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.

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