Claudiu V. Cotta

Sunitinib-induced macrocytosis in patients with metastatic renal cell carcinoma.

Sunitinib and sorafenib are small molecules that inhibit the vascular endothelial growth factor and related receptors with substantial clinical activity reported in metastatic renal cell carcinoma (RCC). Cytopenia and macrocytosis have been described in patients treated with these agents.

Aggressive B-cell lymphomas with translocations involving BCL6 and MYC have distinct clinical-pathologic characteristics.

OBJECTIVES Recently described, aggressive B-cell lymphomas with genetic abnormalities involving MYC and BCL2 have been shown to have a poor prognosis when treated with regimens for diffuse large B-cell lymphomas. Similar data on cases with concurrent MYC and BCL6 translocation are still scant. Moreover, little is known regarding the morphologic and immunophenotypic characteristics of these cases, which further complicates their identification. This study describes six cases of aggressive B-cell lymphoma with translocations involving MYC and BCL6. METHODS Six cases of large B-cell lymphoma with translocation involving MYC and BCL6 confirmed by fluorescence in situ were identified. The morphologic, immunophenotypic, and clinical features of the cases were examined. RESULTS All the patients were older women, and in 50% of cases, the presentation was extranodal. In two cases, the liver was involved at presentation. A starry-sky pattern was a constant feature of the cases in which the morphology could be reliably assessed. Five of six cases had an immunophenotype corresponding to the germinal center B cells, and only one was positive for BCL2, an immunophenotype reminiscent of that of Burkitt lymphoma. CONCLUSIONS B-cell lymphomas with translocations involving MYC and BCL6 have morphologic and immunophenotypic features suggestive of Burkitt lymphoma or gray zone lymphoma, and they tend to be diagnosed mainly in women, often in extranodal locations.

Novel Protein Disulfide Isomerase Inhibitor with Anticancer Activity in Multiple Myeloma

Multiple myeloma cells secrete more disulfide bond-rich proteins than any other mammalian cell. Thus, inhibition of protein disulfide isomerases (PDI) required for protein folding in the endoplasmic reticulum (ER) should increase ER stress beyond repair in this incurable cancer. Here, we report the mechanistically unbiased discovery of a novel PDI-inhibiting compound with antimyeloma activity. We screened a 30,355 small-molecule library using a multilayered multiple myeloma cell-based cytotoxicity assay that modeled disease niche, normal liver, kidney, and bone marrow. CCF642, a bone marrow-sparing compound, exhibited a submicromolar IC50 in 10 of 10 multiple myeloma cell lines. An active biotinylated analog of CCF642 defined binding to the PDI isoenzymes A1, A3, and A4 in MM cells. In vitro, CCF642 inhibited PDI reductase activity about 100-fold more potently than the structurally distinct established inhibitors PACMA 31 and LOC14. Computational modeling suggested a novel covalent binding mode in active-site CGHCK motifs. Remarkably, without any further chemistry optimization, CCF642 displayed potent efficacy in an aggressive syngeneic mouse model of multiple myeloma and prolonged the lifespan of C57BL/KaLwRij mice engrafted with 5TGM1-luc myeloma, an effect comparable to the first-line multiple myeloma therapeutic bortezomib. Consistent with PDI inhibition, CCF642 caused acute ER stress in multiple myeloma cells accompanied by apoptosis-inducing calcium release. Overall, our results provide an illustration of the utility of simple in vivo simulations as part of a drug discovery effort, along with a sound preclinical rationale to develop a new small-molecule therapeutic to treat multiple myeloma. Cancer Res; 76(11); 3340-50. ©2016 AACR.

A Phase 1 study of imatinib mesylate in combination with cytarabine and daunorubicin for c-kit positive relapsed acute myeloid leukemia

The c-kit receptor is expressed in 95% of relapsed acute myeloid leukemias (AMLs) and mediates leukemic proliferation. We conducted a Phase 1 study of the c-kit inhibitor, imatinib mesylate (IM), in combination with cytarabine and daunorubicin (7+3) in c-kit+ relapsed AML. IM was dose escalated using a 3 by 3 design. Phosphorylated STAT5 was absent to minimally present in residual blasts on day 14 bone marrows. The maximum tolerated dose of IM was 300 mg. The dose-limiting toxicity was Grade 3-4 hepatic toxicity. The CR/CRp rate was 57%. Cytotoxic therapy that includes IM for relapsed AML is well-tolerated and effective.

Pathobiology of Mature T-Cell Lymphomas

Mature T- and natural killer (NK)-cell neoplasms are relatively rare forms of leukemia/lymphoma. The diagnosis of these entities is often difficult, necessitating extensive immunophenotypic, molecular, and genetic testing. Despite the accumulating information on the pathobiology of these neoplasms, in many cases the prognosis remains poor. This article presents an updated view of the morphologic, immunophenotypic, genetic, and molecular characteristics of the mature T- and NK-cell neoplasms. For a better understanding of this complex topic, the development of normal T and NK cells is briefly discussed. The presentation of the characteristic features of the neoplasms in the 2008 World Health Organization classification of hematopoietic neoplasms includes advances in the understanding of the pathobiology of each diagnostic category.

Nodular lymphocyte predominant Hodgkin lymphoma and diffuse large B-cell lymphoma: a study of six cases concurrently involving the same site

Cotta C V, Coleman J F, Li S & Hsi E D 
(2011) Histopathology 59, 1194–1203 
Nodular lymphocyte predominant Hodgkin lymphoma and diffuse large B‐cell lymphoma: a study of six cases concurrently involving the same site

Nodular pulmonary light chain deposition disease: an entity associated with Sjögren syndrome or marginal zone lymphoma

Background Light chain deposition disease (LCDD) is usually a systemic disorder characterised by non-amyloid monoclonal immunoglobulin light chain deposition in tissues. Localised nodular pulmonary (NP) LCDD is a rare and poorly characterised entity and, owing to the difficulties in diagnosis, limited data are available. Methods We investigated the clinical, radiological and pathological characteristics of a series of six confidently diagnosed cases of NPLCDD. Results There were three men and three women with ages ranging from 33 to 74 years. In all cases there were single or multiple pulmonary nodules, in one case associated with cysts. Two patients had no previous history of a lymphoproliferative or autoimmune disorder, two had Sjögren syndrome (SS) and two had extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). Lung biopsies led to diagnoses of MALT lymphoma in four patients, including both of those with a previous history of lymphoma and one with SS. In five cases the diagnosis was confirmed by liquid chromatography–tandem mass spectrometry (LC–MS/MS) and in one by electron microscopy. There was no evidence of systemic LCDD in any of the cases. Five patients had an indolent course in spite of limited therapeutic intervention while, in the patient who died, the cause of death was related to the spread of the lymphoma and was not due to the pulmonary lesions. Conclusions NPLCDD is an indolent disease, in most cases associated with MALT lymphoma or autoimmune disease.

Nodular lymphocyte predominant Hodgkin lymphoma with clusters of LP Cells, acute inflammation, and fibrosis: a syncytial variant.

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) has clinicopathologic, immunophenotypic, and molecular features that are distinct from classical Hodgkin lymphoma (cHL). Distinguishing these entities is usually straightforward, but unusual variants of NLPHL have been described that can be problematic diagnostically and potentially have clinical significance. We describe a case of NLPHL showing a variant histologic pattern characterized by small and large clusters of lymphocyte predominance cells within nodules defined by follicular dendritic cell meshworks, associated with numerous neutrophils and areas of internodular fibrosis. Focally, the neoplastic cells had lacunar cell-like cytologic features. The resulting combination, not previously reported, closely mimicked the syncytial variant of nodular sclerosis cHL. After chemotherapy the patient was free of disease 14 years later. In our review of the literature we identified rare cases of NLPHL that had similar histologic features, but lacked the neutrophilic infiltration. Recognition of this rare variant, facilitated by immunohistochemical studies in this case, further expands the morphologic spectrum of NLPHL.

Anaplastic lymphoma kinase positive large B-cell lymphoma: Literature review and report of an endoscopic fine needle aspiration case with tigroid backgrounds mimicking seminoma

Anaplastic lymphoma kinase‐positive large B‐cell lymphoma (ALK+ LBCL) is a rare distinct type of non‐Hodgkins lymphoma that arises in association with alterations of the ALK gene. This distinct disease entity is typically associated with an aggressive clinical course and appears in light microscopic preparations as a monomorphic population of large, immunoblast‐like cells. In this report, we describe a case of ALK+ LBCL diagnosed by transgastric endoscopic ultrasound‐guided fine needle aspiration (EUS FNA) of splenic hilar lymph nodes. Modified Giemsa stained direct smears from the FNA sample demonstrated large lesional cells with foamy cytoplasm and macronucleoli admixed with small lymphocytes in tigroid backgrounds, mimicking the cytologic appearance of seminoma. Ancillary immunohistochemical studies subsequently confirmed the diagnosis of ALK+ LBCL with the lesional cells being immunoreactive for CD138, VS38c, MUM1, ALK1, and lambda light chain. The cohesiveness of the cells, the cellular morphology, and the tigroid backgrounds were all pitfalls for accurate diagnosis of this rare specific type of lymphoid malignancy by cytology. To our knowledge this is the first case report detailing the diagnosis of ALK+ LBCL by EUS FNA and the first report describing a glycogen‐rich tigroid background in direct FNA smears. Establishing a refined diagnosis in cases of this rare form of LBCL is necessary, as therapies targeting ALK may be of value in clinical management. Diagn. Cytopathol. 2017;45:148–155.

The prognostic significance of an inv(3)(q21q26.2) in addition to a t(9;22)(q34;q11.2) in patients treated with tyrosine kinase inhibitors

In chronic myelogenous leukemia, BCR-ABL1 positive detection of cytogenetic abnormalities in addition to the t(9;22) is thought to portend a poor prognosis; however, not all abnormalities associated with the t(9;22) have the same impact. Inv(3) defines a group of aggressive neoplasms with poor response to conventional treatment options. In this study, four cases with the t(9;22) and inv(3) treated with tyrosine kinase inhibitors (TKI) were investigated. In three cases, the inv(3) was not detected at the initial diagnosis and the patients initially responded to TKI therapy; the inv(3) was detected at blast crisis in all three cases, and one case had both abnormalities at the initial presentation, but this case presented as acute myeloid leukemia. In all cases, detection of an inv(3) was associated with a high blast count and a lack of response to treatment regimens including TKI. All patients died within months from the detection of inv(3). This indicates that cases with the t(9;22) and inv(3) have a clinical course similar to that of cases with an inv(3) and no other therapeutically targetable abnormality.