German Ott

Structural aberrations affecting the MYC locus indicate a poor prognosis independent of clinical risk factors in diffuse large B-cell lymphomas treated within randomized trials of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL)

Recent retrospective studies of heterogeneously treated patients have suggested that chromosomal aberrations of the MYC gene locus indicate an unfavorable prognosis in diffuse large B-cell lymphoma (DLBCL). Here, we investigated the prognostic impact of MYC aberrations analyzed by interphase fluorescence in situ hybridization in 177 patients with de novo DLBCL treated within the two prospective, randomized trials non-Hodgkins lymphoma NHL-B1 and NHL-B2. MYC aberrations were detected in 14 DLBCL (7.9%). In a univariate analysis compared with MYC-negative DLBCL, MYC-positive cases showed a significantly shorter overall survival (OS) (P=0.047) and relevantly, though not significantly, shorter event-free survival (EFS) (P=0.062). In a Cox model adjusted for the international prognostic index, the presence of a MYC gene rearrangement was the strongest statistically independent predictor of OS (relative risk 3.4, P=0.004) and EFS (relative risk 2.5, P=0.015), and this also held true when the cell-of-origin signature detected by immunohistochemistry was included in the model.

Pathway activation patterns in diffuse large B-cell lymphomas.

Deregulation of cell signaling pathways controlling cell growth and cell survival is a common feature of all cancers. Although a core repertoire of oncogenic mechanisms is widely conserved between various malignancies, the constellation of pathway activities can vary even in patients with the same malignant disease. Modern molecularly targeted cancer drugs intervene in cell signaling compensating for pathway deregulation. Hence characterizing tumors with respect to pathway activation will become crucial for treatment decisions. Here we have used semi-supervised machine learning methodology to generate signatures of eight oncogene-inducible pathways, which are conserved across epithelial and lymphoid tissues. We combined them to patterns of pathway activity called PAPs for pathway activation patterns and searched for them in 220 morphologically, immunohistochemically and genetically well-characterized mature aggressive B-cell lymphomas including 134 cases with clinical data available. Besides Burkitt lymphoma, which was characterized by a unique pattern, the PAPs identified four distinct groups of mature aggressive B-cell lymphomas across independent gene expression studies with distinct biological characteristics, genetic aberrations and prognosis. We confirmed our findings through cross-platform analysis in an independent data set of 303 mature aggressive B-cell lymphomas.

Gain of chromosome region 18q21 including the MALT1 gene is associated with the activated B-cell-like gene expression subtype and increased BCL2 gene dosage and protein expression in diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma is the most common lymphoma worldwide. Recent studies of gene expression profiling have identified subgroups of this lymphoid neoplasm with different prognosis. This study suggests that a gain of chromosome 18q21 including the MALT1 gene may involve an unfavorable prognosis. See related perspective article on page 641. Background The aim of this study was to determine the impact of a gain of the MALT1 gene on gene expression and clinical parameters in diffuse large B-cell lymphoma. Design and Methods We analyzed 116 cases of diffuse large B-cell lymphoma by fluorescence in situ hybridization, array-based comparative genomic hybridization, and transcriptional profiling. Results A gain of 18q21 including MALT1 was detected in 44 cases (38%) and was accompanied by a gain of BCL2 in 43 cases. All cases with a 18q21/MALT1 gain showed BCL2 protein whereas 79% in the group without a 18q21/MALT1 gain did so (p<0.001). Cases with 18q21/MALT1 gain more frequently showed an activated B-cell-like (ABC) gene expression signature (65%) than a germinal center B-cell-like (GCB) one (23%) (p<0.001). Ninety-eight genes including MALT1, BCL2, and some selected nuclear factor-κB target genes were differentially expressed between the two genetic groups of diffuse large B-cell lymphoma. By global testing of each chromosome, we identified 33 genes, all located on chromosome 18q, which were differentially expressed between the two genetic groups independently of the ABC/GCB status. In multivariate analysis, the 18q21/MALT1 status represented an independent negative prognostic factor for overall survival (p=0.03). Conclusions In diffuse large B-cell lymphoma, gain of 18q21 including MALT1 is significantly associated with differential expression of genes located on 18q, the ABC gene expression subtype, increased BCL2 gene and protein expression and might indicate an unfavorable prognosis.

Detection of Rearrangements and Transcriptional Up-Regulation of ALK in FFPE Lung Cancer Specimens Using a Novel, Sensitive, Quantitative Reverse Transcription Polymerase Chain Reaction Assay

Introduction: The approved dual-color fluorescence in situ hybridization (FISH) test for the detection of anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangements in non-small-cell lung cancer (NSCLC) is complex and represents a low-throughput assay difficult to use in daily diagnostic practice. We devised a sensitive and robust routine diagnostic test for the detection of rearrangements and transcriptional up-regulation of ALK. Methods: We developed a quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay adapted to RNA isolated from routine formalin-fixed, paraffin-embedded material and applied it to 652 NSCLC specimens. The reliability of this technique to detect ALK dysregulation was shown by comparison with FISH and immunohistochemistry. Results: qRT-PCR analysis detected unbalanced ALK expression indicative of a gene rearrangement in 24 (4.6%) and full-length ALK transcript expression in six (1.1%) of 523 interpretable tumors. Among 182 tumors simultaneously analyzed by FISH and qRT-PCR, the latter accurately typed 97% of 19 rearranged and 158 nonrearranged tumors and identified ALK deregulation in two cases with insufficient FISH. Six tumors expressing full-length ALK transcripts did not show rearrangements of the gene. Immunohistochemistry detected ALK protein overexpression in tumors with gene fusions and transcriptional up-regulation, but did not distinguish between the two. One case with full-length ALK expression carried a heterozygous point mutation (S1220Y) within the kinase domain potentially interfering with kinase activity and/or inhibitor binding. Conclusions: Our qRT-PCR assay reliably identifies and distinguishes ALK rearrangements and full-length transcript expression in formalin-fixed, paraffin-embedded material. It is an easy-to-perform, cost-effective, and high-throughput tool for the diagnosis of ALK activation. The expression of full-length ALK transcripts may be relevant for ALK inhibitor therapy in NSCLC.

Primary Pulmonary Synovial Sarcoma: A Rare Primary Pulmonary Tumor

IntroductionPulmonary sarcomas overall are very uncommon and comprise only 0.5xa0% of all primary lung malignancies. The diagnosis is established only after sarcoma-like primary lung malignancies and a metastatic extrathoracic sarcoma have been excluded. Synovial sarcoma accounts for ~8xa0% of soft-tissue sarcomas. Synovial sarcoma arising from the pleura has rarely been reported.MethodsWe report a case of a 58-year-old woman who complained of right-sided chest pain and shortness of breath. Chest CT scan revealed a large heterogeneous mass, occupying most of the right hemithorax. Histologic diagnosis was supplemented by interphase cytogenetic (FISH) analysis.ResultsComputed tomography guided Tru-cut biopsy was suspicious for a sarcomatous or fibrous malignancy. However, intraoperative frozen-section diagnostics confirmed the diagnosis of a sarcoma. Immunohistochemistry showed that tumor cells expressed epithelial membrane antigen, CD99 and BCL2. Based on immunohistochemistry, the diagnosis of synovial sarcoma was suspected and was confirmed by FISH analysis. The patient was treated with right upper bilobectomy. Due to R1-resection status, postsurgical systemic chemotherapy was administered.ConclusionsPrimary pulmonary synovial sarcoma is a rare primary lung tumor. Due to extensive size of the tumor with pleural and mediastinal invasion only a R1-resection status could be achieved by thoracic surgery.

Advanced patient age at diagnosis of diffuse large B-cell lymphoma is associated with molecular characteristics including ABC-subtype and high expression of MYC

Abstract The incidence of diffuse large B-cell lymphoma (DLBCL) increases with age being patient age at diagnosis an adverse prognostic factor. However, elderly patients are often underrepresented in common studies. To investigate the effect between age and biological characteristics in DLBCL, we analyzed data of 1534 patients encompassing all adult age groups, enriched for the age ≥75 years. Follicular lymphoma (FL) grade 3B with histopathological characteristics of DLBCLs were included. Gender, centroblastic cytology, FL grade 3B morphology, CD10 expression, and ABC/non-GCB-subtype were significantly associated with age after correction for multiple testing and after adjusting for cohorts. Analysis of a subgroup points towards an association of MYC expression with age. Our data indicate that biological features of DLBCL and FL grade 3B are associated with increasing age among adult patients. The prevalence of the ABC/non-GCB-subtype in elderly patients suggests that therapies targeting this molecular subtype should be specifically explored in this subgroup.

Late lung metastasis of primary endometrial cancer

PurposeFemale genital tract tumors are an extremely infrequent cause of pulmonary metastasis. The longest interval of lung metastasis from endometrial cancer was initially reported 17 years after standard surgical treatment. Usually, nearly 80xa0% of all recurrences of endometrial cancer occur within 3 years after the initial treatment. We report two cases where pulmonary metastasis was observed 14 and 17 years after the initial surgical treatment, respectively.PatientsA 71-year-old female was referred to our center for diagnosis of suspicious bilateral lung nodules. She had a history of a resected adenocarcinoma of the lung 5 years ago. Histological examination of the excised lung lesion represented lung metastasis of an endometrial adenocarcinoma which was diagnosed and treated 17 years ago. The second patient, a 77- year-old female was also referred to our center for histological diagnosis of multiple lung lesions and clavicle metastasis. Histological examination of the bone biopsy and lung biopsy both revealed metastasis of a primary endometrial adenocarcinoma diagnosed and treated 14 years ago.ResultsOur first patient was able to be treated with standard surgical therapy with organ-preserving metastatic surgery with atypical segmental resection and wedge resection. Our second patient with widespread pulmonary and osseous metastasis was treated with multimodal treatments (palliative radiotherapy and chemotherapy).ConclusionThis case report points out the rare situation of lung metastasis from endometrial cancer with a latency period of 14 and 17 years, respectively. To our knowledge, in the literature there is only one case reported with a similar extreme latency.

Pulmonary leiomyosarcoma mimicking glomus tumor at first biopsy and surgically treated with isolated left main bronchus resection: rare clinical documentation

Soft tissue tumors originating within the endobronchial tree are extremely rare and most of them correspond to lipomas or leiomyomas. We here report a rare clinical presentation of leiomyosarcoma mimicking glomus tumor at initial biopsy arising from the left main bronchial trunk leading to left lower lobe atelectasis. Primary leiomyosarcoma of the lung is an unusual malignancy. Among this entity, the endobronchial form is very rare and the preoperative diagnosis is extremely difficult. We documented two different presentations and outcomes of primary endobronchial leiomyosarcoma of the lung. In this clinical presentation, histological study and immunohistochemical stain of the surgical resection provided the final diagnosis. Through the following we present the diagnostic and therapeutic difficulties encountered with endobronchial leiomyosarcoma.