Introduction: Salivary duct carcinoma (SDC) is an aggressive and rare subtype of salivary gland carcinoma. Surgical excision and radiotherapy are standard of care for early cancer. Chemotherapies with taxanes and platinum show overall response rates between 39% and 50%. SDCs are often associated with an overexpression of the androgen receptor (AR) and HER2/neu which have recently become druggable targets. Case Presentation: Here, we report on an 84-year-old male patient with metastatic SDC of the right parotid gland. In 2017, he underwent a right total parotidectomy, a right neck dissection, and an infratemporal fossa clearance followed by 6 weeks of radiotherapy. In 2018, due to metastatic spread in the lungs, bones, and pararenal gland, a pathological workup of the tumor tissue was performed and revealed both AR and HER2 overexpression, respectively. Consequently, he underwent androgen deprivation therapy and, due to asymptomatic progression, sequentially human epidermal growth factor receptor 2 (HER-2)-targeted therapy with ado-trastuzumab emtansine and neratinib, which led to stable disease during the course of about 18 months. The electronically captured patient-reported outcome had demonstrated a good tolerance of all three therapeutic lines. Conclusion: In conclusion, since effective standard therapeutic treatment options for SDC may often not be tolerable in older patients, the implementation of personalized and adaptive treatments, especially in patients with rare tumor types, might offer valuable treatment options.

Integration of digital pathology (DP) into clinical diagnostic workflows is increasingly receiving attention as new hardware and software become available. To facilitate the adoption of DP, the Swiss Digital Pathology Consortium (SDiPath) organized a Delphi process to produce a series of recommendations for DP integration within Swiss clinical environments. This process saw the creation of 4 working groups, focusing on the various components of a DP system (1) scanners, quality assurance and validation of scans, (2) integration of Whole Slide Image (WSI)-scanners and DP systems into the Pathology Laboratory Information System, (3) digital workflow—compliance with general quality guidelines, and (4) image analysis (IA)/artificial intelligence (AI), with topic experts for each recruited for discussion and statement generation. The work product of the Delphi process is 83 consensus statements presented here, forming the basis for “SDiPath Recommendations for Digital Pathology”. They represent an up-to-date resource for national and international hospitals, researchers, device manufacturers, algorithm developers, and all supporting fields, with the intent of providing expectations and best practices to help ensure safe and efficient DP usage.

Introduction Thrombotic thrombocytopenic purpura (TTP) can be difficult to diagnose. Gold standard treatment to date is plasma-based with or without immunosuppresssion depending on the absence or presence of autoantibodies in hereditary and acquired forms. We describe the first compassionate use case of recombinant ADAMTS13 (rADAMTS13) therapy in a pregnant patient with hereditary TTP (hTTP) who had previously suffered 2 ischemic strokes and one intra-uterine fetal death.

The expression of human epidermal growth factor receptor 2 (HER2) protein or gene transcripts is critical for therapeutic decision making in breast cancer. We examined the performance of a digitalized and artificial intelligence (AI)-assisted workflow for HER2 status determination in accordance with the American Society of Clinical Oncology (ASCO)/College of Pathologists (CAP) guidelines. Our preliminary cohort consisted of 495 primary breast carcinomas, and our study cohort included 67 primary breast carcinomas and 30 metastatic deposits, which were evaluated for HER2 status by immunohistochemistry (IHC) and in situ hybridization (ISH). Three practicing breast pathologists independently assessed and scored slides, building the ground truth. Following a washout period, pathologists were provided with the results of the AI digital image analysis (DIA) and asked to reassess the slides. Both rounds of assessment from the pathologists were compared to the AI results and ground truth for each slide. We observed an overall HER2 positivity rate of 15% in our study cohort. Moderate agreement (Cohen's κ 0.59) was observed between the ground truth and AI on IHC, with most discrepancies occurring between 0 and 1+ scores. Inter-observer agreement amongst pathologists was substantial (Fleiss´ κ 0.77) and pathologists' agreement with AI scores was 80.6%. Substantial agreement of the AI with the ground truth (Cohen´s κ 0.80) was detected on ISH-stained slides, and the accuracy of AI was similar for the primary and metastatic tumors. We demonstrated the feasibility of a combined HER2 IHC and ISH AI workflow, with a Cohen's κ of 0.94 when assessed in accordance with the ASCO/CAP recommendations.

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Background: When surgical axillary staging reveals residual metastatic deposits in breast cancer (BC) patients who had received neoadjuvant chemotherapy (NACT), axillary lymphonodectomy is indicated. In this study, we investigate whether it is reasonable to perform intraoperative frozen section (FS) of the removed sentinel lymph nodes (SLNs) in cases where NACT had been administered in patients who had a clinically negative nodal status at the time of diagnosis.Patients and methods: We analyzed data from 101 BCE patients with 103 carcinomas who were diagnosed between 2014 and 2021 and met the above-mentioned criteria.Results: In three cases (2.8% of the study group), histologically active tumor tissue was detected in the removed axillary LNs. Discontinuation of therapy/the use of a low-dose NACT regimen was a significant factor for positive LNs (p = 0.02) at the subsequent surgical procedure; tumor progression during therapy approached borderline significance (p = 0.058). Among patients who had completed NACT with the planned standard dose regimen, and in which the primary tumors showed a response to therapy (n = 94), only one case had histologically detected residual metastases in the SLNs.Conclusions: Certified breast centers aim to improve the outcome of the patients. However, these specialized centers should also focus on economic aspects. This means that diagnostic and therapeutic procedures should be continuously critically reviewed in order to avoid unnecessary expenses. In BC patients with clinically node negative disease who completed NACT as planned and in which the tumor showed a good response to therapy, time consuming and costly FS of the SLNs removed should be omitted.& COPY; 2023 Elsevier Ltd, BASO -The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Sickle cell disease (SCD) is an autosomal recessive, single gene disorder caused by a point mutation in the beta globin (HBB) gene. The single amino acid substitution of the haemoglobin molecule leads to aberrant β-chain formation, polymerizing sickled haemoglobin (HbS) molecules together during episodes of deoxygenation and therefore causing intracellular sickling. Hydroxyurea (HU) is still the most indicated drug inducing fetal hemoglobin (HbF) production for SCD treatment, especially for the SCD patients with a severe clinical profile. In this study we could identify transcriptional profiles in erythroid cells of SCD patients, which have been treated with HU in comparison to untreated SCD patients and healthy controls.Our present transcriptomic profile analysis contained a new subset of genes identified for the first time as associated with SCD. In SCD non-treated-derived erythroid cells compared to controls, 398 differentially expressed genes (DEGs) were identified, of which 100 genes were upregulated and 298 genes were downregulated in the SCD patient cells. 65 DEGs were identified in SCD HU-treated patient-derived erythroid cells compared to controls, of which 37 genes were upregulated and 28 genes were downregulated. 212 DEGs were identified in SCD HU-treated patient-derived compared to SCD non-treated derived erythroid cells, of which 113 genes were upregulated and 99 genes were downregulated. 141 DEGs were identified in SCD derived erythroid cells compared to controls, of which 58 genes were upregulated and 83 genes were downregulated. We found biological processes such as oxidative phosphorylation pathway, Fanconi anaemia pathway, adaptive immune response or inflammatory response to be part of our significantly enriched Gene Ontology (GO) terms. Further genes encoding significantly enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways for proteasome, autophagy, immune response, platelet activation, as well as for natural killer cell (NK) cytotoxicity, oxidative phosphorylation, Fanconi anaemia pathway, ribosome biogenesis were upregulated in both SCD non treated and SCD HU-treated patient-derived erythroid cells in comparison to healthy controls. Our findings collectively suggest different as well as common molecular signatures between SCD non-treated, SCD HU-treated compared to HC. We could validate 12 of our top significant genes by qRT-PCR (calneuron 1 (CALN1), nucleoporin 85 (NUP85), tumor protein 63 (TP63), ras and rab interactor 2 (RIN2), solute carrier family 44 member 5 (SLC44A5), phenylethanolamine N-methyltransferase (PNMT), stabilin 1/ clever-1 (STAB1), SLX1 Homolog A, Structure-Specific Endonuclease Subunit (SLX1A), ATPase phospholipid transporting 9A (ATP9A), MSH5-SAPCD1, G protein subunit gamma 4 (GNG4) and glutathione S-transferase theta 2B (GSTT2B)) and compare their mRNA levels in bone marrow and spleen tissue from the Berkely SCD mouse model.In short, our study could identify new genes and pathways that may be involved in the SCD disease pathogenesis and that may be influenced by the HU treatment. The findings encourage future characterization of their roles in SCD to establish these findings as basis for new therapeutic targets.### Competing Interest StatementThe authors have declared no competing interest.

A 27-year-old patient with a history of severe obstetrical complications and arterial thrombosis received a diagnosis of hereditary thrombotic thrombocytopenic purpura (TTP) due to severe ADAMTS13 deficiency when she presented with an acute episode in the 30th week of her second pregnancy. When the acute episode of hereditary TTP became plasma-refractory and fetal death was imminent, weekly injections of recombinant ADAMTS13 at a dose of 40 U per kilogram of body weight were initiated. The patient's platelet count normalized, and the growth of the fetus stabilized. At 37 weeks 1 day of gestation, a small-for-gestational-age boy was delivered by cesarean section. At the time of this report, the patient and her son were well, and she continued to receive injections of recombinant ADAMTS13 every 2 weeks. (Funded by the Swiss National Science Foundation.).

Abstract Immunotherapy, including PD-1/PD-L1 agonists, has shown limited efficacy in pancreatic ductal adenocarcinoma (PDAC). We examined the PD-1/PD-L1 expression and immunoarchitectural features by automated morphometric analysis using multiplex immunofluorescence and 118 microsatellite-stable, treatment–naïve, surgically resected PDACs (study cohort). Five microsatellite-instable cases were stained in parallel (MSI cohort). Molecular analysis was additionally performed. An independent PDAC cohort (n = 226) was immunostained for PD-L1 and used as a validation cohort. PD-L1 expression on tumor cells (TC) and/or immune cells (IC) was present in 32% and 30% of the study and validation cohorts, respectively, and assigned into one of four patterns: “adaptive-1” (TC: 0, IC > 1%), “adaptive-2” (TC > 1% to < 25%, IC > 1%), “constitutive” (TC ≥ 25%, IC: 0), and “combined” (TC ≥ 25%, IC > 1%). “Constitutive” tumors were characterized by reduced numbers of all ICs and poor outcome. In contrast, “adaptive-1” tumors exhibited abundant T cells, including high counts of cytotoxic CD3+CD8+ and PD-1+CD3+CD8+ cells, but low counts of PD-L1+CD3+CD8+ cells and associated with the best outcome. “Adaptive-2” tumors displayed higher proportions of PD-L1+CD3+CD8+ T cells and tumor-associated macrophages (CD68+ and CD68+CD206+) compared with “adaptive-1” tumors. In the “combined” pattern, extensive PD-L1 expression on TCs was accompanied by increased numbers of T cells and improved overall survival. ICs were closer to PD-L1− than to PD-L1+ PDAC cells. TP53 and PIK3CA alterations tended to be more frequent in PD-L1+ tumors. The 5 MSI cases were PD-L1−. The distinct PD-1/PD-L1–associated immunoarchitectural patterns underpin the heterogeneity of the immunologic responses and might be used to inform patient outcomes and therapeutic decisions in pancreatic cancer.

Background Effective workflow management in a diagnostic pathology laboratory is critical to achieve rapid turnover while maintaining high quality. Fluorescence in situ hybridization analysis (FISH) is the preferred technique for detecting single chromosomal aberrations in diagnostic surgical pathology. Material and methods FISH analysis applying a rapid hybridization protocol and using an automated whole-slide fluorescence scanning device (3DHISTECH, Sysmex, Switzerland) were implemented in our workflow. By analyzing 42 diagnostic cases, effects of two different scanning profiles on scanning time, and device memory usage were investigated. Manual signal counting (CaseViewer) and software based signal counting (FISHQuant) were compared. Results The two scanning profiles, both including a Z-stack function, differed in their exposure time and digital gain. The “low profile” setting (LP) resulted in a significantly shorter scanning time and lower storage volume compared to the “high profile” (HP) setting, making the LP ideal for routine applications. Both signal counting methods (manual versus software based) provided similar cut-offs on a test-cohort of 13 samples. Conclusion Scanning FISH slides provides good picture quality, reduces the analysis time and allows easy picture archiving and facilitates remote diagnostics, allowing an effective workflow.

Pleomorphic lobular carcinoma (PLC) of the breast with osteoclast like giant cells (OGC) is a very rare variant of lobular carcinoma associated with tumour-associated macrophages (TAM) in the microenvironment. High content of TAM in breast cancer is associated with poor survival rates. Using genomic testing for the individual risk assessment in breast cancers with special features of their microenvironment might be skewed by the fact, that most recommended tests investigate proliferation and oestrogen receptor associated genes of tumour cells in their risk stratification but do not take into consideration the microenvironment. So far, no disease-specific molecular alteration could be identified in NST and lobular invasive carcinoma with OGC.

Mixed adenoneuroendocrine carcinoma (MANEC) is a rare, aggressive tumor arising from different localizations along the gastrointestinal tract with generally poor prognosis. We present the case of a 51-year-old female patient with histopathologically confirmed diagnosis of a MANEC of the descending colon. At presentation, the tumor had already spread to the liver causing extensive hepatic metastases. Immunohistochemical examination showed 5%-10% of tumor cells to express the programmed cell death receptor ligand 1 and FoundationOne testing revealed a high mutational tumor burden with 149 Muts/Mb. The patient responded very well clinically and radiologically to anti-programmed death 1 receptor monoclonal antibody pembrolizumab therapy after having undergone 3 previous systemic treatment regimens as well as selective internal radiation therapy of her hepatic metastases. Clinical improvement was evident after the first infusion already and is ongoing for 10 months so far with very little side effects including initial and short lived skin irritation as well as muscle pain. To our knowledge, this is the first published case where a MANEC was successfully treated with immunotherapy targeting the programmed death 1 receptor.

This study was designed to investigate the presence of residual breast tissue (RBT) after skin-sparing mastectomy (SSM) and nipple-sparing mastectomy (NSM) and to analyse patient- and therapy-related factors associated with RBT. Skin-sparing mastectomy and NSM are increasingly used surgical procedures. Prospective data on the completeness of breast tissue resection is lacking. However, such data are crucial for assessing oncologic safety of risk-reducing and curative mastectomies.

Lobular neoplasia (LN), invasive lobular breast cancer (ILBC) and related pleomorphic variants represent a distinct group of neoplastic mammary gland lesions. This study assessed the inter-observer agreement of histological grading in a series of ILBC and LN. 54 cases (36x ILBC, 18x LN) were evaluated by 17 observers. 3978 classification calls on various histological features, including nuclear grade, proliferative activity (Ki67 immunohistochemistry, categorical scoring), histological grade and pleomorphism were obtained. Pairwise Cohen's kappa values were calculated and compared between various features and different observer subsets with variable histomorphological experience. In ILBC, pairwise inter-observer agreement for histological grade ranged from poor to almost perfect concordance and was higher in advanced and experienced histopathologists compared with beginners (P < 0.001). Agreement for proliferation (Ki67) ranged from slight to almost perfect concordance and was also higher in advanced and experienced histopathologists (P < 0.001). Considering different features, agreement for proliferation (Ki67) was superior to agreement for histological grade and nuclear grade, even among advanced and experienced histopathologists (P < 0.001). In LN, agreement for B-classification ranged from poor to almost perfect concordance and was higher in advanced and experienced histopathologists (P < 0.001). Considering different features, agreement for proliferation (Ki67 in LN) was superior to subclassification agreement based on conventional features, such as acinar distention and nuclear grade (P < 0.001). In summary, pairwise inter-observer concordance of histological grading of ILBC and LN is dependent on histomorphological experience. Assessment of proliferation by Ki67 immunohistochemistry is associated with favorable inter-observer agreement and can improve histological grading of ILBC as well as LN.

BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) is a potentially life-threatening complication of transplantation occurring in the setting of immunosuppression and oncogenic viral infections. However, little is known about the cumulative incidence, histological subtypes, risk determinants and outcome of PTLD in solid organ transplant (SOT) recipients in Switzerland. METHODS: This retrospective observational study investigated adult SOT recipients from two sequential cohorts, the pre-SCTS (Swiss Transplant Cohort Study) series, with data collected from January 1986 to April 2008, and the STCS series, with data collected from May 2008 to December 2014 in Switzerland. SOT recipients were cross-referenced with the data of all the patients with a lymphoma diagnosis in each transplant centre and with the data of the Swiss Transplant Cohort Study (STCS) to determine the cumulative incidence of PTLD, pre-therapeutic clinical features, clinical course and outcome. Kaplan-Meier analysis was performed for overall survival after PTLD. RESULTS: We identified 79 cases of PTLD during the study period in the two cohorts: pre-STCS from 1986 to 2008 (n = 62) and STCS from 2008 to 2014 (n = 17). Histological subgroups included: early lesions (pre-STCS n = 2, STCS n = 0); polymorphic PTLD (pre-STCS n = 8, STCS n = 7); monomorphic PTLD (pre-STCS n = 47, STCS n = 10), and Hodgkin's lymphoma (pre-STCS n = 5, STCS n = 0). Median time to PTLD diagnosis was 90 months (range 3-281 months) and 14 months (range 2-59 months) in the pre-STCS and STCS cohorts, respectively. Median follow-up after transplantation was 141 months for the pre-STCS patients and 33 months for the STCS patients. Cumulative incidences of PTLD during the STCS period at 0.5, 1 and 5 years were 0.17% (95% confidence interval 0.07-0.46%), 0.22% (0.09-0.53%) and 0.96% (0.52-1.80%), respectively. For the pre-STCS case series, it was not possible to estimate the incidence rate of PTLD. Survival after PTLD diagnosis was 80% (68-87%) at 1 year and 56% (42-68%) at 5 years for the pre-STCS and STCS cohorts combined. CONCLUSIONS: At 5 years, the cumulative incidence of PTLD, regardless of the organ transplanted, was only 0.96% in the STCS cohort, which is lower than that reported in the literature.

BACKGROUND:Primary cutaneous marginal zone lymphoma (PCMZL) is the second most common B-cell lymphoma of the skin. A recent study has demonstrated a strikingly high prevalence of immunoglobulin (Ig)G4 expression in PCMZL with plasmacytic differentiation.OBJECTIVE:The objective was to investigate the incidence of IgG4 expression in PCMZL, and its correlation with clinical and immunophenotypic features.MATERIALS AND METHODS:Multicenter study that utilized immunohistochemistry and in-situ hybridization to evaluate the expression of IgG4, Ig light (κ and λ), and heavy chains (IgM, IgG), and the ratio of T (CD3+) and B (CD20+) cells in biopsy specimens from 30 patients with PCMZL and to correlate these findings with the clinical features.RESULTS:IgG4 expression was observed in 4 out of 30 patients (13%) with PCMZL. Patients with IgG4-positive lymphomas were 57 to 77 years of age (mean, 69) at biopsy. The lesions were solitary in 2 patients with IgG4-positive lymphomas, and were most commonly located on the trunk. Patients with IgG4-negative lymphomas experienced earlier disease onset at an average age of 53 years. The majority of the IgG4-negative cases presented with localized disease, on the trunk and upper extremities. There was no significant difference in the IgG4-positive versus negative cases for the following parameters: Ig κ or λ restriction, B-cell or T-cell predominance, and site of the lesions.CONCLUSIONS:IgG4 expression was observed in a minority of PCMZL patients. We did not identify significant clinical or immunophenotypic differences between IgG4 positive and negative cases.

ABSTRACT Chromosomal translocations involving the immunoglobulin loci represent frequent oncogenic events in B-cell lymphoma development. Although IRF8 (ICSBP-1) protein expression has been demonstrated in germinal centre B-cells and related lymphomas in a single report, the IRF8 gene was not described as an IGH translocation partner. In a discovery driven approach we searched for new translocation partners of the IGH in DLBCL by long distance inverse (LDI) PCR and Sanger sequencing. A t(14;16)(q32.33;q24.1) IGH/IRF8 was detected in a CD5+ de novo DLBCL, confirmed by translocation specific PCR and FISH analysis. No further IRF8 aberration could be identified neither by LDI-PCR in additional five CD5+ DLBCL nor by FISH on 78 FFPE biopsies. Subsequent screening for IRF8 by immunohistochemistry revealed IRF8 expression in 18/78 (23%) correlating with a GCB type of DLBCL. This hitherto unknown translocation t(14;16)(q32.33;q24.1) is alike to represent the initiator of a multistep lymphomagenesis in a CD5+ de novo DLBCL. DOI: https://doi.org/10.3109/10428194.2013.793324 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-77888 Accepted Version Originally published at: Tinguely, Marianne; Thies, Svenja; Frigerio, Simona; Reineke, Tanja; Korol, Dimitri; Zimmermann, Dieter R (2014). IRF8 is associated with a GCB-type of DLBCL and exceptionally involved in a translocation t(14;16) (q32.33;q24.1). Leukemia Lymphoma, 55(1):136-142. DOI: https://doi.org/10.3109/10428194.2013.793324 © 2013 Informa UK, Ltd. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily refl ect those of Informa Healthcare (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted articles have undergone full scientifi c review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the fi nal print and fi nal online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication. Just Accepted by Leukemia & Lymphoma IRF8 is associated with a GCB-type of DLBCL and exceptionally involved in a translocation t(14;16) (q32.33;q24.1) Marianne Tinguely , Svenja Thies , Simona Frigerio , Tanja Reineke , Dimitri Korol , Dieter R. Zimmermann 10.3109/10428194.2013.793324

BACKGROUND:The tumor microenvironment is essential for tumor survival, growth and progression. There are only a few studies on the tumor microenvironment in cutaneous CD30-positive lymphoproliferative disorders. METHODS:We assessed the composition of the tumor microenvironment using immunohistochemistry studies in skin biopsies from cases diagnosed with lymphomatoid papulosis (LyP: 18 specimens), primary cutaneous anaplastic large-cell lymphoma (PC-ALCL: 8 specimens), and reactive diseases harboring CD30-positive cells (18 specimens). RESULTS:The predominant cells present in LyP and PC-ALCL were CD163+ M2 macrophages (44.7%, 35%), followed by CD8+ tumor infiltrating lymphocytes (11%, 15%), FOXP3+ T-regulatory cells (9%, 4.5%) and programmed cell death 1(PD-1) + lymphocytes (2.2%, 6.8%). In contrast, CD30-positive reactive inflammatory and infectious disorders were characterized by higher numbers of CD123+ plasmacytoid dendritic cells (6.3%) when compared to LyP (1%), and PC-ALCL (1.1%). CONCLUSIONS:Key differences exist between the microenvironment of CD30-positive lymphoproliferative disorders and reactive conditions harboring CD30-positive lymphocytes. The high number of tumor associated macrophages, and the close vicinity of these immune cells to the CD30-positive tumor cells might suggest that tumor associated macrophages have direct influence on tumorigenesis in LyP and ALCL. Therefore, modulation of M2 macrophages may represent a new therapeutic strategy in cutaneous CD30-positive lymphoproliferative disorders.