Category: Issue

Diagnosis of classic Hodgkin lymphoma (CHL) is quite straightforward with the integrated
clinical, morphological, and immunophenotypic studies. Due to the variation in morphology and immunophenotype, CHL diagnosis remains a challenge. Based on their many years of experience in diagnostic practice, the authors summarized eleven uncommon variants of CHL: 1) CHL with xanthogranulomatous inflammation, foamy histiocytes and loose granulation tissue-like stroma; 2) epithelioid cell-rich and granulomatous CHL; 3) CHL with prominent keloid-like fibrosis; 4) CHL rich in plump histiocytes arranging in a fascicular pattern; 5) intrasinusoidal CHL; 6) interfollicular CHL: 7) neutrophil-rich CHL; 8) neoplastic cell-rich CHL; 9) lymphocyte depleted CHL; 10) CHL with aberrant immunophenotypes; 11) grey-zone CHL. These variants pose diagnostic pitfalls to the practicing pathologists.

The expression of cyclin D1 in diffuse large B-cell lymphomas has been reported in the literature several times. However, cases with the t(11;14)(q13;q32) are very uncommon. Herein, we present two cases of diffuse large B-cell lymphoma with the t(11;14)(q13;q32) and cyclin D1 expression, BCL6 rearrangement and BCL2 amplification, but negative for SOX11 expression. Although presence of the t(11;14)(q13;q32) is a hallmark of mantle cell lymphoma, it can also be seen in diffuse large B-cell lymphoma, sometimes as a secondary aberration.

In the era of precision medicine, complex disease-specific and host-specific metrics are becoming essential and must be implemented in patients care. Because of cancer heterogeneity, precision medicine is more impactful in oncology than any other field. However, it is becoming increasingly difficult to keep up with the vast knowledge and fast pace of advances in cancer management and therapy. For that current cancer care requires multidisciplinary team approach. Pathologists are very important component of this team and their role is expanding significantly. Pathologists must not only provide the morphologic diagnosis, but they are required to provide information on the biological and molecular characteristics of the disease and the host. They must present and discuss the clinical relevance of the various molecular and biological findings in selecting therapy, predicting prognosis and planning the course of management. This article discusses the changing role of pathologists in the era of precision medicine and the importance of more engagement of pathologists in the daily clinical decisions and patient care.

Multiple myeloma (MM) is a diverse clonal plasma cell malignancy with resultant organ
damage including renal and bone marrow effects, as well as neurologic and immune dysfunction. MM is characterized as clinically and pathologically heterogeneous with significant variability in treatment response and survival. The genetically high-risk myeloma is often manifested as clinical relapsed and refractory disease. In this article, we summarize the most recent progress of molecular diagnosis and targeted treatment of multiple myeloma. We review the landscape of chromosomal abnormalities in myeloma and discuss the clinical impact on patient outcomes. We also present case report of a rare myeloma complication: central nervous system (CNS) myelomatosis. This study will help to understand the biology of CNS myeloma and its therapeutic implications in the era of precision medicine.

Niemann-Pick disease (NPD) is a rare inherited autosomal recessive neurodegenerative disease usually diagnosed at young age. Type A and B Patients are characterized by Sphingomyelin phosphodiesterase 1 (SMPD1) gene mutation and frequently have ataxia, dystonia, early-onset cognition decline or even dementia. However, type C patients have NPD Type C (NPC1) gene mutation and can show a wide spectrum of clinical presentations, leading to potential delayed diagnosis. A 31-year-old Caucasian woman presented with dyspnea on exertion, massive splenomegaly and progressive thrombocytopenia. CT showed multiple bilateral lung nodules. Lung biopsy demonstrated intra-alveolar collection of foamy, vacuolated histiocytes. Bone marrow biopsy revealed collection of foamy, vacuolated histiocytes characteristic of NPD. Molecular test detected heterozygous A196P mutation of SMPD1 gene and one heterozygous mutation of NPC1 gene. The diagnosis of NPD type C is rendered by biochemical testing that demonstrates impaired cholesterol esterification and positive filipin staining in cultured fibroblasts.

B-lymphoblastic leukemia/lymphoma with CRLF2 overexpression belongs to the BCR-ABL1–
like B- lymphoblastic leukemia / lymphoma group (BCR-ABL1-like B-ALL), also known as Philadelphia chromosome-like B-ALL, a recently recognized provisional entity in the latest edition of World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissues (2016). Although lacking the classic t(9;22) BCR-ABL1, BCR-ABL1-like B-ALL shares a similar gene expression profile with BCR-ABL1 translocation associated B-ALL. BCR-ABL1-like B-ALL often have translocations involving CRLF2, EPOR, or other tyrosine kinases. Due to prognostic importance and potential therapeutic differences, it is important to recognize and diagnose BCR-ABL1-like B-ALL in a timely manner. In this report, we describe a series of three adult patients with the diagnosis of B-ALL with CRLF2 overexpression and present all relevant clinical and pathologic findings.

Composite lymphomas (CLs) containing both T- and B-cell lymphomas are very rare. We describe an unusual case of a CL consisting of angioimmunoblastic T-cell lymphoma (AITL) and B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL). A 68-year old male presented with skin rash, hand pain and lymphadenopathy. The lymph node contained small lymphocytes intermixed with medium to large-sized atypical cells, and arborizing blood vessels. Flow cytometry, immunohistochemistry, EBER and molecular studies confirmed the presence of CL: predominantly AITL with small portion of B-CLL/SLL. In bone marrow, multiple lymphoid aggregates were identified and proved to be composite B-CLL/SLL and AITL. The patient received R-CHOP (Rituxan, cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy. His skin rash improved but he developed bilateral finger gangrene and nine affected digits were amputated. To the best of our knowledge, this is the first report of CL containing concurrent AITL and B-CLL/SLL involving both lymph node and bone marrow.

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.

Pathology as a discipline can be traced to the 17th Century, B.C. Over the past 4,000 years, pathology has experienced four eras: the morphological, immunological, genetic, and molecular eras. Molecular pathology emerged in 1970s when Southern blot was employed to detect gene rearrangements in cancer cells. DNA sequencing and polymerase chain reaction (PCR) further revolutionized the diagnosis of human diseases. Gene profiling array and next generation sequencing are being applied in clinical diagnostics. While marveling at the advancement of new technologies, pathologists should be aware of the many challenges over the horizon. These include: 1) atypical morphology and aberrant gene expression make it more and more difficult to classify cancers; 2) genetic studies that play more and more important roles in diagnosing diseases; 3) precision medicine which renders morphology-based diagnosis less and less meaningful; 4) the reality of robust and affordable global sequencing of tumors. With development of various omics, traditionally morphology-based pathology will face even more challenges. However, these challenges can also be opportunities for pathologists, such as diagnosing diseases based on biology; classifying diseases based on therapeutic targets; getting more involved in clinical decision making; and discovering new biomarkers and therapeutic targets. Seizing these opportunities will be essential for pathology to play a central role in the 21st Century medicine.

Aims: There is a paucity of evidence-based guidelines supporting test selection after allogeneic stem cell transplantation for the assessment of residual disease and bone marrow chimerism, although common clinical practice typically includes some measures of both. This study aims to evaluate the accuracy of chimerism studies to predict residual disease and clinical outcome.
Methods: We retrospectively reviewed both chimerism and residual disease studies associated with 334 bone marrow samples from 143 patients with a range of hematologic malignancies, with a mean of over 2 years of additional follow-up to assess relapse rate.
Results: Of 334 cases, 266 showed no histologic evidence of disease. Ancillary tests for residual disease were available in 260/266 cases, with negative results in 87% (227/260) of cases. Mixed chimerism (MC) was found in 48% (108/227) of these cases. In addition, 30.3% of cases with residual disease by ancillary testing demonstrated complete engraftment (CE). No significant difference in relapse rates between MC (19.5%) and CE (16.3%) patients was found in patients who received reduced intensity chemotherapy conditioning regimens (RIC) (p=0.69). Similarly, relapse rates of MC and CE in patients who received myeloablative conditioning (MAC) were 11.1% and 17.5%, respectively (p=0.47).
Conclusions: Bone marrow engraftment analysis did not reliably correlate with residual disease status as measured by a number of different methods in the setting of typical preparative regimens (classified as either RIC or MAC). In addition, we found no uniform association between chimerism status and relapse. This study raises concerns about the value of chimerism studies to predict clinical outcomes related to disease status.

We present a case of a 41-year-old male who was admitted to an outside hospital for abdominal
pain with increasing severity and reported past medical history of seizures and pancreatitis. Abdominal CT imaging revealed acute mesenteric ischemia and a splenic infarction. Concurrently, the patient’s white blood cell count showed minimal leukocytosis with relative monocytosis. Patient underwent a laparotomy that resulted in a mesenteric embolectomy and splenectomy. Reviewing the histological sections of the spleen, accessory spleen and mesenteric emboli clot sections along with additional studies performed at our institution confirmed the diagnosis of an isolated de-novo myeloid sarcoma with monocytic differentiation. Staging of the disease included trephine bone marrow biopsy and ancillary testing on the bone marrow aspirate (i.e. cytogenetics and FISH studies). These studies were negative for bone marrow involvement by acute myeloid leukemia. Follow up positron emission tomography/computed tomography highlighted no new sites of involvement. To the best of our knowledge, this is the second reported case in the literature of an isolated splenic myeloid sarcoma without bone marrow involvement and no history of receiving any treatment. This is the first reported case in the medical literature of this disease entity clinically presenting as mesenteric artery occlusion.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 (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.

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.

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.

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.

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.

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.

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.