Myxoid pleomorphic liposarcoma-a clinicopathologic, immunohistochemical, molecular genetic and epigenetic study of 12 cases, suggesting a possible relationship with conventional pleomorphic liposarcoma.

Myxoid pleomorphic liposarcoma is a recently defined subtype of liposarcoma, which preferentially involves the mediastinum of young patients and shows mixed histological features of conventional myxoid liposarcoma and pleomorphic liposarcoma. While myxoid pleomorphic liposarcoma is known to lack the EWSR1/FUS-DDIT3 fusions characteristic of the former, additional genetic data are limited. To further understand this tumor type, we extensively examined a series of myxoid pleomorphic liposarcomas by fluorescence in situ hybridization (FISH), shallow whole genome sequencing (sWGS) and genome-wide DNA methylation profiling. The 12 tumors occurred in 6 females and 6 males, ranging from 17 to 58 years of age (mean 33 years, median 35 years), and were located in the mediastinum (n = 5), back, neck, cheek and leg, including thigh. Histologically, all cases consisted of relatively, bland, abundantly myxoid areas with a prominent capillary vasculature, admixed with much more cellular and less myxoid foci containing markedly pleomorphic spindled cells, numerous pleomorphic lipoblasts and elevated mitotic activity. Using sWGS, myxoid pleomorphic liposarcomas were found to have complex chromosomal alterations, including recurrent large chromosomal gains involving chromosomes 1, 6-8, 18-21 and losses involving chromosomes 13, 16 and 17. Losses in chromosome 13, in particular loss in 13q14 (including RB1, RCTB2, DLEU1, and ITM2B genes), were observed in 4 out of 8 cases analyzed. Additional FISH analyses confirmed the presence of a monoallelic RB1 deletion in 8/12 cases. Moreover, nuclear Rb expression was deficient in all studied cases. None showed DDIT3 gene rearrangement or MDM2 gene amplification. Using genome-wide DNA methylation profiling, myxoid pleomorphic liposarcomas and conventional pleomorphic liposarcomas formed a common methylation cluster, which segregated from conventional myxoid liposarcomas. While the morphologic, genetic and epigenetic characteristics of myxoid pleomorphic liposarcoma suggest a link with conventional pleomorphic liposarcoma, its distinctive clinical features support continued separate classification for the time being.

Endobronchial ultrasound elastography for diagnosing mediastinal and hilar lymph nodes. / Elastografía asociada a la ecografía endobronquial en el estudio de adenopatías hiliares y mediastínicas.

INTRODUCTION: The main objective was to analyze the technical variability of EBUS-elastography in the differentiation of benign and malignant hilar and mediastinal lymph nodes. As a secondary objective, the results of the EBUS-elastography in said differentiation were analyzed, comparing them with the anatomopathological results. MATERIAL AND METHODS: Prospective and analytical study of lymph nodes in which EBUS-elastography was performed. Elastographic variables and their variability were analyzed. RESULTS: 24 patients and 38 lymph nodes were evaluated. Of these, 60.5% had a history of neoplasia, 71% of them were EBUS-elastography with diagnostic intention, 53% were mediastinal staging of lung cancer. Both procedures were performed in 25% of the patients. Lymph nodes were classified into elastographic colour patterns, red being characteristic of elastic tissues and blue of rigid tissues. The lymphadenopathies with apredominantly blue pattern were associated with an anatomopathological result of malignancy (86% vs. 14%, OR 20.4 (3.1 -245.1) p-value = .00015). Malignant lymph nodes presented less colour dispersion in the frequency histograms and a higher ratio of blue pixels and higher strain ratio. These variables showed a variability of 8.7, 9.9 and 31.6% respectively in repetitions in the same adenopathy. Finally, a 66% of consistency was obtained in the event of colour pattern variability (p .0000). CONCLUSIONS: EBUS-elastography is feasible during EBUS and may be helpful in predicting malignant lymph node infiltration. The quantitative elastographic data show low variability in repetitions in the same adenopathy. The strain ratio is the most variable elastographic parameter.

Hitting back at lymphoma: How do modern diagnostics identify high-risk diffuse large B-cell lymphoma subsets and alter treatment?

Diffuse large B-cell lymphoma (DLBCL) is a clinically and biologically heterogeneous disease. Diagnostic tools in the clinic can now identify distinct subsets characterized by unique molecular features, which are increasingly transforming how these patients are managed. Activated B-cell-like DLBCL is characterized by NF-κB activation and chronic B-cell receptor signaling and may be targeted with lenalidomide or ibrutinib in the relapsed setting. Germinal center-like DLBCL is enriched for activating EZH2 mutations, and encouraging activity has been observed for the EZH2 inhibitor tazemetostat, which now has a fast-track US Food and Drug Administration designation. Double-hit lymphoma is a high-grade B-cell lymphoma characterized by translocations of MYC and BCL2 and/or BCL6 and carries a poor prognosis. Intensive chemoimmunotherapy strategies appear to be superior to standard R-CHOP (rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone) as initial therapy, and anti-CD19 chimeric antigen receptor T cells are inducing remission in patients with relapsed/refractory disease who previously had few available options. Primary mediastinal (thymic) large B-cell lymphoma is a molecularly distinct large-cell lymphoma with clinical and molecular features that overlap with those of classical Hodgkin lymphoma. R-CHOP has been associated with an unacceptably high rate of primary treatment failure in this young population, whereas dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab) produces durable remissions without the need for radiotherapy in most patients. For relapsed/refractory disease, immune checkpoint inhibitors targeting PD-1 have shown promising activity in chemotherapy-refractory disease, as have anti-CD19 chimeric antigen receptor T cells. Additional therapeutic targets, including JAK2, continue to be evaluated. The identification of discrete biological subsets is steadily moving us away from a "one-size-fits-all" approach in DLBCL.

Molecular classification of primary mediastinal large B-cell lymphoma using routinely available tissue specimens.

Primary mediastinal large B-cell lymphoma (PMBCL) is recognized as a distinct entity in the World Health Organization classification. Currently, the diagnosis relies on consensus of histopathology, clinical variables, and presentation, giving rise to diagnostic inaccuracy in routine practice. Previous studies have demonstrated that PMBCL can be distinguished from subtypes of diffuse large B-cell lymphoma (DLBCL) based on gene expression signatures. However, requirement of fresh-frozen biopsy material has precluded the transfer of gene expression-based assays to the clinic. Here, we developed a robust and accurate molecular classification assay (Lymph3Cx) for the distinction of PMBCL from DLBCL subtypes based on gene expression measurements in formalin-fixed, paraffin-embedded tissue. A probabilistic model accounting for classification error, comprising 58 gene features, was trained on 68 cases of PMBCL and DLBCL. Performance of the model was subsequently evaluated in an independent validation cohort of 158 cases and showed high agreement of the Lymph3Cx molecular classification with the clinicopathological diagnosis of an expert panel (frank misclassification rate, 3.8%). Furthermore, we demonstrate reproducibility of the assay with 100% concordance of subtype assignments at 2 independent laboratories. Future studies will determine Lymph3Cx's utility for routine diagnostic purposes and therapeutic decision making.

[Which surgery for mediastinum tumor: Experience of the Department of thoracic surgery of CHU Hassan II of Fès]. / Quelle chirurgie pour quelle tumeur du médiastin : expérience du service de chirurgie thoracique de CHU Hassan II de Fès.

INTRODUCTION: Tumors of the mediastinum are a heterogeneous group of dysembryoplatic and neoplastic diseases essentially with different prognoses and therapeutic. These tumors develop slowly and remain long asymptomatic in 40-50% of cases. The purpose of our work is to bring the result of surgical management in diagnostic and therapeutic of principal mediastinum tumors framework. PATIENTS AND METHOD: We reviewed retrospectively the records of 68 patients in our training, between January 2009 and December 2013, for tumor of the mediastinum in the diagnostic framework and or therapy. RESULTS: There were 37 men and 31 women with a mean age of 37 years with extremes ranging from 11 to 73 years and 77.94% had an age between 11 and 50. In 39 patients, surgery had a diagnostic purpose (2 benign tumors and 37 malignancies including 27 cases of lymphomas). Curative surgery was performed in 34 patients, dominated by the tumors of thymic origin in 15 cases. Conventional surgery had involved 32 patients. The surgical approach was a total vertical sternotomy in 14 patients, in 17 patients was posterolateral thoracotomy and a left anterior thoracotomy in 1 patient. Video assisted thoracic surgery had been done in 3 patients under resection of a pleuropericardique cyst. Overall mortality was 4.41 percent. It is a death at D17 of the postoperative (thymoma with myasthenia) following a myasthenic crisis requiring a tracheotomy. A patient operated on for invasive thymoma developed myopathy and died at D44 of the postoperative following a difficulty of weaning. Another patient had a thymoma B3 benefited from 6 courses of neoadjuvant chemotherapy and then a thymectomy had presented a respiratory distress with bilateral pleural effusion, death at D10 of the postoperative by septic shock following a nosocomial infection. CONCLUSION: Tumors of the mediastinum are infrequent, discovered more often by chance. The main prognostic factor is the completeness of tumor resection without taking the break. Conventional surgery always keeps a place in our context, despite the advent of minimally invasive surgery.

[Mediastinal germ cell tumors]. / Mediastinale Keimzelltumoren.

The mediastinum is among the most frequent anatomic region in which germ cell tumors (GCT) arise, second only to the gonads. Mediastinal GCT (mGCT) account for 16 % of all mediastinal neoplasms. Although the morphology and (according to all available data) the molecular genetics of mediastinal and gonadal GCT are identical, a number of unique aspects exist. There is a highly relevant bi-modal age distribution. In pre-pubertal children of both sexes, mGCT consist exclusively of teratomas and yolk sac tumors. The prognosis is generally favorable with modern treatment. In post-pubertal adults, virtually all patients with malignant mGCT are males; the prognosis is more guarded and depends (among other factors) on the histological GCT components and is similar to GCT in other organs. So-called somatic type malignancies (i. e. clonally related, non-germ cell neoplasias arising in a GCT) are much more frequent in mGCT than in other organs, and the association between mediastinal yolk sac tumors and hematological malignancies, such as myelodysplasias and leukemias, is unique to mediastinal tumors. The prognosis of GCT with somatic type malignancies is generally dismal.

[Mediastinal lymphomas]. / Lymphome des Mediastinums.

Lymphomas infiltrating the mediastinum are a challenge for the treating physician as well as for the pathological diagnostics. The clinical scenario is often an emergency situation, while the pathologist is usually confronted only with small biopsy samples. Classical Hodgkin's lymphoma is by far the most frequently occurring lymphoma in the mediastinum and predominantly the nodular sclerosis subtype. In small and very sclerotic specimens it can be difficult to morphologically detect Hodgkin and Reed-Sternberg cells and to identify the characteristic phenotype by immunohistochemistry. Primary mediastinal large B­cell lymphomas should be distinguished from classical Hodgkin's lymphomas as the treatment is different. This is characterized by the detection of sheets of blast cells, which immunohistochemically show a strong B­cell phenotype (positivity for CD20 and CD79a), while CD30 can also often be expressed. The intimate biological relationship between classical Hodgkin's lymphomas and mediastinal large B­cell lymphomas is illustrated by the existence of B­cell lymphomas with intermediate features (so-called mediastinal grey zone lymphomas). It is important to recognize and diagnose these lymphomas as they are associated with a slightly inferior prognosis. Extranodal thymic marginal zone lymphomas of the mucosa-associated lymphoid tissue (MALT) type are a rare form of lymphoma encountered in the mediastinum, which can be associated with autoimmune diseases. T­lymphoblastic lymphomas and leukemia, which occur predominantly in children and young adults, represent a rapidly growing precursor cell neoplasia and must be distinguished from thymomas in the differential diagnostics as well as from normal and hyperplastic thymus glands.

Mediastinal Gray Zone Lymphoma: A Wider Category Than We Think?

AIM: To identify aggressively behaving classical Hodgkin lymphoma (CHL) of mediastinum and primary mediastinal B-cell lymphoma (PMBCL) and to classify them as mediastinal gray zone lymphoma(MGZL) and to define a minimum immunopanel for the diagnosis of MGZL. MATERIALS AND METHODS: Ninety-two mediastinal B-cell lymphomas were reviewed with a wide immunopanel and were classified as CHL, PMBCL, or MGZL. CHL with an expression of 3 or 4 transcription factors performed worse, and hence the CHL with ≥3 transcription factors were classified as MGZL-CHL. In PMBCL, the cases with a weak or negative CD20 and positive CD15 as well as those cases showing cyclin E positivity with a negative or focal LCA and any one of the transcription factors were classified as MGZL-PMBCL. RESULTS: The MGZL cases expanded from 9 to 28 cases after using an extended immunopanel. CHL and PMBCL had a disease-free survival rate of 86.8% and 69.2% and an overall survival rate of 97.4% and 80.8%, respectively. MGZL-CHL and MGZL-PMBCL had a disease-free survival rate of 33% and 40% and an overall survival rate of 66.7% and 60%, respectively. CONCLUSION: Thus, the MGZL may be a wider category than we think and hence the use of a wide immunopanel is recommended to identify the aggressively behaving mediastinal B-cell lymphomas.

Utility of immunohistochemistry in the diagnosis of pleuropulmonary and mediastinal cancers: a review and update.

CONTEXT: Immunohistochemistry has become an indispensable ancillary tool for the accurate classification of pleuropulmonary and mediastinal neoplasms necessary for therapeutic decisions and predicting prognostic outcome in the era of personalized medicine. Diagnostic accuracy has significantly improved because of the continuous discoveries of tumor-associated biomarkers and the development of effective immunohistochemical panels. OBJECTIVE: To increase the accuracy of diagnosis and classify pleuropulmonary neoplasms through immunohistochemistry. DATA SOURCES: Literature review, authors' research data, and personal practice experience. CONCLUSIONS: This review article has shown that appropriately selecting immunohistochemical panels enables pathologists to effectively diagnose most primary pleuropulmonary neoplasms and differentiate primary lung tumors from a variety of metastatic tumors to the lung. The discovery of new mutation-specific antibodies identifying a subset of specific gene-arranged lung tumors provides a promising alternative and cost-effective approach to molecular testing. Knowing the utilities and pitfalls of each tumor-associated biomarker is essential to avoiding potential diagnostic errors.

Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small-cell lung cancer.

Accurate preoperative staging and restaging of mediastinal lymph nodes in patients with potentially resectable non-small-cell lung cancer (NSCLC) is of paramount importance. In 2007, the European Society of Thoracic Surgeons (ESTS) published an algorithm on preoperative mediastinal staging integrating imaging, endoscopic and surgical techniques. In 2009, the International Association for the Study of Lung Cancer (IASLC) introduced a new lymph node map. Some changes in this map have an important impact on mediastinal staging. Moreover, more evidence of the different mediastinal staging technique has become available. Therefore, a revision of the ESTS guidelines was needed. In case of computed tomography (CT)-enlarged or positron emission tomography (PET)-positive mediastinal lymph nodes, tissue confirmation is indicated. Endosonography [endobronchial ultrasonography (EBUS)/esophageal ultrasonography (EUS)] with fine-needle aspiration (FNA) is the first choice (when available), since it is minimally invasive and has a high sensitivity to rule in mediastinal nodal disease. If negative, surgical staging with nodal dissection or biopsy is indicated. Video-assisted mediastinoscopy is preferred to mediastinoscopy. The combined use of endoscopic staging and surgical staging results in the highest accuracy. When there are no enlarged lymph nodes on CT and when there is no uptake in lymph nodes on PET or PET-CT, direct surgical resection with systematic nodal dissection is indicated for tumours ≤ 3 cm located in the outer third of the lung. In central tumours or N1 nodes, preoperative mediastinal staging is indicated. The choice between endoscopic staging with EBUS/EUS and FNA or video-assisted mediastinoscopy depends on local expertise to adhere to minimal requirements for staging. For tumours >3 cm, preoperative mediastinal staging is advised, mainly in adenocarcinoma with high standardized uptake value. For restaging, invasive techniques providing histological information are advisable. Both endoscopic techniques and surgical procedures are available, but their negative predictive value is lower compared with the results obtained in baseline staging. An integrated strategy using endoscopic staging techniques to prove mediastinal nodal disease and mediastinoscopy to assess nodal response after induction therapy needs further study.

Proposal for a new mediastinal compartment classification of transverse plane images according to the Japanese Association for Research on the Thymus (JART) General Rules for the Study of Mediastinal Tumors.

There is no existing worldwide published method for mediastinum compartment classification based on transverse section images for the differential diagnosis of mediastinal tumors. Herein, we describe a new method for anatomic mediastinal compartment classification using transverse section computed tomography (CT) images and the use of this method to classify mediastinal lesions, and thus evaluate whether the method is sufficiently user-friendly and useful. In a publication of the Japanese Association for Research on the Thymus (JART), we proposed the following four mediastinal compartments based on transverse CT images: superior portion of mediastinum, anterior mediastinum (prevascular zone), middle mediastinum (peri-tracheoesophageal zone), and posterior mediastinum (paravertebral zone). In the present study, we retrospectively analyzed 445 pathologically proven mediastinal mass lesions, and categorized them into the proposed four compartments by consensus reading. Mass lesions were classified into compartments based on the location of the lesion centroid, and each lesion was satisfactorily categorized into a compartment. Almost all thymic epithelial tumors (99%, 244/246), all 24 thymic malignant lymphomas and a majority of germ cell neoplasms (93%, 54/58) were classified as being in the anterior mediastinum compartment. The majority of intrathoracic goiters (82%, 14/17) were categorized as being in the superior portion of the mediastinum compartment. Approximately two-thirds of mass lesions in the middle mediastinum were cysts, including foregut and pericardial cysts. Approximately 80% of 37 mass lesions in the posterior mediastinum were neurogenic tumors. Correspondingly, 29 of the 49 neurogenic tumors (60%) were categorized as being in the posterior mediastinum, while 10 (20%) were in the superior portion of the mediastinum, 4 (8%) in the anterior mediastinum, and 6 (12%) in the middle mediastinum. Our findings showed that the newly proposed mediastinal compartment classification using transverse images appears to be user-friendly enough for practical clinical application and may be helpful in differential diagnoses.

Clinicopathological analysis of small-sized anterior mediastinal tumors.

PURPOSE: The purpose of this study was to determine the clinicopathological findings and prognosis of small-sized anterior mediastinal tumors (SSAMTs). METHODS: A retrospective study was conducted on 43 patients who underwent surgery between January 1989 and December 2011 for SSAMTs. RESULTS: From the preoperative radiological findings, the tumors were classified into solid (n = 28) and cystic lesions (n = 15). The pathological diagnoses of the solid lesions included thymoma (n = 24), thymic carcinoma (n = 1), mucosa-associated lymphoid tissue lymphoma (n = 1), teratoma (n = 1) and neurofibroma (n = 1), and those of the cystic lesions included thymic cysts (n = 8), thymoma (n = 3), bronchogenic cysts (n = 2), teratoma, (n = 1) and a pericardial cyst (n = 1). The 27 thymomas were composed of stages I (n = 22), II (n = 3), III (n = 1) and IVb (n = 1). The overall survival in the 43 patients was 97.1 % at 5 years. In the 28 patients with solid lesions, the overall survival was 95.8 % at 5 years. All patients with cystic lesions were still alive at the last follow-up. CONCLUSION: Cystic lesions of SSAMTs were benign lesions or stage I thymoma, and most of the solid lesions of SSAMTs were stage I or II thymomas. SSAMTs are good candidates for video-assisted thoracic surgery procedures, as conversion to sternotomy can be selected based on the intraoperative findings of pericardial invasion and a rapid pathological diagnosis of thymic carcinoma.

[Lymph node pathology - an update]. / Lymphknotenpathologie - ein Update.

Immune suppression is a risk factor for malignant lymphoma development. Progress in medical science has increased the numbers of immunosuppressed patients due to organ transplantations or successful treatment of autoimmune diseases. Different forms of immune suppression and the respective lymphoma entities are discussed in this article. Another issue treated are gray zone lymphomas between Hodgkin's lymphoma and diffuse large B cell lymphoma. This category not only represents a diagnostic challenge but also represents more a true biological continuum.

Gray zone lymphoma: better treated like hodgkin lymphoma or mediastinal large B-cell lymphoma?

Although primary mediastinal large B-cell lymphoma (PMBL) and classic Hodgkin lymphoma of the nodular sclerosis type (CHL-NS) are distinct diseases, they share several clinical characteristics and biologic features. Given that, it is not surprising that there exist mediastinal lymphomas that do not fit well into either category but have clinical and morphologic features overlapping and transitional between PMBL and CHL-NS. The term mediastinal gray zone lymphoma (MGZL) has been used for these tumors, which are included in the World Health Organization classification as "B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classic Hodgkin lymphoma." Although several studies have evaluated different therapeutic strategies in PMBL and CHL-NS, there is a paucity of prospective experience treating MGZL, given its rarity and relatively recent recognition. Historically, diseases that today would be categorized as MGZL were probably called "anaplastic large-cell lymphoma Hodgkin-like," and their outcome with standard approaches was poor, with short overall survivals. In this review-following a discussion of the biology and clinical features of MGZL, and how they compare to PMBL and CHL-NS-we outline how the treatment of PMBL and CHL-NS has evolved in recent years, and how we believe MGZL should be approached therapeutically.

Fine-needle aspiration of ganglioneuroma, maturing type (a.k.a., "borderline ganglioneuroblastoma") in the mediastinum of a young man: Case report and discussion of classification.

We report a very unusual case of a posterior mediastinal tumor in a young man, which we diagnosed by fine-needle aspiration cytology as most consistent with ganglioneuroma, maturing subtype. The cytopathologic features were interpreted using the classification of neuroblastic tumors as defined by the International Neuroblastoma Pathology Committee. Neuroblastic tumors are peculiar tumors that have capacity for maturation, and hence they present as a spectrum of tumors, ranging from the undifferentiated neuroblastoma, to ganglioneuroblastoma, to the mature version ganglioneuroma. The practicing surgical pathologist or cytopathologist who does not regularly encounter pediatric specimens may experience difficulty interpreting a specimen from one of these tumors. The following case report discusses application of these criteria to cytopathologic diagnosis of these tumors.

Gray zone lymphoma: chromosomal aberrations with immunophenotypic and clinical correlations.

The term gray zone lymphoma has been applied to tumors that demonstrate transitional morphologic and immunophenotypic features between classical Hodgkin's lymphoma and diffuse large B-cell lymphoma, especially primary mediastinal large B-cell lymphoma. Histopathological and genetic data are limited for these unusual cases. We analyzed cases of gray zone lymphoma (n=27), mediastinal composite lymphoma (n=3) and mediastinal synchronous/metachronous lymphoma (n=3) by morphology, immunophenotyping and fluorescence in situ hybridization. Mediastinal involvement was assured in 24/33 patients (73%). The patient cohort showed a male predominance (M:F ratio; 20:13) and a median age of 32 years (range, 16-91 years). Patients with mediastinal disease were significantly younger (median age: 29.5 years) than patients presenting without evident mediastinal disease (median age: 55 years). Gains including amplifications in 2p16.1 (REL/BCL11A locus) were observed in 33% of all patients, whereas alterations affecting the JAK2/PDL2 locus in 9p24.1 were present in 55%. Further studies revealed rearrangement of the CIITA locus at 16p13.13 in 8/30 cases (27%) and 7/26 cases (27%) demonstrated gains of 8q24 (MYC). Genetic aberrations involving 2p16.1, 9p24.1 and 8q24 showed a higher incidence in cases with evident mediastinal involvement. However, this was not statistically significant when compared with cases without known mediastinal involvement. Twelve of the 27 cases of gray zone lymphoma were morphologically more reminiscent of classical Hodgkin's lymphoma, whereas the other gray zone lymphomas presented with morphological features more closely resembling large B-cell lymphoma. Both morphological groups of gray zone lymphoma were similarly positive for Cyclin E (75 and 93%) and p63 (50 and 53%, respectively) expression. These findings further support a close relationship between gray zone lymphoma, classical Hodgkin's lymphoma and primary mediastinal large B-cell lymphoma, and suggest that some cases of gray zone lymphoma without mediastinal disease may share similar genetic alterations.