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The morphologic distinction of benign and malignant thyroid follicular lesions can sometimes be challenging, therefore an immunohistochemical marker to aid in this distinction would be useful. beta-Catenin is one such potential marker. It is part of a membrane-bound cell growth-signaling complex that plays a role in cell adhesion, as well as in promotion of growth through activation of the Wnt signaling pathway. Oncogenic signaling occurs when beta-catenin is released, accumulates in the cytoplasm, translocates into the nucleus, and promotes transcription of genes including bcl-1 (cyclin D1) and c-myc that induce cell proliferation. Paraffin blocks from 133 thyroidectomy specimens were stained with monoclonal antibodies reactive with beta-catenin and cyclin D1. These included 53 cases of papillary thyroid carcinoma (PTC), 46 cases of follicular variant of papillary carcinoma (FVPC), 10 cases of follicular carcinoma (FC), and 24 cases of follicular adenoma (FA). Tissue from six normal thyroid specimens served as a control. The malignant lesions (PTC, FC, and FVPC) expressed strong cytoplasmic/nuclear staining and minimal residual membranous staining in 87%, 80%, and 71% of cases, respectively. In contrast, all normal thyroid tissue and 79% of FAs showed strong membranous reactivity with very minimal cytoplasmic staining. Interestingly, in 83% of PTC cases and 20% FVPCs, the intranuclear inclusions were distinctly beta-catenin positive. Cyclin D1 over expression correlated with cytoplasmic relocalization of beta-catenin in almost all cases, and no evidence of cyclin D1 gene amplification was observed. beta-Catenin can be of a diagnostic utility for thyroid lesions, because it highlights intranuclear inclusions in PTC, and shifts from a membranous localization to a cytoplasmic localization in malignant lesions. We speculate that the localization of beta-catenin in intranuclear inclusions may reflect a cytoskeletal remodeling activity of beta-catenin that is functionally significant for the PTC pathway.

The morphologic distinction of benign and malignant thyroid follicular lesions can sometimes be challenging, therefore an immunohistochemical marker to aid in this distinction would be useful. beta-Catenin is one such potential marker. It is part of a membrane-bound cell growth-signaling complex that plays a role in cell adhesion, as well as in promotion of growth through activation of the Wnt signaling pathway. Oncogenic signaling occurs when beta-catenin is released, accumulates in the cytoplasm, translocates into the nucleus, and promotes transcription of genes including bcl-1 (cyclin D1) and c-myc that induce cell proliferation. Paraffin blocks from 133 thyroidectomy specimens were stained with monoclonal antibodies reactive with beta-catenin and cyclin D1. These included 53 cases of papillary thyroid carcinoma (PTC), 46 cases of follicular variant of papillary carcinoma (FVPC), 10 cases of follicular carcinoma (FC), and 24 cases of follicular adenoma (FA). Tissue from six normal thyroid specimens served as a control. The malignant lesions (PTC, FC, and FVPC) expressed strong cytoplasmic/nuclear staining and minimal residual membranous staining in 87%, 80%, and 71% of cases, respectively. In contrast, all normal thyroid tissue and 79% of FAs showed strong membranous reactivity with very minimal cytoplasmic staining. Interestingly, in 83% of PTC cases and 20% FVPCs, the intranuclear inclusions were distinctly beta-catenin positive. Cyclin D1 over expression correlated with cytoplasmic relocalization of beta-catenin in almost all cases, and no evidence of cyclin D1 gene amplification was observed. beta-Catenin can be of a diagnostic utility for thyroid lesions, because it highlights intranuclear inclusions in PTC, and shifts from a membranous localization to a cytoplasmic localization in malignant lesions. We speculate that the localization of beta-catenin in intranuclear inclusions may reflect a cytoskeletal remodeling activity of beta-catenin that is functionally significant for the PTC pathway.

The role of cell cycle protein expression in gestational trophoblastic disease is poorly understood. In this study we investigated the immunostaining patterns of G(1) restriction point and G(1)-S regulatory proteins E2F-1, Cdk2, cyclin E, p27(kip1), and the proliferation marker Ki-67 on routinely processed sections of 29 hydatidiform moles (10 partial moles and 19 complete moles, including 9 persistent moles), 7 choriocarcinomas, and 7 normal placentas. Ki-67 trophoblast staining decreased with increasing gestational age of the placenta, and showed maximal expression in gestational trophoblastic disease. Cyclin-dependent kinase activity, as reflected by Cdk2 expression patterns, also decreased with placental maturation. E2F-1 was uniquely expressed by trophoblasts of moles and choriocarcinoma. Cyclin E was maximally expressed by complete moles and choriocarcinomas, and showed an inverse relationship with the cyclin-dependent kinase inhibitor p27(kip1). Abnormal trophoblastic proliferations may be mediated through interactions of Cdk-2, E2F-1, cyclin E, and p27(kip1). Overexpression of cyclin E was associated with more aggressive forms of gestational trophoblastic disease. However, we did not find distinguishing features between complete moles that spontaneously resolved after evacuation and persistent moles that required chemotherapy. The different expression patterns of cyclin E and E2F-1 in partial and complete moles may be useful in distinguishing these two entities. Furthermore, loss of p27(kip1) in malignant trophoblast may represent a necessary step in the development of choriocarcinoma.

Transient stress lymphocytosis (TSL) is an under-recognized phenomenon associated with an acute stressful event such as physical trauma or various emergency medical conditions. Lymphocytosis generally resolves within several hours to days of the stressor. While most reports of TSL predominantly involve adult patients, it has only rarely been reported in pediatric patients. Here, we describe the clinical course of a 9-year-old male who developed TSL following a traumatic fall from a second-story balcony and provide a systematic literature review of TSL.

Competing Interests: The authors report no conflicts of interest.

Lymphoid aggregates are found in a minority of bone marrow biopsy and aspirate specimens, and when present, the distinction between benign and malignant aggregates can represent a diagnostic challenge. Morphologic and immunophenotypic evaluation of the aggregates can aid in that distinction but in a few cases, detection of immunoglobulin heavy chain (IGH) and kappa light chain (IGK) gene rearrangements may be needed to rule in or out a malignant disease process. We studied the role of testing for IGH/IGK rearrangements in the distinction between benign and malignant B cell-predominant lymphoid aggregates. Only a few studies have addressed this issue and most lacked an adequate number of cases for establishing statistical significance. Our study retrospectively evaluated 120 bone marrow aspirate and biopsy specimens, 79 cases originally diagnosed with benign lymphoid aggregates [4,5], and 41 demonstrating a B-cell lymphoma with malignant aggregates. Immunohistochemical stains were performed on all cases in our study and flow cytometry results were available in the vast majority of cases (98%). All patients included in our study but 9 had at least 2 years of clinical follow-up information. Of the malignant lymphoma cases, IGH/IGK rearrangements were demonstrated by polymerase chain reaction in 60% of the cases. Moreover, clonal rearrangements were identified in 15% of the cases with benign aggregates. After at least 2 years of follow-up, only one case with a positive clonality study occurring in the setting of morphologically benign-appearing bone marrow lymphoid aggregates experienced a relapse of non-Hodgkin lymphoma. Molecular analysis of the IGH and IGK genes may have utility in confirming the presence of malignancy in bone marrow aspirates and biopsy specimens. False-negative results, however, are possible due to testing limitations and sampling issues. Moreover, patients with conditions such as autoimmune disorders or infectious diseases are shown to also develop clonal B-cell lymphoid aggregates. As a result, we recommend a thorough morphological examination, informative immunohistochemical staining, accurate flow cytometric analysis, and current IGH/IGK rearrangement testing when evaluating bone marrow specimens containing B cell-predominant lymphoid aggregates, with the knowledge that molecular clonality results should be carefully interpreted in the context of morphological and immunophenotypic findings to prevent misdiagnosis., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Development of post-chemotherapy histiocyte-rich pseudotumor (PHP) is an underrecognized event following therapy in lymphoma patients and may mimic residual tumor using current therapy monitoring protocols. We report a series of 5 patients with PHP along with a review of the literature. In our series, we describe 3 patients with persistent hypermetabolic masses by positron emission tomography-computed tomography, one with persistent terminal ileal nodules on endoscopy, and one with bone marrow involvement, a site not associated with mass-like disease. Twenty-three patients with long-term follow-up were identified from our series and review of the literature. Forty-four percent of patients received additional therapy, and only 4% of patients died of lymphoma. This study illustrates that PHPs are not identified using current lymphoma therapy monitoring algorithms and may result in overtreatment with risk for additional therapy-related complications. The need for confirmatory tissue biopsy in this setting is recommended., (© 2021 S. Karger AG, Basel.)

Kikuchi-Fujimoto disease is a self-limited disease of unknown etiology that is clinically defined by fevers accompanied by tender posterior cervical lymphadenopathy. It often presents acutely or sub-acutely, and due to its non-specific features, the differential diagnosis is broad and includes infectious, autoimmune, and malignant causes. Although cases of extra-cervical disease are not uncommon, involvement of retroperitoneal lymph nodes has only rarely been reported. Here, we describe a patient with Kikuchi-Fujimoto disease who presented with fever of unknown origin, abdominal pain, and enlarged hypermetabolic retroperitoneal lymph nodes., Competing Interests: Conflict of interest: The authors declare no conflict of interest., (©Copyright: the Author(s).)

Gelatinous bone marrow transformation (GBMT) is a rare pathologic entity of unclear etiology characterized by adipose cell atrophy, focal hematopoietic tissue hypoplasia, and a distinct eosinophilic substance that stains with Alcian blue at pH 2.5. It is traditionally described in the context of malnutrition and cachexia from generalized disease and is important to identify because of its potential reversibility. Several recent case reports have described GBMT in patients with chronic myeloid leukemia (CML) on the first-generation tyrosine-kinase inhibitor (TKI) imatinib. Here, we describe a case of gelatinous transformation in a patient with CML receiving the second-generation TKI dasatinib who subsequently developed clonal cytogenetic abnormalities in Philadelphia chromosome negative cells with excess peripheral blasts consistent with advanced secondary myelodysplastic syndrome. While the development of clonal cytogenetic abnormalities in Philadelphia-negative cells has been frequently described in the setting of TKI, most abnormalities are transient and generally do not effect disease progression and/or transformation like in this case. Remarkably, after TKI discontinuation, repeat bone marrow biopsies had markedly diminished amounts of gelatinous transformation - supporting reversible GBMT with TKI removal. We review the relevant pathophysiology underlying our patient's possible therapeutic-mediated complications during CML therapy in an attempt to better understand the role of TKIs in the pathogenesis of these conditions.

Objectives: To assess bone marrow (BM) sampling in academic medical centers., Methods: Data from 6,374 BM samples obtained in 32 centers in 2001 and 2011, including core length (CL), were analyzed., Results: BM included a biopsy (BMB; 93%) specimen, aspirate (BMA; 92%) specimen, or both (83%). The median (SD) CL was 12 (8.5) mm, and evaluable marrow was 9 (7.6) mm. Tissue contraction due to processing was 15%. BMB specimens were longer in adults younger than 60 years, men, and bilateral, staging, and baseline samples. Only 4% of BMB and 2% of BMB/BMA samples were deemed inadequate for diagnosis. BM for plasma cell dyscrasias, nonphysician operators, and ancillary studies usage increased, while bilateral sampling decreased over the decade. BM-related quality assurance programs are infrequent., Conclusions: CL is shorter than recommended and varies with patient age and sex, clinical circumstances, and center experience. While pathologists render diagnoses on most cases irrespective of CL, BMB yield improvement is desirable.

Introduction: Evaluation of cellularity is an essential component of bone marrow trephine biopsy examination. The standard practice is to report the results as visual estimates (VE). Digital image analysis (DIA) offers the promise of more objective measurements of cellularity., Methods: Adult bone marrow trephine biopsy sections were assessed for cellularity by VE. Sections were scanned using an Aperio AT2 Scanscope and analyzed using a Cytonuclear (version 1.4) algorithm on halo software. Intraclass correlation (ICC) was used to assess relatedness between VE and DIA, and between MRI and DIA for a separate subset of patients. Trephine biopsy sections from a subset of patients with bone marrow biopsies uninvolved by malignancy were assessed for age-related changes., Results: Interobserver VE agreement was good to excellent. The ICC value was 0.81 for VE and DIA, and 0.50 for MRI and DIA. Linearity studies showed no statistically significant trend for age-related changes in cellularity in our cohort (r = -.29, P = .06)., Conclusions: Agreement was good between VE and DIA. It may be possible to use DIA or VE to measure cellularity in the appropriate clinical scenario. The limited sample size precludes similar determinations for MRI calculations. Further studies examining healthy donors are necessary before making definitive conclusions regarding age and cellularity., (© 2017 John Wiley & Sons Ltd.)

Background: The long-term effects of eltrombopag on bone marrow (BM) reticulin and/or collagen deposition in previously treated adults with chronic immune thrombocytopenia (ITP) were assessed., Methods: Three BM biopsies were collected at baseline and after 1 and 2 years of eltrombopag treatment. Specimens were centrally processed, stained for reticulin and collagen, independently reviewed by 2 hematopathologists, and rated according to the European Consensus 0-3 scale of marrow fibrosis (MF)., Results: Of 162 patients enrolled, 93 completed all 3 protocol-specified BM biopsies. All patients with a baseline assessment were negative for collagen. Of 159 patients assessed at baseline, 150 (94%) had normal reticulin (MF-0) and 9 (6%) had minimally increased reticulin (MF-1). After 2 years, 83/93 patients (89%) with BM biopsies had MF-0, 10 (11%) had MF-1, and none had MF-2 or MF-3. Five out of 127 patients (4%) at 1 year and 1 out of 93 (1%) at 2 years had collagen deposition. None of the patients had clinical symptoms typical of BM dysfunction or abnormalities of clinical concern based on white blood cell count or peripheral blood smear., Conclusion: For most patients with chronic ITP, eltrombopag is not associated with clinically relevant increases in BM reticulin or collagen formation., (© 2016 S. Karger AG, Basel.)

Background: Autoimmune myelofibrosis (AIMF) is an underrecognized cause of nonmalignant bone marrow fibrosis which occurs in the presence or absence of a defined systemic autoimmune disease. Patients with AIMF present with cytopenias and autoantibodies, and have a distinctive nonclonal myelofibrosis on bone marrow examination. AIMF is distinguished from primary myelofibrosis by the absence of splenomegaly, eosinophilia, or basophilia, and the absence of abnormal myeloid, erythroid, or megakaryocytic morphology., Objectives: The objective of the study was to describe the clinical presentation and outcomes of patients with AIMF., Methods: We conducted a single-institution, retrospective chart review of patients diagnosed with AIMF to investigate clinical presentations, therapies, and outcomes., Results: Twelve patients with AIMF were identified with a mean follow-up of 5.8 years. All patients had detectable autoantibodies and the majority had concomitant autoimmune disorders. Four patients experienced a complete response of cytopenias and 3 patients experienced a partial response (PR) of cytopenias with immunosuppressive therapy. One patient achieved a PR following splenectomy. No patients were diagnosed with myeloproliferative neoplasms during the follow-up period., Conclusions: AIMF contributes to cytopenias in the subset of patients with various autoimmune disorders. The majority of patients with AIMF experience an improvement in cytopenias with immunosuppressive therapy., (© 2017 S. Karger AG, Basel.)

A predominantly diffuse growth pattern and CD23 co-expression are uncommon findings in nodal follicular lymphoma and can create diagnostic challenges. A single case series in 2009 (Katzenberger et al) proposed a unique morphologic variant of nodal follicular lymphoma, characterized by a predominantly diffuse architecture, lack of the t(14;18) IGH/BCL2 translocation, presence of 1p36 deletion, frequent inguinal lymph node involvement, CD23 co-expression, and low clinical stage. Other studies on CD23+ follicular lymphoma, while associating inguinal location, have not specifically described this architecture. In addition, no follow-up studies have correlated the histopathologic and cytogenetic/molecular features of these cases, and they remain a diagnostic problem. We identified 11 cases of diffuse, CD23+ follicular lymphoma with histopathologic features similar to those described by Katzenberger et al. Along with pertinent clinical information, we detail their histopathology, IGH/BCL2 translocation status, lymphoma-associated chromosomal gains/losses, and assessment of mutations in 220 lymphoma-associated genes by massively parallel sequencing. All cases showed a diffuse growth pattern around well- to ill-defined residual germinal centers, uniform CD23 expression, mixed centrocytic/centroblastic cytology, and expression of at least one germinal center marker. Ten of 11 involved inguinal lymph nodes, 5 solely. By fluorescence in situ hybridization analysis, the vast majority lacked IGH/BCL2 translocation (9/11). Deletion of 1p36 was observed in five cases and included TNFRSF14. Of the six cases lacking 1p36 deletion, TNFRSF14 mutations were identified in three, highlighting the strong association of 1p36/TNFRSF14 abnormalities with this follicular lymphoma variant. In addition, 9 of the 11 cases tested (82%) had STAT6 mutations and nuclear P-STAT6 expression was detectable in the mutated cases by immunohistochemistry. The proportion of STAT6 mutations is higher than recently reported in conventional follicular lymphoma (11%). These findings lend support for a clinicopathologic variant of t(14;18) negative nodal follicular lymphoma and suggests importance of the interleukin (IL)-4/JAK/STAT6 pathway in this variant.

Patients with chronic myelogenous leukemia (CML) present typically with an elevated white blood cell count (WBC) and cytogenetic or molecular genetic evidence of t(9;22)/BCR-ABL1 fusion gene. Rarely, CML patients may present with a normal or mildly elevated WBC and are asymptomatic, and we describe 7 patients in this study. The WBC in these patients ranged from 3.6 to 14.3 K/mm(3) with 50% to 73% granulocytes and 0% blasts. In all patients, t(9;22)(q34;q11.2) was detected by conventional cytogenetics, and BCR-ABL1 fusion was shown, supporting the diagnosis of preleukemic CML (pre-CML). We compared these patients with a group of 5 cases of CML in chronic phase (CML-CP) and 5 bone marrow specimens with a leukemoid reaction (n=5). Reticulin, CD34, and CD61 immunostains were performed on all bone marrow biopsy specimens. Peripheral blood absolute basophilia (≥200/mm(3)) was noted in only 4 of 7 pre-CML cases, whereas it was present in all CML-CP cases and absent in leukemoid reaction cases. The mean ±SD of microvascular density of pre-CML cases (10.0 ± 4.3 vessels/200× field) was twice that of leukemoid reaction cases (5.0 ± 1.0) (P=.02; Student t test) but similar to that of CML-CP cases (12.5 ± 3.6). Microvessels in pre-CML, highlighted by CD34, were tortuous with abnormal branching, although to a lesser extent than those found in CML-CP. Microvessels in leukemoid reaction were generally straight. The percentage of small, hypolobated megakaryocytes, highlighted by CD61 in pre-CML, was 40%, 3 times that found in leukemoid reaction cases (13%) but less than that of CML-CP cases (86%). We conclude that pre-CML should be suspected in patients with a normal to mildly elevated WBC and absolute basophilia. Bone marrow examination can usually distinguish pre-CML from a leukemoid reaction based on the percentage of small, hypolobated megakaryocytes; microvascular density; and morphologic features., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Pegylated interferon α-2a (Peg-IFN) has been shown to induce hematologic and molecular responses in patients with the Philadelphia-negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV) and essential thrombocythemia (ET). We describe a series of patients with long-standing MPNs among whom Peg-IFN was initiated when they developed anemia and increased bone marrow reticulin fibrosis suggestive of early transformation to post-ET (PET) or post-PV (PPV) myelofibrosis (MF). Six patients were treated with Peg-IFN for a mean duration of 33.8 months (range 2-63 months). Five patients had long-standing ET (three were calreticulin (CALR)-positive, one janus kinase 2 (JAK2)-positive, and one JAK2-negative and CALR-negative), and one had long-standing JAK2-positive PV prior to starting Peg-IFN. This is the first study to report that, concurrent with the improvement in anemia, serial laboratory studies demonstrate an increase in serum LDH and left-shifted myeloid cells in the peripheral circulation over approximately 6 months, followed by a gradual normalization of these findings. Splenomegaly also increased and then resolved among responding patients. Serial bone marrow biopsies were available, which showed little change except for improvement in the grade of reticulin fibrosis in two patients. Among patients with early transformation to PET or PPV MF, our data support the efficacy of Peg-IFN in improving hemoglobin levels and reducing splenomegaly. These peripheral blood findings should not, therefore, be considered evidence of treatment failure within the first year of Peg-IFN therapy.

This review examines handling and processing of spleen biopsies and splenectomy specimens with the aim of providing the pathologist with guidance in optimizing examination and diagnosis of splenic disorders. It also offers recommendations as to relevant reporting factors in gross examination, which may guide diagnostic workup. The role of splenic needle biopsies is discussed. The International Spleen Consortium is a group dedicated to promoting education and research on the anatomy, physiology, and pathology of the spleen. In keeping with these goals, we have undertaken to provide guidelines for gross examination, sectioning, and sampling of spleen tissue to optimize diagnosis (Burke). The pathology of the spleen may be complicated in routine practice due to a number of factors. Among these are lack of familiarity with lesions, complex histopathology, mimicry within several types of lesions, and overall rarity. To optimize diagnosis, appropriate handling and processing of splenic tissue are crucial. The importance of complete and accurate clinical history cannot be overstated. In many cases, significant clinical history such as previous lymphoproliferative disorders, hematologic disorders, trauma, etc, can provide important information to guide the evaluation of spleen specimens. Clinical information helps plan for appropriate processing of the spleen specimen. The pathologist should encourage surgical colleagues, who typically provide the specimens, to include as much clinical information as possible., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Bone marrow (BM) tissue biopsy evaluation, including trephine biopsy and clot section, is an integral part of BM investigation and is often followed by ancillary studies, in particular immunohistochemistry (IHC). IHC provides in situ coupling of morphological assessment and immunophenotype. The number of different IHC tests that can be applied to BM trephine biopsies and the number of indications for IHC testing is increasing concurrently with the development of flow cytometry and molecular diagnostic methods. An international Working Party for the Standardization of Bone Marrow IHC was formed by the International Council for Standardization in Hematology (ICSH) to prepare a set of guidelines for the standardization of BM IHC based on currently available published evidence and modern understanding of quality assurance principles as applied to IHC in general. The guidelines were discussed at the ICSH General Assemblies and reviewed by an international panel of experts to achieve further consensus and represent further development of the previously published ICSH guidelines for the standardization of BM specimens handling and reports., (© 2015 John Wiley & Sons Ltd.)

Thrombopoietin receptor agonists, which raise platelet counts in patients with chronic immune thrombocytopenia, may be associated with increases in bone marrow (BM) reticulin. Patients with chronic immune thrombocytopenia participating in the Eltrombopag Extended Dosing (EXTEND) study underwent BM biopsies to identify clinically relevant BM fibrosis-related increases. Specimens were centrally reviewed by 2 hematopathologists. Two hundred thirty-two biopsy specimens were collected from 117 patients treated for ≤5.5 years. Moderate to marked reticulin fibrosis was found in 2 patients. After withdrawing from the study, the biopsy of 1 patient reverted to normal. There were no other pathologic changes identified among on-treatment specimens, and no pattern of abnormal reticulin deposition associated with eltrombopag treatment was evident., (© 2015 Wiley Periodicals, Inc.)

Context: Lymphoid aggregates are seen in a minority of bone marrow biopsy specimens, and when present, their neoplastic nature is often apparent by morphologic evaluation. However, the distinction between benign and malignant aggregates can be a diagnostic challenge when there are multiple aggregates with no documented history of lymphoma., Objective: To aid in the distinction between benign and malignant B-cell lymphoid aggregates., Design: Previously, we described specific distribution patterns for B and T lymphocytes within bone marrow aggregates. To statistically analyze the significance of these patterns as well as previously reported criteria, we examined 128 bone marrow specimens with benign aggregates and 78 specimens with documented malignant B-cell aggregates and calculated specific odds ratios (ORs) and 95% confidence intervals (CIs) to aid in differentiating between benign and malignant B-cell aggregates., Results: Aggregates with infiltrative edges (OR, 80.54; 95% CI, 31.76-204.21), a B-cell pattern (OR, 30.08; 95% CI, 13.28-68.10), paratrabecular location (OR, 10.17; 95% CI, 3.96-26.12), size greater than 600 μm (OR, 6.83: 95% CI, 3.61-12.93), or cytologic atypia correlated with malignancy., Conclusions: When taken collectively, the presence of more than 2 of these characteristic features was strongly predictive of malignancy.

Autoimmune myelofibrosis (AIMF) is a distinct clinicopathological entity associated with diffuse bone marrow fibrosis and a benign clinical course. Distinction from neoplastic etiologies of marrow fibrosis, particularly primary myelofibrosis, is imperative, but few studies have documented histopathologic features in a large series. We describe 29 patients with AIMF, defined as marrow reticulin fibrosis and lymphocytic infiltration in the context of an established autoimmune disorder (secondary AIMF) or autoantibodies without a defined disorder (primary AIMF). Excluded were cases with atypical megakaryocytes, dysplasia, basophilia, osteosclerosis, unexplained splenomegaly, or neoplasms associated with myelofibrosis (MF). All cases were stained for reticulin, CD3, and CD20, with a subset additionally stained for CD138, κ, λ, immunoglobulin G (IgG), and IgG4. Lymphoid aggregates, where present, were classified into T-cell and B-cell patterns of distribution. Most patients (93%) presented with cytopenias. Sixty-nine percent (n = 20) were considered secondary AIMF and the remainder primary AIMF (n = 9). Peripheral blood showed absent-to-rare blasts and teardrop erythrocytes and absence of eosinophilia or basophilia. Characteristic bone marrow findings included hypercellularity with erythroid and megakaryocytic hyperplasias, mild reticulin fibrosis, intrasinusoidal hematopoiesis, T-cell pattern in lymphoid aggregates, mild polytypic plasmacytosis, and absence of IgG4-positive plasma cells. Primary and secondary AIMF were pathologically indistinguishable, except for an increased incidence of granulocytic hyperplasia in primary AIMF. This series confirms and expands the utility of the original diagnostic criteria for AIMF. Recognizing the characteristic morphology of AIMF and its associated clinical and laboratory features distinguishes autoimmune from neoplastic causes of MF and guides further evaluation and management., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Maximum diagnostic information is obtained when peripheral blood smears, bone marrow aspiration smears, trephine biopsy imprints, trephine and clot biopsy sections are simultaneously examined. Peripheral blood smears reflect end organ function and provide clues to underlying hematolymphoid pathology that may prompt additional studies including bone marrow examination. Bone marrow aspiration alone has diagnostic utility in the evaluation of a limited number of primary hematological conditions including: megaloblastic anemias, hyporegenerative anemias, certain hemolytic anemias, normochromic normocytic anemias, neutropenias, thrombocytopenias, immunoglobulin disorders, storage diseases, and leukemias (Bain, J Clin Pathol 54:657-663, 2001). Bone marrow trephine biopsy is indicated in those situations where marrow aspiration is unsuccessful; in evaluation of cytopenias, myelofibrosis, suspicion of lymphoma, metastatic tumor, granulomatous disease, evaluation of myeloproliferative neoplasms, and for the examination of trabecular bone in metabolic diseases (Bain, J Clin Pathol 54:737-742, 2001). Many of the indications for marrow aspiration overlap with those for trephine biopsy. Because it is not possible to predict which patients will have diagnostic aspiration biopsies and which will have diagnostic trephine biopsies, both procedures are routinely performed together (Brynes et al., Am J Clin Pathol 70:753-759, 1978; Cotelingam, Adv Anat Pathol 10:8-26, 2003; Lee et al., Int J Lab Hematol 30:349-364, 2008; Peterson et al., Arch Pathol Lab Med 126:1050-1056, 2002).

Iatrogenic immunodeficiency-associated lymphoproliferative disorders are rare. A small subset of these lesions resembles classical Hodgkin lymphoma (CHL), but there are few data in the literature about these lesions. We describe 10 patients with autoimmune diseases treated with immunomodulator therapeutic agents who developed CHL. The autoimmune diseases included rheumatoid arthritis (n=5), systemic lupus erythematosus (n=2), dermatomyositis (n=1), autoimmune hepatitis (n=1), and Crohn disease (n=1), and the immunomodulatory therapies were methotrexate, azathioprine, tumor necrosis factor-α inhibitors, and thalidomide alone or in various combinations. The study group included 9 women and 1 man with a median age of 50 years (range, 25 to 77 y). The histologic features supported CHL in all cases with Reed-Sternberg (RS) and Hodgkin (H) cells in an inflammatory cell background, although the neoplasm could only be subclassified in 3 patients: 2 nodular sclerosis and 1 mixed cellularity. Immunohistochemical analysis supported the diagnosis of CHL. In all cases the RS-H cells were CD30. Nine of 10 cases were CD15, whereas CD20 was expressed variably in 4/10 cases. CD45/LCA was negative in 8 cases assessed. In situ hybridization for Epstein-Barr virus-encoded RNA was positive in the RS-H cells in 8/10 cases. The microenvironment of these lesions depicted a predominance of T-regulatory cells and M2 histiocytes. Clinical follow-up data were available for 7 patients, with a median posttreatment period of 27 months (range, 12 mo to 7 y). In all 7 patients immunomodulatory drug therapy was discontinued, and chemotherapy for CHL was administered; 2 patients also received local radiation. All 7 patients achieved complete remission and are alive. We conclude that iatrogenic immunodeficiency-associated CHL is highly associated with Epstein-Barr virus infection, and patients usually have a good outcome after discontinuation of immunomodulatory agents and chemotherapy for CHL.

Benign lymphoid aggregates are seen in only a minority of bone marrow specimens, but their distinction from non-Hodgkin lymphoma, particularly B-cell lymphomas, can represent a diagnostic challenge. Although criteria have been proposed to help distinguish between benign and malignant aggregates, a detailed description of the distribution patterns of B and T lymphocytes within benign lymphoid aggregates has not been investigated. One hundred thirty-seven cases of bone marrow specimens containing benign aggregates were studied with a panel of immunostains. A subset of these cases was also examined for immunoglobulin gene rearrangements by polymerase chain reaction. The aggregates were categorized based on size, location (paratrabecular or random), presence of infiltrating edges, and distribution of lymphoid cell populations. In addition, we examined 40 cases of bone marrow biopsies with documented malignant lymphoid aggregates for comparison purposes. We report that the distribution of B and T lymphocytes within lymphoid aggregates may serve as a useful criterion to aid in the separation between benign and malignant aggregates. When aggregates exhibit a predominance of T cells, consist of a central core of T cells surrounded by a rim of B cells, or have a mixed distribution of B and T cells, they are more likely to be benign. On the other hand, an increased likelihood of malignancy occurs when aggregates exhibit a predominance of B cells or consist of a central core of B cells surrounded by a rim of T cells (excluding germinal center formation), and assessing other features worrisome of malignancy (large aggregate size, presence of infiltrative edges, cellular atypia, and paratrabecular location, among others) is warranted., (Copyright © 2013 Elsevier Inc. All rights reserved.)

IgG4-related sclerosing disease encompasses a family of disorders associated with increased numbers of IgG4 plasma cells and mass forming lesions in various tissues. Lymphadenopathy is a common finding, seen in up to 80% of cases. In the largest series of cases to date, we describe histologic, immunohistochemical, special stain and flow cytometric findings in 29 cases of enlarged lymph nodes with increased IgG4 plasma cells. Lymph node biopsies showed all resection specimens; no needle core biopsies of tissue were evaluated. Cases were considered to have increased numbers of IgG4 plasma cells using the histological criteria outlined by Cheuk and Chan (2010): IgG4 plasma cells >50 cells in a high-power field and >40% of IgG-positive plasma cells positive for IgG4. Additionally, increased intrafollicular plasma cells were a common finding. The lymph nodes showed a variety of reactive histological features including follicular hyperplasia, progressive transformation of germinal centers, interfollicular expansions, variable degrees of fibrosis, increased histiocytes and occasionally an appearance similar to that of plasma cell Castleman disease.

Hyaline vascular Castleman disease (HV-CD) is a localized benign mass characterized by follicular hyperplasia with atrophic germinal centers, mantle zone hyperplasia, hyaline deposits, and vascular proliferation. Before establishing a diagnosis of CD, several B-cell lymphomas (BCLs) must be considered, including follicular lymphoma (FL), mantle cell lymphoma (MCL), and nodal marginal zone lymphoma (NMZL). Conversely, BCLs with prominent atrophic germinal centers and hyaline vascular penetration may closely resemble HV-CD, leading to misdiagnosis. We report 6 cases of BCL with prominent HV-CD-like features, including FL (2 cases), MCL, NMZL (2 cases), and interfollicular large B-cell lymphoma. Histologically, all were initially considered to be HV-CD before additional tests revealed a neoplastic B-cell proliferation. We highlight the clinicopathologic features of these cases in comparison with cases diagnostic of HV-CD. In contrast with HV-CD, BCLs with HV-CD-like features are more likely to manifest clinically with systemic symptoms or generalized lymphadenopathy. Careful histopathologic examination, supported with immunohistochemical studies, flow cytometric immunophenotyping, and judicious use of cytogenetic and molecular analyses, allows identification of the masked neoplastic process. A multifaceted approach, integrating clinical, histologic, and ancillary tests, can help avoid this diagnostic pitfall.

Angioimmunoblastic T-cell lymphoma (AITL) is a unique type of peripheral T-cell lymphoma. Patients with AITL may have occasional reactive plasma cells present in the peripheral circulation. Prominent peripheral blood polyclonal plasmacytosis mimicking plasma cell leukemia, however, is distinctly uncommon. Here we describe 3 such cases from two large tertiary medical centers and discuss the role of ancillary studies in the differential diagnosis of peripheral blood plasmacytosis.

Background: Leukemic synovitis is a rare complication of adult myeloid leukemias characterized by joint pain and swelling. It is important to recognize this diagnostic challenge as it may be the initial manifestation of leukemia or of relapse., Methods: A retrospective search of patient files from 2 teaching hospitals identified 4 adult patients who presented with large joint arthritis and concurrent or subsequent leukemic synovitis. All patients presented with inflammatory arthritis of large joints, and leukemic synovitis was identified by the presence of leukemic cells in the synovial fluid or infiltrating the synovial membrane seen at biopsy., Results: A leukemia of monocytic origin-acute myelomonocytic leukemia or chronic myelomonocytic leukemia-was diagnosed in all 4 patients. In 2 cases, leukemic synovitis was the initial manifestation of leukemia. In the third case, it was the first sign of relapse, and in the remaining case, it developed shortly after diagnosis of leukemia. All patients had either osteoarthritis or rheumatoid arthritis. One patient was diagnosed simultaneously with osteoarthritis and leukemia. The remaining patients had a prior history of arthritis., Conclusions: Adult leukemic synovitis occurs in association with leukemias of monocytic differentiation. Data presented here, and review of isolated case reports, support this association. The finding of large joint arthritis as a comorbidity in these 4 cases raises questions about the role of antecedent arthritis as a predisposing factor in the pathophysiology of leukemic synovitis.

Phlegmonous gastritis is a rare acute bacterial infection of the gastric wall with an extremely high mortality rate. Early diagnosis is crucial for immediate treatment that could improve the outcomes. Here we report a case in which a patient with underlying chronic myelomonocytic leukemia was diagnosed with phlegmonous gastritis on biopsy. This 57-year-old man presented with shortness of breath and intermittent upper quadrant abdominal pain for 4 days. Laboratory tests showed markedly increased white blood cell. A diagnosis of chronic myelomonocytic leukemia was made based on a peripheral blood smear and flow cytometry. Gastric biopsy showed suppurative inflammation in the submucosal region, prompting the diagnosis of phlegmonous gastritis. The patient was given empirical antibiotic treatment, and the white blood cell decreased dramatically. Surgical intervention was discussed but deferred. Despite continued antibiotics treatment, the patient died. The limited autopsy confirmed the diagnosis of phlegmonous gastritis. Immunohistochemical studies further revealed the occurrence of myeloid sarcoma that involved the gastrointestinal tract.

Although KIT mutations are present in 20-25% of cases of t(8;21)(q22;q22) acute myeloid leukemia (AML), concurrent development of systemic mastocytosis (SM) is exceedingly rare. We examined the clinicopathologic features of SM associated with t(8;21)(q22;q22) AML in ten patients (six from our institutions and four from published literature) with t(8;21) AML and SM. In the majority of these cases, a definitive diagnosis of SM was made after chemotherapy, when the mast cell infiltrates were prominent. Deletion 9q was an additional cytogenetic abnormality in four cases. Four of the ten patients failed to achieve remission after standard chemotherapy and seven of the ten patients have died of AML. In the two patients who achieved durable remission after allogeneic hematopoietic stem cell transplant, recipient-derived neoplastic bone marrow mast cells persisted despite leukemic remission. SM associated with t(8;21) AML carries a dismal prognosis; therefore, detection of concurrent SM at diagnosis of t(8;21) AML has important prognostic implications.

Background: The higher incidence of acute lymphoblastic leukemia (ALL) among Hispanic children relative to that in other racial/ethnic groups is well-known. We evaluated the incidence patterns of ALL in adults., Methods: We analyzed the incidence patterns of ALL (International Classification of Diseases for Oncology 3 codes 9835-9837) among all patients diagnosed from 1988 to 2004 in California using data from the California Cancer Registry to determine whether adult Hispanics also had higher incidence rates of ALL compared with non-Hispanic Whites (Whites). Age-adjusted incidence rates (AAIR), incidence rate ratios (IRR), and 5-year survival rates were obtained using SEER*Stat. AAIRs of other leukemia subtypes and IRRs relative to non-Hispanic Whites were also examined as references for ALL., Results: AAIRs of ALL in Hispanic males and females ages 20 to 54 years were higher compared with those in White males and females (IRR, 1.99; 95% confidence interval, 1.74-2.28 and IRR, 1.91; 95% confidence interval, 1.60-2.25, respectively). A higher AAIR of ALL was also observed among older (55+ years) Hispanic females (IRR, 1.84; 95% confidence interval, 1.52-2.21), but not in males (IRR, 1.07; 95% confidence interval, 0.84-1.34). Among Hispanics, low socioeconomic status was associated with a higher AAIR compared with high/middle socioeconomic status (IRR, 1.33; 95% confidence interval, 1.04-1.70). The respective 5-year survival rates among ALL patients were 38% and 30% for Whites and Hispanics ages 20 to 54 years, and 8% and 12% for patients 55 years of age or older. Compared with other racial/ethnic groups, Hispanics did not have an increased IRR of the other major leukemia subtypes., Conclusion: Hispanics experience a higher incidence of ALL throughout life, but not other subtypes.

Indeterminate cell tumor (ICT) is a rare neoplastic dendritic cell disorder that has been poorly defined due to its rarity and poorly understood histogenesis and pathogenesis. It is characterized by a proliferation of dendritic cells, which mimic Langerhans cells immunophenotypically (positive for CD1a and S-100 protein), but lack Birbeck granules characteristic of Langerhans cells. The clinical, morphologic, immunophenotypic, and ultrastructural features of 5 ICT cases are reported in an attempt to further define ICT and to examine the postulated relationship between indeterminate cells and Langerhans cells. Four of 5 patients were females, and 4 of 5 were older than 68 years. Three of 5 patients had cutaneous lesions, whereas 2 presented with cervical lymph node involvement. Two patients had a possible association with lymphoma: first patient had a history of progressive follicular lymphoma that led to patient's demise and the second patient had unexplained systemic lymphadenopathy and died 1 week after the biopsy. All 5 ICT cases expressed CD1a and S-100 protein, but lacked Langerin expression and Birbeck granules ultrastructurally. Interestingly, a t(14;18) was detected by fluorescence in situ hybridization in the ICT cells of the patient with previous follicular lymphoma and a monoclonal kappa light chain gene rearrangement was detected by polymerase chain reaction in the patient with systemic lymphadenopathy. In both cases, there was no morphologic or immunophenotypic evidence of a concurrent B-cell lymphoma. In conclusion, ICT is a rare neoplasm that can occur de novo or in association with a B-cell lymphoma, possibly as a result of B-cell dedifferentiation caused by relatively unknown mechanisms. Finally, Langerin immunostaining may be used as a surrogate marker for the ultrastructural demonstration of Birbeck granules, the absence of which represents a strong diagnostic criterion for ICT.

We describe an unusual case of a 31-year-old Mexican woman who presented with pleural and peritoneal effusions involved by Epstein-Barr virus-positive non-Hodgkin's lymphoma of natural killer (NK)-cell lineage. The patient had no symptoms that could be related to her nasal region, and physical examination and radiologic studies showed no evidence of lymphadenopathy, organomegaly, or other extranodal masses. Thus, this case clinically mimicked body cavity-based lymphoma. Extranodal NK/T-cell lymphoma of nasal type is the current designation for these neoplasms in the recently proposed World Health Organization classification of lymphoid neoplasms. These tumors previously have been referred to many other names, including lethal midline granuloma, midline malignant reticulosis, polymorphic reticulosis, angiocentric immunoproliferative lesion, and angiocentric lymphoma. Nasal-type NK/T-cell lymphomas typically involve the nasal region, but may involve other extranodal sites, such as skin and gastrointestinal tract. The malignant cytologic features and the presence of azurophilic granules within the cell cytoplasm observed in Wright-Giemsa-stained cytocentrifuge preparations led to immunophenotypic and molecular genetic studies that were essential in establishing the correct diagnosis. As demonstrated in the case reported, extranodal NK/T-cell lymphomas of nasal-type can be clinically aggressive and may be associated with paraneoplastic phenomena.