Publications by authors named "Aliyah R Sohani"

90 Publications

Clinicopathologic Features of Peripheral T-Cell Lymphoma in Sub-Saharan Africa.

Am J Clin Pathol 2021 Feb 2. Epub 2021 Feb 2.

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Objectives: Peripheral T-cell lymphomas (PTCLs) are heterogeneous, clinically aggressive, and rare. Subtype distribution varies by geographic location; however, data from sub-Saharan Africa (SSA) are lacking. We sought to elucidate clinicopathologic features of PTCL in SSA.

Methods: We reviewed PTCL consultation cases from three SSA countries. PTCL subtype was determined per 2017 World Health Organization classification. Cases with sufficient material were evaluated by polymerase chain reaction for human T-cell leukemia virus type 1 (HTLV-1) and T-cell receptor γ (TCRG) rearrangement.

Results: Among 32 cases, median age was 45 years and male-to-female ratio was 1.7. Thirty (94%) of 32 cases required additional workup for subclassification. PTCL, not otherwise specified (PTCL-NOS) was the most common subtype (13/32, 41%), followed by PTCL with T-follicular helper phenotype (6/32, 19%) and systemic anaplastic large cell lymphoma (6/32, 19%). Four (16%) of 25 cases were Epstein-Barr virus positive (EBV+) (2/2 extranodal natural killer/T-cell lymphoma, 1/13 PTCL-NOS, and 1/4 angioimmunoblastic T-cell lymphoma with EBV+ immunoblasts). Two (15%) of 13 patients with PTCL-NOS were human immunodeficiency virus positive. No cases with evaluable DNA (0/15) were HTLV-1 positive, and 9 of 10 showed clonal TCRG rearrangements.

Conclusions: In comparison to Western studies, PTCLs from SSA show similar subtype distribution and male predominance but a younger age at diagnosis. Appropriate diagnosis of PTCL requires extensive ancillary testing not readily available in low-income countries, including much of SSA.
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http://dx.doi.org/10.1093/ajcp/aqaa201DOI Listing
February 2021

Improving Malignancy Detection Rates in Body Fluids Submitted to the Hematology Laboratory for Nucleated Cell Count and Differential: A Quality Improvement Study.

Arch Pathol Lab Med 2021 02;145(2):201-207

the Department of Pathology, Harvard Medical School, Massachusetts General Hospital, Boston (Tambouret, Sohani).

Context.—: Body fluid specimens are regularly submitted to the hematology laboratory for cell count and differential. Unless there is high clinical suspicion for malignancy, most cases lack concurrent cytology review and may not benefit from more focused examination for malignancy.

Objective.—: To compare rates of malignancy detection before and after fluid-focused training for hematology technologists as part of a quality improvement initiative.

Design.—: During an 8-week pretraining period, body fluids submitted to the cytology laboratory were correlated with concurrent hematology specimens. After slide review and training sessions for the hematology technologists, the same data were collected for a 4-week period. Discrepant cases were reviewed by hematology laboratory supervisors and pathologists.

Results.—: We collected 465 pretraining and 249 posttraining body fluids with concurrent cytology and hematology evaluation. In the pretraining cohort, 48 cases (10.3%) were diagnosed as malignant by cytology; of those, 33 were detected by hematology. In the posttraining cohort, 30 cases (12.0%) were diagnosed as malignant by cytology of which 27 were detected by hematology. Of the 18 discrepant cases (all carcinomas), hematology slide review showed definite features of malignancy in 15 and no tumor cells in 3. The malignancy detection rate by the hematology laboratory significantly improved after training (68.8% versus 90.0%, P = .01).

Conclusions.—: We demonstrate the comparatively lower malignancy detection rate for body fluid specimens processed in our hematology laboratory, particularly for carcinomas. Hematology technologist education/training improved the malignancy detection rate, an important quality improvement given the large proportion of body fluids undergoing hematology evaluation without concurrent cytology reviews.
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http://dx.doi.org/10.5858/arpa.2019-0617-OADOI Listing
February 2021

CD30-positive lymphomatous (nonleukemic) variant of adult T-cell leukemia/lymphoma, HTLV-1 associated.

Clin Case Rep 2020 Dec 20;8(12):2395-2397. Epub 2020 Jul 20.

Department of Pathology Massachusetts General Hospital Boston MA USA.

Nonleukemic variant of HTLV-1-associated adult T-cell leukemia lymphoma (ATLL) is a rare variant, and herein, we describe a case with strong and diffuse positivity of neoplastic cells for CD30. Even though ATLL is aggressive entity with poor prognosis, in our case, there was very good clinical response achieved with brentuximab-containing regimen. Therefore, HTLV-1-associated ATLL can be included in the differential diagnostic approach of CD30-positive lymphoproliferative disorders.
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http://dx.doi.org/10.1002/ccr3.3092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752401PMC
December 2020

Simultaneous Identification of Cell of Origin, Translocations, and Hotspot Mutations in Diffuse Large B-Cell Lymphoma Using a Single RNA-Sequencing Assay.

Am J Clin Pathol 2020 Dec 1. Epub 2020 Dec 1.

Department of Pathology, Massachusetts General Hospital, Boston.

Objectives: Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma with a heterogenous genetic landscape that can require multiple assays to characterize. We reviewed a 1-step RNA-based assay to determine cell of origin (COO), detect translocations, and identify mutations and to assess the role of the assay in diagnosis.

Methods: Using a single custom Archer FusionPlex Lymphoma panel, we performed anchored multiplex polymerase chain reaction-based RNA sequencing on 41 cases of de novo DLBCL. Each case was subclassified by COO, and gene fusions and hotspot mutations were identified. The findings were then compared with COO classification by the Hans immunohistochemical algorithm and NanoString technology, cytogenetics, and fluorescence in situ hybridization results.

Results: Concordant COO classification by the FusionPlex panel and NanoString was observed in 35 of 41 cases (85.3%), with NanoString and Hans concordant in 33 of 41 cases (80.5%) and FusionPlex and Hans concordant in 33 of 41 cases (80.5%). The FusionPlex assay also detected 6 of 11 BCL6 translocations (4 cryptic), 2 of 3 BCL2 translocations, and 2 of 4 MYC translocations. Mutations were detected in lymphoma-related genes in 24 of 41 cases.

Conclusion: This FusionPlex assay offers a single method for COO classification, mutation detection, and identification of important translocations in DLBCL. Although not replacing traditional testing, it could offer useful data when limited tissue is available.
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http://dx.doi.org/10.1093/ajcp/aqaa185DOI Listing
December 2020

Unusual inclusions in cerebrospinal fluid macrophages of spinal muscular atrophy patients treated with nusinersen.

Int J Lab Hematol 2020 Nov 17. Epub 2020 Nov 17.

Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.

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http://dx.doi.org/10.1111/ijlh.13392DOI Listing
November 2020

Biomarkers for Risk Stratification in Patients With Previously Untreated Follicular Lymphoma Receiving Anti-CD20-based Biological Therapy.

Am J Surg Pathol 2021 Mar;45(3):384-393

Cleveland Clinic, Cleveland, OH.

Follicular lymphoma (FL) is an indolent B-cell neoplasm of germinal center origin. Standard treatment regimens consist of anti-CD20 therapy with or without chemotherapy. While high response rates to initial therapy are common, patients ultimately relapse or have progressive disease. Clinical risk factors such as the Follicular Lymphoma International Prognostic Index (FLIPI) have been identified, but there is a need for prognostic and predictive biomarkers. We studied markers of lymphoma cells and tumor microenvironment by immunohistochemistry in tissue samples from patients enrolled in 1 of 4 phase 2 trials of anti-CD20-based biological therapy for previously untreated grades 1 to 2 or 3A FL. Results were correlated with progression-free survival (PFS) and PFS status at 24 months. The 4 trials included 238 patients (51.1% male, median age: 55 y) with stage III, IV, or bulky stage II disease. By FLIPI, 24.6% had low-risk, 56.8% had intermediate-risk, and 18.6% had high-risk disease. The outcome differed significantly for patients treated with lenalidomide and rituximab (CALGB 50803) compared with the other 3 trials (median: PFS not reached vs. 3.0 y, hazard ratio=3.47, 95% confidence interval: 2.11-5.72); therefore, data were stratified by clinical trial (CALGB 50803 vs. all others) and adjusted for FLIPI risk group. Among 154 patients with available tissue, interfollicular BCL6 positivity, interfollicular CD10 positivity, and elevated Ki67 proliferation index ≥30% within neoplastic follicles were each associated with inferior PFS and a high risk of the early event by PFS status at 24 months. We identify promising biomarkers for FL risk stratification that warrant further validation in phase 3 trials.
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http://dx.doi.org/10.1097/PAS.0000000000001609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878306PMC
March 2021

Falling prey to a wolf in sheep's clothing: T and NK cell neoplasms with aberrant CD20 expression.

Authors:
Aliyah R Sohani

Virchows Arch 2020 Dec 15;477(6):897-899. Epub 2020 Aug 15.

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit St., WRN 219, Boston, MA, 02114, USA.

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http://dx.doi.org/10.1007/s00428-020-02911-8DOI Listing
December 2020

Peripheral blood morphologic findings in patients with COVID-19.

Int J Lab Hematol 2020 Dec 30;42(6):e248-e251. Epub 2020 Jul 30.

Pathology Department, Massachusetts General Hospital, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1111/ijlh.13300DOI Listing
December 2020

Reply to M. Romero et al.

J Clin Oncol 2020 08 17;38(24):2819-2820. Epub 2020 Jun 17.

Elaine S. Jaffe, MD, Hematopathology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD; Andrew L. Feldman, MD, Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN; Philippe Gaulard, MD, PhD, Departement de Pathologie, Hôpital Henri Mondor, Inserm U955, Université Paris-Est, Créteil, France; Roberto N. Miranda, MD, Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX; and Aliyah R. Sohani, MD, Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA.

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http://dx.doi.org/10.1200/JCO.20.00931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430216PMC
August 2020

Lymphomas of the Mediastinum and Their Differential Diagnosis.

Semin Diagn Pathol 2020 Jul 15;37(4):156-165. Epub 2020 May 15.

Department of Pathology, Massachusetts General Hospital, Boston, MA.

Lymphoma is the most common malignancy involving the mediastinum but can be challenging to diagnose on small biopsy specimens. This review provides a pattern-based approach to help triage small tissue samples for the diagnosis of mediastinal lymphoid proliferations, with focus on the main primary mediastinal lymphomas. The use of ancillary studies is highlighted, along with considerations to avoid misdiagnosis and scenarios to request additional tissue.
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http://dx.doi.org/10.1053/j.semdp.2020.04.005DOI Listing
July 2020

Plasmablastic Lymphomas: Characterization of Tumor Microenvironment Using CD163 and PD-1 Immunohistochemistry.

Ann Clin Lab Sci 2020 Mar;50(2):213-218

Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA

This study aims to characterize the tumor microenvironment of plasmablastic lymphoma (PBL) in regard to the quantities of CD163(+) tumor associated macrophages (TAM) and PD1(+) tumor infiltrating lymphocytes (TIL). This article also reviews the existing knowledge of the role of PD-1/PD-L1 pathway in the tumor microenvironment of hematopoietic neoplasms, discusses potential mechanisms to explain our findings, and outlines areas for future studies. We performed CD163 and PD1 immunohistochemical studies in 11 cases classified as plasmablastic lymphoma, and recorded the percentages of positive TAMs and TILs. Based on previous studies, cut off values of ≥30% and >5% were used to classify the cases into high TAMs and TILs, respectively. We determined that the majority of cases (8 of 11, or 73%) had high percentage of TAMs, while only a minority had high percentage of TILs (3 of 11, or 27%). Our data shows a trend towards a negative correlation between TAMs and TILs (=0.08), and a predominance of the pattern TAM/TIL (7 of 11, or 63%) compared to other patterns. The microenvironment of plasma-blastic lymphoma tends to show high percentage of TAMs (≥30%) combined with low percentage of TILs (≤5%). Additional studies are needed to determine the clinical significance of TILs and the influence of EBV and HIV infections on numbers of TILs in PBL. As high microenvironment TAMs have been associated with high microenvironment PD-L1 in other hematopoietic malignancies, our data supports the need for future studies on the expression of PD-L1 in PBL.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439522PMC
March 2020

A Case of Fever and Erythema Nodosum-Like Lesions Leading to a New Diagnosis of Gamma-Delta T-Cell Lymphoma Complicated by Hemophagocytic Lymphohistiocytosis.

Dermatopathology (Basel) 2019 Oct-Dec;6(4):266-270. Epub 2020 Feb 18.

Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts, USA.

A 69-year-old Vietnamese female presented with fever and new-onset tender subcutaneous nodules on her trunk and lower extremities initially thought to be clinically consistent with erythema nodosum. A biopsy showed an atypical, predominantly lobular lymphocytic panniculitis with admixed neutrophils, karyorrhectic debris, and histiocytes with subcutaneous fat necrosis. Immunohistochemistry was consistent with gamma-delta T-cell lymphoma. The patient was initiated on a chemotherapy regimen of cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone (CHOEP) with partial remission, and is currently undergoing evaluation for bone marrow transplant. This case highlights the ability of cutaneous gamma-delta T-cell lymphoma to mimic more common cutaneous conditions such as erythema nodosum, and stresses the importance of a broad differential for new presentation of tender subcutaneous nodules with concomitant systemic symptoms.
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http://dx.doi.org/10.1159/000505471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098367PMC
February 2020

Best Practices Guideline for the Pathologic Diagnosis of Breast Implant-Associated Anaplastic Large-Cell Lymphoma.

J Clin Oncol 2020 04 11;38(10):1102-1111. Epub 2020 Feb 11.

Office of Surgical and Infection Control Devices, Office of Product Evaluation and Quality, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, MD.

Purpose: To provide guidelines for the accurate pathologic diagnosis of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL), the preoperative evaluation of the patient with suspected BIA-ALCL, and the pathologic evaluation of the capsulectomy specimen.

Methods: To better inform patients and healthcare providers about BIA-ALCL, we convened to review diagnostic procedures used in the evaluation of patients with suspected BIA-ALCL. We focused on the processing of the seroma fluid/effusion surrounding the implant, the handling of capsulectomy specimens following removal of implant(s), and the preoperative evaluation of the patient with suspected BIA-ALCL. Recommendations were based on the published literature and our experience to optimize procedures to obtain an accurate diagnosis and assess for tumor invasion and the extent of the disease.

Recommendations: Early diagnosis of BIA-ALCL is important as the disease can progress and deaths have been reported. Because the most common presentation of BIA-ALCL is swelling of the breast with fluid collection, an accurate diagnosis requires cytologic evaluation of the effusion fluid surrounding the affected implant. The first priority is cytocentrifugation and filtration of fresh, unfixed effusion fluid to produce air-dried smears that are stained with Wright-Giemsa or other Romanowsky-type stains. Preparation of a cell block is desirable to allow for hematoxylin and eosin staining and immunohistochemical analysis of formalin-fixed, paraffin-embedded histologic sections. Cell block sections can be used for polymerase chain reaction-based investigation of T-cell receptor gene rearrangement to detect clonality. Fixation and mapping of the capsulectomy specimen to select multiple representative sections are advised to assess for microscopic tumor involvement and capsular invasion. It is appropriate to assess lymph node involvement by excisional biopsy material rather than fine needle aspiration, due to propensity for focal involvement.
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http://dx.doi.org/10.1200/JCO.19.02778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7106983PMC
April 2020

Diagnostic utility of STAT6 expression in classical Hodgkin lymphoma and related entities.

Mod Pathol 2020 05 10;33(5):834-845. Epub 2019 Dec 10.

Department of Pathology, The University of Chicago Medicine, Chicago, IL, USA.

Although the distinction of classical Hodgkin lymphoma from nodular lymphocyte predominant Hodgkin lymphoma using morphology and immunostains is straightforward in most instances, occasional cases pose diagnostic challenge. We sought to determine the utility of the novel YE361 STAT6 rabbit monoclonal antibody in Hodgkin lymphoma and diagnostically challenging B- and T-cell non-Hodgkin lymphoma entities with Hodgkin-like features. Cases from seven institutions included: 57 classical Hodgkin lymphomas (31% EBV+), 34 nodular lymphocyte predominant Hodgkin lymphomas, 34 mimicking B- and T-cell non-Hodgkin lymphomas, and 7 reactive lymphoproliferations. After review of histology, STAT6 immunostaining was performed. The intensity and spatial localization of immunopositivity was assessed in neoplastic cells. Additional FISH for programmed death ligand-1 (PD-L1) was performed in one patient in paired treatment-naive and relapse biopsy tissues. Two STAT6 immunopositive cases were examined by whole-exome sequencing after flow sorting to assess mutations in STAT6 pathway genes. Most classical Hodgkin lymphomas showed nuclear staining for STAT6 [46/57 cases (80%)] on Hodgkin cells. Staining was exclusively nuclear in a minority [12/46 (26%)], while dual nuclear and cytoplasmic localization was more common [34/46 (74%)]. In contrast, all nodular lymphocyte predominant Hodgkin lymphomas [0/34 (0%)] were negative for nuclear STAT6 staining on the lymphocyte predominant cells. Within B- and T-cell non-Hodgkin lymphomas, nuclear STAT6 was seen in: B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, and in primary mediastinal large B-cell lymphoma. Strong PD-L1 gene amplification was noted in the paired cHL and relapse B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, although STAT6 was negative in both biopsies. Whole-exome sequencing identified mutations in B2M, XPO1, and ITPKB as well CISHP213L (in the STAT pathway) in one classical Hodgkin lymphoma patient positive for nuclear STAT6 although no underlying STAT6 mutations were observed in either sample examined. STAT6 nuclear staining has 100% positive predictive value and 85.7% negative predictive value in confirming or excluding classical Hodgkin lymphoma diagnosis in the distinction from nodular lymphocyte predominant Hodgkin lymphoma and other benign and malignant entities.
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http://dx.doi.org/10.1038/s41379-019-0428-0DOI Listing
May 2020

Case 34-2019: A 16-Year-Old Boy with Jaundice.

N Engl J Med 2019 10;381(18):1763-1772

From the Department of Pediatrics, Warren Alpert Medical School of Brown University, Providence, RI (B.K.A.); and the Departments of Radiology (A.K.), Pediatrics (A.M.F.), and Pathology (A.R.S.), Massachusetts General Hospital, and the Departments of Radiology (A.K.), Pediatrics (A.M.F.), and Pathology (A.R.S.), Harvard Medical School - both in Boston.

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http://dx.doi.org/10.1056/NEJMcpc1904047DOI Listing
October 2019

Machine Learning Models Improve the Diagnostic Yield of Peripheral Blood Flow Cytometry.

Am J Clin Pathol 2020 01;153(2):235-242

Department of Pathology, Massachusetts General Hospital, Boston.

Objectives: Peripheral blood flow cytometry (PBFC) is useful for evaluating circulating hematologic malignancies (HM) but has limited diagnostic value for screening. We used machine learning to evaluate whether clinical history and CBC/differential parameters could improve PBFC utilization.

Methods: PBFC cases with concurrent/recent CBC/differential were split into training (n = 626) and test (n = 159) cohorts. We classified PBFC results with abnormal blast/lymphoid populations as positive and used two models to predict results.

Results: Positive PBFC results were seen in 58% and 21% of training cases with and without prior HM (P < .001). % neutrophils, absolute lymphocyte count, and % blasts/other cells differed significantly between positive and negative PBFC groups (areas under the curve [AUC] > 0.7). Among test cases, a decision tree model achieved 98% sensitivity and 65% specificity (AUC = 0.906). A logistic regression model achieved 100% sensitivity and 54% specificity (AUC = 0.919).

Conclusions: We outline machine learning-based triaging strategies to decrease unnecessary utilization of PBFC by 35% to 40%.
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http://dx.doi.org/10.1093/ajcp/aqz150DOI Listing
January 2020

Diffuse Large B-Cell Lymphoma in Kenya: MYC, BCL2, and the Cell of Origin.

J Glob Oncol 2019 05;5:1-8

Massachusetts General Hospital, Boston, MA.

Purpose: Diffuse large B-cell lymphoma (DLBCL) is the most commonly diagnosed non-Hodgkin lymphoma in adults in Kenya. Cell of origin (COO) and double expression of MYC and BCL2 are two important prognostic factors for DLBCL. A small subset (5% to 10%) of DLBCL cases show positivity for CD5 and are associated with poor prognosis, whereas CD30 antigen, seen in up to 10% of cases, may be a useful target for therapy. We sought to determine the prevalence of MYC/BCL2 double expression, COO, and proportion of Epstein-Barr virus positivity among patients with DLBCL diagnosed at a tertiary referral laboratory in Kenya.

Patients And Methods: All cases of DLBCL diagnosed from 2012 through 2015 in our pathology department were analyzed. Tumor tissue microarray sections were stained with CD20, CD3, CD5, CD30, BCL2, BCL6, CD10, MUM1, MYC, and Ki67, classified for COO on the basis of the Hans algorithm, and subjected to Epstein-Barr virus-encoded small RNAs in situ hybridization.

Results: Among 165 DLBCL cases, the median age was 50 years, and there was no sex predilection. Only 18 (10.9%) cases showed double expression for MYC and BCL2. Germinal center B (GCB)-cell type DLBCL accounted for 67 cases (40.6%) and 97 cases (59.4%) were classified as non-GCB. The mean Ki67 proliferation index was significantly higher in the double-expressing (45%) and non-GCB groups (36%) compared with the non-double-expressing group (29%) and GCB group (26%). Sixteen cases (9.7%) were Epstein-Barr virus-encoded small RNAs positive, 12 (75%) of which were non-GCB.

Conclusion: DLBCL in Kenya is seen in much younger patients with the poor prognostic non-GCB-type accounting for 59.4% of cases. MYC and BCL2 double expression was seen in fewer tumors than reported in the literature and in significantly older patients.
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http://dx.doi.org/10.1200/JGO.18.00203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657604PMC
May 2019

Design and clinical validation of a point-of-care device for the diagnosis of lymphoma via contrast-enhanced microholography and machine learning.

Nat Biomed Eng 2018 Sep 23;2(9):666-674. Epub 2018 Jul 23.

Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA.

The identification of patients with aggressive cancer who require immediate therapy is a health challenge in low-income and middle-income countries. Limited pathology resources, high healthcare costs and large-case loads call for the development of advanced standalone diagnostics. Here, we report and validate an automated, low-cost point-of-care device for the molecular diagnosis of aggressive lymphomas. The device uses contrast-enhanced microholography and a deep-learning algorithm to directly analyse percutaneously obtained fine-needle aspirates. We show the feasibility and high accuracy of the device in cells, as well as the prospective validation of the results in 40 patients clinically referred for image-guided aspiration of nodal mass lesions suspicious for lymphoma. Automated analysis of human samples with the portable device should allow for the accurate classification of patients with benign and malignant adenopathy.
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http://dx.doi.org/10.1038/s41551-018-0265-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291220PMC
September 2018

Impact of HIV Infection on the Clinical Presentation and Survival of Non-Hodgkin Lymphoma: A Prospective Observational Study From Botswana.

J Glob Oncol 2018 09;4:1-11

Michael G. Milligan, Jeremy S. Abramson, Aliyah R. Sohani, Shahin Lockman, Bruce A. Chabner, and Scott L. Dryden-Peterson, Harvard Medical School; Elizabeth Bigger, Jeremy S. Abramson, and Aliyah R. Sohani, Massachusetts General Hospital; Shahin Lockman and Scott L. Dryden-Peterson, Brigham and Women's Hospital and Harvard T.H. Chan School of Public Health, Boston, MA; Michael G. Milligan, Elizabeth Bigger, Shahin Lockman, Bruce A. Chabner, and Scott L. Dryden-Peterson, Botswana Harvard AIDS Institute Partnership; Musimar Zola, Princess Marina Hospital; Mukendi K.A. Kayembe and Heluf Medhin, Botswana Ministry of Health, Gaborone, Botswana; and Gita Suneja, Duke University, Durham, NC.

Purpose: Botswana has a high prevalence of HIV infection. Currently, there are few data regarding the sociodemographic factors, clinical characteristics, and outcomes of non-Hodgkin lymphoma (NHL)-an AIDS-defining cancer-in the country.

Patients And Methods: This study used a prospective cancer registry to identify patients with a new diagnosis of NHL reporting for specialty cancer care at three hospitals in Botswana between October 2010 and August 2016. Treatment patterns and clinical outcomes were analyzed.

Results: One hundred four patients with a new diagnosis of NHL were enrolled in this study, 72% of whom had HIV infection. Compared with patients not infected with HIV, patients infected with HIV were younger (median age, 53.9 v 39.1 years; P = .001) and more likely to present with an aggressive subtype of NHL (65.5% v 84.0%; P = .008). All patients infected with HIV received combined antiretroviral therapy throughout the course of the study, and similar chemotherapeutic regimens were recommended for all patients, regardless of subtype or HIV status (six to eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone; or cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab). There was no difference in 1-year mortality among patients not infected with HIV and patients infected with HIV (unadjusted analysis, 52.9% v 37.1%; hazard ratio [HR], 0.73; P = .33; adjusted analysis, HR, 0.57; P = .14). However, when compared with a cohort of patients in the United States matched by subtype, stage, age, sex, and race, patients in Botswana fared worse (1-year mortality, 22.8% v 46.3%; HR, 1.89; P = .001).

Conclusion: Among patients with NHL reporting for specialty cancer care in Botswana, there is no association between HIV status and 1-year survival.
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http://dx.doi.org/10.1200/JGO.17.00084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223476PMC
September 2018

Heavy Chain Disease of the Small Bowel.

Curr Gastroenterol Rep 2018 Jan 25;20(1). Epub 2018 Jan 25.

James Homer Wright Pathology Laboratories of the Massachusetts General Hospital and Department of Pathology, Harvard Medical School, 55 Fruit St., WRN 219, Boston, MA, 02114, USA.

Purpose Of Review: The purpose of this review is to discuss current knowledge and recent findings regarding pathogenesis, outcome, and treatment for heavy chain disease (HCD) involving the small bowel, focusing on alpha HCD or immunoproliferative small intestinal disease (IPSID), the HCD subtype typically affecting the small bowel.

Recent Findings: A link between Campylobacter jejuni infection and IPSID has been established, but there is controversy as to the role played by this organism in disease pathogenesis. While cytogenetic abnormalities involving various immunoglobulin loci and PAX5 have been reported, these have been described in rare, single cases, limiting their ability to shed further light on disease pathogenesis. IPSID is typically regarded as a pre-lymphomatous condition with eventual progression to frank lymphoma; however, recent reports of longstanding non-progressive cases have expanded its clinical spectrum. IPSID is an uncommon disorder affecting the small intestine. This review focuses on current knowledge and novel insight regarding its pathogenesis, outcome, and treatment, with an emphasis on future directions.
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http://dx.doi.org/10.1007/s11894-018-0608-yDOI Listing
January 2018

Outcomes after Allogeneic Stem Cell Transplantation in Patients with Double-Hit and Double-Expressor Lymphoma.

Biol Blood Marrow Transplant 2018 03 28;24(3):514-520. Epub 2017 Nov 28.

Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts.

Double-hit lymphomas (DHLs) and double-expressor lymphomas (DELs) are associated with resistance to frontline and salvage immunochemotherapy, as well as autologous stem cell transplantation (SCT). We hypothesized that allogeneic SCT (alloSCT) could overcome the chemoresistance associated with DEL/DHL. We retrospectively studied the impact of DEL/DHL status in a multicenter cohort of patients who underwent alloSCT for relapsed/refractory (rel/ref) aggressive B cell non-Hodgkin lymphoma (B-NHL). Seventy-eight patients transplanted at 3 centers in whom tumor tissue was available for immunohistochemistry and fluorescence in situ hybridization were enrolled; 47% had DEL and 13% had DHL. There were no significant differences in 4-year progression-free (PFS) or overall survival (OS) between patients with DEL compared with patients without DEL (PFS 30% versus 39%, P = .24; OS 31% versus 49%, P = .17) or between patients with DHL compared with patients without DHL (PFS 40% versus 34%, P = .62; OS 50% versus 38%, P = .46). The lack of association between DEL or DHL and outcome was confirmed in multivariable models, although inadequate sample size may have limited our ability to detect significant differences. In our cohort alloSCT produced durable remissions in patients with rel/ref aggressive B-NHL irrespective of DEL and DHL status, justifying its consideration in the treatment of patients with rel/ref DEL/DHL.
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http://dx.doi.org/10.1016/j.bbmt.2017.11.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826860PMC
March 2018

Clinicopathologic Features and Prognostic Impact of Lymph Node Involvement in Patients With Breast Implant-associated Anaplastic Large Cell Lymphoma.

Am J Surg Pathol 2018 03;42(3):293-305

Departments of Hematopathology.

Breast implant-associated anaplastic large cell lymphoma (BI-ALCL) is a rare T-cell lymphoma that arises around breast implants. Most patients manifest with periprosthetic effusion, whereas a subset of patients develops a tumor mass or lymph node involvement (LNI). The aim of this study is to describe the pathologic features of lymph nodes from patients with BI-ALCL and assess the prognostic impact of LNI. Clinical findings and histopathologic features of lymph nodes were assessed in 70 patients with BI-ALCL. LNI was defined by the histologic demonstration of ALCL in lymph nodes. Fourteen (20%) patients with BI-ALCL had LNI, all lymph nodes involved were regional, the most frequent were axillary (93%). The pattern of involvement was sinusoidal in 13 (92.9%) cases, often associated with perifollicular, interfollicular, and diffuse patterns. Two cases had Hodgkin-like patterns. The 5-year overall survival was 75% for patients with LNI and 97.9% for patients without LNI at presentation (P=0.003). Six of 49 (12.2%) of patients with tumor confined by the capsule had LNI, compared with LNI in 8/21 (38%) patients with tumor beyond the capsule. Most patients with LNI achieved complete remission after various therapeutic approaches. Two of 14 (14.3%) patients with LNI died of disease compared with 0/56 (0%) patients without LNI. Twenty percent of patients with BI-ALCL had LNI by lymphoma, most often in a sinusoidal pattern. We conclude that BI-ALCL beyond capsule is associated with a higher risk of LNI. Involvement of lymph nodes was associated with decreased overall survival. Misdiagnosis as Hodgkin lymphoma is a pitfall.
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http://dx.doi.org/10.1097/PAS.0000000000000985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500854PMC
March 2018

Syphilis of the Aerodigestive Tract.

Am J Surg Pathol 2018 04;42(4):472-478

Department of Pathology, Massachusetts General Hospital, Boston, MA.

Syphilis, a sexually transmitted infection caused by the Gram-negative bacterium Treponema pallidum, is increasing in prevalence in the United States. It has been our experience that primary and secondary syphilis of the aerodigestive tract can afflict a large age spectrum with varied clinical and histopathologic findings, which can lead to diagnostic problems and frequent misdiagnosis. In this study, we describe the histopathologic patterns of syphilis of the aerodigestive tract to expand awareness of its varied appearance. We identify 3 patterns of inflammatory response to syphilis: plasma cell-rich, lymphohistiocytic, and lymphoma-like. We also report the presence of immunoglobulin G4-predominant plasma cells in the inflammatory response as a potential mimicker of immunoglobulin G4-related disease. Lastly, we found that use of T. pallidum immunohistochemical stain is more reliable than Steiner silver stain at the identification of spirochetes. Our study highlights that despite convention, plasma cells are not always abundant in syphilis. Awareness of the histopathologic range of syphilis in the aerodigestive tract by the surgical pathologist can lead to the correct diagnosis and guide appropriate treatment.
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http://dx.doi.org/10.1097/PAS.0000000000000987DOI Listing
April 2018

Case 25-2017.

N Engl J Med 2017 Aug;377(7):677-688

From the Department of Medical Oncology, Dana-Farber Cancer Institute (A.S.L.), the Departments of Radiology (E.J.F.), Medicine (R.H.G.), and Pathology (A.R.S.), Massachusetts General Hospital, and the Departments of Medicine (A.S.L., R.H.G.), Radiology (E.J.F.), and Pathology (A.R.S.), Harvard Medical School - all in Boston.

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http://dx.doi.org/10.1056/NEJMcpc1706099DOI Listing
August 2017

mTOR, VEGF, PDGFR, and c-kit signaling pathway activation in Kaposi sarcoma.

Hum Pathol 2017 07 12;65:157-165. Epub 2017 May 12.

Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. Electronic address:

Kaposi sarcoma (KS) is a locally progressive, intermediate-grade vascular neoplasm with no known cure, high recurrence rates, and potential for wide dissemination. Low efficacy and high toxicity limit current therapeutic options for advanced disease. Activation of mammalian target of rapamycin (mTOR), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and c-kit signaling pathways has been implicated in KS pathogenesis and may suggest a role for targeted inhibitors. KS cases were retrospectively retrieved (N=274), most (90%) associated with human immunodeficiency virus. Tissue microarray slides were stained with human herpes virus-8, Friend leukemia integration 1 transcription factor, CD117 (c-kit), phospho-S6 (pS6), PDGF receptor-β, VEGF, and phospho-mTOR. Both intensity and extent of staining were scored. Multiplying these scores for each core yielded total staining H-scores. Human herpes virus-8 was positive in 87% and Friend leukemia integration 1 transcription factor in 95.7% of cases. Most were also VEGF+ (97.6%), pS6+ (95.7%), CD117+ (92.5%), and PDGFRB+ (87.4%). Approximately half (55.6%) were phospho-mTOR+. There was no significant difference in staining among patients with low (<500 cells/mm) or preserved CD4 T-cell counts. Immunohistochemistry confirms upregulation of the mTOR, PDGF, VEGF, and c-kit pathways in a large cohort of KS samples. Of proteins tested, pS6, downstream of mTOR, demonstrated the highest proportion of strong positivity (67.1%). These results support the possibility of using targeted inhibitors in KS. Overexpression was independent of CD4 count, suggesting that even patients with low counts may be targeted therapy candidates.
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http://dx.doi.org/10.1016/j.humpath.2017.05.002DOI Listing
July 2017

Diffuse large B-cell lymphoma with concurrent high MYC and BCL2 expression shows evidence of active B-cell receptor signaling by quantitative immunofluorescence.

PLoS One 2017 17;12(2):e0172364. Epub 2017 Feb 17.

Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, United States of America.

B-cell receptor (BCR)-mediated signaling plays an important role in the pathogenesis of a subset of diffuse large B-cell lymphoma (DLBCL), and novel agents targeting this pathway are now in clinical use. We have previously identified a signature of active BCR signaling on formalin-fixed paraffin-embedded specimens using quantitative immunofluorescence, allowing for identification of patients who might benefit from anti-BCR therapies. We sought to characterize the clinicopathologic significance of active BCR signaling in DLBCL by correlating measures of signaling intensity with clinical features and various tumor cell characteristics. High MYC and concurrent high MYC and BCL2 double-expression was positively correlated with individual markers of active BCR signaling and cases with MYC/BCL2 double-expression showed overall greater BCR activation compared to cases lacking double-expression. Our findings suggest that the BCR signaling pathway may be more active in MYC/BCL2 double-expressor DLBCL and may represent a rational therapeutic target in this aggressive DLBCL subgroup.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0172364PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5315400PMC
August 2017

Fibrin-associated EBV-positive Large B-Cell Lymphoma: An Indolent Neoplasm With Features Distinct From Diffuse Large B-Cell Lymphoma Associated With Chronic Inflammation.

Am J Surg Pathol 2017 Mar;41(3):299-312

*Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI †Department of Pathology, The James Homer Wright Pathology Laboratories of the Massachusetts General Hospital, Harvard Medical School, Boston ‡‡Department of Pathology, North Shore Medical Center, Salem, MA ‡Department of Anatomical Pathology, St Vincent's Hospital, Melbourne, Vic., Australia §Institut Universitaire de Pathologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland ∥Department of Laboratory Medicine, University of Washington, Seattle, WA ¶Department of Pathology, Samsung Medical Center, Sungkyunkwan University, Seoul, Republic of Korea #Herbert Wertheim College of Medicine, Florida International University, Miami, FL **Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN ††Department of Pathology, Holmes Regional Medical Center, Melbourne, FL §§NeoGenomics Laboratories, Aliso Viejo, CA ∥∥Department of Pathology, Johns Hopkins University School of Medicine, Baltimore ¶¶Laboratory of Pathology, Hematopathology Section, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Incidental cases of localized fibrin-associated Epstein-Barr virus (EBV)+ large B-cell proliferations have been described at unusual anatomic sites and have been included in the category of diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI) in the WHO Classification. We describe 12 cases and review the literature to define their clinicopathologic spectrum and compare features with typical cases of DLBCL-CI. Median age was 55.5 years with a M:F ratio of 3. In all 12 cases, the lymphoma was an incidental microscopic finding involving atrial myxomas (n=3), thrombi associated with endovascular grafts (n=3), chronic hematomas (n=2), and pseudocysts (n=4). All cases tested were nongerminal center B-cell origin, type III EBV latency, and were negative for MYC rearrangements and alternative lengthening of telomeres by FISH. Most showed high CD30, Ki67, and PD-L1, and low to moderate MYC and p53 expression. Among 11 patients with detailed follow-up, 6 were treated surgically, 3 with cardiac or vascular lesions had persistent/recurrent disease at intravascular sites, and 4 died of causes not directly attributable to lymphoma. Reports of previously published fibrin-associated cases showed similar features, whereas traditional DLBCL-CI cases with a mass lesion had significantly higher lymphoma-associated mortality. Fibrin-associated EBV+ large B-cell lymphoma is clinicopathologically distinct from DLBCL-CI, warranting separate classification. Most cases, particularly those associated with pseudocysts, behave indolently with the potential for cure by surgery alone and may represent a form of EBV+ lymphoproliferative disease rather than lymphoma. However, primary cardiac or vascular disease may have a higher risk of recurrence despite systemic chemotherapy.
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http://dx.doi.org/10.1097/PAS.0000000000000775DOI Listing
March 2017

Simple matters in complex times.

Authors:
Aliyah R Sohani

Am J Hematol 2017 03 4;92(3):230-231. Epub 2017 Feb 4.

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1002/ajh.24652DOI Listing
March 2017

Diagnostic work-up of acute myeloid leukemia.

Am J Hematol 2017 Mar 3;92(3):317-321. Epub 2017 Feb 3.

Department of Pathology, Harvard Medical School, Boston, Massachusetts.

Acute myeloid leukemia (AML) is characterized by a clonal expansion of undifferentiated myeloid precursors resulting in impaired hematopoiesis and bone marrow failure. In 2016, the World Health Organization (WHO) published revisions to the classification of myeloid neoplasms and acute leukemias. Similar to the 2008 classification, the updated classification incorporates clinical features, morphology, immunophenotyping, and cytogenetics, with greater emphasis on molecular genetics, to define disease entities. This brief review addresses the various components of pathologic assessment to establish a diagnosis of AML and to help risk stratify patients, with an emphasis on newer techniques used in the detection of mutations with prognostic significance, as well as assays employed in the evaluation of minimal residual disease following treatment.
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http://dx.doi.org/10.1002/ajh.24648DOI Listing
March 2017

Relapsed or Refractory Double-Expressor and Double-Hit Lymphomas Have Inferior Progression-Free Survival After Autologous Stem-Cell Transplantation.

J Clin Oncol 2017 Jan 24;35(1):24-31. Epub 2016 Oct 24.

Alex F. Herrera, Matthew Mei, Lawrence Low, Joo Y. Song, Victoria Bedell, Lithua Budde, Wing C. Chan, Robert Chen, Joyce Murata-Collins, Auayporn P. Nademanee, Raju Pillai, Leslie Popplewell, Tanya Siddiqi, Jasmine Zain, Steven T. Rosen, Larry W. Kwak, Stephen J. Forman, Dennis D. Weisenburger, Young Kim, Amrita Krishnan, Tanya Paris, Tracey Stiller, Joycelynne M. Palmer, City of Hope National Medical Center, Duarte, CA; Haesook T. Kim, Jennifer R. Brown, Matthew S. Davids, Arnold S. Freedman, David C. Fisher, Eric D. Jacobsen, Caron A. Jacobson, Ann S. LaCasce, David M. Weinstock, Scott J. Rodig, Philippe Armand, Dana-Farber Cancer Institute; Gabriel K. Griffin, Reid W. Merryman, Christine Pak, Heather Sun, Brigham and Women's Hospital; German A. Pihan, Beth Israel Deaconess Medical Center; and Aliyah R. Sohani, Massachusetts General Hospital, Boston, MA.

Purpose Double-hit lymphomas (DHLs) and double-expressor lymphomas (DELs) are subtypes of diffuse large B-cell lymphoma (DLBCL) associated with poor outcomes after standard chemoimmunotherapy. Data are limited regarding outcomes of patients with relapsed or refractory (rel/ref) DEL or DHL who undergo autologous stem-cell transplantation (ASCT). We retrospectively studied the prognostic impact of DEL and DHL status on ASCT outcomes in patients with rel/ref DLBCL. Methods Patients with chemotherapy-sensitive rel/ref DLBCL who underwent ASCT at two institutions and in whom archival tumor material was available were enrolled. Immunohistochemistry for MYC, BCL2, and BCL6 and fluorescence in situ hybridization (FISH) for MYC were performed. In cases with MYC rearrangement or copy gain, FISH for BCL2 and BCL6 was also performed. Results A total of 117 patients were included; 44% had DEL and 10% had DHL. DEL and DHL were associated with inferior progression-free survival (PFS), and DHL was associated with poorer overall survival (OS). The 4-year PFS in patients with DEL compared with those with non-DEL was 48% versus 59% ( P = .049), and the 4-year OS was 56% versus 67% ( P = .10); 4-year PFS in patients with DHL compared with those with non-DHL was 28% versus 57% ( P = .013), and 4-year OS was 25% versus 61% ( P = .002). The few patients with concurrent DEL and DHL had a poor outcome (4-year PFS, 0%). In multivariable models, DEL and DHL were independently associated with inferior PFS, whereas DHL and partial response ( v complete response) at transplant were associated with inferior OS. Conclusion DEL and DHL are both associated with inferior outcomes after ASCT in patients with rel/ref DLBCL. Although ASCT remains a potentially curative approach, these patients, particularly those with DHL, are a high-risk subset who should be targeted for investigational strategies other than standard ASCT.
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http://dx.doi.org/10.1200/JCO.2016.68.2740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455688PMC
January 2017