How I investigate monocytosis.

Monocytosis is a common finding that is caused by a wide variety of neoplastic and non-neoplastic conditions. The adequate evaluation of monocytosis involves the integration of laboratory data, morphology, clinical findings, and the judicious use of ancillary studies. We review the literature on monocytosis, including the 2017 revised 4th edition of the World Health Organization classification of hematopoietic neoplasms. We present a review of monocytosis with practical guidelines on how to approach both routine and challenging cases.

Does morphology matter in 2017? An approach to morphologic clues in non-neoplastic blood and bone marrow disorders.

Numerous non-neoplastic and neoplastic conditions manifest with distinctive features in blood. Although automated complete blood count (CBC) data are essential, CBC information alone is insufficient for diagnosis. Consequently, morphologic review of blood smears is still relevant in the era of sophisticated automated analyzer systems. Pathologist interpretation of the peripheral blood smear, in conjunction with CBC and clinical information, can provide rapid diagnostic information and guide cost-effective targeted laboratory testing. Pathologist review of blood smears can be used to diagnose cases in which the clinical findings are misleading or nonspecific. Here, we discuss a selection of cases in which the pathologist examination of the blood smear can aid in rapid and accurate diagnosis and guide appropriate treatment. Exemplary non-neoplastic disorders with distinctive morphologic blood features of RBC, neutrophils, monocytes, and lymphocytes will be highlighted. The differential diagnostic considerations in blood smears with RBC destruction will be presented, expanding beyond microangiopathic hemolytic anemia. Lymphocyte morphologic assessment guides differential diagnosis including the identification of rare germline disorders. In each case presented, the integration of morphologic features guided additional testing with confirmation of the diagnosis. Peripheral blood smear review is timely and cost effective, even in an era of sophisticated automated laboratory testing.

A retrospective study to assess the relative value of peripheral blood, bone marrow aspirate and biopsy morphology, immunohistochemical stains, and flow cytometric analysis in the diagnosis of chronic B cell lymphoproliferative neoplasms.

INTRODUCTION: The successful diagnosis of chronic B cell lymphoproliferative neoplasms (B-CLPN) requires the integration of multiple parameters, beginning with clinical information, CBC data, and morphology review. Immunophenotyping is essential and genetic testing may also be necessary. However, the relative value of each specimen or ancillary study in the diagnosis and classification has not been systematically established. We have performed a blinded retrospective review to assess what in our laboratory was the relative value of each specimen type and ancillary study in the diagnostic workup of B-CLPN. METHODS: A total of 185 cases of PB, BM, spleen and lymph nodes were analyzed for relative value of morphology, IHC, flow cytometry study in the diagnosis of B-CLPN. RESULTS: 'High yield' specimen was identified in most B-CLPN categories, which was highly predictive of the final WHO diagnosis. CONCLUSION: The goal of this retrospective study was to attempt to assess what was the relative value of morphology, immunophenotype, and molecular/cytogenetic study in various sites in the overall diagnostic process in our institution. We investigated the utility of the 'high yield' specimens in achieving the correct final diagnosis. In our study, some B-CLPNs notably splenic marginal zone lymphoma and hairy cell leukemia variant, required all studies for a 'best fit' type of diagnosis. In other cases, the morphology of a single specimen type was highly predictive of the final diagnosis, although confirmatory studies are recommended for definitive diagnosis.

Rapid presumptive diagnosis of hantavirus cardiopulmonary syndrome by peripheral blood smear review.

Hantavirus cardiopulmonary syndrome (HCPS) is a rare but frequently lethal acute zoonotic viral infection in rural North America. The rapidity of progression from febrile prodrome to cardiogenic shock and noncardiogenic pulmonary edema requiring intensive care creates high diagnostic urgency and a need for a rapid screening tool. In this retrospective cohort study, 2 pathologists scored blinded peripheral blood smears from 52 patients with HCPS and 128 seronegative patients referred for diagnosis of suspected hantavirus infection. During the prodromal phase, thrombocytopenia was the only consistent abnormality and could be used to indicate hantavirus serologic testing. After the onset of pulmonary edema detected radiographically, the presence of 4 of 5 findings (thrombocytopenia, myelocytosis, hemoconcentration, lack of significant toxic granulation in neutrophils, and more than 10% of lymphocytes with immunoblastic morphologic features) has a sensitivity for HCPS of 96% and a specificity of 99% and missed no patients with HCPS who required intensive care. While each abnormality is commonly seen, the combination of at least 4 of these CBC count data and peripheral blood smear findings can guide early treatment and patient transport decisions until rapid, specific, serologic testing becomes widely available.

Benign hematogone-rich lymphoid proliferations can be distinguished from B-lineage acute lymphoblastic leukemia by integration of morphology, immunophenotype, adhesion molecule expression, and architectural features.

Distinction of normal B-lymphoid proliferations including precursors known as hematogones from acute lymphoblastic leukemia (ALL) is critical for disease management. We present a multiparameter assessment of 27 bone marrow samples containing at least 25% hematogones (range, 25%-72%) by morphologic review. We used flow cytometry to evaluate B-cell differentiation antigen and adhesion molecule expression and immunohistochemistry on clot sections to evaluate architectural distribution. Flow cytometry revealed that intermediately differentiated cells (CD19+, CD10+) predominated, followed in frequency by CD20+, surface immunoglobulin-positive cells, with CD34+, terminal deoxynucleotidyl transferase (TdT)-positive cells as the smallest subset. Adhesion molecules (CD44, CD54) were expressed more heterogeneously compared with expression in acute lymphoblastic leukemia. Immunohistochemistry revealed that CD34+, TdT-positive cells were dispersed without significant clustering, while CD20+ cells exceeded CD34/TdT-positive cells in 24 of 25 cases. This multidisciplinary study demonstrates that hematogone-rich lymphoid proliferations exhibit a spectrum of B-lymphoid differentiation antigen expression with predominance of intermediate and mature B-lineage cells, heterogeneity of adhesion molecule expression, and nonclustered bone marrow architectural distribution.

Blastic mantle cell leukemia: an unusual presentation of blastic mantle cell lymphoma.

Six patients had blood and bone marrow manifestations characterized by the presence of morphologically immature or blastic B-lineage lymphoid cells expressing CD5 antigen. The median patient age was 70 years, and the male-to-female ratio was 5:1. The presence or degree of lymphadenopathy and splenomegaly was variable among this group at staging evaluation, although two patients did not have these features. One patient had an antecedent diagnosis of classical nodal mantle cell lymphoma, without prior morphologic blood or bone marrow involvement. Other patients lacked a history of underlying lymphoproliferative disorders. The median white blood cell count was 120 x 10(9)/L. Most patients had thrombocytopenia, whereas only one patient had neutropenia at presentation. Leukemic peripheral blood cells in these six cases were small to medium in size with fine or granular nuclear chromatin and small or inconspicuous nucleoli. The pattern of marrow involvement was interstitial or diffuse, with cells showing immature nuclear features resembling acute leukemia or blastic lymphoma. All tumors demonstrated a consistent immunophenotype of B-cell lineage, surface immunoglobulin positivity, and CD5 antigen expression. The progenitor cell-associated markers CD34 and TdT were not expressed, and CD23 antigen was either negative (three of four cases) or only weakly present (one of four cases). The presence of a karyotypic t(11;14)(q13;q32) was documented in one tumor, whereas two other cases had BCL-1 gene rearrangements by either polymerase chain reaction or Southern blot analysis. Cyclin D1 mRNA overexpression was noted in three of four cases tested. This patient group was characterized by very poor overall survival (median, 3 months; range, 0.5 to 6 months). The aggregate clinical, pathologic, and genetic data in these unusual cases are consistent with de novo or predominant leukemic presentations of blastic mantle cell lymphoma. Accurate diagnosis in such cases is greatly facilitated by cytogenetic studies or the demonstration of BCL-1/cyclin D1 abnormalities.

Myelodysplastic syndromes in the adolescent.

Myelodysplastic syndromes (MDS) are a group of acquired blood diseases that are the result of abnormal bone marrow function. The ineffective production of red cells, platelets, and white blood cells can lead to symptomatic anemia, bruising, infections, and the likelihood of evolution into acute myelogenous leukemia. While MDS is uncommon in the adolescent patient, a surprising number of affected individuals are also affected with a predisposing constitutional syndrome. The treatment of MDS in the adolescent patient is in part determined by symptoms and also by the historical outcomes associated with each of five morphologic categories of presentation. Improved supportive care has allowed for increasingly more children with MDS to survive into the second decade of life. The management of MDS in affected adolescents presents a number of interesting and worthwhile challenges to health care professionals.

The histopathology of cutaneous lesions of Kikuchi's disease (necrotizing lymphadenitis): a report of five cases.

Kikuchi's disease (KD) is an idiopathic, self-limited necrotizing lymphadenitis that can clinically and histologically mimic high-grade lymphoma, including Hodgkin's disease, or can be mistaken for the lymphadenitis of systemic lupus erythematosus (SLE). Involvement of extranodal sites is unusual but well documented, especially in Asia, where KD is more common than in North America or Europe. The successful distinction of KD from malignant lymphoma and SLE is imperative for the appropriate treatment of affected patients. We describe five patients with cutaneous involvement by KD, all of whom presented with fever, lymphadenopathy, and an eruption on the skin of the upper body, which in one case was clinically suspected to be due to SLE and in another, polymorphous light eruption. The patients ranged in age from 10 months to 42 years (median, 33 years) and included three females and two males. All five patients had negative serologic studies for collagen vascular disease. Each patient had a lymph node biopsy showing the typical necrotizing lymphadenitis of KD. Skin biopsies from all five patients shared a specific constellation of histologic features: vacuolar interface change with necrotic keratinocytes, a dense lymphohistiocytic superficial and deep perivascular and interstitial infiltrate, varying amounts of papillary dermal edema, and abundant karyorrhectic debris with a conspicuous absence of neutrophils and a paucity of plasma cells, paralleling the nodal histology in KD. CD68 immunohistochemistry on paraffin-embedded sections showed many histiocytes and plasmacytoid monocytes in all cases, whereas CD3, CD4, and CD8 showed highly variable staining among the cases. There was only rare staining with TIA-1 and CD30. We believe that the papular eruption of KD has recognizable histopathologic features and that a CD68 stain that marks many cells that initially seem to be lymphocytes can be performed to confirm the diagnosis.

Minimal residual disease in patients with hairy cell leukemia in complete remission treated with 2-chlorodeoxyadenosine or 2-deoxycoformycin and prediction of early relapse.

The purine nucleoside analogues 2-chlorodeoxyadenosine (2-CdA) and 2'-deoxycoformycin (2'-DCF) induce complete remission (CR) in the majority of patients with hairy cell leukemia. However, minimal residual disease (MRD) has been detected in bone marrow core biopsies using immunohistochemical techniques in patients achieving CR by conventional criteria. This study was designed to compare the prevalence of MRD with each agent in patients in CR by using conventional criteria and the relapse-free survival for patients with and without MRD. Bone marrow biopsies from 39 patients treated with a single cycle of 2-CdA and 27 patients treated with multiple cycles of 2'-DCF were studied. The monoclonal antibodies anti-CD20, DBA.44, and anti-CD45RO were used to evaluate the paraffin-embedded bone marrow core biopsies for MRD. Five of 39 patients (13%) treated with 2-CdA had MRD, as compared to 7 of 27 patients (26%) treated with 2'-DCF (two-tailed P = 0.21). Relapse has occurred in two of the five patients with MRD after 2-CdA treatment and in four of the seven patients with MRD after 2'-DCF treatment. In total, 6 of the 12 patients (50%) with MRD have relapsed, whereas 3 of 54 patients (6%) without MRD have relapsed, and 2 patients have died without evidence of relapse. The estimated 4-year relapse-free survival among patients with MRD is 55% (+/- 15%, SE), compared to 88% (+/- 5%, SE) among patients without MRD (two-tailed P = 0.0023). The prevalence of MRD detected in a subset of patients in CR after either 2-CdA or 2'-DCF treatment did not differ significantly. However, the presence of MRD is associated with an increased risk of relapse.

Cutaneous Waldenstrom macroglobulinemia in transformation.

Waldenstrom macroglobulinemia is a low-grade B-cell lymphoproliferative disorder of the elderly with characteristic monoclonal IgM-producing neoplastic infiltrates of the bone marrow, lymph node, and spleen. Cutaneous manifestations are usually nonspecific such as purpura, ulcers, and urticarial lesions. These lesions are caused by hyperviscosity of the blood, immune complex-mediated vascular damage, paraprotein deposition, and amyloid deposition. Specific skin lesions occur rarely and generally consist of translucent, flesh-colored papules composed of monoclonal IgM deposits. Rarely, there may be violaceous lesions composed of low-grade lymphoplasmacytic infiltrates characteristic of Waldenstrom macroglobulinemia. Both cutaneous manifestations of the disease, as well as disease transformation to high-grade, large cell lymphoma are rare. We report two very unusual cases of Waldenstrom macroglobulinemia with documented skin disease that demonstrated transformation to high-grade lymphoma. Both patients were elderly men with long-standing Waldenstrom macroglobulinemia involving the bone marrow, who subsequently developed skin involvement by the disease. Waldenstrom macroglobulinemia can rarely manifest as cutaneous disease, sometimes as a high-grade transformation of low-grade Waldenstrom macroglobulinemia elsewhere. Distinction of cases of transformed Waldenstrom macroglobulinemia from de novo cutaneous large cell lymphoma may be important, because the two entities are likely biologically different.

Chronic lymphoid leukemias and lymphoproliferative disorders.

Chronic lymphoproliferative disorders (CLPDs) are derived from the clonal proliferation of cytologically and immunophenotypically mature B or T cells. Although overlap is prominent, the CLPDs can generally be segregated into leukemias (predominant blood and bone marrow manifestations) and lymphomas (predominant extramedullary manifestations). This review discusses the leukemic processes, with emphasis placed on the blood and bone marrow features of these disorders. Many distinct types of B-cell and T-cell CLPDs have been described, and the classification of CLPDs requires the integration of morphologic features, immunophenotype, and clinical information; genotypic analyses might provide prognostic and biologic information. The various classification systems for the CLPDs will be presented, as well as a discussion of specific disease types, emphasizing those most commonly encountered in clinical practice.

The presence of CD34+ cell clusters predicts impending relapse in children with acute lymphoblastic leukemia receiving maintenance chemotherapy.

Early detection of relapse in children with acute lymphoblastic leukemia (ALL), as well as distinction of leukemic blasts from hematogones, can be difficult by morphologic examination alone. Using CD34 and terminal deoxynucleotidyl transferase (TdT) immunoperoxidase stains, we studied specimens from 25 children with ALL in morphologic remission to determine if we could identify children at risk of relapse. We studied morphologic remission bone marrow specimens from 9 patients who experienced relapse during the subsequent 6 months and 16 children who remained in complete remission, including 10 specimens with increased numbers of hematogones. Despite morphologic remission, clusters of more than 5 CD34+ and/or TdT-positive cells were identified before overt relapse in 6 of 9 cases of relapse, but were noted in only 1 of 10 specimens from children in continuous complete remission and none of 10 specimens with increased numbers of hematogones. Clusters of CD34+ or TdT-positive cells can identify individual patients at risk for imminent relapse. Hematogones may be differentiated from lymphoblasts by this method.

A B-cell "chameleon": striking clinical, morphological, and immunophenotypic diversity of a single low-grade B cell clone.

A patient with an 18-year history of low-grade B-cell lymphoproliferative disorders is presented. Although the precise classification of these B-cell disorders was problematic, the blood, bone marrow, spleen, lymph node, and gastrointestinal lesions evaluated were compatible morphologically with such apparently disparate diagnoses as hairy cell leukemia, marginal zone lymphoma, mantle cell lymphoma, and gastrointestinal multiple lymphomatous polyposis. Although each low-grade disease that developed over an 18-year interval was clinically, morphologically, and immunophenotypically distinct, genotyping showed their derivation from a single B cell clone. This case emphasizes that a single B-cell clone may give rise to several distinct low-grade B-cell lymphoproliferative disorders with diverse clinical and pathological features.

Hantaviral biosafety issues in the autopsy room and laboratory: concerns and recommendations.

The need to perform autopsies on and examine laboratory specimens from patients with hantavirus pulmonary syndrome (HPS) has raised questions about biosafety. Human illness associated with hantaviruses is usually the result of exposure to infectious aerosols from saliva or excreta of wild rodents. It is unclear whether or nor certain autopsy and laboratory procedures can also generate similar potentially infectious aerosols. As the biosafety information developed for the HPS agent is limited and the consequences of infection are serious we recommend a cautious approach. Autopsy prosectors should use N-95 particulate respirators as a minimum standard. If aerosols will be generated they should use N-100 particulate respirators or powered air purifying respirators with high-efficiency particulate air (HEPA) filters. Centrifugation and cytocentrifugation of blood or body fluid samples should be performed in bio-contained systems and these specimen containers should be opened in a class II biological safety cabinet.

Multidrug resistance-1 (MDR1) expression and functional dye/drug efflux is highly correlated with the t(8;21) chromosomal translocation in pediatric acute myeloid leukemia.

Resistance to chemotherapy is a major problem in acute myeloid leukemia (AML). An important resistance mechanism in adult AML is active drug efflux mediated by the multidrug resistance protein-1 (MDR1). To determine if MDR1 is important in childhood AML, we examined MDR1 expression and functional dye/drug efflux in 20 pediatric/adolescent AML patients; results were correlated with cytogenetics and clinical outcome. Using flow cytometry, MDR1 protein expression on the leukemic blasts was measured with the antibody MRK16, while efflux was measured by extrusion of the fluorescent dye DiO(C2)3 in the presence/absence of cyclosporin A (CsA). Six of 20 cases expressed MDR1. While all six MDR1+ cases were efflux+, three of 14 MDR1- cases also demonstrated efflux. Both MDR1 and efflux were strongly correlated with the t(8;21). All six MDR1 +/efflux+ cases and 2/3 MDR1 -/efflux+ cases had a t(8;21), while no MDR1-/efflux- cases had a t(8;21) (P < 0.0005). This correlation between MDR1, efflux, and the t(8;21) in pediatric AML was not found in 11 adult t(8;21) cases similarly studied. Although the clinical relevance of MDR1 in pediatric AML awaits larger studies, our results suggest a biologic subset of pediatric AML patients may benefit from regimens which include MDR1-reversing agents or non-MDR1 substrates.

Kikuchi's histiocytic necrotizing lymphadenitis associated with ruptured silicone breast implant.

OBJECTIVE: In this report we explore the relationship between Kikuchi's necrotizing lymphadenitis (Kikuchi-Fujimoto disease, KD) and a leaky silicone breast implant. PATIENT: The simultaneous occurrence of KD and silicone lymphadenopathy in an axillary lymph node of a patient with a leaking silicone breast implant is reported. Since both KD and silicone implants have been implicated in autoimmune diseases, including systemic lupus erythematosus, serologic tests for antinuclear antibodies and rheumatoid factor were performed. RESULTS: Axillary lymph nodes showed both silicone lymphadenopathy, as well as classic morphologic and immunophenotypic features of KD. Screening tests for systemic autoimmune disorders were within normal range, suggesting that the unusual Kikuchi's-like immune reaction in one axillary lymph node was localized. The patient has no evidence of progressive immunologic disorders 3 years later. Subsequent lymph node biopsies showed silicone adenopathy with no evidence of KD. CONCLUSIONS: Our findings indicate that silicone compounds may be associated with transient abnormal immune reactions and lend further support to the hypothesis that KD represents an exuberant T-cell-mediated immune response to a variety of nonspecific stimuli.

Effect of aggressive daunomycin therapy on survival in acute promyelocytic leukemia.

The Southwest Oncology Group analyzed outcome with cytotoxic chemotherapy for previously untreated acute myeloblastic leukemia (AML) from 1982 through 1986. Results with acute promyelocytic leukemia (APL) prompted comparison with patients from 1986 through 1991 and analysis of factors contributing to APL results. Patient and disease characteristics and treatment outcome were compared for all evaluable patients, with more detailed analysis of factors affecting APL treatment outcome. From 1982 through 1986, median survival and disease-free survival in 45 APL patients were 106 months and greater than 105 months, respectively, versus 6 and 14 months for 417 other AML patients. Such differences were not seen from 1986 through 1991. In the 141 APL patients from 1982 through 1991, after adjusting for significant patient and disease characteristics, higher daunomycin (DNR) doses during induction were significantly associated with higher complete remission rates (P < .0001), longer survival (P < .0001), and longer DFS (P < .0001). Cytosine arabinoside (Ara-C) induction dose, the inclusion of other chemotherapy agents in induction, postremission therapy (consolidation, maintenance, or bone marrow transplantation) other than DNR, APL subtype, and patient age did not appear to significantly affect outcome of APL, except for a significant detrimental effect of high-dose Ara-C in consolidation (P = .0042). Morphologic AML subtypes other than APL did not affect outcome. We conclude that high-dose DNR selectively increases survival in APL. This good survival is important for evaluation of combined all-trans retinoic acid (ATRA)/chemotherapy protocols and for planning future combinations of chemotherapy and ATRA. These results illustrate the need to individualize chemotherapy for subtypes of AML. Therapeutic response of APL is independent of age. Except for APL, morphologic subclassification of AML contributed little prognostic information.