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When evaluating mediastinal/hilar lymphadenopathy (LAD) or masses, guidelines recommend endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA) as an initial technique for tissue analysis and diagnosis. However, owing to the small sample size obtained by needle aspiration, its diagnostic yield (DY) is limited. EBUS transbronchial forceps biopsy (TBFB) used as a complimentary technique to EBUS-TBNA might allow for better histopathological evaluation, thus improving DY. In this retrospective bicentric study, we assessed the DY and safety of an EBUS-guided 1.5 mm mini-forceps biopsy combined with EBUS-TBNA for the diagnosis of mediastinal/hilar LAD or masses compared to EBUS-TBNA alone. In total, 105 patients were enrolled. The overall DY was 61.9% and 85.7% for TBNA alone and EBUS-TBNA combined with EBUS-TBFB, respectively (p < 0.001). While the combined approach was associated with a significantly higher DY for lung cancer diagnosis (97.1% vs. 76.5%, p = 0.016) and sarcoidosis (85.2% vs. 44.4%, p = 0.001), no significant differences in DY were calculated for subgroups with smaller sample sizes such as lymphoma. No major adverse events were observed. Using a 1.5 mm mini-forceps is a safe and feasible technique for biopsy of mediastinal or hilar LAD or masses with superior overall DY compared to EBUS-TBNA as a standalone technique.

Rearrangements of the transcription factors FOS and FOSB have recently been identified as the genetic driver event underlying osteoid osteoma and osteoblastoma. Nuclear overexpression of FOS and FOSB have since then emerged as a reliable surrogate marker despite limitations in specificity and sensitivity. Indeed, osteosarcoma can infrequently show nuclear FOS expression and a small fraction of osteoblastomas seem to arise independent of FOS/FOSB rearrangements. Acid decalcification and tissue preservation are additional factors that can negatively influence immunohistochemical testing and make diagnostic decision-making challenging in individual cases. Particularly aggressive appearing osteoblastomas, also referred to as epithelioid osteoblastomas, and osteoblastoma-like osteosarcoma can be difficult to distinguish, underlining the need for additional markers to support the diagnosis. Methylation and copy number profiling, a technique well established for the classification of brain tumors, might fill this gap. Here, we set out to comprehensively characterize a series of 77 osteoblastomas by immunohistochemistry, fluorescence in-situ hybridization as well as copy number and methylation profiling and compared our findings to histologic mimics. Our results show that osteoblastomas are uniformly characterized by flat copy number profiles that can add certainty in reaching the correct diagnosis. The methylation cluster formed by osteoblastomas, however, so far lacks specificity and can be misleading in individual cases.

Fur die Klassifikation von Knochentumoren ist die integrative Beurteilung von Histologie und korrespondierender Bildgebung essenziell. Wahrend es bis vor wenigen Jahren kaum diagnostisch nutzbare molekulare Marker gab, haben exom- und genomweite Sequenzieranalysen zwischenzeitlich eine Reihe tumorspezifischer Aberrationen aufgedeckt, die in unklaren Fallen sehr hilfreich sein konnen. Neben charakteristischen Genmutationen (z. B. H3F3A und H3F3B in Riesenzelltumoren und Chondroblastomen) spielt auch die Detektion von Fusionstranskripten (z. B. strukturelle Rearrangements in den AP-1-Transkriptionsfaktoren FOS und FOSB bei Osteoidosteomen und Osteoblastomen) eine zunehmende Rolle. Der Artikel gibt einen Uberblick uber den aktuellen Kenntnisstand der wichtigsten Alterationen bei Knochentumoren.

PLAG1 rearrangements have been described as a molecular hallmark of salivary gland pleomorphic adenoma (PA), carcinoma ex pleomorphic adenoma (CEPA), and myoepithelial carcinoma (MECA). Several fusion partners have been described, however, commonly no further assignment to the afore mentioned entities or a morphological prediction can be made based on the knowledge of the fusion partner alone. In contrast, TGFBR3-PLAG1 fusion has been specifically described and characterized as an oncogenic driver in MECA, and less common in MECA ex PA. Here, we describe the clinicopathological features of three TGFBR3-PLAG1 fusion positive salivary gland neoplasms, all of which arose in the deep lobe of the parotid gland. Histopathology showed high morphological similarities, encompassing encapsulation, a polylobular growth pattern, bland basaloid and oncocytoid cells with myoepithelial differentiation, and a distinct sclerotic background. All cases showed at least limited, unusual foci of minimal invasion into adjacent salivary gland tissue, including one case with ERBB2 (Her2/neu) amplified, TP53 mutated high-grade transformation and lymph node metastases. Of note, all cases illustrated focal ductal differentiation. Classification remains difficult, as morphological overlaps between myoepithelial-rich cellular pleomorphic adenoma, myoepithelioma and myoepithelial carcinoma were observed. However, evidence of minimal invasion advocates classification as low-grade myoepithelial carcinoma. This case series further characterizes the spectrum of uncommon cellular myoepithelial neoplasms harboring TGFBR3-PLAG1 fusion, which show recurrent minimal invasion of the adjacent salivary gland tissue, a predilection to the deep lobe of the parotid gland and potential high-grade transformation. This article is protected by copyright. All rights reserved. Keywords: (MeSH): Salivary gland neoplasms; adenoma; parotid gland; pleomorphic; transforming growth factor beta.

Der orale Lichen planus ist eine nichtinfektiose chronische Entzundungsform der Mundschleimhaut, die zusammen mit einer klassischen kutanen Manifestation oder an anderen Schleimhauten wie der Konjunktiva oder im Genitalbereich auftreten kann. Die Ursache dieser Erkrankung ist nach wie vor ungeklart, wahrend die klinisch und histopathologisch sehr ahnliche orale lichenoide Reaktion durch dentale Werkstoffe oder Medikamente ausgelost werden kann. Dieser Beitrag gibt eine Ubersicht uber die wichtigsten Erkenntnisse und therapeutischen Konzepte in Bezug auf diese beiden Erkrankungsformen und versucht somit dem klinisch aktiven Kollegen eine Hilfestellung in Diagnostik und Therapie zu geben.

Highlights • SalvGlandDx includes 27 genes known to be involved in salivary gland neoplasms • Can be applied to FFPE histological and cytological (cell block) specimen • Solely RNA extraction is needed • Gene fusions, hotspot mutations and gene expression levels can be detected • Guides diagnosis in uncertain cases and can detect therapeutically relevant fusions, Diagnosis of salivary gland neoplasms is often challenging due to their high morphological diversity and overlaps. Several recurrent molecular alterations have been described recently, which can serve as powerful diagnostic tools and potential therapeutic targets (e.g. NTRK or RET fusions). However, current sequential molecular testing can be expensive and time consuming. In order to facilitate the diagnosis of salivary gland neoplasms, we designed an all-in-one RNA-based next generation sequencing panel suitable for the detection of mutations, fusions and gene expression levels (including NR4A3) of 27 genes involved in salivary gland neoplasms. Here we present the validation of the “SalvGlandDx” panel on FFPE histological specimen including fine needle aspiration (FNA) cell block material, against the standard methods currently used at our institution. In a second part we describe selected unique cases in which the SalvGlandDx panel allowed proper diagnosis and new insights into special molecular characteristics of selected salivary gland tumors. We characterize a unique salivary gland adenocarcinoma harboring a ZCCHC7-NTRK2 fusion, a highly uncommon spindle cell and pseudoangiomatoid adenoid-cystic carcinoma with MYBL1-NFIB fusion, and a purely oncocytic mucoepidermoid carcinoma, whereas diagnosis could be made by detection of a CRTC3-MAML2 rearrangement on the cell block specimen of the FNA. Further, a rare case of a SS18-ZBTB7A rearranged low-grade adenocarcinoma previously described as potential spectrum of microsecretory adenocarcinoma, is reported. In addition, features of six cases within the spectrum of polymorphous adenocarcinoma / cribriform adenocarcinoma of salivary gland including PRKD1 p.E710D mutations and novel fusions involving PRKAR2A-PRKD1, SNX9-PRKD1 and ATL2-PRKD3, are described.

ZusammenfassungOdontogene Zysten sind Läsionen, die im Patientengut der Mund‑, Kiefer- und Gesichtschirurgie oft zu finden sind. Sie sind um etwa 20-mal häufiger als echte odontogene Tumoren. Allen voran rangiert die entzündlich bedingte radikuläre Zyste, gefolgt von der entwicklungsbedingten follikulären Zyste. Gemeinsam ist allen odontogenen Zysten wie auch Tumoren, dass sie sich radiologisch als Osteolysen manifestieren und sichere radiologische Unterscheidungsmerkmale zwischen den einzelnen Entitäten oftmals fehlen. Klarheit bringt in vielen Fällen erst die histopathologische Untersuchung. Allerdings ist zu beachten, dass eine akkurate Entitätsdiagnose nur in einer engen interdisziplinären Zusammenarbeit möglich ist. Aus histopathologischer Sicht kann der Pathologe/die Pathologin nur eine dezidierte Diagnose stellen, wenn auch ihm/ihr das klinische Bild (Vitalitätsstatus des assoziierten Zahns, Zufallsbefund oder symptomatisch, Lockerung der Zähne etc.) sowie das radiologische Erscheinungsbild (Lokalisation der Osteolyse, Präsenz retinierter Zähne, parallel vorhandene radiologische Auffälligkeiten etc.) bekannt sind. Die Begutachtung des radiologischen Bildes erfordert dabei in aller Regel die Einsicht des gesamten Datensatzes eines digitalen Volumentomogramms oder eines Orthopantomogramms in guter Auflösung, da unvollständige Ausschnitte oder Beschreibungen Fehlinterpretationen begünstigen können. Die zunehmende Digitalisierung ist hier von großem Vorteil und ein Datenträger mit allen relevanten (insbesondere präinterventionellen) Bildern wird von erfahrenen Oralpathologen immer gern entgegengenommen. In jedem Falle sollte bei Diskrepanzen zwischen histopathologischer Diagnose und klinisch-radiologischem Bild bzw. schwierigen oder ungewöhnlichen Fällen eine interdisziplinäre Diskussion angestrebt werden.

Background: Findings from autopsies have provided evidence on systemic microvascular damage as one of the underlying mechanisms of Coronavirus disease 2019 (CO­VID-19). The aim of this study was to correlate autopsy-based cause of death in SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive patients with chest imaging and severity grade of pulmonary and systemic morphological vascular pathology. Methods: Fifteen SARS-CoV-2 positive autopsies with clinically distinct presentations (age 22–89 years) were retrospectively analyzed with focus on vascular, thromboembolic, and ischemic changes in pulmonary and in extrapulmonary sites. Eight patients died due to COVID-19 associated respiratory failure with diffuse alveolar damage in various stages and/or multi-organ failure, whereas other reasons such as cardiac decompensation, complication of malignant tumors, or septic shock were the cause of death in 7 further patients. The severity of gross and histopathological changes was semi-quantitatively scored as 0 (absent), 1 (mild), and 3 (severe). Severity scores between the 2 groups were correlated with selected clinical parameters, initial chest imaging, autopsy-based cause of death, and compared using Pearson χ2 and Mann-Whitney U tests. Results: Severe pulmonary endotheliitis (p = 0.031, p = 0.029) and multi-organ involvement (p = 0.026, p = 0.006) correlated significantly with COVID-19 associated death. Pulmonary microthrombi showed limited statistical correlation, while tissue necrosis, gross pulmonary embolism, and bacterial superinfection did not differentiate the 2 study groups. Chest imaging at hospital admission did not differ either. Conclusions: Extensive pulmonary endotheliitis and multi-organ involvement are characteristic autopsy features in fatal CO­VID-19 associated deaths. Thromboembolic and ischemic events and bacterial superinfections occur frequently in SARS-CoV-2 infection independently of outcome.

The integrative evaluation of histology and corresponding imaging is essential for the classification of bone tumors. Until a few years ago, there were hardly any molecular markers that could be used for diagnostic purposes. However, exome- and genome-wide sequencing analyses have since uncovered a number of tumor-specific aberrations that can be very helpful in ambiguous cases. In addition to characteristic gene mutations (e.g. H3F3A and H3F3B in giant-cell tumors and chondroblastomas), the detection of fusion transcripts (e.g. structural rearrangements in the AP‑1 transcription factors FOS and FOSB in osteoid osteomas and osteoblastomas) plays an increasing role. The article gives an overview of the current state of knowledge of the most important alterations in bone tumors.

Cystic lesions of the jaws comprise a spectrum of inflammatory, developmental and neoplastic changes that can clinically appear strikingly similar. Squamous cell metaplasia due to superinfection can further blur the histologic hallmarks of the individual lesions. In this article an overview of the most important differential diagnoses and the novelties of the latest World Health Organisation (WHO) classification on head and neck tumours released in early 2017 is provided. In contrast to the previous edition, odontogenic cysts have been re-introduced and several changes in terminology and taxonomy have been complemented.

We present the case of a severe and long-standing Dupuytren’s contracture where intraoperatively an ossified nodule was encountered within the diseased tissue. Histologically palmar fibromatosis in contact with cartilaginous tissue with central ossification could be confirmed, compatible with metaplasia. Our finding suggests that metaplastic activity inherent to longstanding, severely diseased Dupuytren’s tissue can lead to heterotopic ossification.

Non‐ossifying fibroma (NOF) has been an intriguing entity since its first description. It is the most common bone tumour, is usually asymptomatic affecting children and adolescents, is composed of a heterogeneous cell population, and undergoes spontaneous regression after puberty. In a recent article in The Journal of Pathology, Baumhoer and colleagues demonstrate mutations activating the RAS‐MAPK pathway (KRAS, FGFR1 and NF1) in ∼80% of the tumours. Activation of the RAS‐MAPK pathway by somatic mutations is found in a plethora of tumour types, both benign and malignant, while germline mutations cause a wide range of syndromes collectively termed the RASopathies. Their findings indicate that NOF, for long thought to be reactive, should be considered a true neoplasm. Moreover, their data suggest that only a subset of cells in the lesion contain the mutation. A second cell population consisting of histiocytes and osteoclast‐like giant cells appears to be reactive. This intimate relation between WT and mutant cells is also frequently encountered in other benign and locally aggressive bone tumours and seems essential for tumourigenesis. The spontaneous regression remains enigmatic and it is tempting to speculate that pubertal hormonal signalling, especially increased oestrogen levels, affect the balance between mutant and WT cells. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

We analyzed morphological and immunohistochemical features in 174 aggressive B-cell lymphomas of nodal and extranodal origin. Morphological features included presence or absence of a follicular component and cytologic criteria according to the Kiel classification, whereas immunohistochemical studies included expression of CD10, BCL-2, BCL-6, IRF4/MUM1, HLA-DR, p53, Ki-67 and the assessment of plasmacytoid differentiation. Patients were treated with a CHOP-like regimen. While the presence or absence of either CD10, BCL-6 and IRF4/MUM1 reactivity or plasmacytoid differentiation did not identify particular cytomorphologic or site-specific subtypes, we found that expression of CD10 and BCL-6, and a low reactivity for IRF4/MUM1 were favourable prognostic indicators. In contrast, BCL-2 expression and presence of a monotypic cytoplasmic immunoglobulin expression was associated with an unfavourable prognosis in univariate analyses. Meta-analysis of these data resulted in the development of a cumulative immunohistochemical outcome predictor score (CIOPS) enabling the recognition of four distinct prognostic groups. Multivariate analysis proved this score to be independent of the international prognostic index. Such a cumulative immunohistochemical scoring approach might provide a valuable alternative in the recognition of defined risk types of aggressive B-cell lymphomas.

Mantle cell lymphoma (MCL) is an aggressive lymphoid tumour characterized by the translocation t(11;14)(q13;q32) and a poor clinical outcome (median survival: 3-4 years). Recent studies revealed that increased proliferation of the tumour cells and certain chromosomal aberrations, such as deletions of 17p13 and 9p21 represent major adverse biological markers in this disease, although the molecular targets of chromosomal imbalances in MCL have not been identified for the large majority of loci affected. To correlate histomorphological and proliferation features of MCL with genetic findings, we investigated 223 MCL by fluorescence in situ hybridization (FISH) (n = 157) and/or classical cytogenetic banding analysis (n = 129). FISH analysis turned out to be distinctly more sensitive in the delineation of aberrations. Complex karyotypic alterations were associated with higher proliferation indices and inferior prognosis. A comprehensive analysis of biological features including genetic alterations in MCL by hierarchical clustering resulted in the delineation of four tumour subgroups differing with respect to their genetic constitution and suggesting different transformation or progression pathways. Moreover, in one of the groups identified, a more indolent clinical behaviour was associated with few secondary aberrations and fewer known high-risk chromosomal aberrations, which points to the importance of the quality of karyotypic evolution in MCL tumours.

Deletions in the short arm of chromosome 17 (17p) involving the tumor suppressor TP53 occur in up to 20% of diffuse large B-cell lymphomas (DLBCLs). Although inactivation of both alleles of a tumor suppressor gene is usually required for tumor development, the overlap between TP53 deletions and mutations is poorly understood in DLBCLs, suggesting the possible existence of additional tumor suppressor genes in 17p. Using a bacterial artificial chromosome (BAC) and Phage 1 artificial chromosome (PAC) contig, we here define a minimally deleted region in DLBCLs encompassing approximately 0.8 MB telomeric to the TP53 locus. This genomic region harbors the tumor suppressor Hypermethylated in Cancer 1 (HIC1). Methylation-specific PCR demonstrated hypermethylation of HIC1 exon 1a in a substantial subset of DLBCLs, which is accompanied by simultaneous HIC1 deletion of the second allele in 90% of cases. In contrast, HIC1 inactivation by hypermethylation was rarely encountered in DLBCLs without concomitant loss of the second allele. DLBCL patients with complete inactivation of both HIC1 and TP53 may be characterized by an even inferior clinical course than patients with inactivation of TP53 alone, suggesting a functional cooperation between these two proteins. These findings strongly imply HIC1 as a novel tumor suppressor in a subset of DLBCLs.

Purpose There is evidence for a direct role of quantitative gene expression deregulation in mantle-cell lymphoma (MCL) pathogenesis. Our aim was to investigate gene expression associations with other pathogenic factors and the significance of gene expression in a multivariate survival analysis. Patients and Methods Quantitative expression of 20 genes of potential relevance for MCL prognosis and pathogenesis were analyzed using real-time reverse transcriptase polymerase chain reaction and correlated with clinical and genetic factors, tumor morphology, and Ki-67 index in 65 MCL samples. Results Genomic losses at the loci of TP53, RB1, and P16 were associated with reduced transcript levels of the respective genes, indicating a gene-dosage effect as the pathomechanism. Analysis of gene expression correlations between the candidate genes revealed a separation into two clusters, one dominated by proliferation activators, another by proliferation inhibitors and regulators of apoptosis. Whereas only weak associations were identified between gene expression and clinical parameters or blastoid morphology, several genes were correlated closely with the Ki-67 index, including the short CCND1 variant (positive correlation) and RB1, ATM, P27, and BMI (negative correlation). In multivariate survival analysis, expression levels of MYC, MDM2, EZH2, and CCND1 were the strongest prognostic factors independently of tumor proliferation and clinical factors. Conclusion These results indicate a pathogenic contribution of several gene transcript levels to the biology and clinical course of MCL. Genes can be differentiated into factors contributing to proliferation deregulation, either by enhancement or loss of inhibition, and proliferation-independent factors potentially contributing to MCL pathogenesis by apoptosis impairment.

Genetic rearrangement of FOXP1 is predominantly detected in a subset of diffuse large B-cell lymphomas with extranodal presentation

For prediction and understanding of underlying mechanisms of organ-specific metastases, various gene and protein expression signatures have been identified in primary breast carcinomas. These expression signatures often include several genes coding for adhesion molecules, such as activated leucocyte cell adhesion molecule (ALCAM/CD166) and carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), both of which may play an important role in the development of distant metastases because of their adherent properties. Owing to their predominantly membranous localisation, they are also considered to have certain therapeutic potential. Apart from expression data obtained in the primary tumour, data for gene and protein expression patterns in distant breast cancer metastases are rare. Therefore this study focuses on analysing the distribution of ALCAM and CEACAM6 protein expression in breast cancer metastases from different sites.Immunohistochemical staining for ALCAM and CEACAM6 in 117 breast cancer metastases derived from liver (n=24), lung (n=19), brain (n=21), bone (n=36) and skin (n=17) was performed.Immunoreactive scores (IRS) for ALCAM in all metastases except skin metastases ranged from 2.63 to 5.10 (membranous) and 2.79 to 3.67 (cytoplasmic), showing a positive correlation with each other (r=0.690, p0.001). In skin metastases, ALCAM expression was significantly stronger (membranous IRS, 8.76; cytoplasmic IRS, 7.12; p0.001). Mean staining intensity for CEACAM6 was IRS 3.88. No or weak CEACAM6 and ALCAM staining (IRS 0-3) was seen in 53% vs 27% of all metastases.Compared with CEACAM6, ALCAM showed significantly stronger protein expression in breast cancer skin metastases compared with metastases in all other sites.

PURPOSE: Vascular invasion is an adverse prognostic factor in colorectal cancer and often is considered an indication for systemic adjuvant therapy. The aim of this study was to develop a predictive model of vascular invasion in a large cohort of colon cancers with use of tumor-related features and immunohistochemical analysis of protein markers. METHODS: A tissue microarray including 427 colon cancers was evaluated for 14 immunohistochemical protein markers. Complete data on pT, pN, tumor grade, tumor border configuration, vascular invasion, and tumor diameter were available. Classification and regression tree analysis was performed. RESULTS: The presence of vascular invasion independently predicted adverse outcome (P > 0.001; hazard ratio = 1.52 (1.3 to 1.8)) and decreased survival from 49.0 to 19.0 months (P > 0.001) even in lymph node-positive patients. Tumor border configuration, Ki67, urokinase plasminogen activator receptor, and Raf-1 kinase inhibitor protein expression were predictive of vascular invasion. The cross-validated misclassification rate was 23.7 percent indicating a significant predictive accuracy of this model. CONCLUSIONS: Tumor border configuration, Ki67, urokinase plasminogen activator receptor, and Raf-1 kinase inhibitor protein immunohistochemistry are highly predictive of vascular invasion and may play a decisive role in individualizing adjuvant treatment.

Mantle cell lymphomas (MCL), characterized by the t(11;14)(q13;q32), frequently carry secondary genetic alterations such as deletions in chromosome 17p involving the TP53 locus. Given that the association between TP53-deletions and concurrent mutations of the remaining allele is weak and based on our recent report that the Hypermethylated in Cancer 1 (HIC1) gene, that is located telomeric to the TP53 gene, may be targeted by deletions in 17p in diffuse large B-cell lymphoma (DLBCL), we investigated whether HIC1 inactivations might also occur in MCL. Monoallelic deletions of the TP53 locus were detected in 18 out of 59 MCL (31%), while overexpression of p53 protein occurred in only 8 out of 18 of these MCL (44%). In TP53-deleted MCL, the HIC1 gene locus was co-deleted in 11 out of 18 cases (61%). However, neither TP53 nor HIC1 deletions did affect survival of MCL patients. In most analyzed cases, no hypermethylation of the HIC1 exon 1A promoter was observed (17 out of 20, 85%). However, in MCL cell lines without HIC1-hypermethylation, the mRNA expression levels of HIC1 were nevertheless significantly reduced, when compared to reactive lymph node specimens, pointing to the occurrence of mechanisms other than epigenetic or genetic events for the inactivation of HIC1 in this entity.

The pathogenesis of mature T-cell non-Hodgkin lymphomas (T-NHLs) is poorly understood. Analogous to B-cell lymphomas, in which the immunoglobulin (IgH) receptor loci are frequently targeted by chromosomal translocations, the T-cell receptor (TCR) gene loci are affected by translocations in a subset of precursor T-cell malignancies. In a large-scale analysis of 245 paraffin-embedded mature T-NHLs, arranged in a tissue microarray format and using improved FISH assays for the detection of breakpoints in the TCRα/δ ,T CRβ, and TCRγ loci, we provide evidence that mature T-NHLs other than T-cell prolymphocytic leukaemia (T-PLL) also occasionally show a chromosomal rearrangement that involves the TCRα/δ locus. In particular, one peripheral T-cell lymphoma (not otherwise specified, NOS) with the morphological variant of Lennert lymphoma displayed a chromosomal translocation t(14;19) involving the TCRα/δ and the BCL3 loci. A second case, an angio-immunoblastic Tcell lymphoma (AILT), carried an inv(14)(q11q32) affecting the TCRα/δ and IgH loci. FISH signal constellations as well as concomitant comparative genomic hybridization (CGH) data were also suggestive of the occurrence of an isochromosome 7, previously described to be pathognomonic for hepatosplenic T-cell lymphomas, in rare cases of enteropathy-type T-cell lymphoma. Copyright  2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Purpose: To determine the methylthioadenosine phosphorylase (MTAP) gene alterations in mantle cell lymphoma (MCL) and to investigate whether the targeted inactivation of the alternative de novo AMP synthesis pathway may be a useful therapeutic strategy in tumors with inactivation of this enzyme. Experimental Design: MTAP gene deletion and protein expression were studied in 64 and 52 primary MCL, respectively, and the results were correlated with clinical behavior. Five MCL cell lines were analyzed for MTAP expression and for the in vitro sensitivity to l-alanosine, an inhibitor of adenylosuccinate synthetase, and hence de novo AMP synthesis. Results: No protein expression was detected in 8 of 52 (15%) tumors and one cell line (Granta 519). Six of these MTAP negative tumors and Granta 519 cell line had a codeletion of MTAP and p16 genes; one case showed a deletion of MTAP, but not p16, and one tumor had no deletions in neither of these genes. Patients with MTAP deletions had a significant shorter overall survival (mean, 16.1 months) than patients with wild-type MTAP (mean, 63.6 months; P < 0.0001). l-Alanosine induced cytotoxicity and activation of the intrinsic mitochondrial-dependent apoptotic pathway in MCL cells. 9-β-d-Erythrofuranosyladenine, an analogue of 5′-methylthioadenosine, selectively rescued MTAP-positive cells from l-alanosine toxicity. Conclusions: MTAP gene deletion and lack of protein expression are associated with poor prognosis in MCL and might identify patients who might benefit from treatment with de novo AMP synthesis pathway–targeted therapies.

Mantle cell lymphoma (MCL) is a distinctive type of non-Hodgkin lymphoma (NHL) that is considered an aggressive neoplasm. The clinical course, however, is variable, with some patients living less than a year while others survive for more than 10 years.[1][1] Therefore, many attempts have been made

Spindle cell tumors of the larynx are rare. In some cases, the dignity is difficult to determine. We report two cases of laryngeal spindle cell tumors. Case 1 is a spindle cell carcinoma (SPC) in a 55 year-old male patient and case 2 an inflammatory myofibroblastic tumor (IMT) in a 34 year-old female patient. A comprehensive morphological and immunohistochemical analysis was done. Both tumors arose at the vocal folds. Magnified laryngoscopy showed polypoid tumors. After resection, conventional histological investigation revealed spindle cell lesions with similar morphology. We found ulceration, mild atypia, and myxoid stroma. Before immunohistochemistry, the dignity was uncertain. Immunohistochemical investigations led to diagnosis of two distinct tumors with different biological behaviour. Both expressed vimentin. Furthermore, the SPC was positive for pan-cytokeratin AE1/3, CK5/6, and smooth-muscle actin, whereas the IMT reacted with antibodies against ALK-1, and EMA. The proliferation (Ki67) was up to 80% in SPC and 10% in IMT. Other stainings with antibodies against p53, p21, Cyclin D1, or Rb did not result in additional information. After resection, the patient with SPC is free of disease for seven months. The IMT recurred three months after first surgery, but no relapses were found eight months after resurgery. Differential diagnosis can be difficult without immunohistochemistry. Therefore, a comprehensive morphological and immunohistochemical analysis is necessary, but markers of cell cycle (apart from the assessment of proliferation) do not help.

Background: Mesenchymal chondrosarcoma (MCS) is a distinct, very rare sarcoma with little evidence supporting treatment recommendations.Patients and methods: Specialist centres collaborated to report prognostic factors and outcome for 113 patients.Results: Median age was 30 years (range: 11-80), male/female ratio 1.1. Primary sites were extremities (40%), trunk (47%) and head and neck (13%), 41 arising primarily in soft tissue. Seventeen patients had metastases at diagnosis. Mean follow-up was 14.9 years (range: 1-34), median overall survival (OS) 17 years (95% confidence interval (CI): 10.3-28.6). Ninety-five of 96 patients with localised disease underwent surgery, 54 additionally received combination chemotherapy. Sixty-five of 95 patients are alive and 45 progression-free (5 local recurrence, 34 distant metastases, 11 combined). Median progression-free survival (PFS) and OS were 7 (95% CI: 3.03-10.96) and 20 (95% CI: 12.63-27.36) years respectively. Chemotherapy administration in patients with localised disease was associated with reduced risk of recurrence (P = 0.046; hazard ratio (HR) = 0.482 95% CI: 0.213-0.996) and death (P = 0.004; HR = 0.445 95% CI: 0.256-0.774). Clear resection margins predicted less frequent local recurrence (2% versus 27%; P = 0.002). Primary site and origin did not influence survival. The absence of metastases at diagnosis was associated with a significantly better outcome (P Conclusions: Prognosis in MCS varies considerably. Metastatic disease at diagnosis has the strongest impact on survival. Complete resection and adjuvant chemotherapy should be considered as standard of care for localised disease. (C) 2014 Elsevier Ltd. All rights reserved.