Volume 2, Issue 2, September 2017

Case Report

A Novel RPL35A Mutation Associated with Diamond-Blackfan Anemia: Report of a Case and Review of the Literature Page 69-74
Guang Yang, Jun Wang, Brissa Martin, Edward Rowsell, and Ross Fisher
Abstract

Diamond Blackfan anemia (DBA) is a genetically and clinically heterogeneous disorder characterized by pure red blood cell aplasia, variable congenital anomalies, and a predisposition to cancer. The genes implicated in DBA all encode ribosomal proteins associated with either the small or large ribosome subunits. We report a novel variant of unknown significance in the RPL35Agene (p.R76P) in an Asian male presenting with macrocytic anemia, neutropenia, genitourinary malformations, and growth retardation without significant erythroid hypoplasia in bone marrow. We postulate that this variant is likely pathogenic and contributing to this patient’s DBA phenotype; the variant has never been reported in the general population, it changes a highly conserved amino acid, and is predicted to be deleterious by in silico models, while clinically this patient responded well to steroid treatment.

Volume 2, Issue 1, March 2017

Opinion

Gene, Life, and Disease – A Node Theory Page 1-13
X. Frank Zhao
Abstract

The 21st century embraces a combination of the Genomic and Information Ages, characterized by enormous genetic data deposition and use of numerous powerful analytical tools. With more and more accumulated data, the concept of genes needs to be redefined and research methods further rationalized based on the properties of life: economy, optimization and survival. Disease should be considered the condition where homeostasis is disrupted. Biological equilibrium is maintained by a network of numerous functional nodes: molecules located in various pathways that are classified into decision nodes and alternative nodes, which shift their roles in response to a changing environment. Organized both spatially and temporally, the nodal network carries out its functions for the optimal outcome of the cell. Although central nodes often play vital roles for cell functions, connector nodes in the “structural hole” are more effective targets for treatment. Resources should be prioritized to delineate the roles of functional nodes and identify critical nodes for optimal therapy.

Case Report

Diagnostic challenge: Acute leukemia with biphenotypic blasts and BCR-ABL1 translocation Page 14-18
Ling Wang and Xiangdong Xu
Abstract

Chronic myelogenous leukemia (CML) and mixed phenotype acute leukemia (MPAL) are two distinct entities according to the current WHO classification. However, the distinction can be difficult when adequate clinical history is not available, because both entities could have BCR-ABL1 translocation and B/myeloid biphenotypic blasts. Here we report a 64-year-old man with no previous history of myeloproliferative disorders who presented with marked leukocytosis and 30% circulating blasts. The bone marrow had 39% of blasts and 32% maturing myeloid cells. The blast population showed both B and myeloid differentiation. Cytogenetics revealed the BCR-ABL1 translocation as the sole abnormality. Based on one small-sized case series, many features of our case favored the diagnosis of CML in blast phase with biphenotypic blasts, including: 1) left-shifted granulocytic maturation in peripheral blood; 2) a significant portion of maturing myeloid cells in bone marrow; 3) the diagnostic marrow with higher percentage of BCR-ABL1 harboring cells than that of the blasts; 4) BCR-ABL1 translocation as the sole cytogenetic abnormality; 5) post-induction marrow showed hypercellularity.

Case Report

CD20-positive primary cutaneous extranodal NK/T-cell lymphoma Page 19-23
Xiangdong Xu, Laura Romero, Young Kim, and X. Frank Zhao
Abstract

Cutaneous extranodal NK/T-cell lymphoma, nasal type, and primary cutaneous g/d T-cell lymphoma (PCGD-TCL) are rare cutaneous lymphoid neoplasms with overlapping features. Although EBV positivity favors the former, EBV+ PCGD-TCL has recently been reported. They also share cytotoxic markers and a poor prognosis. Here we report an unusual case of cutaneous NK/T-cell lymphoma with overlapping features of PCGD-TCL in a 55-year-old man who also developed hemophagocytic lymphohistiocytosis. Although it presents the typical pathological and immunophenotypic features of a cutaneous NK/T-cell lymphoma and PCGD-TCL, it aberrantly expresses CD20, giving an impression of mixed populations of T cells and B cells that are commonly seen in reactive conditions. This rare case represents a diagnostic pitfall and intends to raise more awareness among both pathologists and dermatologists. The CD20 positivity may also provide a target for rituximab therapy.

Case Report

Transient monosomy 7 associated with bicytopenia in a 9-month-old boy: Report of a case and review of the literature Page 24-30
Guang Yang, Ross A. Rowsey, Jun Wang, Rhett P. Ketterling, and Ross Fisher
Abstract

Monosomy 7 or partial loss in the long arm of this chromosome is a recurrent nonrandom
cytogenetic finding associated with a variety of hematological disorders. In the present case, a 9-month-old male presented with a febrile illness along with anemia and thrombocytopenia, and achieved spontaneous remission of the bicytopenia and monosomy 7 without any intervention 28 months after initial diagnosis. To our knowledge and literature search, this is likely the first case report of transient monosomy 7 in a patient with only bicytopenia. It is critical to closely monitor patients with monosomy 7 for evidence of spontaneous remission before proceeding to any major treatment.

Article

Unusual variants of mantle cell lymphoma Page 31-49
Stefano Fratoni
Abstract

Mantle cell lymphoma (MCL) is recognized as an aggressive and incurable small B-cell lymphoma
and represents a group of t(11;14)(q13;q32)/CCND1+ neoplasms with a wide variety of morphology. Thus, the identification of various MCL variants is important for guiding appropriate therapies and predicting outcomes. Histopathologic diagnosis of classical MCL is usually straightforward due to its typical morphology and nuclear overexpression of cyclin D1. However, approximately 10% of the MCL are represented by its own morphologic variants, mimicking other lymphomas, including the challenging cyclin D1-negative MCL. Furthermore, typical MCL immunophenotype and genetic abnormalities may not be found in every case. Therefore, MCL variants may be a diagnostic trap for hematopathologists. Taking into account that histopathological diagnosis remains the gold standard for MCL diagnosis, this paper summarizes the practical approaches to the diagnosis of the uncommon variants of MCL in accordance with the 2016 revised WHO classification of lymphoid neoplasms.

Case Report

Unusual extranodal composite CD5 negative mantle cell lymphoma and CD5 positive marginal zone lymphoma Page 50-57
Jiong Yan and Yue Wu
Abstract

Composite lymphomas composed of two non-Hodgkin small B cell lymphomas are infrequent and composite mantle cell lymphoma and marginal zone lymphoma is extremely rare with 3 cases reported to date. The case presented herein is the first report of extranodal composite CD5 negative mantle cell lymphoma and partially CD5 positive marginal zone lymphoma. The identification of these two histologically indistinct and immunophenotypically unconventional lymphoma components requires a comprehensive study including careful interpretation of immunohistochemical results and the fluorescence in-situ hybridization (FISH) analysis of t(11;14). Clinically, the diagnosis of this composite lymphoma is compatible with patient’s aggressive disease course. Molecular studies for immunoglobulin gene rearrangement indicate that the mantle cell lymphoma and marginal zone lymphoma components are derived from different clones, supporting the notion that composite lymphomas of non-Hodgkin small B cell lymphomas are often biclonal.

Article

PD-L1 protein expression in most EBV-driven lymphoproliferative disorders is not associated with 9p24.1 amplification Page 58-68
Alan F. Brown, Mohamad E. Salama, Jay L. Patel, Christian N. Paxton, Xinjie Xu, Sherrie L. Perkins, and K. David Li
Abstract

Programmed Cell Death 1 Ligand 1 (PD-L1) protein expression by tumor cells appears to mediate immune evasion and can be upregulated by 9p24.1 amplification. Alternatively, PD-L1 expression has been linked to EBV-driven activation of the AP-1 and MAPK pathways in EBV-positive Hodgkin lymphoma. We sought to evaluate the status of 9p24.1 with respect to PD-L1 expression in EBV-driven lymphoproliferative disorders (EBV+ LPDs).
We studied 36 LPDs (8 EBV+ diffuse large B-cell lymphoma (DLBCL), 10 DLBCL, NOS, and 18 others) using two PD-L1 immunohistochemical (IHC) stains and performed genome-wide copy number variation analysis on a subset of cases. Most cases of EBV+ DLBCL (5/8, 63%) showed PD-L1 expression by IHC and had normal copy number at 9p24.1 (7/8; 88%). One case of EBV+ DLBCL expressed PD-L1 with concurrent 9p24.1 amplification. A subset of EBV-negative DLBCLs showed PD-L1 expression without 9p24.1 amplification. Additionally, EBV+ LPDs displayed significantly lower total genomic aberrations and deletion 6q compared with EBV-negative cases.
PD-L1 expression in most EBV+ DLBCL cases is not due to 9p24.1 amplification. EBV infection appears to coincide with PD-L1 expression, supporting the model for EBV-driven PD-L1 upregulation. PD-L1 expression was seen in some cases lacking both EBV and 9p24.1 amplification, suggesting additional pathway(s) of activation.

Volume 1, Issue 2, September 2016

Editorials

MDS or M6: The dilemma in classifying early leukemias Page 74-76
X. Frank Zhao

Articles

The many rare faces of follicular lymphoma – Part 2 Page 77-89
Stefano Fratoni and X. Frank Zhao
Abstract

Follicular lymphoma (FL), a well defined mature B-cell lymphoma, rarely presents with great morphological variations that could mimic either other malignancies or disguise themselves with only subtle neoplastic feature. In the second part of this series, we present more FL morphologic variants, including FL with signet ring cells, FL with HRS-like cells, FL with anaplastic/pleomorphic cells, FL with sclerosis, FL microlymphoma, FL with prominent sinus histiocytosis, and FL neurolymphomatosis. Although uncommon, some of these FL variants pose diagnostic pitfalls for the practicing pathologists.

Case Reports

EBV-positive gastric plasmablastic lymphoma in an HIV-negative adult Page 90-95
Eva M. Amenta, Elvira A. Allakhverdieva, John C. Huston, and Neil G. Haycocks
Abstract

Plasmablastic lymphoma (PBL) is a rare B-cell lymphoma most commonly observed in the oral mucosae of HIV-positive patients, with increasing recognition of cases occurring in HIV-negative individuals. There is a noted association between PBL and Epstein-Barr virus (EBV), and chromosomal rearrangements involving c-MYC have been implicated in oncogenesis. There have been eight previously described cases of PBL involving the stomach in HIV-negative patients. This report details the first known case of EBV- positive gastric PBL, which was identified in an 82-year-old HIV-negative man. The patient was treated with CHOP-based chemotherapy followed by radiation, and expired eleven months after the initial diagnosis. PBL may be an under recognized entity when it presents in HIV-negative individuals, and should be considered in the differential diagnosis of high-grade lymphomas with plasmacytic or plasmablastic differentiation. Further studies are required to elucidate the pathogenesis of this neoplasm and define optimal treatment strategies.

CD34 positive dysplastic giant platelets masquerading as blasts on flow cytometry Page 96-101
Anmaar Abdul-Nabi, Yvette Reese, Susan Treese, John L. Frater, and Nabeel R. Yaseen
Abstract

Giant platelets are commonly seen in myelodysplastic syndrome (MDS), however their immunophenotypic characteristics are not well studied. Here we report a patient with a history of MDS that demonstrated a dysplastic, immunophenotypically abnormal subpopulation of giant platelets. In this patient, flow cytometric analysis of the marrow aspirate showed that 59% of events were with characteristics of CD34 positive blasts, raising the possibility of acute leukemia. However, microscopic examination of the bone marrow aspirate smears showed only 8% blasts and many dysplastic giant platelets. Immunohistochemistry showed CD34 positivity in the patient’s megakaryocytes. Flow cytometric analysis of the patient’s peripheral blood platelets showed that the dysplastic platelets were positive for CD34. This case shows that large dysplastic platelets in MDS may express CD34 and show CD45 staining and side scatter characteristics similar to blasts and can cause a dramatic but spurious increase in the blast count detected by flow cytometry.

ALK-positive Anaplastic Large Cell Lymphoma presenting as a solitary bladder neoplasm: A case report and review of the literature Page 102-107
Ying Huang, Ji Yuan, Hong He, Xiaomei Li, Qiubo Yu, Gang Li, and Dan Li
Abstract

Anaplastic large-cell lymphoma (ALCL) with involvement of the urinary bladder is rare. We report a unique case of ALK-positive ALCL in a 17-year-old male patient. He presented with dysuria for three months and gross hematuria for one month. The computed tomography scan and the cystoscopy revealed a single broad-based lesion measuring 3×2 cm on the right lateral wall of the urinary bladder. There was no lymphadenopathy and no tumor outside of the bladder. Biopsy of the lesion showed diffuse large pleomorphic cells infiltrating the lamina propria and strongly expressing CD30, ALK, and T-cell markers. A clonal TCR-gamma gene rearrangement was detected by PCR and ALK gene rearrangement was observed by fluorescence in situ hybridization. The patient was not treated and remains asymptomatic 6 months after the diagnosis. This is the eleventh documented instance of ALCL involving the bladder and the second reported cases of localized primary bladder ALK-positive ALCL.

Central nervous system relapsed B-Lymphoblastic Leukemia with t(9;22)(q34;q11) BCR/ABL1 mimicking acute myeloid leukemia Page 108-113
Ruijun J Su, Eric C Huang, and Mingyi Chen
Abstract

The presence of the Philadelphia (Ph) chromosome is one of the worst prognostic factors in B-cell acute lymphoblastic leukemia (B-ALL). Cerebrospinal fluid (CSF) involvement is a high-risk factor and serious complication in patients with B-ALL. Here we report a 21-year-old female diagnosed with Ph positive B-ALL and subsequently developed CSF relapse and rapid demise. Her CSF contained numerous blasts resembling myeloblasts. The relevant clinicopathologic distinctive scenarios and differential diagnoses are discussed.

Volume 1, Issue 1, March 2016

Editorials

Unveiling blood diseases Page 1
X. Frank Zhao, Shiyong Li, and Xiangdong Xu

Reviews

The ever evolving hematopathology Page 2-10
X. Frank Zhao
Abstract

Following the first case series of Hodgkin lymphomas described by Thomas Hodgkin in 1832, the field of hematopathology has traversed the (gross and microscopic) morphological, immunological, and genetic eras, to arrive finally at the molecular era. With the efforts of generations of outstanding hematopathologists, each subsequent era has advanced the field further. Meanwhile, as the field has evolved, the role of pathologists has also grown and changed from a histopathology curator to a clinical diagnostician and finally to a vital member of the patient care team. This article, which marks the inaugural issue of Hematopathology, will briefly review milestones in the history and development of hematopathology since Thomas Hodgkin first pioneered the field.

Update on BCR-ABL1-like precursor B-cell acute lymphoblastic leukemia Page 11-15
Parvez M. Lokhandwala and Yi Ning
Abstract

Precursor B-cell acute lymphoblastic leukemia (B-ALL) is the most common type of leukemia in children and young adults. Our understanding of the genetic basis of B-ALL has greatly improved in recent years. Application of genomic profiling and sequencing has led to the identification of a clinically important subgroup of B-ALL patients who are BCR-ABL1 negative, but exhibit a gene expression profile similar to that of BCR-ABL1-positive ALL. This new subgroup has been referred to as BCR-ABL1-like ALL. Like BCR-ABL1-positive ALL, BCR-ABL1-like ALL patients are in the high-risk category, associated with poor outcome. The BCR-ABL1-like patients have a diverse range of genetic alterations that activate tyrosine kinase signaling. The recurrent genetic changes include ABL class- or JAK pathway-associated translocations and IKZF1 deletions. Herein, we review the recent progress in BCR-ABL1-like ALL, the recurrent genetic alterations seen in these patients, and the therapeutic potential of targeting the identified molecular changes.

Chimeric antigen receptor T-cell immunotherapy: What pathologists need to know? Page 16-22
Xiangdong Xu
Abstract

Chimeric antigen receptor T-cell (CAR-T) immunotherapy genetically modifies patients’ own T cells to specifically target cancer antigens on cell surface. CAR-T uses a single chain chimeric antigen receptor and functions in a manner independent of major histocompatibility complex and antigen processing/ presentation. CAR-T has shown dramatic improvements in disease free survival in clinical trials on CD19-positive B-cell malignancies, especially B lymphoblastic leukemia/lymphoma. Because of the revolutionary nature of CAR-T, it is expected to become mainstream anti-cancer therapy in the near future. Pathologists have an essential role in CAR-T related patient care and need to be aware of and prepared for the prime time of CAR-T immunotherapy.

Articles

Transformation of follicular lymphoma into classical Hodgkin lymphoma showing t(14;18) Page 23-33
Xuan J. Wang, Gabriel K. Griffin, Ashwini Yenamandra, Ferrin C. Wheeler, Azra H. Ligon, Meenakshi A. Nandedka, Saad P.Shaheen, Claudio A. Mosse, and Annette S. Kim
Abstract

Follicular lymphomas (FLs) are B-cell lymphomas with a generally indolent clinical course with the propensity to transform to higher grade lymphomas. Most commonly, FL transforms into diffuse large B-cell lymphoma (DLBCL), but transformation to other higher-grade B-cell lymphomas has also been described. Transformation to classical Hodgkin lymphoma (cHL) has been documented only anecdotally. Here we describe five patients diagnosed with FL and also subsequently or synchronously with cHL. For each patient, we demonstrate the clonal relationship between the FL and the cHL by the identification of t(14;18) in both the FL and in the Hodgkin-Reed-Sternberg (HRS) cells, if available. Aneuploidy and atypical expression of BCL2 was commonly seen in the HRS cells. After transformation to cHL, the lymphomas demonstrated a more aggressive clinical behavior. In conclusion, we report five cases of FL with clonal transformation to cHL and aggressive clinical behavior that typifies other more frequently encountered transformed B-cell lymphomas.

The many rare faces of follicular lymphoma – Part 1 Page 34-47
Stefano Fratoni
Abstract

Follicular lymphoma (FL) is the most common well defined malignant lymphoma in the adults. Besides the classical pattern of effaced nodal architecture by back-to-back lymphoid follicles/nodules, it shows many morphological variations. Using actual cases, this article will illustrate the morphological features of these FL variants. In part 1, I will present 6 FL variants: 1) In situ FL and “early” interfollicular/ partial nodal involvement by FL; 2) FL, floral variant (“cloudy variant”); 3) FL with abundant eosinophilic precipitate; 4) FL with marginal zone differentiation; 5) FL with plasmacytic differentiation; and 6) Pediatric FL. Pathologists should be familiar with these morphological variations to avoid mistakes in diagnosing FLs.

Molecular profiling in confirming the diagnosis of early myelodysplastic syndrome Page 48-53
Maya Thangavelu, Ryan Olson, Li Li, Wanlong Ma, Steve Brodie, Chris Mixon, Sally Agersborg, and Maher Albitar
Abstract

Confirming a diagnosis of myelodysplastic syndrome (MDS) in the absence of cytogenetic abnormalities can be very difficult, especially in the early stages of the disease. This study investigated the utility of a 14 gene panel (TET2, IDH1/IDH2, SF3B1, SRSF2, U2AF1, ZRSR2, ASXL1, EZH2, RUNX1, TP53, NRAS, CBL and ETV6) in the diagnosis of suspected MDS. Specimens were analyzed from 137 patients, referred to rule out MDS, who had documented cytopenias with blast count <5% and without cytogenetic abnormalities. Fifty-three of the 137 patients (39%) showed evidence of an abnormal clone, characterized by mutations in one or more genes - including two of the three patients with tricytopenia (66%), nine of 14 with bicytopenia (64%) and 42 of the 120 patients with unilineage cytopenia (35%). Thirty of the 53 patients with mutations (57%) had one mutated gene; of these patients, only 4 (13%) had bi- or tricytopenia. Of the remaining 23 patients with mutations in two or more genes, a higher percentage (30%) of patients had bi- or tricytopenia indicating that cases with bi- or tricytopenia are more likely to be confirmed by molecular testing than cases with unicytopenia. Compared to patients without mutations in the tested genes, those with mutations had significantly lower number of neutrophils (P=0.006), but higher percentage of monocytes (P=0.0002) and slightly higher percentage of lymphocytes (P=0.06). This study demonstrates that a relatively small molecular panel may be a valuable and objective diagnostic means for the diagnosis of MDS patients with <5% blasts and without cytogenetic abnormalities.

Characterization of MPL-mutated myeloid neoplasms: a review of 224 MPL+ cases Page 54-60
Keming Lin, Gang Xu, Jie-Gen Jiang, Mayuko Imai, Zhao Wu, Paris Petersen, Kim Janatpour, and Bashar Dabbas
Abstract

Mutations within the myeloproliferative leukemia virus (MPL) gene have been identified in some myeloid neoplasms; however, myeloid neoplasms with MPL mutations (MPL+) have not been well characterized. This study investigated the disease distribution, morphology, cytogenetic abnormalities, and select clinical features of MPL+ myeloid neoplasms in 224 cases. Results showed that MPL mutations occur in myeloid neoplasms including primary myelofibrosis, essential thrombocytosis, myeloproliferative neoplasm, unclassifiable, polycythemia vera, refractory anemia with ring sideroblasts and marked thrombocytosis, and myeloid neoplasms associated with PDGFB rearrangement. Compared to cases with no MPL mutations (MPL-), MPL+ cases are associated with lower hemoglobin, lower WBC counts, older age, higher reticulin scores, and lower bone marrow cellularity. Compared to MPL-/JAK2+ (with JAK2 mutations), MPL+/JAK2- (with no JAK2 mutation) cases are associated with lower hemoglobin, lower WBC counts, lower bone marrow cellularity, but no significant differences in reticulin scores or patient age. Compared to MPL-/JAK2-, MPL+/JAK2- cases show significantly higher reticulin scores, but no statistical differences in hemoglobin, WBC counts, patient age, or bone marrow cellularity. MPL and JAK2 V617F mutations can coexist (7.9%); however, MPL mutations and BCR/ABL appear mutually exclusive. Overall incidence of cytogenetic abnormalities was not significantly different in cases with or without MPL mutations. In this study, MPL positivity alone does not appear to result in a distinct entity.

Case Reports

Systemic mastocytosis with associated clonal hematologic non-mast cell lineage disease (SM-AHNMD) involving chronic myelogenous leukemia with complex cytogenetics: A case report and literature review Page 61-68
K. David Li, Xinjie Xu, and Anna P. Matynia
Abstract

Systemic mastocytosis with associated clonal hematologic non-mast cell lineage disease (SMAHNMD) is a subtype of systemic mastocytosis (SM) characterized by neoplastic proliferation of mast cells in association with a hematologic neoplasm defined by the World Health Organization (WHO) criteria. SM-AHNMD is more commonly associated with myeloid neoplasms such as, chronic myelomonocytic leukemia (CMML), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN), and occasionally exists with lymphoid neoplasms such as B-cell lymphoproliferative disorders and plasma cell dyscrasia. Although SM-AHNMD is more commonly associated with a myeloid malignancy, an association with chronic myelogenous leukemia (CML) is rarely seen. To date, less than a handful of SM-AHNMD associated with CML cases have been reported. We present another case of SM-AHNMD associated with CML and a review of the literature.

Myelodysplastic syndrome following precursor B-cell acute lymphoblastic leukemia with low hypodiploid / near triploid karyotype and concomitant TP53 mutation: A case report and review of the literature Page 69-73
Suneetha Chintalapati, Robin L. Dietz, Alberto Kheradpour, and Jun Wang
Abstract

Low hypodiploid / near triploid acute lymphoblastic leukemia (LH-ALL) is infrequent in children with precursor B-cell acute lymphoblastic leukemia, and development of a secondary malignancy, particularly myelodysplastic syndrome (MDS), is additionally uncommon. Here we report a case of a 12-year-old girl who initially presented with a precursor B-cell acute lymphoblastic leukemia characterized by a karyotype with a chromosome count of 34 accompanied by a near triploid clone with 63 chromosomes. These findings prompted a TP53 mutation study, which found a deleterious mutation (524G/A) resulting in an amino acid substitution of R175H (Arg175/His). Two years after successful treatment of the LH-ALL a bone marrow examination demonstrated dyserythropoiesis, dysmegakaryopoiesis, increased hematogones, and a 7q deletion consistent with MDS. The development of MDS following treatment of LH-ALL is exceptionally rare, with only one other case found in our search of available literature.