The Usefulness of Short-Interval Sequential FDG PET/CT Studies in Defining the Benignity of Hypermetabolic Lipomatous Tumor.

ABSTRACT: We present an interesting case of incidentally detected lipomatous tumor in an oncological patient that could result in a false-positive interpretation by exhibiting intense FDG activity similar to that of a malignant neoplasm. Careful evaluation of FDG uptake changes on sequential short-interval PET/CT studies was helpful in defining the benign nature of the tumor as the hypermetabolism was gradually disappearing obviating the need for a major surgery.

Progressive Transformation of Germinal Centers Simulating Malignant Axillary Lymphadenopathy in a Breast Cancer Patient on FDG PET/CT.

ABSTRACT: A 64-year-old woman with breast cancer underwent FDG PET/CT for follow-up. The study revealed highly increased FDG uptake in newly diagnosed enlarged axillary lymph nodes, which were worrisome for malignancy. Histopathology revealed a rarely diagnosed benign disease of progressive transformation of germinal centers mimicking malignant lymphadenopathy. As imaging findings of this entity, which usually involves the axillary and cervical areas, have been reported in very few studies, nuclear medicine physicians should be familiar with this potential "false-positive" FDG uptake representing an interpretative pitfall, especially during evaluation of breast cancer patients.

SLP76 Mutation Associated with Combined Immunodeficiency and EBV-Related Lymphoma.

Increased susceptibility to develop severe forms of Epstein-Barr virus (EBV) infection in early age is a significant hallmark of an underlying primary immunodeficiency (PID). Here, we present immunologic and genetic evaluations of a 3-year-old child who was born to first-cousins parents and presented with recurrent infections, failure to thrive, and severe EBV-related infection and proliferation. A diagnosis of diffuse large B cell lymphoma was made and the immunological workup was suggestive of T cell immunodeficiency. Unfortunately, the patient succumbed to EBV-related lymphoma. Whole-exome sequencing revealed a novel homozygous mutation, c.991del.C; p. Q331Sfs*6 in the SLP76 gene. The SLP76 protein, a TCR signaling molecule, was recently linked to a human disease of the immune system. In order to examine the effect of this new SLP76 mutation on T cell signaling, a SLP76-deficient Jurkat-derived T cell line was transduced either with wild-type (WT), or with the specific SLP76 mutant, or with a mock vector. Downstream TCR signaling events, including ERK1/2 phosphorylation, CD69 expression, and Ca2 + mobilization, were reduced in cells harboring the reported mutation, linking this novel mutation to the expected immunological outcome. SLP76 deficiency should be added to the growing list of monogenetic diseases that predispose affected individuals to acquire severe and uncontrolled EBV infections and to develop substantial complications. This case further links mutations in the SLP76 gene to a significant human immunodeficiency and extends its clinical phenotype.

Unusual presentation of aggressive high-grade B-cell lymphoma of colonic origin: A case report and review of the literature.

Colonic lymphoma is a rare disease. The presented case is unique, being manifested with abrupt onset, including circulatory shock and lactic acidosis as the initial presentation.

Splenic Micronodular T-Cell/Histiocyte-Rich Large B-Cell Lymphoma: The Corticosteroid Pretreatment Hypothesis.

Splenic micronodular T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is derived from diffuse large B-cell lymphoma N.O.S., perhaps with some affinity with nodal THRLBCL. Of note, in contrast with the latter, the only lymph nodes involved in association with the splenic micronodular pattern of the disease are the splenic hilar lymph nodes. The possibility that corticosteroids, when prescribed prior to splenectomy, cause histopathological and functional modulations, apoptosis, necrosis, tissue shrinkage, which may obscure the diagnostic morphological features of this variant lymphoma and cause an underdiagnosis of this condition. The indications for glucocorticoid therapy are either related to the lymphoma itself, or else to other comorbidities, like asthma and autoimmune disorders. We propose that patients with the splenic subset of the disease are likely to have been prescribed corticosteroids prior to histopathologic examination of the involved spleen, causing disparate morphologies. However, a reviewer might accidentally dismiss the corticosteroid pretreatment which is thus overlooked. Apoptosis, induced by corticosteroids, is hypothesized as the major mechanism initiating the histopathological and functional changes in the splenic micronodular variant of the lymphoma.

Transformation of low-grade follicular lymphoma with partial marginal zone differentiation: Two cases.

Two cases of low-grade follicular lymphoma, with marginal zone differentiation and/or with high proliferation rate in one of them, are reported with transformation into high grade B-cell and B-lymphoblastic lymphomas. The contribution of these features to the transforming process, although previously described, is infrequent, and has not been deciphered to date.

Multiple Myeloma with Foamy Mott Cells.

Intracytoplasmic assorted vacuoles containing immunoglobulin collections are occasionally seen in multiple myeloma. When abundant, they impart a foamy appearance to the tumor cells, which is a potential source for diagnostic pitfalls. Herein, we report the case of a patient who presented with skeletal pain and CT confirmed lytic lesions. A bone marrow biopsy revealed multiple myeloma with unusual foamy Mott cells. The patient was subsequently treated with four cycles of cyclophosphamide, bortezomib, and dexamethasone induction therapy, followed by 3 cycles of lenalidomide with dexamethasone. A biopsy performed following initial biological and immunomodulatory drugs revealed different morphological and clonal characteristics. These features were modified again, five years later, and again, after two years of close monitoring. Hematopathologists should be aware of this morphologic variant of myeloma as well as for the capacity of clonal characteristics, such as light chain monotype, to fluctuate subsequent to treatment.

Postchemotherapy Histiocyte-Rich Pseudotumor of the Spleen Simulating Residual Disease in a Patient With Non-Hodgkin Lymphoma on FDG PET/CT.

A 64-year-old man was treated with multiagent chemotherapy owing to high-grade non-Hodgkin lymphoma presenting as a bulky disease involving the spleen. Interim and posttreatment sequential FDG PET/CT scans revealed a residual splenic mass showing markedly intense FDG uptake suspected of a residual viable lymphoma. To definitely decide about the appropriate treatment, a laparoscopic splenectomy was performed. Histopathologic specimen was compatible with the rare diagnosis of postchemotherapy histiocyte-rich pseudotumor of the spleen, a potential pitfall simulating viable disease on FDG PET/CT.

Nivolumab Induced Lethal Aplastic Anemia in a Patient with Metastatic Melanoma.

Nivolumab is an active treatment in patients with metastatic melanoma. We report a case of a patient with metastatic malignant melanoma who was given nivolumab as an advanced-line treatment. She received nivolumab 3 mg/kg every 2 weeks for 4 cycles and developed aplastic anemia. To the best of our knowledge, there are only three published case reports that have shown aplastic anemia in patients who have been treated by immunotherapy. This is the first report of a lethal aplastic anemia during nivolumab monotherapy in a metastatic melanoma patient.

Hodgkin's lymphoma, nephrotic syndrome, and echinococcosis cysts: an unusual association and literature review.

We present a 5-year-old female with minimal change nephrotic syndrome (MCNS). Within several months, she became steroid-dependent with progression of edema and ascites. Imaging studies revealed abnormal solid mass and liver cysts and she was diagnosed with both abdominal Hodgkin's lymphoma (cHD) and large hepatic cystic echinococcosis (CE). Association between MCNS and cHL or with CE has been described in the literature in adults and rarely in the pediatric population. We report, for the first time, a simultaneous occurrence of all three: MCNS, cHL, and CE. Literature review and suggested pathophysiologic mechanisms underlying this phenomenon are presented.

Dimethyl fumarate and vitamin D derivatives cooperatively enhance VDR and Nrf2 signaling in differentiating AML cells in vitro and inhibit leukemia progression in a xenograft mouse model.

Acute myeloid leukemia (AML) is one of the deadliest hematological malignancies without effective treatment for most patients. Vitamin D derivatives (VDDs) - active metabolites 1α,25-dihydroxyvitamin D2 (1,25D2) and 1α,25-dihydroxyvitamin D3 (1,25D3) and their analogs - are differentiation-inducing agents which have potential for the therapy of AML. However, calcemic toxicity of VDDs limits their clinical use at doses effective against cancer cells in vivo. Here, we demonstrate that in AML cell cultures, moderate pro-differentiation effects of low concentrations of VDDs can be synergistically enhanced by structurally distinct compounds known to activate the transcription factor Nuclear Factor (Erythroid-derived 2)-Like 2 (NFE2L2 or Nrf2). Particularly, dimethyl fumarate (DMF), which is clinically approved for the treatment of multiple sclerosis and psoriasis, strongly cooperated with 1,25D3, PRI-5100 (19-nor-1,25D2; paricalcitol) and PRI-5202 (a double-point modified 19-nor analog of 1,25D2). The pro-differentiation synergy between VDDs (1,25D3 or PRI-5202) and Nrf2 activators (DMF, tert-butylhydroquinone or carnosic acid) was associated with a cooperative upregulation of the protein levels of the vitamin D receptor (VDR) and Nrf2 as well as increased mRNA expression of their respective target genes. These data support the notion that VDDs and Nrf2 activators synergize in inducing myeloid cell differentiation through the cooperative activation of the VDR and Nrf2/antioxidant response element signaling pathways. We have previously reported that PRI-5202 is more potent by approximately two orders of magnitude than 1,25D3 as a differentiation inducer in AML cell lines. In this study, we found that PRI-5202 was also at least 5-fold less calcemic in healthy mice compared to both its direct precursor PRI-1907 and 1,25D3. In addition, PRI-5202 was remarkably more resistant against degradation by the human 25-hydroxyvitamin D3-24-hydroxylase than both 1,25D2 and 1,25D3. Importantly, using a xenograft mouse model we demonstrated that co-administration of PRI-5202 and DMF resulted in a marked cooperative inhibition of human AML tumor growth without inducing treatment toxicity. Collectively, our findings provide a rationale for clinical testing of low-toxic VDD/DMF combinations as a novel approach for differentiation therapy of AML.

Classification of Solitary Plasmacytoma, Is it more Intricate than Presently Suggested? A Commentary.

A query regarding the definition and the classification of solitary plasmacytoma is apparently still pending. The clinical course, the response to treatment and the propensity to progress to plasma cell myeloma, are all a function of the classification which must be established on a firm basis. Solitary plasmacytoma should be recognized in the continuum of the plasma cell neoplasms. Moreover, whether the solitary plasmacytoma of bone and the extramedullary type of the tumor represent two distinct disease entities, exhibiting separate biological characteristics, has not been finally established. To appraise the similarities and differences between these two types of lesion, we have scrutinized recent investigations relating their classification. A commentary highlighting our conclusions follows.

Management of gastrosplenic fistula in the emergency setting - A case report and review of the literature.

INTRODUCTION: A gastrosplenic fistula (GSF) is a very rare complication that arises mainly from a splenic or gastric large cell lymphoma. The proximity of the gastric fundus to the enlarged fragile spleen may facilitate the fistulisation. This complication can lead to massive bleeding, which, though uncommon, may be lethal. We present a patient with massive upper gastrointestinal bleeding secondary to a GSF. CASE PRESENTATION: We present a 48-year-old man with a refractory diffuse large B-cell lymphoma who was admitted to our hospital due to hematemesis. On arrival, he was in hemorrhagic shock, and was taken directly to the intensive care unit. The source of bleeding could not be identified on gastroscopy, the patient remained hemodynamically unstable and a laparotomy was performed.A fistula between a branch of the splenic artery and the stomach was identified. The stomach appeared to be involved in the malignant process. After subtotal gastrectomy and splenectomy, the bleeding was controlled. After stabilization, the patient was admitted to the intensive care unit, and 24 hours later was discharged in stable condition. DISCUSSION: We describe a fistula between a branch of the splenic artery and the stomach, which was accompanied by massive bleeding. An emergency laparotomy saved the patient's life. CONCLUSION: The purpose of this report is to alert physicians that surgical intervention can be lifesaving in this rare malignant condition. A literature review focusing on the presenting symptoms and the epidemiology of GSF is presented.

Composite Nasopharyngeal plasmacytoma with nodal paraimmunoblastic variant of small lymphocytic lymphoma: A case report.

A 78-year-old male who presented with severe shortness of breath and bilateral nasal congestion was shown to exhibit ta mass localized in the nasopharynx. The tumor was diagnosed as an extramedullary plasmacytoma. Peripheral blood eosinophilia had been persistently noted in the preceding 12 years. The plasmacytoma exhibited a predominance of κ-light chain monotypic Mott cells and was admixed with numerous eosinophils. No history of allergic rhinitis, asthma or aspirin sensitivity was elicited. An axillary lymph node was excised two weeks after the nasopharyngeal biopsy, and it exhibited a paraimmunoblastic transformation of small lymphocytic lymphoma. A review of the literature identified few occurrences of such simultaneous tumors in individual patients.

Angioimmunoblastic T-Cell Lymphoma: A Questionable Association with Follicular Dendritic Cell Sarcoma.

An elderly woman presented with generalized lymphadenopathy, several systemic symptoms, and splenomegaly. An inguinal lymph node excision revealed a compound picture. One aspect of the lymph node morphology, including cells with follicular T-helper cell phenotype, was most consistent with angioimmunoblastic T-cell lymphoma. The other component, revealing spindle cells forming whorls with immunostaining for CD21, CD23, and fascin, might be an integral part of this T-cell lymphoma. However, due to the often massive involvement of the nodal tissue by these follicular dendritic cells, these areas were questionably suggestive of involvement by follicular dendritic cell sarcoma. We raise herein the issue of the borderline area between advanced follicular dendritic cell expansion in angioimmunoblastic T-cell lymphoma and a massive follicular dendritic cell proliferation consistent with follicular dendritic cells sarcoma, in the absence of a genomic analysis.

Relevance of the Measles Virus Expression in Cancer - an Update.

Evidence of an association between classical Hodgkin lymphoma and the measles virus has previously been presented by our group. Arguments held against our thesis were reevaluated. Substantiation of a relationship between the measles virus and additional solid tumors was submitted. Moreover, a pathogenic pathway was suggested to support a possible contribution of the measles virus to the development of classical Hodgkin lymphoma. We have chosen to exclude a discussion of measles virotherapy, since this carries distinct implications. We now add new evidence regarding the expression of the measles virus phosphoprotein in a few cancers. We also suggest a role in this context for atypical measles syndrome in malignant tumors. Last, we propose a collaboration which may make the best, on the one hand of our cohort of classical Hodgkin lymphoma, half of which carry the measles virus expression in their tumor cells. The planned study will also look into the patients vaccination records and into a previous history of the measles disease. On the other hand, cohorts of patients diagnosed with late onset measles will be assessed for the eventual diagnosis of atypical measles syndrome and will be followed up for the subsequent development of a malignant tumor.

Cell surface GRP78: A potential marker of good prognosis and response to chemotherapy in breast cancer.

The 78-kDa glucose-regulated protein (GRP78) is a stress induced heat shock protein which, under limiting conditions, functions as a cell surface signaling receptor. Tumor cells are considered to be subjected to a physiologically stressful microenvironment due to their excessive growth. The role of GRP78 in tumor survival has been of notable interest. The present study aimed to assess the potential prognostic and predictive value of cell surface GRP78 expression in breast cancer tumor cells. Cell surface and cytoplasmic expression of GRP78 was examined by immunohistochemical staining of GRP78 in breast cancer archival paraffin-embedded tumor specimens. The cohort studied included breast cancer patients with operable T1,2, estrogen receptor-positive, node-negative cancer who were assessed using the Oncotype DX gene profile, as well as patients with locally advanced disease prior to and following neoadjuvant systemic treatment. GRP78 values were compared between the 2 groups, and prior to and following systemic treatment. Association analyses between GRP78 expression and prognostic markers were also performed. Cox regression analysis was used to examine the impact of these variables on disease-free survival (DFS). No differences in cytoplasmic GRP78 expression were observed. By contrast, the rates of cell surface GRP78 expression were 74.1% in the early stage operable patients, 36% in neoadjuvant systemic treatment patients prior to treatment and 62.5% in patients following systemic treatment (P<0.039). Positive cell surface GRP78 expression was associated with increased expression of the progesterone receptor (P=0.024), p53 expression (P=0.022) and improved DFS (P=0.047). In the case of GRP78 positivity, a trend for a superior response to chemotherapy was observed (P=0.19). The results of the present study indicated that cell surface GRP78 may be used as a marker for good prognosis in breast cancer and a potential marker for response to chemotherapy.

CD20 Over-Expression in Hodgkin-Reed-Sternberg Cells of Classical Hodgkin Lymphoma: the Neglected Quest.

We have scrutinized a previously analyzed cohort of classical Hodgkin lymphoma patients for evidence of a CD20 over-expression. This was pursued in order to determine whether all the 24 (12.6%) CD20+++ patients had clinical and/or biological profiles which would warrant a separate consideration and treatment or would carry a different outcome from our 166 CD20 (-) classical Hodgkin lymphoma patients. Except for an older age and a significantly lower expression of non-sialyl-CD15 antigen, both previously described in classical Hodgkin lymphoma, no justification to exclude these CD20+++ patients from the cohort at large is apparent. We suggest that the generally accepted view to the contrary be revised. In addition, we propose alternative interpretations for the low expression of CD20 found in a majority of Hodgkin-Reed-Sternberg cells in classical Hodgkin lymphoma.

Targeting natural killer cell reactivity by employing antibody to NKp46: implications for type 1 diabetes.

Natural killer (NK) cells belong to the innate lymphoid cells. Their cytotoxic activity is regulated by the delicate balance between activating and inhibitory signals. NKp46 is a member of the primary activating receptors of NK cells. We previously reported that the NKp46 receptor is involved in the development of type 1 diabetes (T1D). Subsequently, we hypothesized that blocking this receptor could prevent or hinder disease development. To address this goal, we developed monoclonal antibodies for murine NKp46. One mAb, named NCR1.15, recognizes the mouse homologue protein of NKp46, named Ncr1, and was able to down-regulate the surface expression of NKp46 on primary murine NK cells following antibody injection in vivo. Additionally, NCR1.15 treatments were able to down-regulate cytotoxic activity mediated by NKp46, but not by other NK receptors. To test our primary assumption, we examined T1D development in two models, non-obese diabetic mice and low-dose streptozotocin. Our results show a significantly lower incidence of diabetic mice in the NCR1.15-treated group compared to control groups. This study directly demonstrates the involvement of NKp46 in T1D development and suggests a novel treatment strategy for early insulitis.