Hematolymphoid Malignancies Research Articles

Histiocytic/Dendritic Cell Transformation of B-Cell Neoplasms: Pathologic Evidence of Lineage Conversion in Differentiated Hematolymphoid Malignancies

B-cell lymphomas, such as low-grade follicular lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma, can transform to histiocytic/dendritic cell sarcoma (H/DS) in rare cases. The diagnosis of this unconventional neoplastic evolution relies on a combination of immunophenotypic analysis and genotypic studies. A genotype identical to that of the primary B-cell neoplasm in a secondary neoplasm with H/DS immunophenotype supports the lineage conversion to H/DS. Putative mechanisms for this unusual phenomenon include dedifferentiation, common immature progenitor, and transdifferentiation models, the latter of which is suggested by clinical laboratory data at the present time. Elucidation of the molecular mechanisms governing this lineage conversion may facilitate the understanding of carcinogenesis of not only hematopoietic but also nonhematolymphoid neoplasms. The clinical outcome of secondary H/DS is dismal, as observed in sporadic cases, and the optimal treatment remains to be determined.

Predicting complications of chemotherapy-induced febrile neutropenia: A single-center experience.

e20678 Background: Identifying the parameters associated with increased complications would help to formulate a cost-effective and rational therapy in patients with chemotherapy induced febrile neutropenia. Methods: We prospectively collected data from January 2007-December 2011 of consecutive episodes of neutropenic fever at our centre. Clinical features, laboratory characteristics and MASCC score were analysed to identify patients at higher risk for developing complications. Complications were defined as either of the following event: failure of first line antibiotics, organ failure, delay in next cycle of chemotherapy, inpatient admission and death. Results: Three hundred and eighty-eight febrile neutropenia (FN) episodes in 373 patients were included, 256 episodes of FN in hematolymphoid malignancies and 132 episodes of FN in solid tumours. The median age was 31 years (11-76 years). Two hundred and forty-four (65.4%) patients were male. One hundred forty-nine patients (39.94%) had FN during previous cycles, while primary GCSF prophylaxis was used for 205 (52.84%) cases. The median haemoglobin, nadir neutrophil count & median number of days with severe neutropenia (< 1X109/L) were 7.9 gm/dl, 0.04X109/L and 4 days respectively. A clinical focus of infection was present in 174 (44.8%) episodes, with gastrointestinal being the commonest in 70episodes (40.23%). High risk MASCC score (<21) was present in 156 episodes (40%). Complications were seen in 133(34%) instances. On Univariate analysis, age, type of malignancy, prophylactic growth factor use, clinical focus of infection, day of FN, MASCC score, nadir Hb and platelet count were significantly associated with complications. All predictive factors except age and nadir Hb could independently predict complication on multivariate analysis. Conclusions: Clinical and laboratory parameters in addition to MASCC score could help in identifying patients with FN who require hospitalisation and more intensive management strategies.

Expression and possible significance of vascular endothelial growth factor in non-Hodgkin lymphoma

There is little information about the exact trigger mechanisms of vascular endothelial growth factor (VEGF) expression in hematolymphoid malignancies. The aim of this study was to investigate the expression of VEGF in malignant non-Hodgkin lymphoma (NHL), in terms of its immunohistochemical distribution and clinicopathological significance. We evaluated the distribution in tumor cells, macrophages and in non-tumoral cells. VEGF immunoreactivity was esti- mated according to this score: 0 (0% positive cells); 1 ( 30%). Histopathological evaluation revealed 18 cases of diffuse type lymphoma and 3 cases of follicular type lymphoma. VEGF was positive in 95.23% of cases and in one case, VEGF was negative in all cell types. We noticed a significant correlation in VEGF expression between tumor cells and macrophages (p=0,001), tumor cells and non-tumoral cells (p=0,002). In non-Hodgkin lymphoma, the main mecha- nism of angiogenesis seems to be dependent on the VEGF pathway and its expression particularly by stromal cells.

Plasmacytoid urothelial carcinoma of the urinary bladder – a review of the literature

Plasmacytoid urothelial carcinoma is a new variant of urothelial carcinomas that was added to the World Health Organization (WHO) classification list in 2004; therefore, in view of its rarity, most practitioners may not be familiar with its biological behaviour. Various internet databases were searched to identify cases of plasmacytoid urothelial carcinoma of the urinary bladder in order to document the presentation, investigation, management, treatment and outcome of the disease. In addition, the only reported case of plasmacytoid urothelial carcinoma of the ureter is included. Plasmacytoid urothelial carcinoma of the urinary bladder is a rare variant of urothelial carcinoma and fewer than 100 cases have been reported in the literature. It is an aggressive subtype of urothelial carcinoma with plasmacytoid features and the diagnostic features include mimicking haematolymphoid malignancy, a dyscohesive invasive pattern, eccentric nuclei, evidence of prominent eosinophilic cytoplasm (amphophilic cytoplasm may also be observed) and intracytoplasmic mucin-positive lumina may be present. Patients often present with plasmacytoid urothelial carcinoma at a late stage and exhibit peritoneal surface spread. Mucin stains may reveal intracytoplasmic lumina and plasmacytoid urothelial carcinomas tend to depict immunohistochemical staining characteristics such as keratin positivity [cytokeratin (CK)7 and, at times, CK20], CD138 positivity (many carcinomas, not only plasmacytoid urothelial carcinoma, stain positive for CD138), MUM1 and kappa/lambda light chain negativity, E-cadherin negativity (conventional and micropapillary types of urothelial carcinoma tend to stain positive for E-cadherin and signet-ring cell carcinomas of the bladder tend to stain negative). In the differential diagnosis of plasmacytoid urothelial carcinoma, plasmacytoma must be considered, and immunostaining characteristics can be helpful in the confirmation of the diagnosis in that p63-positive staining and strong keratin would indicate carcinoma. Kappa and lambda in situ hybridization or immunoperoxidase would identify most plasmacytomas. CD138 positivity is expressed by many carcinomas and is, therefore, not helpful, whereas MUM1 preferentially stains plasmacytoma. Plasmacytoid urothelial carcinoma of the urinary bladder has characteristic plasmacytoid morphological features and immunohistochemical staining is helpful in differentiating this tumour from other differential diagnoses. Plasmacytoid urothelial carcinomas are aggressive variants of urothelial carcinomas of the urinary bladder that have been associated with poor prognosis and death of patients following various treatment options including transurethral resection of bladder tumour and/or radical cystectomy, transurethral resection biopsy and/or cystectomy and/or chemotherapy, transurethral resection of bladder tumour, and chemotherapy and/or radiotherapy. Most patients do not survive post treatment; however, there are reports of survival following treatments that have included combination systemic chemotherapy.

Collapsing Glomerulopathy Following Anthracycline Therapy

We report 2 cases of anthracycline-induced collapsing glomerulopathy, one in a patient treated for peripheral T-cell lymphoma, and the other in a kidney transplant recipient treated for acute myeloid leukemia. Collapsing glomerulopathy is a distinct variant of focal segmental glomerulosclerosis (FSGS) that has been attributed to several different causes besides human immunodeficiency virus (HIV) in recent years. Previously, anthracycline use has been associated with FSGS, not otherwise specified (NOS). However, in the absence of therapy, various hematolymphoid malignancies have been associated with FSGS, NOS and collapsing glomerulopathy. In individuals who have hematolymphoid malignancy or are being treated with an anthracycline, the frequency of FSGS is extremely low. We suggest that in the following 2 patients, anthracycline use caused collapsing FSGS based on the temporal relationship, but also in the context of potentially underlying predisposing conditions. Host and environmental factors may interact to cause one morphologic form of FSGS or another.

Molecular Diagnosis of Infection-Related Cancers in Dermatopathology

The association between viruses and skin cancer is increasingly recognized in a number of neoplasms, that is, cutaneous squamous cell carcinoma, Kaposi sarcoma, nasopharyngeal carcinoma, and Merkel cell carcinoma, as well as hematolymphoid malignancies such as adult T-cell leukemia/lymphoma and NK/T-cell lymphoma (nasal type) and post-transplant lymphoproliferative disorders. Molecular assays are increasingly used to diagnose and manage these diseases. In this review, molecular features of tumor viruses and related host responses are explored. The tests used to identify such features are summarized. Evaluation of the utility of these assays for diagnosis and/or management of specific tumor types is presented.

Discovery and Characterization of Chemical Inhibitors of UBC13.

Abstract 2950Poly-ubiquitination of signaling proteins via lysine 63 (K63)-linked chains is recognized as a critical post-translational modification involved in activation of NF-kB and stress kinases in the context of signaling by Tumor Necrosis Factor Receptors (TNFRs), Toll-like receptors (TLRs), and antigen receptors. UBC13 is a K63-specific ubiquitin conjugating enzyme that partners with TNFR-associated factors (TRAFs) to mediate K63-linked ubiquitination. Gene ablation studies have shown UBC13 is required for NF-kB signaling induced by a variety of stimuli in specific types of immune cells, making it a potential target for certain cancers, autoimmune and inflammatory diseases. UBC13 operates together with obligatory cofactors, either UEV1A in the cytosol or MMS2 in the nucleus. The nuclear function of UBC13 is evolutionarily conserved, where it plays a critical role in double strand DNA repair, making UBC13 a potential chemo- and radio-sensitizer target for oncology.To identify chemical inhibitors of UBC13, we developed a HTS assay measuring UBC13-UEV1A enzymatic activity by TR-FRET, screening altogether ∼450,000 diverse compounds. Hit compounds were characterized using a rigorous testing funnel consisting of (a) informatics filtering against a database of > 100 HTS campaigns conducted with the same libraries, to eliminate promiscuous compounds; (b) counter-screens against E1, another cysteine-dependent enzyme (caspase-3), and against an irrelevant target formatted as a TR-FRET assay; and (c) ordering compounds from fresh powders and demonstrating reproducible concentration-dependent inhibition of UBC13. The surviving hits were then analyzed by cell-based assays for suppression of TRAF6 ubiquitination but not Mdm2-mediated ubiquitination of p53, resulting in 14 promising hits that included two chemical series. While suppressing TRAF6 ubiquitination (UBC13-dependent) in cells, these compounds did not interfere with either SUMOylation (UBC9-dependent) or NEDDylation (UBC12-dependent) of cellular proteins. UBC13 inhibitors also suppressed NF-kB activity (measured using stably integrated NF-kB-driven luciferase reporter gene) induced by PKC activators (Carma/Bcl-10/MALT pathway) and DNA damaging agent (Doxorubicin) but not by TNF-a. Investigations of the bioactivity of these UBC13 inhibitory compounds and their analogs will be described for a variety of hematolymphoid malignancies. (Supported by NIH R03-MH085677, NIH U54–005033, and by a fellowship grant from International Myeloma Foundation). Disclosures:No relevant conflicts of interest to declare.

Anatomic distribution of hematolymphoid malignancies in the head and neck: 7 years of experience with 122 patients in a single institution

Conclusion: Most hematolymphoid malignancies in the head and neck were malignant lymphomas that most often occurred in sexagenarian men. Approximately 80% of them were B-cell lymphomas with a predominance of diffuse large B-cell lymphoma (DLBCL) in both nodal and extranodal sites. Our results were compatible with those in a previous study that was conducted in the central part of Japan. Objectives: This analysis was performed to describe the anatomic distribution of hematolymphoid malignancies that were diagnosed by biopsy in our department. Methods: Clinical medical records of 122 patients with hematolymphoid malignancies in the head and neck from January 2004 to December 2010 were retrospectively reviewed. The anatomic site of origin according to the histopathology of each malignancy was analyzed. Results: The incidence ratio of hematolymphoid malignancies was 15.1%. The male:female ratio was 2.3:1. Ages ranged from 17 to 89 years (median, 66). Of the 122 cases, 121 were lymphoid neoplasms (4 cases of Hodgkin lymphoma and 117 cases of non-Hodgkin lymphoma) and the remaining 1 was myeloid. The most common histopathology was DLBCL (54.9%), followed by follicular lymphoma (8.2%), and peripheral T-cell lymphoma (8.2%). Most commonly, the oropharynx (36.1%) and the cervical lymph node (34.4%) were affected.

Cytodiagnosis and cytomorphologic analysis of hematolymphoid malignancy in serous effusion: a study of 23 cases

To evaluate the value of cytomorphologic and immunocytochemical approaches in the diagnosis of hematologic neoplasms in serous effusion. The cytospin and Thinprep smears of effusion specimens were prepared from 23 cases of lymphoid malignancies with histological confirmation and 30 cases of benign effusions used as control. Morphological assessment of the cellular components was conducted, including the ratio of mesothelium to lymphocyte, karyomorphism of lymphoid cell and the presence of apoptosis and mitosis. Immunocytochemical study was performed in all the cases, with flow cytometry in one case. Among the 23 tumor cases, 14 represented disease relapse, and in the remaining nine cases, the serous effusion was the primary manifestation. The proportion of mesothelium was low in the tumor group, being less than 10% in 20 cases (87.0%, 20/23). It was more than 10% in most of benign cases (20/30, 66.7%). Lymphoid cells were prominent (> 80% cells) in 69.6% of the tumor cases, and the cellular component in some control cases (63.3%, 19/30) showed fewer lymphocytes. Nipple-like projection of lymphocytic nuclei could be detected in almost all the tumor cases (91.3%, 21/23), but was occasionally found in the control group (26.7%, 8/30). Apoptosis and mitosis were obvious in lymphomatous effusion, but observed in only 6.7% of the control cases. Significant difference of the previously mentioned cytomorphologic features existed between the tumor and control groups (P < 0.01). The results of immunocytochemical staining in cell block were identical to the corresponding immunohistochemistry, and one case of mantle cell lymphoma was confirmed by flow cytometry. The cytologic findings seen in all the 23 studied cases were in agreement with the corresponding histologic diagnosis. Some cytomorphologic features, including decreased number of mesothelium, increased number of lymphoid cells, nuclear nipple-like projection, and the presence of apoptosis and mitosis, are very useful for diagnosing lymphoid malignancy in serous effusion. Immunocytochemistry is an important approach to the cytodiagnosis and classification of lymphoma.

Next-generation sequencing in hematologic malignancies: what will be the dividends?

The application of high-throughput, massively parallel sequencing technologies to hematologic malignancies over the past several years has provided novel insights into disease initiation, progression, and response to therapy. Here, we describe how these new DNA sequencing technologies have been applied to hematolymphoid malignancies. With further improvements in the sequencing and analysis methods as well as integration of the resulting data with clinical information, we expect these technologies will facilitate more precise and tailored treatment for patients with hematologic neoplasms.

Targeting the vascular endothelial growth factor in hematologic malignancies

There exists increasing evidence that apart from solid tumors, angiogenic growth factors also play important roles in the development and/or maintenance of hematolymphoid malignancies. Thus, in these cancers, angiogenesis and bone marrow microvessel density often correlate with prognosis and disease burden. Several reports speculated on the role of angiogenesis and the resulting possible therapeutic options in hematologic malignancies. The most prominent angiogenic factor, vascular endothelial growth factor (VEGF), is expressed in a number of established leukemic cell lines as well as in freshly isolated human leukemias and lymphomas, and several human leukemias express VEGF receptor 1 and/or VEGF receptor 2. VEGF/VEGF-receptor interactions are also involved in proliferation, migration, and survival of leukemic cells by autocrine and paracrine mechanisms. As a consequence, a possible drugable effect by inhibiting VEGF signaling in different hematologic malignancies has been discussed. This review focuses on angiogenesis-independent effects of VEGF on survival and proliferation of leukemic or lymphoma cells and on possible therapeutic approaches using anti-VEGF/VEGF-receptor therapies to inhibit proliferation or induce apoptosis of malignant cells in hematologic diseases.

Role of VEGF/VEGFR in the pathogenesis of leukemias and as treatment targets (Review)

Angiogenesis plays an important role in solid tumor growth, progression and metastasis. Evidence suggests that the progression of hematolymphoid malignancies also depends on the induction of new blood vessel formation under the influence of acute leukemia, myelodysplastic syndromes, myeloproliferative neoplasms, multiple myeloma and lymphomas. The vascular endothelial growth factor (VEGF) is the most important proangiogenic agent that activates receptors on vascular endothelial cells and promotes blood vessel regeneration. It has been demonstrated that VEGF/VEGF receptor (VEGFR) expression is upregulated in several types of hematolymphoid tumor cells accompanied with angiogenesis. The levels of VEGF/VEGFR are correlated with the treatment, relapse and prognosis of hematolymphoid tumors. In order for VEGF family and their receptors as antiangiogenic targets to treat solid tumors, several antiangiogenic agents targeting VEGF-related pathways have been used for the treatment of hematolymphoid malignancies in clinical trials. The results demonstrate a promising therapeutic intervention in multiple types of hematolymphoid tumors. This review aims to summarize recent advances in understanding the role of VEGF and angiogenesis in leukemias, mainly focusing on their upstream transcriptors, downstream targets and the correlation of VEGF/VEGFR with the treatment, relapse or prognosis of leukemia. The progress of VEGF and its receptors as attractive targets for therapies are also discussed in clinical application.

Leukemia cutis in association with cutaneous epidermal malignancies

Epidermal malignancies developing in association with hematolymphoid malignancies are exceptional. Only one prior case of myeloid leukemia cutis with a cutaneous epidermal malignancy has been reported. We report two cases; one occurred in association with squamous cell carcinoma (SCC) and another with basal cell carcinoma (BCC). Both patients were 83-year-old males without established histories of systemic hematopoietic disorders; one presented with an erythematous papule on the right upper back and the other with a nodule on the left wrist. One biopsy revealed nodular BCC with an associated perivascular myeloid leukemic infiltrate showing immunohistochemical positivity for CD43 and CD45. The other biopsy showed SCC associated with a leukemic infiltrate in sheets with myeloid blasts, eosinophilic myelocytes and maturing myeloid precursors. The myeloid cells showed immunohistochemical expression of CD43, CD68, CD33, CD117 and myeloperoxidase. Both patients had myeloblasts on peripheral blood smear. One patient declined further treatment and died of disease 5 weeks after the initial biopsy. The other patient underwent chemotherapy and is alive after 6 months. Although most inflammatory infiltrates associated with cutaneous epidermal malignancies are reactive, careful examination is necessary to exclude systemic hematopoietic disease, especially in elderly patients.

Conidiobolomycosis in a Young Malaysian Woman Showing Chronic Localized Fibrosing Leukocytoclastic Vasculitis

Conidiobolomycosis (also known as rhinoentomophthoramycosis) is a rare cutaneous/mucosal fungal infection seen mainly in the tropical rain forest regions of the world that can be associated with disfiguring facial elephantiasis, and rarely, death. To present an exemplary case report and perform a systematic review of the world's literature to more accurately describe the natural history and the effect of therapy on outcome in conidiobolomycosis. Case report and meta-analysis of published case reports and series of conidiobolomycosis to determine which clinical, pathologic, mycologic, and treatment factors impact on prognosis. We document delay in diagnosis of conidiobolomycosis in a young Malaysian woman, whose biopsy showed pathognomonic features-massive tissue eosinophilia and Splendore-Hoeppli phenomenon surrounding broad hyphae. These findings coexisted with granuloma faciale-like changes (fibrosing leukocytoclastic vasculitis) and lymphedema. Treatment with multiple antifungals was followed by complete resolution. For the meta-analysis, pooled data from 199 cases (162 with full outcome data) from 120 reports revealed a similar course for most cases: a disease affecting healthy young adults who present with progressive nasal symptoms (eg, nasal obstruction) and central facial swelling and show improvement or cure after surgical excision and/or treatment with one or more antifungal agents in 83%. Persistent-progressive facial disease occurred in 11%, and 6% died rapidly of fungal infection. Presentation with facial elephantiasis correlated with persistent-progressive rhinoentomophthoramycosis and a longer duration of disease before diagnosis (P = 0.02). Lethal infections were significantly associated with nonstereotypical presentation (eg, orbital cellulitis), visceral infection, absence of the Splendore-Hoeppli phenomenon, presence of comorbidities (eg, immunosuppression, hematolymphoid malignancy), infection with Conidiobolus incongruus or Conidiobolus lamprauges (not Conidiobolus coronatus), lack of response to amphotericin B, and female sex (all P ≤ 0.002). The few sensitivity studies performed demonstrated in vitro multidrug resistance of Conidiobolus species to most available antifungal agents. Publication bias, reporting heterogeneity, and data deficits may affect results. Conidiobolomycosis should be included in the differential diagnosis of patients who present with nasal symptoms and painless centrofacial swelling. Massive tissue eosinophilia and Splendore-Hoeppli material coating thin-walled hyphae confirms the clinical diagnosis. The granuloma faciale-like histology found in this case can explain the onset of facial lymphedema by fibroinflammatory destruction of lymphatic vessels; the duration of disease and severity of inflammation likely predicts whether the lymphedema is reversible or not. Although rhinoentomophthoramycosis ostensibly responds in vivo to most available antifungal agents, routine culture and susceptibility testing is recommended to better define the efficacy of these therapeutic agents.

Mast Cells and Eosinophils in Mastocytosis, Chronic Eosinophilic Leukemia, and Non-clonal Disorders

Mast cells and eosinophils often travel in the same biologic circles. In non-clonal states, such as allergic and inflammatory conditions, cell-to-cell contact and the pleiotropic actions of multiple cytokines and chemokines, derived from local tissues or mast cells themselves, foster the co-recruitment of these cells to the same geographic cellular niche. While eosinophils and mast cells serve critical roles as part of the host immune response and in maintenance of normal homeostasis, these cell types can undergo neoplastic transformation due to the development of clonal molecular abnormalities that arise in early hematopoietic progenitors. The dysregulated tyrosine kinases, D816V KIT and FIP1L1-PDGFRA, are the prototypic oncogenic lesions resulting in systemic mastocytosis (SM) and chronic eosinophilic leukemia, respectively. We review the pathobiology of these myeloproliferative neoplasms (MPNs) with a focus on the relationship between mast cells and eosinophils, and discuss murine models, which further elucidate how the phenotype of these diseases can be influenced by stem cell factor (SCF) and expression of the potent eosinophilopoietic cytokine, interleukin-5 (IL-5). Therapy of SM and FIP1L1-PDGFRA-positive disease and the prognostic relevance of increased peripheral blood and tissue mast cells in hematolymphoid malignancies will also be addressed.

Down Syndrome with Different Hematological Manifestations: A Short Series of 3 Cases with Review of Literature

Children with Down syndrome (DS) present with a spectrum of hematolymphoid malignancies ranging from transient myeloproliferative disorder (TMD) which regress spontaneously to frank acute leukemia of both myeloid and lymphoid lineage. Here we present a series of three cases with different manifestation in DS. Three cases of DS presented with TMD, acute myeloid leukemia (AML-M2) and acute megakaryoblastic leukemia (AMKL), respectively. This case series displays the spectrum of hematological manifestations in children with DS. Although TMD and AMKL are strongly associated with DS, other AML subtypes can also be seen in such patients.

Evidence-Based, Patient-Specific Guidelines Provide Efficient and Cost-Effective Molecular and Cytogenetic Testing in Hematologic Malignancy

Abstract 2073 Introduction:Molecular and cytogenetic testing is critical in diagnosis and management of hematologic malignancies. These tests are expensive, complex, and frequently inappropriately ordered. There are no comprehensive guidelines to assist in the disease- and patient-specific selection of these tests. Traditionally, most tests are ordered before morphologic evaluation of the specimen, which could help guide test selection. We hypothesize that this leads to significant over-ordering of tests unnecessary for diagnosis or monitoring, as well as under-ordering of necessary tests. As part of the hematopathology diagnostic management team (DMT) effort, we evaluated this hypothesis by establishing evidence-based rules for molecular and cytogenetic test ordering that are applied by the pathologist after review of clinical history and bone marrow aspirate smears. Methods:Using published evidence and best clinical practices, a team of clinical hematologists and hematopathologists developed rules, termed standard operating procedures (SOPs), for selecting cytogenetic and molecular tests on bone marrow biopsies from adult patients performed for myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), plasma cell myeloma, lymphoma, myeloproliferative neoplasms, lymphoblastic leukemia, and bone marrow failure. The rules specify testing in five clinical scenarios: diagnosis or follow-up with morphologically overt disease, bone marrow staging (for lymphoma), routine follow-up without overt disease, evaluation prior to stem cell transplant (pre-SCT), and follow-up after stem cell transplant (post-SCT). To determine the effect that application of these SOPs would have had on test ordering and results, bone marrow biopsies from adults (>18 years) were evaluated retrospectively over a six-month time period. Each test was ruled concordant or discordant with the corresponding SOP. Omitted tests, those recommended by the SOPs, but not performed, were also identified. Statistical analysis of concordant and discordant tests was performed using the Chi-square test. Results:A total of 3,007 tests (769 karyotypes, 1,790 FISH, and 448 molecular tests) were performed on 804 adult bone marrows. Of these, 1,080 (36%) were discordant with the SOPs. Discordant tests were most frequent in myeloma (471), MDS/AML (231), and lymphoma (215). The most common clinical settings for discordant tests were routine follow-up (403) and post-SCT (417). To determine if these tests were necessary, we determined the positive rate of both concordant and discordant tests. The positive rate was significantly higher in the concordant (490/1,929; 25%) than the discordant tests (38/1,078; 4%) (P<0.001). Of the 38 positive discordant tests, 15 were redundant, i.e., a more sensitive test for the abnormality was positive on the same sample. An additional 13 discordant tests were only weakly positive. Of these, most were negative at diagnosis or at subsequent bone marrow testing, suggesting that they may represent false positive results. Thus, only 10/1,080 (<1%) discordant tests had potential clinical significance. In 145 of the marrows (18%), there were 308 omitted tests. By eliminating the discordant tests and including the omitted tests, we estimate that institution of these SOPs would reduce the total number of cytogenetic and molecular tests by 26%, from 3,007 to 2,235. Conclusions:Retrospective analysis of cytogenetic and molecular test ordering demonstrates that more than one-third of cytogenetic or molecular tests ordered on bone marrow specimens at a large tertiary care institution were discordant with rules (SOPs) based on published literature and best clinical practices. Furthermore, the vast majority (>99%) of these discordant tests were negative for any abnormality, redundant, or potential false positives, suggesting that the exclusion of these tests would have little negative clinical impact. In addition, there were a large number of omitted tests, seen in 18% of all marrows. This analysis predicts that institution of rules-based morphology-influenced test ordering would decrease uninformative testing, while increasing appropriate informative tests, leading to more cost-effective, accurate, and complete diagnosis and monitoring of hematolymphoid malignancies. We have therefore instituted a rules-based, morphology-directed approach at our institution. Disclosures:No relevant conflicts of interest to declare.

A review of uncommon cytopathologic diagnoses of pleural effusions from a chest diseases center in Turkey

Background:After pneumonia, cancer involving the pleura is the leading cause of exudative pleural effusion. Cytologic examination of pleural effusions is an important initial step in management of malignant effusions. The aim of this study is to evaluate the spectrum of uncommon malignant pleural effusions in a chest disease center in Turkey.Materials and Methods:A retrospective study of samples of pleural effusions submitted to Ataturk Chest Diseases and Chest Surgery Education and Research Hospital Department of Pathology between March 2005 and November 2008 was performed.Results:Out of a total of 4684 samples reviewed 364 (7.8%) were positive for cancer cells. Of the malignant pleural effusions 295 (81%) were classified as adenocarcinoma or carcinoma not otherwise specified (NOS). Pleural effusion specimens revealing a diagnosis other than adenocarcinoma/carcinoma NOS were: 32 (8.8%) malignant mesotheliomas, 14 (3.8%) small cell carcinomas, 13 (3.5%) hematolymphoid malignancies and 10 (2.7%) squamous cell carcinoma. Hematolymphoid malignancies included non- Hodgkin lymphoma (diffuse B large cell lymphoma, mantle cell lymphoma), multiple myeloma, chronic myeloid leukemia, and acute myeloid leukemia.Conclusions:Despite that adenocarcinoma is the most common cause of malignant pleural effusions, there is a significant number of hematological and non-hematological uncommon causes of such effusions. Cytopathologists and clinicians must keep in mind these uncommon entities in routine practice for an accurate diagnosis.

A Case of Acute Renal Failure Caused by Hodgkin's Lymphoma: Concurrent Membranous Glomerulonephritis and Interstitial HL-CD 20 Lymphoid Infiltration

Although acute renal failure developing due to malignancies is a frequent condition, malignant renal infiltration is rarely observed among these causes. Among all malignant diseases, the hematolymphoid malignancies are the most prone to renal infiltration. Other types involved in cases with lymphoma are glomerulopathies, including immune-complex glomerular diseases such as minimal change disease, membranous glomerulonephritis, membranoproliferative glomerulonephritis, and focal segmental glomerulosclerosis. We present herein the rare case of a 22-year-old male with both membranous glomerulonephritis and CD20 (+) lymphoid infiltration related to Hodgkin's lymphoma in the renal interstitial tissue, as detected on biopsy. The patient was treated with adriamycin, bleomycin, vinblastine, and dacarbazine protocol after pulse corticosteroid treatment, and a dramatic improvement in renal function was observed after 2 days of treatment. In this article, an exceptional renal involvement of Hodgkin's lymphoma is discussed in light of the related literature.

Practical Immunohistochemistry in Hematopathology

This review article offers some useful panels of immunohistochemical stains and discusses their use in determining a hematopathology diagnosis. As a comprehensive review of the vast array of hematolymphoid malignancies is beyond the scope of this study, the suggestions are based on broad morphologic categories such as follicular proliferations, paracortical expansions, diffuse small-cell infiltrates, diffuse large-cell infiltrates, and Hodgkin-like infiltrates. The review article also discusses the most common hematolymphoid malignancies and their immunohistochemical profiles, and how to use immunophenotyping to differentiate them from other entities. Common diagnostic pitfalls and misconceptions about certain antibodies will also be discussed. New antibodies, such as SOX11, will also be explored in the context of specific disease entities for which they may be of use.