Hematolymphoid Malignancies Research Articles

Skin metastasis: from conceptual to practical guidelines.

Of the outward manifestations of visceral malignancy, cutaneous metastases are of particular interest for their impact on identification, prognosis, and management of the primary tumor. Their diagnosis is often challenging and requires high clinical suspicion. The infrequency and clinicopathologic variability of cutaneous metastases can impede their recognition by physical exam and even histopathology. This review offers a practical approach to judicious utilization of the full repertoire of clinical and pathologic data in precise characterization of metastases to the skin. Highlighted are commonly encountered entities, with emphasis on clinical and pathologic differential diagnoses, and clues to identification. Special mention is made of metastases of unknown primary and the special position occupied by hematolymphoid malignancies directly manifesting in skin.

Cutaneous Adverse Events of Targeted Therapies for Hematolymphoid Malignancies.

The identification of oncogenic drivers of liquid tumors has led to the rapid development of targeted agents with distinct cutaneous adverse event (AE) profiles. The diagnosis and management of these skin toxicities has motivated a novel partnership between dermatologists and oncologists in developing supportive oncodermatology clinics. In this article we review the current state of knowledge of clinical presentation, mechanisms, and management of the most common and significant cutaneous AEs observed during treatment with targeted therapies for hematologic and lymphoid malignancies. We systematically review according to drug-targeting pathway the cutaneous AE profiles of these drugs, and offer insight when possible into whether pharmacologic target versus immunologic modulation primarily underlie presentation. We include discussion of tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib, bosutinib, ponatinib), blinatumomab, ibrutinib, idelalisib, anti-B cell antibodies (rituximab, ibritumomab, obinutuzumab, ofatumumab, tositumomab), immune checkpoint inhibitors (nivolumab, pembrolizumab), alemtuzumab, brentuximab, and proteasome inhibitors (bortezomib, carfilzomib, ixazomib). We highlight skin reactions seen with antiliquid but not solid tumor agents, draw attention to serious cutaneous AEs that might require therapy modification or cessation, and offer management strategies to permit treatment tolerability. We emphasize the importance of early diagnosis and treatment to minimize disruptions to care, optimize prognosis and quality of life, and promptly address life-threatening skin or infectious events. This evolving partnership between oncologists and dermatologists in the iterative characterization and management of skin toxicities will contribute to a better understanding of these drugs' cutaneous targets and improved patient care.

Associated Hematolymphoid Malignancies in Patients With Lymphomatoid Papulosis: A Canadian Retrospective Study.

Lymphomatoid papulosis is one of the primary cutaneous CD30+ T-cell lymphoproliferative disorders. Although considered a benign disease, lymphomatoid papulosis has been associated potentially with an increased risk of secondary hematolymphoid malignancies. The aim of this study was to assess the clinical characteristics and histologic subtypes of lymphomatoid papulosis, identify the prevalence and types of secondary hematolymphoid malignancies, and determine the potential risk factors for development of these hematolymphoid malignancies. A retrospective chart review was performed for all histologically confirmed cases of lymphomatoid papulosis between 1991 and 2016. Seventy patients with lymphomatoid papulosis were identified. Thirty patients (43%) experienced a secondary hematolymphoid malignancy. Twenty-four (80%) of the hematolymphoid malignancies occurred after the onset of lymphomatoid papulosis. Older age at diagnosis of lymphomatoid papulosis, male sex, histology type B, and the presence of T-cell receptor gene rearrangement are associated with higher risk of developing hematolymphoid malignancy. Lymphomatoid papulosis is associated with increased risk of developing secondary hematolymphoid malignancies, particularly mycosis fungoides and cutaneous anaplastic large cell lymphoma.

Pediatric salivary gland tumors and tumor-like lesions

Salivary gland tumors and tumor-like lesions in the pediatric population are uncommon. They comprise aheterogeneous group of infectious/inflammatory and neoplastic conditions. Pediatric salivary neoplasms include benign tumors of mesenchymal or epithelial origin as well as malignancies of epithelial (carcinomas), mesenchymal (sarcoma) or hematolymphoid (lymphoma) derivation. Infectious/inflammatory conditions and hematolymphoid malignancies may represent either genuine parenchymal pathology or conditions involving intraglandular lymph nodes of the parotid glands (intraglandular lymphadenopathy and intraglandular nodal lymphomas). Pediatric sialadenitis may be of diverse etiologies including viral (mumps, CMV, HIV, etc.), bacterial, autoimmune (juvenile Sjögren syndrome) or idiopathic (chronic recurrent juvenile sialectatic sialadenitis). Angiomatous lesions (juvenile capillary hemangioma, lymphangioma and vascular malformation) and pleomorphic adenomas represent the most common pediatric benign mesenchymal and benign epithelial tumors, respectively. The vast majority of salivary gland carcinomas in children and adolescents represent low-grade mucoepidermoid carcinomas followed by acinic cell and adenoid cystic carcinomas (together >80% of carcinomas). Other malignant neoplasms include (rhabdomyo-) sarcomas, malignant lymphomas and very rarely sialoblastomas. This long differential diagnosis list of etiologically and biologically highly heterogeneous entities, their shared clinical presentation as "salivary gland enlargement" and the significant differences in their therapeutic strategies and prognosis underline the need for careful assessment to identify the correct diagnosis. Diagnosis is mainly based on aset of typical clinical and imaging features, serological/microbiological findings and, in selected cases, histomorphological characteristics in biopsy specimens.

Role of Sex Hormone Levels and Psychological Stress in the Pathogenesis of Autoimmune Diseases.

The aim of this review article is to assess the connection between psychological stress and sex hormones and their effect on the development of autoimmune diseases. Psychological stress describes what people feel when they are under mental, physical, or emotional pressure. We searched for online articles using MEDLINE®, Embase, Cochrane Library and Google Scholar. Our research yielded a total of 165 articles out of which 30 articles were considered for further perusal. The articles were reviewed from February 2016 to February 2017. Case reports and patients suffering from hematolymphoid malignancies and active infections were excluded from the review. Estrogen and testosterone are potential physiological regulatory factors for the peripheral development of CD4+CD25+ T regulatory cells. Stress at any age leads to the depletion of estrogen and testosterone stores in the body, leading to the loss of expansion of T regulatory cells, making the immature B cells evade the negative selection at the germinal center, or in other words, leading to the loss of central tolerance, a triggering event in autoimmune diseases like systemic lupus erythematosus. Autoimmune diseases in women are most likely due to changes in estrogen levels during mental, physical, pre-menopausal, post-menopausal, and pregnancy-induced stress. We conclude that modulating estrogen in females (pre-menopausal and post-menopausal) and testosterone in males can be used to treat stress-related immune imbalance resulting in autoimmune diseases in both sexes.

Hematolymphoid lesions of the breast.

Hematolymphoid malignancies of the breast are most commonly neoplasms of mature B-lymphocytes, and may arise as a primary disease or by secondary involvement of a systemic disease. Primary breast lymphomas (PBL) account for 0.04-0.5% of breast malignancies, less than 1% of all non-Hodgkin's lymphomas (NHL), and less than 5% of extranodal lymphomas (Lakhani et al., 2012; Swerdlow et al., 2008; Joks et al., 2011; Barişta et al., 2000; Giardini et al., 1992; Brogi and Harris, 1999; Topalovski et al., 1999).1-7 Secondary breast lymphomas (SBL) are also rare, with an estimated annual incidence of 0.07% (Domchek et al., 2002; Talwalkar et al., 2008).8,9 Recognition of breast lesions as hematolymphoid is critical to distinguish them from other entities that can occur in the breast.

Occurrence of ALK fusions in cancers other than non-small cell lung cancer in a wide variety of tumor types and response to anti-ALK targeted therapy.

11595 Background: Genomic fusions of the anaplastic lymphoma kinase gene ( ALK) are an established therapy target for patients with non-small cell lung cancer (NSCLC), but are not well-characterized in non-NSCLC malignancies. Methods: Comprehensive genomic profiling (CGP) of 92,784 clinically advanced malignancies was performed using a hybrid-capture, adaptor ligation based NGS assay to a mean coverage depth of >600X. Tumor mutational burden (TMB) was calculated from a minimum of 1.1 Mb of sequenced DNA. Results: 17,127/92,784 (18.5%) were NSCLC and 75,657 (81.5%) were non-NSCLC. Of the 697 (0.8%) of cases with ALK fusions, 554 (79%) were identified in NSCLC and 143 (21%) in non-NSCLC including 67 carcinomas; 39 sarcomas including 30 non-uterine and uterine leiomyosarcomas and inflammatory myofibroblastic tumors; 24 in hematolymphoid malignancies including non-Hodgkins lymphomas, myelomas and histiocytic malignancies; 3 in gliomas; 2 each in mesotheliomas, neuroblastomas and undifferentiated malignancies and 1 in melanoma. ALK fusions were significantly more frequently identified in NSCLC (3.2%) than in non-NSCLC (p<0.0001). The non-NSCLC ALK fusion positive patients were significantly older (p<0.0001) and more often female (p<0.0001) than the NSCLC ALK fusion positive patients. At 84%, the more frequent finding of EML4 as the fusion partner in the NSCLC patients versus non-NSCLC patients at 31% was significant (p<0.0001). ALK fusion positive non-NSCLC had significantly lower TMB (mean 5.01 mutations/Mb) than non- ALK altered non-NSCLC (p=0.006). Non-NSCLC ALKfusion positive cases responding to ALK inhibitors will be presented. Conclusions: In non-NSCLC patients ALK fusions are rare and found in both epithelial and mesenchymal malignancies. Initial evidence strongly suggests that anti-ALK therapies can be effective in ALK fusion driven non-NSCLC .

Clinical Relevance of Multicolour Flow Cytometry in Plasma Cell Disorders.

Multicolor flow cytometric (MFC) immunophenotyping is one of the basic test that is needed in the evaluation of hematolymphoid malignancies. Previously, there has been some reluctance in the use of MFC in plasma cell disorders (PCD). It was mainly due tolack of standardization, inadequate experience and detection of the lower number of plasma cells by MFC as compared to morphology. However, MFC has gone through many technological advancements in the last few years and a wide variety of reagents are now commercially available which worldwide allowed the establishment of standardized sensitive MFC-based immunophenotypic assay for PCD. Various studies have proven that MFC has a high clinical relevance in the diagnosis and risk stratification of multiple myeloma, its precursor conditions and other PCDs. Moreover, recent studies have shown that MFC is a highly sensitive and reliable technique for the monitoring of clinical response in the era of novel therapies. In this review, we have discussed the various applications of MFC in the management of PCD and their clinical relevance.

Histiocytic sarcoma: New insights into FNA cytomorphology and molecular characteristics.

Histiocytic sarcoma (HS) is a rare malignant neoplasm showing morphologic and immunophenotypic features of histiocytes. Molecular characteristics of HS and fine-needle aspiration (FNA) criteria for its diagnosis have not been established. A case series of HS in 8 FNA samples from 6 patients was reviewed along with histopathologic and clinical data. Immunohistochemistry was performed on cell blocks (3 cases), core biopsies (5 cases), and surgical specimens (4 cases). Targeted-exome next-generation sequencing (NGS) was performed on surgical resection specimens in 4 cases. Four patients had a known history of hematolymphoid malignancy. Cytomorphologic features included variably cellular smears composed of large epithelioid cells with reniform nuclei and abundant vacuolated cytoplasm, in an inflammatory background, with occasional cytophagocytosis and lymphoglandular bodies. Marked pleomorphism, multinucleated monster cells, and binucleated histiocytoid cells with partially overlapping, eccentrically placed nuclei resembling Pac-Man were common. Most cases expressed histiocytic markers CD68 (6 of 7 cases), CD163 (5 of 5 cases), and PU.1 (3 of 4 cases). In 3 cases, NGS analysis revealed alterations in lysine methyltransferase 2D (KMT2D)/mixed-lineage leukemia 2 (MLL2), a gene involved in chromatin regulation and previously implicated in the pathogenesis of follicular lymphoma. Although diagnosing HS with FNA alone is extremely challenging, the presence of pleomorphic and epithelioid large cells with binucleation and/or multinucleation in an inflammatory background should prompt the diagnosis of HS with judicious use of confirmatory histiocytic lineage markers. The detection of recurrent KMT2D/MLL2 alterations implicates epigenetic regulation in the pathogenesis of HS and supports the notion of transdifferentiation from a genetically similar but phenotypically distinct tumor of a different lineage. Cancer Cytopathol 2017;125:604-14. © 2017 American Cancer Society.

Chronic lymphocytic leukaemia with concomitant plasmablastic lymphoma

Plasmablastic lymphomas are high-grade lymphomas that usually occur in immune-suppressed patients. Occasionally, they can arise from an underlying haematolymphoid malignancy, termed ‘transformed plasmablastic lymphoma’. In this report, we describe a case of chronic lymphocytic leukaemia and plasmablastic lymphoma in an elderly HIV-negative patient.

Aligning the flow cytometric evaluation with the diagnostic need: an evidence-based approach

AimsElimination of non-value added testing without compromising high-quality clinical care is an important mandate for laboratories in a value-based reimbursement system. The goal of this study was to determine the...

Practice of I.V access in children with hemato-lymphoid malignancies in India- A mixed method study

Practice of I.V access in children with hemato-lymphoid malignancies in India- A mixed method study

Anti-Vascular Endothelial Growth Factor Effects of Sorafenib and Arsenic Trioxide in Acute Myeloid Leukemia Cell Lines

Acute myeloid leukemia (AML), is a clonal disorder caused by acquired somatic mutations and chromosomal rearrangements. According to some evidence, progression of hematolymphoid malignancies depends on the induction of new blood vessel formation under the influence of acute leukemia. Various factors are produced by cancer cells under hypoxic conditions to increase vascular formation. Among these, vascular endothelial growth factor (VEGF) plays a crucial role. Cytotoxicity and anticancer effects of arsenic trioxide (ATO) have been reported in many cancers. Sorafenib, known as an angiogenic inhibitor, decreases leukemic cell survival. The aim of this study was to indicate combination effects of ATO and sorafenib in two AML cell lines, KG-1 and U937. Effective doses was determined by MTT assay for both single and combination treatments. Percentages of apoptotic cells were evaluated by Annexin V FITC staining and mRNA levels of VEGF isoforms and receptor expression were investigated by Real-Time PCR. Our data show that sorafenib (5μM and 7μM in KG-1 and U937 cell lines respectively), ATO (1.618μM and 1μM in KG-1 and U937 cell lines respectively), and also their combination significantly increased the percentage of apoptotic cells. In addition the mRNA level of VEGF isoforms was downregulated in the U937 cell line while upregulated in KG-1 cells. Taken together, our results suggest that the VEGF autocrine loop may have an influence on AML development and progression and could be consider as a therapeutic target. The combination of sorafenib as a VEGF inhibitor with ATO synergistically inhibits cell proliferation and promotes apoptosis.

Clinicoepidemiological profiles, clinical practices, and the impact of holistic care interventions on outcomes of pediatric hematolymphoid malignancies - A 7-year audit of the pediatric hematolymphoid disease management group at Tata Memorial Hospital.

The Pediatric Hematolymphoid Disease Management Group (PHL-DMG) at a tertiary cancer care hospital developed extensive patient support programs to improve retention and outcomes while focusing on protocols adapted to meet patient needs. An audit of measures and outcomes was done for a 7-year period from January 2010 to December 2016. DMG protocols and patient support activities over the study period were documented and audited. Data was retrieved from internal databases and records. Measures taken and their impact were assessed by descriptive analytical tools. Survival outcomes were calculated using Kaplan-Meier method on SPSS v. 24™ software. Holistic patient support measures were undertaken through a charitable foundation entirely under pediatric oncology. Activities included infrastructure growth, socioeconomic support, provision of accommodation, nutrition, education, and multiple blood component donation drives. Patient registrations increased from 502 in 2009 to 874 in 2016, with the steepest rise in acute lymphoblastic leukemia (ALL) - 330 (2009) to 547 (2016). Treatment refusal and abandonment rates decreased from 32% to 3.4% over the same period, and male to female ratio decreased from 2.56 to 2.28:1. Early mortality in acute myeloid leukemia (AML) fell within 2 years from 26.7% in 2009 to 7%. Five-year overall survival (OS) was 69.5% for all patients registered in 2010, whereas disease-specific 5-year OS was ALL 67.1%, AML 49.3%, chronic myeloid leukemia 100%, Hodgkin lymphoma 90.4%, and non-Hodgkin lymphoma 74.2%. Holistic patient support-specific activities and adapted protocols made a measurable impact on patient outcomes. High survival outcomes of patients have been achieved despite relatively few receiving salvage therapies or stem cell transplant.

Relapse of Multiple Myeloma Presenting as Lower Lip Numbness.

Multiple myeloma (MM) is an uncommon malignancy characterised by the proliferation of clonal plasma cells. There are few published reports describing the extramedullary presentation of MM manifesting primarily in the head and neck region. In addition, the occurrence of an isolated relapse of MM in these sites is exceedingly rare. We report a 56-year-old female who presented to the Sultan Qaboos University Hospital, Muscat, Oman, in 2010 with sudden-onset numbness of the lower lip. She had a history of MM in remission following chemotherapy and a bone marrow transplant. Clinical and radiographic examinations were indicative of a possible relapse of MM, which was subsequently confirmed by bone marrow aspiration and histopathological evaluation. This unique case highlights the unusual site of relapse of a haematolymphoid malignancy.

Clinicopathologic analysis of malignant effusions in pediatric patients

The utility of cytologic evaluation of effusion fluids in adults is well established but has been less well documented in the pediatric population. We examined the clinicopathologic characteristics of children with malignant effusions to establish the value of cytologic examination of these specimens. Pleural, pericardial, peritoneal, and intraoperative washing specimens obtained between January 2000 and October 2015 were identified via surgical pathology database search. Relevant clinical and pathologic data was recorded. Statistical analysis of patient groups was performed via two-sided heteroscedastic Student t tests, and Kaplan-Meier analysis was used to compare overall survival between patient groups. 474 effusion/washing specimens obtained from 342 patients were identified: 179 pleural effusions, 220 peritoneal fluids, 28 pericardial effusions, and 47 intraoperative washing specimens. Of these, 13.7% (56 of 474) effusion specimens were positive for malignancy. Among cancer patients with effusions, malignant effusions were seen in 54.5% of patients with rhabdomyosarcoma and 28.8% of patients with hematolymphoid malignancies. Regarding patient outcomes, malignant effusions were associated with statistically significantly shorter overall survival (P = 0.019). When compared with stage IV patients with benign effusions, those with malignant effusions had a shorter 5-year overall survival (P = 0.042); multiple malignant effusions were associated with a dramatically shorter survival than a single malignant effusion. The overall rate of malignant effusions in our patient population was 13.7%. Malignant effusions in children, particularly multiple, portend a poor prognosis. Our observations emphasize the importance of accurate cytologic diagnosis of effusion fluids, and reinforce the value of their cytologic evaluation.

Incidental identification of Strongyloides stercoralis infection by broad-range 28S rDNA gene sequencing in a patient with a hematolymphoid malignancy

Strongyloides stercoralis is an important human parasite, especially in rural areas and developing countries. Infected immunosuppressed patients are at risk for hyperinfection, with severe clinical consequences. Here we describe the incidental detection and diagnosis of an unexpected S. stercoralis infection by methods designed to detect fungal 28S ribosomal DNA.

Flow Cytometric Analysis: Four-Year Experience in a Tertiary Care Centre of Pakistan.

Purpose: This study summarizes a four-year experience from the analysis of hematolymphoid malignancies in Pakistani population using a database of six-colored flow cytometry.Methods:A cross-sectional survey of 323 specimens of hematolymphoid malignancies using six-colored flow cytometry (FC) was carried out in Shifa International Hospital, Islamabad, Pakistan from June 2012 to June 2016. The criterion for specimen adequacy was that the cases have abnormal populations by FC, and the specimen age (time from biopsy to being examined by the six-color FC tube) of three days or less was to be included in the study. Clinical follow-up of greater than six months was required for a negative flow cytometric study without a subsequent biopsy. Data analysis was done using Statistical Package for the Social Sciences (SPSS) version 21. One-way analysis of variance (ANOVA) was used to compare diagnosis with some antibodies used.Results: The number of specimen within certain age groups included were: 0-15 years; 111 (34.3%), 16-30 years; 65 (20.12%), 31-45 years; 47 (14.5%), 46-60 years; 46 (14.2%) and ≥ 60 years; 54 (16.7%). Hematological malignancies were documented in descending order of sequence with B-cell acute lymphoblastic leukemia (27.9%), acute myeloid leukemia (26.3%), chronic lymphocytic leukemia (13.3%), T cell acute lymphoblastic leukemia (7.7%), non-Hodgkin's lymphomas (5%), hairy cell leukemia (1.9%), chronic myeloid leukemia (0.3%), paroxysmal nocturnal hemoglobinuria (0.6%) and plasma cell dyscrasias (0.6%). The mean number of antibodies used were 12.68 ± 2.97. One-way ANOVA was used to compare diagnosis with some antibodies used. Statistical significance was found between diagnosis and number of antibodies used (F= 5.23 p<0.001).Conclusion: B cell acute lymphoblastic leukemia is most commonly diagnosed at tertiary care units in Pakistan using six-colored flow cytometry. Adoption of these complicated techniques has reinforced the need for optimization and further enhancement of flow cytometric procedures.

Diagnosis of mediastinal lesions unassociated with lung carcinoma diagnosed by endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA)

Endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) is a safe, cost-effective, and accurate diagnostic modality for the lung/mediastinum. Although some studies have been published on EBUS-TBNA of isolated mediastinal lesions, none have been reported from the United States. This study examines EBUS-TBNA for diagnosis of isolated mediastinal lesions. All cases of mediastinal EBUS-TBNA (defined in radioanatomic terms) during a 7-year period (July 2007-September 2014) were obtained from the anatomic pathology database. Pathologic reports, clinical notes, bronchoscopy notes, and imaging studies were reviewed. Only patients with a mediastinal lesion or non-pulmonary parenchyma-based lesions sampled by EBUS-TBNA without a prior or synchronous lung carcinoma were included in this study. Of the 3005 EBUS-TBNA cases accessioned during this time period at our institute, 47 fulfilled the inclusion criteria. The median patient age was 61 years (range: 27-84 years). Both genders were nearly equally represented. A definitive cytologic interpretation was rendered in 40 out of 47 cases (85.1%). Malignancies included non-pulmonary carcinomas (8), sarcomas (5), hematolymphoid malignancies (5), neuroendocrine neoplasm (1), melanoma (1), and undifferentiated malignancy (1). Surgical follow-up was available in 18 of 47 cases (38.3%). There was cytologic-histologic correlation in 16 of 18 cases (88.9%). Surgical follow-up of all cysts diagnosed by cytology were benign cysts. Over the 7-year period, an increasing proportion of all EBUS-TBNAs performed were for mediastinal lesions unassociated with lung carcinoma. EBUS-TBNA has a high accuracy rate when used to diagnose mediastinal lesions unassociated with lung carcinoma. Its utility as a primary diagnostic modality in this setting needs to be explored further.

A bright and colorful future for DNA cell cycle analysis.

A bright and colorful future for DNA cell cycle analysis.