Clinicopathologic studies underlying the WHO-EORTC classification and new guidelines for the treatment of cutaneous lymphomas

Primary cutaneous lymphoma form a seperate group of non-Hodgkin lymphoma. Apart from the usual nodal presentation of a lymphoma, less frequently a lymphoma develops in an extranodal site. The skin is, after the gastrointestinal tract, the most frequent site of extranodal lymphoma. If the skin is the primary site of involvement, i.e. no extracutaneous sites are involved at diagnosis, these lymphomas are called primary cutaneous lymphoma. In this thesis different types of primary cutaneous lymphoma are evaluated and discussed. In chapter 2 a large group of primary cutaneous CD30+ lympoproliferations is described and compared with a group of systemic CD30+ ALCL with skin localisations. Lymphomatoid papulosis and primary cutaneous CD30+ CTCL are closely related conditions and should be considered as a spectrum, with a comparable, excellent, prognosis. Multiagent chemotherapy (MAC) could not induce long lasting remissions, in fact all patients treated with MAC developed one or more (cutaneous) relapses. Therefor MAC is only indicated in case of extracuteneous localisations. In chapter 3 a group of CD30-negative T-cell lymphomas presenting in the skin that could not be diagnosed as MF, SS or SPTL are evaluated. In this group there were few survivors, apart from a rare group of patients with primary cutaneous lymphoma with small-medium sized CD4+/CD8-neoplastic T-cells (less than 30% large cells). In particular, patients with localized disease had an excellent prognosis. In chapter 4 haematological malignancies presenting in the skin and expressing CD56 were collected, both from the Dutch cutaneous lymphoma group and literature. In general these types of malignancies had a poor prognosis, except for patients with primary cutaneous CD30+ LPD, that showed a similar good prognosis as CD56-negative cases. Most cases belonged to the group of nasal-type NK/T-cell lymphoma and the group of CD4+, CD56+ hematodermic neoplasm (formerly also designated as blastic NK-cell lymphoma. In addition, CD56 was expressed in some SPTL, rare primary cutaneous CD30-negative large T-cell lymphomas, skin localisations of acute myeloid leukemia and CD30+ CTCL. In most of these groups CD56 expression did not affect prognosis. However, in SPTL CD56 expression proved a marker for gamma/delta T-cell origin and these cases showed a poorer prognosis as compared to SPTL with an alpha/beta phenotype (that were usually CD56-negative). In the new WHO-EORTC classification the category of SPTL only includes cases with an alpha/beta-positive phenotype, whereas cases with a gamma/delta positive phenotype are included in the provisional category of cutaneous gamma/delta-positive T-cell lymphoma. In chapter 5 a rare case of lymphomatoid papulosis with CD56-expression was presented and the frequency of co-expression of CD56 in primary cutaneous CD30+ LPD was analyzed. CD56 expression was found in approximately 10% of CD30+ LPD (both LyP and primary CD30+ CTCL). However, these CD56+ cases were not found to have a different prognosis from CD56 negative cases. In chapter 6 a European multicenter study on primary cutaneous large B-cell lymphomas is presented. Patients with primary cutaneous large B-cell lymphoma of the leg showed a poorer prognosis as patients with primary cutaneous follicle center cell lymphoma (PCFCCL). Moreover, round cell morphology was identified as a poor prognostic parameter. Although this was closely related to presentation on the leg(s), also in the group of PCFCCL the presence of a predominance of cells with round nuclei (centroblasts and immunoblasts) was associated with a poorer prognosis. The results of this study contributed to a new category in the WHO-EORTC classification, designated primary cutaneous large B-cell lymphoma (PCLBCL), leg-type, indicating that both patients with the classical presentation on the leg(s) as patients showing the same morphology and immunophenotype (bcl-2+, Mum-1/ IRF4+) on other sites are included in this group. Presentation with multifocal lesions proved to be a poor prognostic parameter for PCLBCL-leg-type, but not for PCFCCL. In chapter 7 treatment results in multifocal primary CBCL were analyzed. The main question in this study was if PCFCCL presenting with multifocal skin lesions should be treated with MAC. The study showed that MAC is only indicated in PCLBCL, leg-type and not in (multifocal) PCFCCL. Radiotherapy on multiple sites appeared equally effective as MAC in these patients. In chapter 8 the frequency of CNS-involvement in CBCL patients of the Dutch cutaneous lymphoma group. was evaluated. The frequency was low. Only 4/140 patients with a primary CBCL developed CNS involvement in the course of their disease. Interestingly 3 of these 4 patients were PCFCCL, a lymphoma usually with an excellent prognosis. Only 4 disease related deaths were reported in this group of which 3 with CNS involvement. The reason for this relatively high prevalence of CNS involvement in PCFCCL is unclear. The studies presented in this thesis have provided important information, which has contributed to the recent development of the WHO-EORTC classification. Moreover, they have contributed to updated guidelines for the treatment of the different types of primary cutaneous lymphomas, as presented in TABLE 2 in chapter 9.Beka-Nova informatiesystemen BV, GlaxoSmithKline/ GlaxoWellcome, 3M Nederland B.V., Leo-pharma BV, Bauerfeind Benelux BV, Novartis, Galderma, Fagron, Wyeth pharmaceuticals BV, Roche Nederland BV, Ligand pharmaceuticals.UBL - phd migration 201

Clinicopathological Profile of Sinonasal Tumors – A Five Year Study.

The nasal cavity and paranasal sinuses including the maxillary, ethmoid, sphenoid and frontal sinuses are collectively referred to as the sinonasal tract. The sinonasal tract is anatomically and embryologically distinct from the nasopharynx. Although the sinonasal tract and nasopharynx have identical appearing ciliated respiratory epithelium, the epithelium of the sinonasal tract is ectodermally derived, while that of nasopharynx is endodermally derived. This embryologic difference may be a factor in the development of certain epithelial lesions unique to these surfaces eg.schneiderian papillomas of sinonasal tract and nasopharyngeal carcinomas.7 The mucosa of the nasal cavity and paranasal sinuses is often referred to as schneiderian mucosa to emphasize its ectodermal origin as opposed to the endodermal origin of the morphologically identical mucosa lining the rest of the respiratory tract. Nasal stroma is well vascularised fibromuscular tissue. This is occasionally misinterpreted as a vascular malformation or a vascular tumour. In the paranasal sinuses a layer of thin cancellous bone supports this mucosal and stromal arrangement.8 Tumors of the nasal cavity and paranasal sinuses are rare pathologies with extremely varied etiopathology,clinical behaviour,treatment and prognosis. The symptoms of the neoplastic processes are essentially similar to inflammatory pathology of the sinonasal tract with resultant delay of diagnosis. The clinical and radiological features of masses of nasal cavity and paranasal sinuses are overlapping and often only a provisional diagnosis is possible. Definite diagnosis requires histopathological examination as most of the lesions are inaccessible for fine needle aspiration or FNAC is not recommended because of fear of haemorrhage. In our attempt at a comprehensive analysis of 200 sinonasal tumors a heterogenous and a wide variety of benign and malignant neoplasms were encountered. Rare entities like craniopharyngioma,schwannoma and osteoid osteoma among benign tumors and malignant melanoma,fibrosarcoma, metastatic clear cell carcinoma among malignant tumors were reported. To conclude, categorizing the sinonasal tumors according to histopathological features into various types helps us to understand the clinical presentation, treatment, clinical outcome and prognosis. The key in the diagnosis and treatment of sinonasal tumors remains a high index of suspicion and early diagnosis, as late presentation and delay in early diagnosis are major constraints to favourable outcome of treatment

International Consensus Statement on Allergy and Rhinology: Sinonasal Tumors

BACKGROUND: Sinonasal neoplasms, whether benign and malignant, pose a significant challenge to clinicians and represent a model area for multidisciplinary collaboration in order to optimize patient care. The International Consensus Statement on Allergy and Rhinology: Sinonasal Tumors (ICSNT) aims to summarize the best available evidence and presents 48 thematic and histopathology-based topics spanning the field. METHODS: In accordance with prior International Consensus Statement on Allergy and Rhinology documents, ICSNT assigned each topic as an Evidence-Based Review with Recommendations, Evidence-Based Review, and Literature Review based on the level of evidence. An international group of multidisciplinary author teams were assembled for the topic reviews using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses format, and completed sections underwent a thorough and iterative consensus-building process. The final document underwent rigorous synthesis and review prior to publication. RESULTS: The ICSNT document consists of four major sections: general principles, benign neoplasms and lesions, malignant neoplasms, and quality of life and surveillance. It covers 48 conceptual and/or histopathology-based topics relevant to sinonasal neoplasms and masses. Topics with a high level of evidence provided specific recommendations, while other areas summarized the current state of evidence. A final section highlights research opportunities and future directions, contributing to advancing knowledge and community intervention. CONCLUSION: As an embodiment of the multidisciplinary and collaborative model of care in sinonasal neoplasms and masses, ICSNT was designed as a comprehensive, international, and multidisciplinary collaborative endeavor. Its primary objective is to summarize the existing evidence in the field of sinonasal neoplasms and masses

Epidemiology, prognosis and treatment of aggressive non-Hodgkin lymphomas

PhD ThesisThe concept of aggressive non-Hodgkin lymphoma (NHL) originates in the Working Formulation classification of NHL and describes a heterogeneous group of NHLs. Despite the introduction of the WHO classification the term ‘aggressive non- Hodgkin lymphoma’ still remains in clinical use. This work will focus on some important aspects of epidemiology, clinical presentation, prognosis, treatment and treatment outcome in two main subtypes of aggressive lymphoma: diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma (PTCL). DLBCL is the most common NHL occurring more frequently in older patients and is characterised by heterogeneous histology. The current standard treatment is immunochemotherapy with cyclophosphamide, doxorubicine, vincristine, prednisone (CHOP) and anti-CD20 antibody rituximab. Approximately 50-60% of patients eventually die from DLBCL. Depending on the patient’s age, two different approaches can be defined in order to improve the outcome in DLBCL. In younger patients, the better risk stratification and prediction of response to standard therapy can help to define the high-risk groups suitable for new, more intensive therapy approaches. In elderly patients, where already delivery of standard chemotherapy is difficult, the introduction of the targeted therapies and its combination with new less toxic chemotherapy regimens could be seen as a future approach. Targeted therapies can be also adopted in younger patients. It was aimed to describe DLBCL in a population-based setting in order to obtain the realistic picture of disease, define the needs of patients and develop a prognostic model based on expression of molecular factors in routine formalin fixed paraffin embedded (FFPE) tissue samples using quantitative polymerase chain reaction (qPCR) for identification of high risk patients. A population-based study on 1863 DLBCL patients described picture of disease, therapy and outcome. Importantly, it revealed that a significant number of patients (30%) who did not receive standard chemotherapy were characterised by a very bad prognosis. Additionally, the duration of first remission was one of the most important factors for patient survival, suggesting first-line treatment should be escalated in suitable high-risk patients. The model based on expression of MYC, HLA-DRΒ and variant 2 of the C13orf25 locus (v2-transcript) using qPCR was successfully established in FFPE tissue. Unfortunately, we could not confirm its predictive value in patient cohort. The preliminary work on expression of microRNA encoded in v2-transcript as predictive biomarker was performed in FFPE tissue and delivered promising results. PTCL is characterised by dismal outcome when treated with standard CHOP. The rarity and heterogeneity of the PTCL, lack of prospective trials in homogenous types of the PTCL as well as hesitation to use high intensity treatments can contribute to the poor outcome. It was aimed to collect prospective data in a population-based setting on clinical presentation, treatment and outcome of patients with enteropathy associated T-cell lymphoma (EATL), a subtype of PTCL, and to assess the role of a novel high-dose chemotherapy with ifosfamide, epirubicin, etoposide/methotrexate and autologous stem cell transplantation (IVE/MTX-ASCT) in EATL and other PTCL subtypes. The incidence of EATL in the studied population was 0.14/100 000 per year. The detailed picture of the disease at presentation was obtained. The prognosis was dismal when treated with conventional treatment with 5-years PFS and OS of 18% and 20%, respectively. The new IVE/MTX–ASCT regimen improved the patient outcome with the 5-years PFS and OS of 52% and 60%, respectively. The results of IVE/MTXASCT in other PTCL were also promising with 3-years PFS and OS of 65% and 72%, respectively.Bright Red Charity

Das Extramedulläre Plasmozytom - Recherche zu Tumorcharakteristika und Therapieprinzipien anhand von Literatur (1998-2018) und eigenem Patientenkollektiv -

1. Zusammenfassung 1.1. Hintergrund und Ziele Das Extramedulläre Plasmozytom (EMP) ist ein Plasmazelltumor, der formal zu den plasmozy-tischen Non-Hodgkin-Lymphomen zählt und eine lokale Manifestation außerhalb des Knochens zeigt. Das EMP gehört zu den niedrig-malignen Tumoren und kann mit einer Inzidenz von 4/100.000 als seltener Tumor bezeichnet werden. Die Therapie des EMP stellt eine Herausfor-derung dar, da es keine Leitlinien oder Ähnliches gibt, worauf sich Behandler stützen könnten. In dieser Arbeit soll durch eine umfangreich angelegte Literaturrecherche und eigene Patienten-untersuchungen eine möglichst repräsentative Fallzahl erreicht werden, um eine Empfehlung für eine Therapie hinsichtlich dieser Tumorentität zu formulieren. 1.1. Methoden (Patienten, Material, Untersuchungsmethoden) Diese retrospektive Literaturrecherche untersucht wichtige Charakteristika (Alter, Geschlecht, Lokalisation, Immunhistochemie, Leichtketten im Serum) des EMP sowie dessen Therapiemög-lichkeiten und deren Behandlungserfolg. Das Material, das für diese Arbeit analysiert wurde, setzt sich aus den Patientenfällen zusammen, die in der Uniklinik Erlangen an einem EMP be-handelt wurden, sowie dem Patientengut, welches über eine Literaturrecherche der Datenbank PubMed für den Zeitraum vom 01.01.1998 bis zum 31.12.2018 mit den Suchbegriffen „Extramedullary Plasmocytoma“ und „Extramedullary Plasmacytoma“ generiert werden konn-ten; wobei nur Artikel in deutsch und englisch berücksichtigt wurden. Die PubMed-Suche ergab 929 Artikel die darauf geprüft wurden, ob sie für die Auswertung relevant sind. Den Kri-terien dieses Auswahlprozesses entsprachen 408 Veröffentlichungen. Die Daten waren haupt-sächlich deskriptiver Natur. Die Überlebenszeitanalyse der vier untersuchten Therapiegruppen wurde anhand von Kaplan-Meier-Kurven durchgeführt. 1.2. Ergebnisse und Beobachtungen Aus der Literaturrecherche und dem eigenen Patientengut wurden 1.050 Fälle von EMPs ge-sammelt. Der Hauptteil der diagnostizierten EMPs befand sich mit 655 (62,38%) im oberen Aerodigestivtrakt (OAD), wohingegen 395 (37,62%) außerhalb des oberen Aerodigestivtrakts (AOAD) auftraten. Im OAD wurde für die rein chirurgische Therapie (OP) ein 5-Jahres-Überleben von 89,6% festgestellt. Die Radiotherapie (RT) zeigte ein 5-Jahres-Überleben von 91%. Bei der Kombina-tion Operation und Bestrahlung (OPRT) wurde ein 5-Jahres-Überleben von 96,5% beobachtet, während die sonstigen Therapieformen ein 5-Jahres-Überleben von lediglich 72,7% erzielten. Für den AOAD wurde für die rein chirurgische Therapie ein 5-Jahres-Überleben von 82,8% festgestellt. Die Radiotherapie zeigte ein 5-Jahres-Überleben von 90,6%. Bei der Kombination Operation und Bestrahlung wurde ein 5-Jahres-Überleben von 96,2% beobachtet, wobei mit 82,6% für die sonstigen Therapieformen ebenfalls hohe Werte erzielt wurden. 1.3. Schlussfolgerung Diese Arbeit stellt eine detaillierte Analyse von EMP-Fällen, die zwischen 1998 und 2018 ver-öffentlicht wurden, hinsichtlich der Charakteristika, Diagnostik und Therapie dieses seltenen Tumors dar. Es wird deutlich, dass das EMP vornehmlich im OAD auftritt und dass es sich für gewöhnlich an Stellen des Körpers manifestiert, an denen die Schleimhaut äußeren Einflüssen ausgesetzt ist. Basierend auf den Therapieangaben stellen die chirurgische Behandlung, die Strahlentherapie und die Kombination aus beiden die häufigsten Behandlungsstrategien der EMP dar, sowohl bei OAD als auch bei AOAD. Schlussendlich kann diese Arbeit keine definitive Aussage darüber treffen, welche der drei The-rapiemodalitäten die am besten geeignete zur Behandlung des EMP ist. Allerdings kann abgelei-tet werden, dass hohe Tumorkontrolle und lange Nachbeobachtungszeiten mit allen drei haupt-sächlich angewandten Therapien möglich ist und diese sich im Outcome nur geringfügig unter-scheiden. Weiterhin zeigt diese Untersuchung des EMP, dass weitere Studien, bestenfalls pros-pektive randomisierte Multicenterstudien, nötig sind, um die Frage nach der optimalen Behand-lung des EMP klären zu können

Acute Leukemia

This book provides a comprehensive overview of he basic mechanisms underlying areas of acute leukemia, current advances, and future directions in management of this disease. The first section discusses the classification of acute leukemia, taking into account diagnoses dependent on techniques that are essential, and thankfully readily available, in the laboratory. The second section concerns recent advances in molecular biology, markers, receptors, and signaling molecules responsible for disease progression, diagnostics based on biochips and other molecular genetic analysis. These advances provide clinicians with important understanding and improved decision making towards the most suitable therapy for acute leukemia. Biochemical, structural, and genetic studies may bring a new era of epigenetic based drugs along with additional molecular targets that will form the basis for novel treatment strategies. Later in the book, pediatric acute leukemia is covered, emphasizing that children are not small adults when it comes to drug development. The last section is a collection of chapters about treatment, as chemotherapy-induced toxicity is still a significant clinical concern. The present challenge lies in reducing the frequency and seriousness of adverse effects while maintaining efficacy and avoiding over-treatment of patients

Evaluation of PD-L1 expression in various formalin-fixed paraffin embedded tumour tissue samples using SP263, SP142 and QR1 antibody clones

Background & objectives: Cancer cells can avoid immune destruction through the inhibitory ligand PD-L1. PD-1 is a surface cell receptor, part of the immunoglobulin family. Its ligand PD-L1 is expressed by tumour cells and stromal tumour infltrating lymphocytes (TIL). Methods: Forty-four cancer cases were included in this study (24 triple-negative breast cancers (TNBC), 10 non-small cell lung cancer (NSCLC) and 10 malignant melanoma cases). Three clones of monoclonal primary antibodies were compared: QR1 (Quartett), SP 142 and SP263 (Ventana). For visualization, ultraView Universal DAB Detection Kit from Ventana was used on an automated platform for immunohistochemical staining Ventana BenchMark GX. Results: Comparing the sensitivity of two different clones on same tissue samples from TNBC, we found that the QR1 clone gave higher percentage of positive cells than clone SP142, but there was no statistically significant difference. Comparing the sensitivity of two different clones on same tissue samples from malignant melanoma, the SP263 clone gave higher percentage of positive cells than the QR1 clone, but again the difference was not statistically significant. Comparing the sensitivity of two different clones on same tissue samples from NSCLC, we found higher percentage of positive cells using the QR1 clone in comparison with the SP142 clone, but once again, the difference was not statistically significant. Conclusion: The three different antibody clones from two manufacturers Ventana and Quartett, gave comparable results with no statistically significant difference in staining intensity/ percentage of positive tumour and/or immune cells. Therefore, different PD-L1 clones from different manufacturers can potentially be used to evaluate the PD- L1 status in different tumour tissues. Due to the serious implications of the PD-L1 analysis in further treatment decisions for cancer patients, every antibody clone, staining protocol and evaluation process should be carefully and meticulously validated

Lymphoma in Australian Pet Dog and Cat Populations

This thesis is a study of the epidemiology, clinical presentations, response to treatment, and outcomes for dogs and cats in Australia. Included is a published paper that reviews the outcomes and prognostic factors in dogs with lymphoma, that highlights the deficiences many of the studies in the veterinary literature. The studies have identified novel breed risks in both dogs and cats and the relationships in cats between breed and the anatomical location of lymphoma. The outcome studies show that the response to treatment in dogs and cats in Australia align with those reported from Europe and North America. A finding in many of the analyses in the canine study, but in only one analysis in the feline study, was that the hospital was a statistically significant predictor of outcome. Additionally multiple breeds of dogs were able to be evaluated and assessed for the influence of breed on outcomes. These studies provide a needed update on lymphoma in Australian dog and cat populations. The inconsistencies in the veterinary literature on this topic is an area that needs to be noted and reduced. Detailed studies comparing the patient demographics and other factors influencing treatment choices or outcomes, between referral and primary care practices is needed. The overall poor outcomes presented support the need for exploring novel therapies and prognostic markers to guide their use