoma in the glandula parotis. Concerning the group of malignant epithelial salivary gland tumors adenoid cystic carcinoma located in theminor salivary glands were most common.

Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls .

β2-m, β2-microglobulin; CAF, cancer associated fibroblast; CSC, cancer stem cell; CTL, cytotoxic T lymphocyte; DC, dendritic cell; ECM, extracellular matrix; EGF-R, epidermal growth factor receptor; ER, endoplasmic reticulum; FDA, Food and Drug Administration; HLA, human leukocyte antigen; HNSCC, head and neck squamous cell carcinoma; HPV, human papilloma virus; ICP immune checkpoint; ICPi, immune checkpoint inhibitor; IFN, interferon; LMP, low molecular weight protein; mAb, monoclonal antibody; MDSC, myeloid-derived suppressor cell; mTOR, mammalian target of rapamycin; MSI, multispectral imaging; NK, natural killer; OS, overall survival; PBL, peripheral blood lymphocytes; PBMNC, peripheral blood mononuclear cells; PD1, programmed death receptor 1; PD-L1, programmed death ligand 1; PFS, progression-free survival; PI3K, phosphatidyl-linositol-3-kinase; R/M, recurrence and or metastatic; STAT, signal transducer and activator of transcription; TAA, tumor-associated antigen; TAM, tumor associated macrophages; TAP, transporter associated with antigen processing; TCR, T cell receptor; TIL, tumor-infiltrating lymphocyte; TLS, tertiary lymphoid structure; TME, tumor microenvironment; Treg, regulatory T cell; TSA, tumor-specific antigen; VEGF, vascular endothelial growth factor; VEGF-R, vascular endothelial growth factor receptor.

Immunotherapy has been recently approved for the treatment of relapsed and metastatic human papilloma virus (HPV) positive and negative head and neck squamous cell carcinoma (HNSCC). However, the response of patients is limited and the overall survival remains short with a low rate of long-term survivors. There exists growing evidence that complex and partially redundant immune escape mechanisms play an important role for the low efficacy of immunotherapies in this disease. These are caused by diverse complex processes characterized by (i) changes in the expression of immune modulatory molecules in tumor cells, (ii) alterations in the frequency, composition and clonal expansion of immune cell subpopulations in the tumor microenvironment and peripheral blood leading to reduced innate and adaptive immune responses, (iii) impaired homing of immune cells to the tumor site as well as (iv) the presence of immune suppressive soluble and physical factors in the tumor microenvironment. We here summarize the major immune escape strategies of HNSCC lesions, highlight pathways, and molecular targets that help to attenuate HNSCC-induced immune tolerance, affect the selection and success of immunotherapeutic approaches to overcome resistance to immunotherapy by targeting immune escape mechanisms and thus improve the HNSCC patients' outcome.