Diffuse large B cell lymphoma presenting as Horner's syndrome in a patient diagnosed with neurofibromatosis type 1: a case report and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>Horner's syndrome has a variety of etiologies ranging from benign to serious life-threatening conditions and has been infrequently reported as a presenting symptom of patients with lymphoid neoplasms. Only one case of Burkitt's lymphoma presenting with toothache, paresthesia, and Horner's syndrome has been described and no case reports of diffuse large B-cell lymphoma as the etiology of Horner's syndrome currently exist in the literature. In addition, lymphoid neoplasms have rarely been reported to occur in patients with neurofibromatosis type 1 despite an increased risk of many types of cancer in such cases.</p> <p>Case presentation</p> <p>A 28-year-old Thai man presented with a progressively enlarged left supraclavicular mass together with a significant weight loss and night sweating for four months. He also noticed hoarseness and ptosis of his left eye associated with double vision for two months. Physical examination revealed large supraclavicular lymphadenopathy and Horner's syndrome (ptosis, miosis, and anhydrosis) on the left side of his face. A large mediastinal mass was clearly detected by chest X-ray and computed tomography and subsequent lymph node biopsy provided a diagnosis of diffuse large B-cell lymphoma. Interestingly, the patient was also definitely diagnosed with neurofibromatosis type 1 from multiple café au lait macules, axillary freckles, three neurofibromas, multiple Lisch nodules, and a history of affected family members. He subsequently received chemotherapy with a good response. Twenty-seven cases of various types of lymphoid neoplasms previously reported to occur in neurofibromatosis type 1 patients were also extracted from the literature. All cases were non-Hodgkin lymphoma and the major subtype was T-cell. Only nine cases were B-cell lymphoma. The majority of cases were young with a median age at lymphoma diagnosis of 9.4 years (range 1.1 to 77 years). Two-thirds of the cases were boys or men. Other concomitant malignancies were brain tumor, colorectal cancer, pheochromocytoma, and acute lymphoblastic leukemia.</p> <p>Conclusions</p> <p>We describe for the first time a case of diffuse large B-cell lymphoma that occurred in a neurofibromatosis type 1 patient with Horner's syndrome. Horner's syndrome can be an initial manifestation of diffuse large B-cell lymphoma. Patients who present with a classical triad of Horner's syndrome should always be fully investigated for lymphomatous involvement, especially in the thorax. The exact molecular mechanism for diffuse large B-cell lymphoma development in neurofibromatosis type 1 cases remains to be elucidated.</p

Molecular alterations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) metabolic genes and additional genetic mutations in newly diagnosed acute myeloid leukemia patients

<p>Abstract</p> <p>Background</p> <p>Isocitrate dehydrogenase 1 and 2 (<it>IDH1 </it>and <it>IDH2</it>) metabolic genes encode cytosolic and mitochondrial enzymes that catalyze the conversion of isocitrate to α-ketoglutarate. Acquired somatic mutations of <it>IDH1 </it>and <it>IDH2 </it>have recently been reported in some types of brain tumors and a small proportion of acute myeloid leukemia (AML) cases.</p> <p>Methods</p> <p>Two-hundred and thirty newly diagnosed AML patients were analyzed for the presence of <it>IDH1 </it>and <it>IDH2 </it>heterozygous mutations by polymerase chain reaction-denaturing high performance liquid chromatography (PCR-DHPLC) followed by direct sequencing. Clinical and biological characteristics were analyzed and correlated to the <it>IDH </it>mutational status. Coexisting mutations such as <it>FLT3</it>, <it>PML-</it>RARA, <it>RAS</it>, <it>AML1</it>, and <it>NPM1 </it>mutations were additionally explored.</p> <p>Results</p> <p>The prevalence of <it>IDH1 </it>and <it>IDH2 </it>mutations was 8.7% (20/230) and 10.4% (24/230), respectively. Six missense mutations were identified among <it>IDH1</it>-mutated cases; p.R132H (n = 8), p.R132C (n = 6), p.R132S (n = 2), p.R132G (n = 2), p.R132L (n = 1), and p.I99M (n = 1). Two missense mutations were found in <it>IDH2</it>-mutated cases; p.R140Q (n = 20) and p.R172K (n = 4). No patients had dual <it>IDH1 </it>and <it>IDH2 </it>mutations. About 18% of AML with normal cytogenetics and 31% of acute promyelocytic leukemia had <it>IDH </it>mutations. Half of the <it>IDH</it>-mutated cohort had normal karyotype and the major FAB subtype was AML-M2. Interestingly, <it>IDH1</it>- and <it>IDH2</it>-mutated cases predominantly had <it>NPM1 </it>mutations (60-74%) as compared to the wild type (P < 0.001). Very few <it>IDH</it>-mutated cases had <it>FLT3 </it>and/or <it>RAS </it>abnormalities and none of them had <it>AML1 </it>mutations. Older age and higher median platelet counts were significantly associated with <it>IDH2 </it>mutations although the clinical impact of either <it>IDH1 </it>or <it>IDH2 </it>mutations on patients' overall survival could not be observed.</p> <p>Conclusion</p> <p>Overall, 19% of newly diagnosed AML patients had alterations of <it>IDH </it>genes. No patients concurrently carried both <it>IDH1 </it>and <it>IDH2 </it>mutations suggesting that these mutations were mutually exclusive. <it>NPM1 </it>mutation appears as a major coexisting genetic mutation in <it>IDH</it>-mutated patients. Our present data failed to support the prognostic relevance of <it>IDH </it>mutations although alterations of these metabolic genes potentially have an important role in leukemia development.</p

AML1 mutation and its coexistence with different transcription factor gene families in de novo acute myeloid leukemia: redundancy or synergism

AML1 mutations were identified in 6.3% of AML patients with chromosomal translocations involving CBF, PML-RARα, HOX, or ETS transcription factor (TF) gene families. Rare chromosomal abnormalities, t(16;21) and t(7;11), were also found. This study represents the first series to demonstrate the coexistence of known and novel AML1 mutations with different TF gene mutations. Although the occurrence of two TF gene mutations may appear unnecessary, the possible synergistic mechanism between different TF gene families cannot be excluded and needs to be further explored

A single-tube allele specific-polymerase chain reaction to detect T315I resistant mutation in chronic myeloid leukemia patients

<p>Abstract</p> <p>Background</p> <p><it>BCR-ABL </it>kinase domain (KD) mutation is the major mechanism contributing to suboptimal response to tyrosine kinase inhibitors (TKI) in <it>BCR-ABL</it>-positive chronic myeloid leukemia (CML) patients. T315I mutation, as one of the most frequent KD mutations, has been shown to be strongly associated with TKI resistance and subsequent therapeutic failure. A simple and sensitive method is thus required to detect T315I mutation at the earliest stage.</p> <p>Methods</p> <p>A single-tube allele specific-polymerase chain reaction (AS-PCR) method was developed to detect T315I mutation in a mixture of normal and mutant alleles of varying dilutions. Denaturing high performance liquid chromatography (DHPLC) and direct sequencing were performed as a comparison to AS-PCR.</p> <p>Results</p> <p>T315I mutant bands were observed in the mixtures containing as low as 0.5-1% of mutant alleles by AS-PCR. The detection sensitivity of DHPLC was around 1.5-3% dilution whereas sequencing analysis was unable to detect below 6.25% dilution.</p> <p>Conclusion</p> <p>A single-tube AS-PCR is a rapid and sensitive screening method for T315I mutation. Detection of the most resistant leukemic clone in CML patients undergoing TKI therapy should be feasible with this simple and inexpensive method.</p

Combined Visual and Semi-quantitative Evaluation Improves Outcome Prediction by Early Mid-treatment 18 F-fluoro-deoxi-glucose Positron Emission Tomography in Diffuse Large B-cell Lymphoma

The purpose of this study was to assess the predictive and prognostic value of interim FDG PET (iPET) in evaluating early response to immunochemotherapy after 2 cycles (PET-2) in diffuse large B-cell lymphoma (DLBCL) by applying 2 different methods of interpretation: the Deauville visual 5-point scale (5-PS) and a change in SUV (\u394SUV) by semiquantitative evaluation. Methods: In total, 145 patients with newly diagnosed DLBCL underwent pretreatment PET and PET-2 assessment. PET-2 was classified according to both 5-PS and percentage \u394SUV. Receiver-operating-characteristic analysis was performed to compare the accuracy of the 2 methods for predicting progression-free survival. Survival estimates, based on each method separately and combined, were calculated for iPET-positive (iPET+) and iPET-negative (iPET-) groups and compared. Results: Both with 5-PS and with \u394SUV-based evaluations, significant differences were found between the progression-free survival of iPET- and iPET+ patient groups (P &lt; 0.001). Visually, the best negative predictive value (NPV) and positive predictive value (PPV) occurred when iPET was defined as positive if the Deauville score was 4-5 (89% and 59%, respectively). Using the 66% \u394SUV cutoff reported previously, NPV and PPV were 80% and 76%, respectively. \u394SUV at the 48.9% cutoff, reported for the first time here, produced 100% specificity along with the highest sensitivity (24%). The 5-PS and a semiquantitative \u394SUV of less than 48.9% for each PET-2 gave the same PET-2 classification (positive or negative) in 70% (102/145) of all patients. This combined classification delivered NPV and PPV of 89% and 100%, respectively, and all iPET+ patients failed to achieve or remain in remission. Conclusion: In this large consistently treated and assessed series of DLBCL patients, iPET had good prognostic value interpreted either visually or semiquantitatively. We determined that the most effective \u394SUV cutoff was 48.9% and that when combined with 5-PS assessment, a positive PET-2 result was highly predictive of treatment failure.cases, and MRI in 92.5% of cases; no false negative cases were observed. These results suggest the use of PET/CT as a unique diagnostic imaging tool after CCRT, to correctly assess residual and progression disease