Publications by authors named "Steven H Kroft"

79 Publications

Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.

J Exp Med 2021 Jul 5;218(7). Epub 2021 May 5.

Department of Genetics, University of Alabama at Birmingham, Birmingham, AL.

The pioneer transcription factor (TF) PU.1 controls hematopoietic cell fate by decompacting stem cell heterochromatin and allowing nonpioneer TFs to enter otherwise inaccessible genomic sites. PU.1 deficiency fatally arrests lymphopoiesis and myelopoiesis in mice, but human congenital PU.1 disorders have not previously been described. We studied six unrelated agammaglobulinemic patients, each harboring a heterozygous mutation (four de novo, two unphased) of SPI1, the gene encoding PU.1. Affected patients lacked circulating B cells and possessed few conventional dendritic cells. Introducing disease-similar SPI1 mutations into human hematopoietic stem and progenitor cells impaired early in vitro B cell and myeloid cell differentiation. Patient SPI1 mutations encoded destabilized PU.1 proteins unable to nuclear localize or bind target DNA. In PU.1-haploinsufficient pro-B cell lines, euchromatin was less accessible to nonpioneer TFs critical for B cell development, and gene expression patterns associated with the pro- to pre-B cell transition were undermined. Our findings molecularly describe a novel form of agammaglobulinemia and underscore PU.1's critical, dose-dependent role as a hematopoietic euchromatin gatekeeper.
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http://dx.doi.org/10.1084/jem.20201750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105723PMC
July 2021

A Different Kind of Laboratory Stewardship.

Authors:
Steven H Kroft

Am J Clin Pathol 2021 Apr 5. Epub 2021 Apr 5.

Medical College of Wisconsin, Milwaukee, WI, USA.

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http://dx.doi.org/10.1093/ajcp/aqab008DOI Listing
April 2021

Laboratory Workup of Lymphoma in Adults.

Am J Clin Pathol 2021 01;155(1):12-37

Department of Medicine, Odette Cancer Centre/Sunnybrook Health Sciences Centre, Toronto, Canada.

Objectives: The diagnostic workup of lymphoma continues to evolve rapidly as experience and discovery lead to the addition of new clinicopathologic entities and techniques to differentiate them. The optimal clinically effective, efficient, and cost-effective approach to diagnosis that is safe for patients can be elusive, in both community-based and academic practice. Studies suggest that there is variation in practice in both settings.

The Aim Of This Review Is To: develop an evidence-based guideline for the preanalytic phase of testing, focusing on specimen requirements for the diagnostic evaluation of lymphoma.

Methods: The American Society for Clinical Pathology, the College of American Pathologists, and the American Society of Hematology convened a panel of experts in the laboratory workup of lymphoma to develop evidence-based recommendations. The panel conducted a systematic review of the literature to address key questions. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, recommendations were derived based on the available evidence, the strength of that evidence, and key judgments as defined in the GRADE Evidence to Decision framework.

Results: Thirteen guideline statements were established to optimize specimen selection, ancillary diagnostic testing, and appropriate follow-up for safe and accurate diagnosis of indolent and aggressive lymphoma.

Conclusions: Primary diagnosis and classification of lymphoma can be achieved with a variety of specimens. Application of the recommendations can guide decisions about specimen suitability, diagnostic capabilities, and correct utilization of ancillary testing. Disease prevalence in patient populations, availability of ancillary testing, and diagnostic goals should be incorporated into algorithms tailored to each practice environment.
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http://dx.doi.org/10.1093/ajcp/aqaa191DOI Listing
January 2021

Laboratory Workup of Lymphoma in Adults: Guideline From the American Society for Clinical Pathology and the College of American Pathologists.

Arch Pathol Lab Med 2021 03;145(3):269-290

The Department of Medicine, Odette Cancer Centre/Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (Cheung).

Context.—: The diagnostic workup of lymphoma continues to evolve rapidly as experience and discovery led to the addition of new clinicopathologic entities and techniques to differentiate them. The optimal clinically effective, efficient, and cost-effective approach to diagnosis that is safe for patients can be elusive, in both community-based and academic practice. Studies suggest that there is variation in practice in both settings.

Objective.—: To develop an evidence-based guideline for the preanalytic phase of testing, focusing on specimen requirements for the diagnostic evaluation of lymphoma.

Design.—: The American Society for Clinical Pathology, the College of American Pathologists, and the American Society of Hematology convened a panel of experts in the laboratory workup of lymphoma to develop evidence-based recommendations. The panel conducted a systematic review of literature to address key questions. Using the Grading of Recommendations Assessment, Development, and Evaluation approach, recommendations were derived based on the available evidence, strength of that evidence, and key judgements as defined in the Grading of Recommendations Assessment, Development, and Evaluation Evidence to Decision framework.

Results.—: Thirteen guideline statements were established to optimize specimen selection, ancillary diagnostic testing, and appropriate follow-up for safe and accurate diagnosis of indolent and aggressive lymphoma.

Conclusions.—: Primary diagnosis and classification of lymphoma can be achieved with a variety of specimens. Application of the recommendations can guide decisions on specimen suitability, diagnostic capabilities, and correct use of ancillary testing. Disease prevalence in patient populations, availability of ancillary testing, and diagnostic goals should be incorporated into algorithms tailored to each practice environment.
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http://dx.doi.org/10.5858/arpa.2020-0261-SADOI Listing
March 2021

Well-Being, Burnout, and the Clinical Laboratory.

Authors:
Steven H Kroft

Am J Clin Pathol 2020 03;153(4):422-424

Medical College of Wisconsin, Milwaukee.

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http://dx.doi.org/10.1093/ajcp/aqaa022DOI Listing
March 2020

ASCP Continues to Choose Wisely.

Lab Med 2019 10;50(4):331-332

Editor in Chief, Laboratory Medicine.

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http://dx.doi.org/10.1093/labmed/lmz071DOI Listing
October 2019

ASCP Continues to Choose Wisely.

Am J Clin Pathol 2019 10;152(5):542-543

Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas.

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http://dx.doi.org/10.1093/ajcp/aqz174DOI Listing
October 2019

Stratification of Follicular Lymphoma: Time for a Paradigm Shift?

Authors:
Steven H Kroft

Am J Clin Pathol 2019 05;151(6):539-541

Medical College of Wisconsin, Milwaukee.

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http://dx.doi.org/10.1093/ajcp/aqz008DOI Listing
May 2019

Carcinocythemia: A rare entity becoming more common? A 3-year, single institution series of seven cases and literature review.

Int J Lab Hematol 2019 Feb 14;41(1):69-79. Epub 2018 Sep 14.

Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin.

Introduction: Carcinocythemia is a rare phenomenon defined as morphologically identifiable, circulating tumor cells in the peripheral blood. No modern case series of carcinocythemia exists in the literature.

Methods: Blood smears from carcinocythemia patients were reviewed and associated clinicopathologic findings described and compared to the literature. When available, bone marrows were examined.

Results: We identified 7 carcinocythemia cases over 3 years at our institution in 5 females and 2 males with a median age of 57 and compare them to 26 case reports in the literature (19 females, 10 males; median age 57). The primary neoplasms were carcinomas of breast (3 cases), lung, non-small cell (2 cases), prostate (1), and 1 case of unknown primary. Circulating tumor cells were associated with fragmentation hemolysis (2 cases), asplenic RBC changes (3 cases), and myeloid antigen expression by flow cytometry (2 cases) and were most commonly found at the feathered edge of the slide (6 cases) as single cells or in clusters.

Conclusions: This represents the largest series of carcinocythemia reported. The identification of 7 cases at one institution over a 3-year period suggests carcinocythemia may becoming more common. Raising awareness of this entity and its associated clinicopathologic findings may help avoid diagnostic pitfalls in blood smear examinations and may guide timely clinical management.
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http://dx.doi.org/10.1111/ijlh.12924DOI Listing
February 2019

The Evolution of the Clinical Pathologist.

Authors:
Steven H Kroft

Am J Clin Pathol 2018 08;150(4):283-284

Department of Pathology, Medical College of Wisconsin, Milwaukee.

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http://dx.doi.org/10.1093/ajcp/aqy119DOI Listing
August 2018

Flow Cytometry of B-Cell Neoplasms.

Clin Lab Med 2017 12 31;37(4):697-723. Epub 2017 Aug 31.

Department of Pathology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.

Flow cytometric evaluation is considered a standard ancillary study for the diagnosis of most B-cell lymphoproliferative disorders. Establishing a neoplastic B-cell population depends on identification of light chain restriction or lack of light chain expression in mature neoplasms and demonstration of aberrant antigen expression in both immature and mature neoplasms, as compared with normal counterparts. The immunophenotypes of the most common B-cell neoplasms are herein described, with an emphasis on their immunophenotypic differential diagnosis and prognostic and therapeutic implications.
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http://dx.doi.org/10.1016/j.cll.2017.07.001DOI Listing
December 2017

CD30 Expression in Monomorphic Posttransplant Lymphoproliferative Disorder, Diffuse Large B-Cell Lymphoma Correlates With Greater Regulatory T-Cell Infiltration.

Am J Clin Pathol 2017 Nov;148(6):485-493

Department of Pathology, Medical College of Wisconsin, Milwaukee.

Objectives: CD30 is a protein thought to promote cell proliferation/survival and downregulate the immune response. Twenty percent to 40% of de novo diffuse large B-cell lymphomas (DLBCLs) express CD30, and some patients have been treated with the anti-CD30 agent brentuximab. In the solid organ transplant setting, allograft regulatory T cells (Tregs) have been shown to be modulated via CD30 signaling.

Methods: Posttransplant lymphoproliferative disorders (PTLDs) constitute a heterogeneous group of lymphomas, and since CD30 expression has been rarely formally assessed in PTLDs, we analyzed a cohort of PTLDs.

Results: We found that 26 (79%) of 33 PTLDs were CD30+. Of these, 17 (77%) of 22 DLBCL monomorphic PTLDs were CD30+ compared with 56 (38%) of 148 de novo DLBCLs (P = .009). The median FoxP3+ Treg count was higher in CD30+ than in CD30- PTLDs, 3.0 vs 0 (P = .012).

Conclusions: These findings suggest a pathophysiologic link between CD30 activity and Tregs and may indicate differential expression of CD30 in B-cell lymphomas arising in the setting of immune dysregulation.
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http://dx.doi.org/10.1093/ajcp/aqx097DOI Listing
November 2017

Evaluation of CD43 expression in non-hematopoietic malignancies.

Ann Diagn Pathol 2017 Aug 26;29:23-27. Epub 2017 Apr 26.

Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, United States. Electronic address:

Objectives: CD43 is normally expressed only on the surface of leukocytes, and is considered a sensitive and specific marker for hematologic malignancies. As such, it may have diagnostic utility in confirming hematolymphoid lineage in cases that are negative for CD45. Aberrant CD43 expression has been described in non-hematopoietic tumors, although literature data on this topic is variable and sometimes contradictory. To clarify and expand on existing literature findings, we evaluated CD43 expression by immunohistochemistry (IHC) in a large cohort (307) of non-hematopoietic neoplasms, including poorly differentiated malignancies.

Methods: 17 tissue microarrays and sections from 19 individual cases were stained with CD43 (clone DF-T1) monoclonal antibody. The proportion of positive cells, stain localization (nuclear, cytoplasmic or membranous), and intensity (compared to internal leukocyte controls) were recorded in all cases.

Results: There were 98/307 (32%) positive cases, that showed focal weak nuclear staining in 1-25% of cells, including 23/25 (92%) pancreatic ductal adenocarcinomas; 31/34 (91%) breast invasive ductal carcinomas; 13/15 (87%) papillary thyroid carcinomas; 3/4 (75%) follicular thyroid carcinomas; 6/15 (40%) renal cell carcinomas; 9/28 (32%) lung adenocarcinomas; 1/13 (8%) lung squamous cell carcinomas (SCCs); 2/8 (25%) prostate adenocarcinomas; 8/62 (13%) colon adenocarcinomas; and 2/21 (10%) neuroendocrine neoplasms. None of the positive cases demonstrated strong, membranous CD43 expression comparable to that seen in background mature lymphocytes or segmented neutrophils. Negative cases included 11 cervical SCCs, 12 cervical adenocarcinomas, 19 urothelial carcinomas, 10 lung small cell carcinomas, 11 sarcomas, and 19 poorly differentiated carcinomas from various tissue sites.

Conclusions: In our cohort, most non-hematopoietic neoplasms are negative for CD43 expression, with a subset showing focal, weak nuclear positivity. This data indicates that uniform and strong membranous staining appears to be specific to hematopoietic neoplasms.
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http://dx.doi.org/10.1016/j.anndiagpath.2017.04.010DOI Listing
August 2017

Proliferation centers in bone marrows involved by chronic lymphocytic leukemia/small lymphocytic lymphoma: a clinicopathologic analysis.

Ann Diagn Pathol 2016 Dec 18;25:15-19. Epub 2016 Aug 18.

Department of Pathology, Medical College of Wisconsin, Milwaukee, WI. Electronic address:

Objectives: Proliferation centers (PCs) are a characteristic finding in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) lymph nodes, and their presence and extent in this site are not currently felt to be related to clinical course. In contrast, detailed clinicopathologic analyses of bone marrow (BM) PCs have not been previously reported.

Methods: The PCs in 88 CLL/SLL BMs from 45 patients (pts) were graded (0-4) and were correlated with other morphologic, immunophenotypic, cytogenetic, and laboratory features.

Results: Proliferation centers were present in 69 BMs (78%) from 32 pts (71%) and were distinct/prominent (grades 2-4) in 21 pts (47%), with the latter more commonly found in follow-up BMs (1/7 diagnostic BMs vs 49/81 follow-up BMs; P=.04). When present, PCs were most commonly graded as distinct nodules easily visible on ×10. No relationships were identified between PCs and any complete blood count parameter, serum lactate dehydrogenase or IgG levels, degree or pattern of BM involvement, blood morphology, CD38 and FMC7 expression by flow cytometry, or fluorescence in situ hybridization results, when the first encountered BM was considered for each patient.

Conclusions: This represents the first detailed analysis of PCs in CLL/SLL BMs. In our tertiary center, PCs were seen frequently, in approximately three-fourths of cases. There were no statistical associations identified between PCs and cytogenetic, immunophenotypic, or other laboratory and morphologic findings.
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http://dx.doi.org/10.1016/j.anndiagpath.2016.07.011DOI Listing
December 2016

Immunophenotypes of Chronic Myelomonocytic Leukemia (CMML) Subtypes by Flow Cytometry:  A Comparison of CMML-1 vs CMML-2, Myeloproliferative vs Dysplastic, De Novo vs Therapy-Related, and CMML-Specific Cytogenetic Risk Subtypes.

Am J Clin Pathol 2016 Aug 13;146(2):170-81. Epub 2016 Jul 13.

From the Department of Pathology, Medical College of Wisconsin, Milwaukee.

Objectives: We sought to immunophenotype blasts, monocytes, and granulocytes in chronic myelomonocytic leukemias (CMMLs) and compare CMML subtypes, to identify if significant antigen expression differences existed.

Methods: Bone marrow blasts, monocytes, and granulocytes from CMML subgroups (n = 30; World Health Organization types 1/2, proliferative/dysplastic, therapy related/de novo, and low/intermediate/high cytogenetic risk) were immunophenotypically compared by flow cytometry with 10 nonneoplastic control marrows.

Results: Aberrancies were present in blasts of 26 (87%) of 30 CMMLs (26 diagnostic; four follow-up) and six (60%) of 10 controls (P = .089), monocytes of 28 (93%) of 30 CMMLs and six (60%) of 10 controls (P = .026), and granulocytes of eight (28%) of 29 CMMLs and zero of 10 controls (P = .166). Underexpression of CD14 and CD15 on monocytes was more common in CMMLs compared with controls (P = .008 and P = .043). Statistical analysis showed no significant difference in antigen expression between the CMML subgroups on blasts or monocytes; granulocytes demonstrated more common HLA-DR expression in CMML-2 vs CMML-1.

Conclusions: These findings confirm heterogeneity within CMML subgroups and find no specific qualitative or quantitative findings characteristic of a subgroup.
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http://dx.doi.org/10.1093/ajcp/aqw084DOI Listing
August 2016

Rosai-Dorfman disease: Familiar yet enigmatic.

Authors:
Steven H Kroft

Semin Diagn Pathol 2016 Sep 20;33(5):244-53. Epub 2016 May 20.

Medical College of Wisconsin, Milwaukee, Wisconsin. Electronic address:

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http://dx.doi.org/10.1053/j.semdp.2016.05.008DOI Listing
September 2016

Pure Erythroid Leukemia and Erythroblastic Sarcoma Evolving From Chronic Myeloid Neoplasms.

Am J Clin Pathol 2016 Apr 22;145(4):538-51. Epub 2016 Apr 22.

From the Department of Pathology, Medical College of Wisconsin, Milwaukee

Objectives: Pure erythroid leukemia (PEL) is an extremely rare entity that may, even more rarely, evolve from a preexisting chronic myeloid neoplasm (CMN); there is minimal literature regarding this latter phenomenon.

Methods: We describe 14 patients with PEL that represented progression from a preexisting myelodysplastic syndrome (MDS, n = 8) or myeloproliferative neoplasm (MPN, n = 6), three of which manifested as erythroblastic sarcoma (EBS), a rare entity. These patients had a highly complex karyotype with prominent clonal evolution and a very aggressive clinical course.

Results: Patients with PEL from MDS showed a more rapid progression time to PEL and had lower platelet counts compared with PEL from MPN. No other significant differences were found between the two groups.

Conclusions: These data represent the largest cohort of patients with PEL and an antecedent CMN, as well as the largest series of EBS reported to date, and underscore the unique morphologic, cytogenetic, immunophenotypic, and clinical features of this uncommon entity.
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http://dx.doi.org/10.1093/ajcp/aqw033DOI Listing
April 2016

Teamwork key to reducing lab-results errors.

Authors:
Steven H Kroft

Mod Healthc 2014 May;44(20):25

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May 2014

CD200 expression in plasma cells of nonmyeloma immunoproliferative disorders: clinicopathologic features and comparison with plasma cell myeloma.

Am J Clin Pathol 2012 Dec;138(6):867-76

Dept of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.

The majority of plasma cell myelomas (PCMs) are positive for CD200, a membrane protein with immunosuppressive function. There are no flow cytometry data in the literature on plasma cell CD200 expression in other immunoproliferative disorders. Therefore we used flow cytometry to study the expression of CD200 on plasma cells in diagnostic bone marrow aspirates from 61 patients with monoclonal gammopathy of undetermined significance (MGUS) and 10 patients with lymphoplasmacytic lymphoma (LPL). For comparison, we evaluated CD200 expression in 74 PCM bone marrow biopsies. Thirty-three (54.1%) of 61 MGUS cases and 2 (20.0%) of 10 LPL cases were CD200+. Comparative clinicopathologic parameters for MGUS cases, based on CD200 expression status, showed no differences between the 2 groups. The proportion of CD200+ PCMs (73.0%) in our series was significantly higher than that of CD200+ MGUS (P = .030) and CD200+ LPL (P = .002) cases.
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http://dx.doi.org/10.1309/AJCP3TQR1TFHHGASDOI Listing
December 2012

Time and temperature stability of T-cell subsets evaluated by a dual-platform method.

Am J Blood Res 2012 25;2(2):128-35. Epub 2012 May 25.

Introduction: T-cell subset enumeration in HIV patients is routinely performed for monitoring infection stage and response to antiretroviral therapy. Studies have examined the effect of specimen refrigeration and age for single-platform (SP) methods, but there is limited data for time and temperature requirements of dual-platform (DP) methods.

Methods: Using a DP method, we analyzed peripheral blood (PB) from 52 HIV patients at room temperature (RT) at 24, 72, and 96 hours. PBs from 34 HIV patients had baseline RT analysis within 24 hours, and then were refrigerated and analyzed at 24, 48, and 72 hours. The coefficient of variation (CV) and residuals (changes in lymphocyte subsets) were recorded at each time point and compared to assess the precision and bias under the various conditions. Testing performance under different conditions was compared by linear regression.

Results: Mean CV was ≤7.3% and median residuals were <30/μl for absolute CD4 and CD8 determinations. There was good correlation between baseline analysis data at RT and at various time points, both at RT and 4°C.

Conclusions: Our results are similar to those published for SP methods for aging or refrigerated specimens. The high level of agreement between measurements supports the robustness of this DP methodology.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3384401PMC
August 2012

A dissection of the CD45/side scatter "blast gate".

Am J Clin Pathol 2012 May;137(5):800-4

Department of Pathology, Medical College of Wisconsin, Milwaukee, USA.

CD45/side scatter (SS) gating is widely used for isolating blasts by flow cytometry (FC). However, other cells contaminate the "blast gate" (BG); CD45/SS gating is thus imprecise, particularly when there are few blasts. We studied the BG contents in 21 myelodysplastic syndromes (MDSs), 14 myeloproliferative neoplasms (MPNs), 7 chronic myelomonocytic leukemias (CMMLs), and 40 nonneoplastic control samples using 4-color FC with cluster analysis. There were no significant differences across groups in the median percentage of BG events represented by blasts (14.7%-22%), granulocytes (23.3%-33.2%), lymphocytes (2.1%-3.2%), and erythroids (1.0%-9.8%). Monocytes were a larger percentage of BG events in CMML (24.2%). Basophils averaged 35.4% of the BG in MPNs. The percentage of blasts within the BG averaged 94.2% in control samples vs 88.2% in MDSs and 80.7% in CMMLs. Blasts averaged about 20% of events in the BG. About 10% to 20% of blasts fell outside the BG in CMMLs and MDSs. Our data highlight pitfalls in using a traditional BG for blast analysis in nonacute myeloid disorders.
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http://dx.doi.org/10.1309/AJCPN4G1IZPABRLHDOI Listing
May 2012

Immunophenotypic stability of Sézary cells by flow cytometry: usefulness of flow cytometry in assessing response to and guiding alemtuzumab therapy.

Am J Clin Pathol 2012 Mar;137(3):403-11

Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.

Flow cytometry (FC) is frequently used to detect aberrant peripheral blood (PB) T cells ("Sézary cells") in patients with mycosis fungoides (MF) and Sézary syndrome (SS). However, immunophenotypic stability of MF/SS over time is not well characterized. We analyzed 141 PB samples from 9 cases (2 SS, 7 MF). At diagnosis, there were 3 to 5 immunophenotypic aberrancies per case (median, 4), including dim or absent CD2, CD3, CD4, CD5, CD7, or CD26 and bright CD45RO. Of 9 patients, 7 had a subsequent change in immunophenotype. All patients retained multiple aberrancies at follow-up (median, 3 per analysis; range, 2-6), of which 22.0% (81/369) were new. In 5 patients, a more than 99% decrease in absolute Sézary cell (ASC) counts by FC after alemtuzumab therapy or total skin electron beam radiation was associated with clinical improvement. We observed minor immunophenotypic changes over time in most patients with MF/SS; however, the Sézary clones maintain persistently aberrant immunophenotypes and seem amenable to follow-up with limited FC panels. ASC counts by FC correlated well with clinical response.
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http://dx.doi.org/10.1309/AJCP7QHH5XASTJPLDOI Listing
March 2012

Gamma heavy-chain disease: defining the spectrum of associated lymphoproliferative disorders through analysis of 13 cases.

Am J Surg Pathol 2012 Apr;36(4):534-43

Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Gamma heavy-chain disease (gHCD) is defined as a lymphoplasmacytic neoplasm that produces an abnormally truncated immunoglobulin gamma heavy-chain protein that lacks associated light chains. There is scant information in the literature regarding the morphologic findings in this rare disorder, but cases have often been reported to resemble lymphoplasmacytic lymphoma (LPL). To clarify the spectrum of lymphoproliferative disorders that may be associated with gHCD, this study reports the clinical, morphologic, and phenotypic findings in 13 cases of gHCD involving lymph nodes (n=7), spleen (n=2), bone marrow (n=8), or other extranodal tissue biopsies (n=3). Clinically, patients showed a female predominance (85%) with frequent occurrence of autoimmune disease (69%). Histologically, 8 cases (61%) contained a morphologically similar neoplasm of small lymphocytes, plasmacytoid lymphocytes, and plasma cells that was difficult to classify with certainty, whereas the remaining 5 cases (39%) showed the typical features of one of several other well-defined entities in the 2008 WHO classification. This report demonstrates that gHCD is associated with a variety of underlying lymphoproliferative disorders but most often shows features that overlap with cases previously reported as "vaguely nodular, polymorphous" LPL. These findings also provide practical guidance for the routine evaluation of small B-cell neoplasms with plasmacytic differentiation that could represent a heavy-chain disease and give suggestions for an improved approach to the WHO classification of gHCD.
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http://dx.doi.org/10.1097/PAS.0b013e318240590aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3715127PMC
April 2012

Flow cytometric analysis of surface light chain expression patterns in B-cell lymphomas using monoclonal and polyclonal antibodies.

Am J Clin Pathol 2011 Dec;136(6):954-9

Department of Pathology, Medical College of Wisconsin, Milwaukee, 53226, USA.

Light chain (LC) expression by flow cytometry (FC) in B cell non-Hodgkin lymphomas (B-NHLs) can occasionally be detected with one anti-LC antibody but not with another. We retrospectively analyzed 564 four-color FC files from B-NHLs, assessing LC staining with monoclonal antibodies (mAbs) and polyclonal antibodies (pAbs). Discrepancies in LC expression between mAbs and pAbs were present in 9.2% of cases, mainly in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; 11.1%), diffuse large B-cell lymphoma (DLBCL; 10.2%), follicular lymphoma (9.5%), and mantle cell lymphoma (11.1%) and most frequently in body fluids. Equal proportions of cases were LC+ only with pAbs (4.8%) or mAbs (4.4%). Negative LC expression with both antibodies was present in 7.5% of cases, most frequently in DLBCL (21.6%) and body fluids (27.6%). Evaluation with both mAbs and pAbs increases the sensitivity for LC detection, with no single reagent outperforming the other, although CLL/SLL preferentially showed LC expression with pAbs.
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http://dx.doi.org/10.1309/AJCP3C2QZZBPTMLBDOI Listing
December 2011

Clinicopathologic analysis of the impact of CD23 expression in plasma cell myeloma with t(11;14)(q13;q32).

Ann Diagn Pathol 2011 Dec 2;15(6):385-8. Epub 2011 Jul 2.

Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.

A recent study has shown that 10% of plasma cell myelomas (PCMs) express CD23 and that expression is associated with abnormalities of chromosome 11, mainly t(11;14)(q13;q32); however, only 40% of t(11;14)(+) PCMs express CD23. Because these results were generated in a limited patient cohort and because the clinical relevance of CD23 expression in PCMs with t(11;14)(q13;q32) has not been fully characterized, we addressed this question in a large series of patients with t(11;14)(+) PCM. Forty-two bone marrow biopsies from patients with t(11;14)(+) PCM were evaluated for CD23 expression by immunohistochemistry. CD23 expression was correlated with laboratory and clinical data and outcome after autologous stem cell transplantation, including event-free survival and overall survival (OS). Plasma cell myelomas with t(11;14)(q13;q32) were frequently CD20(+) (46.4%) and CD56(-) (53.8%) and had a nonhyperdiploid karyotype (97.6%) with frequent 13q deletion (33.3%). Of 42 cases, 19 (45.2%) expressed CD23. CD23(+) PCMs were more likely to present with platelet counts less than 150 × 10(3)/μL (100% vs 50%, P = .006). There were no significant differences in other laboratory or presenting clinical data. The median event-free survival in patients treated with autologous stem cell transplantation (n = 29) was similar regardless of CD23 status, whereas the median OS (all patients) was longer in CD23(-) than in CD23(+) PCMs: not reached vs 3365 days (P = .08). Our findings suggest that patients with t(11;14)(+)/CD23(+) PCM present with lower platelet counts and may have a shorter OS than those with t(11;14)(+)/CD23(-) PCM.
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http://dx.doi.org/10.1016/j.anndiagpath.2011.04.004DOI Listing
December 2011

Immunophenotypic signatures of benign and dysplastic granulopoiesis by cytomic profiling.

Cytometry B Clin Cytom 2011 Sep 1;80(5):282-90. Epub 2011 Apr 1.

Department of Pathology, University of Michigan, 1301 Catherine Road, Ann Arbor, MI 48109-5602, USA.

Background: The role of flow cytometry (FCM) in diagnosing myelodysplastic syndromes (MDS) remains controversial, because analysis of myeloid maturation may involve subjective interpretation of sometimes subtle patterns on multiparameter FCM.

Methods: Using six-parameter marker combinations known to be useful in evaluating the myeloid compartment in MDS, we measured objective immunophenotypic differences between non-neoplastic (n = 25) and dysplastic (n = 17) granulopoiesis using a novel method, called Fisher information nonparametric embedding (FINE), that measures information distances among FCM datasets modeled as individual high-dimensional probability density functions, rather than as sets of two-dimensional histograms. Information-preserving component analysis (IPCA) was used to create information-optimized "rotated" two-dimensional histograms for visualizing myelopoietic immunophenotypes for each individual sample.

Results: There was a consistent trend of segregation of higher-grade MDS (RAEB and RCMD) from benign by FINE analysis. This difference was accentuated in cases with morphologic dysgranulopoiesis and in cases with clonal cytogenetic abnormalities. However, lower grades of MDS or cases that lacked morphologic dysgranulopoiesis showed much greater overlap with non-neoplastic cases. Two cases of reactive left shift were consistently embedded within the higher-grade MDS group. IPCA yielded two-dimensional histogram projections for each individual case by relative weighting of measured cellular characteristics, optimized for preserving information distances derived through FINE.

Conclusions: Objective analysis by information geometry supports the conclusions of previous studies that there are immunophenotypic differences in the maturation patterns of benign granulopoiesis and high grade MDS, but also reinforces the known pitfalls of overlap between low-grade MDS and benign granulopoiesis and overlap between reactive granulocytic left shifts and dysplastic granulopoiesis.
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http://dx.doi.org/10.1002/cyto.b.20592DOI Listing
September 2011