Publications by authors named "Elizabeth A Morgan"

76 Publications

Genomic landscape of cutaneous follicular lymphomas reveals 2 subgroups with clinically predictive molecular features.

Blood Adv 2021 Feb;5(3):649-661

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

Primary cutaneous follicle center lymphomas (PCFCLs) are indolent B-cell lymphomas that predominantly remain skin restricted and manageable with skin-directed therapy. Conversely, secondary cutaneous involvement by usual systemic follicular lymphoma (secondary cutaneous follicular lymphoma [SCFL]) has a worse prognosis and often necessitates systemic therapy. Unfortunately, no histopathologic or genetic features reliably differentiate PCFCL from SCFL at diagnosis. Imaging may miss low-burden internal disease in some cases of SCFLs, leading to misclassification as PCFCL. Whereas usual systemic FL is well characterized genetically, the genomic landscapes of PCFCL and SCFL are unknown. Herein, we analyzed clinicopathologic and immunophenotypic data from 30 cases of PCFCL and 10 of SCFL and performed whole-exome sequencing on 18 specimens of PCFCL and 6 of SCFL. During a median follow-up of 7 years, 26 (87%) of the PCFCLs remained skin restricted. In the remaining 4 cases, systemic disease developed within 3 years of diagnosis. Although the SCFLs universally expressed BCL2 and had BCL2 rearrangements, 73% of the PCFCLs lacked BCL2 expression, and only 8% of skin-restricted PCFCLs had BCL2 rearrangements. SCFLs showed low proliferation fractions, whereas 75% of PCFCLs had proliferation fractions >30%. Of the SCFLs, 67% had characteristic loss-of-function CREBBP or KMT2D mutations vs none in skin-restricted PCFCL. Both SCFL and skin-restricted PCFCL showed frequent TNFRSF14 loss-of-function mutations and copy number loss at chromosome 1p36. These data together establish PCFCL as a unique entity with biological features distinct from usual systemic FL and SCFL. We propose 3 criteria based on BCL2 rearrangement, chromatin-modifying gene mutations (CREBBP, KMT2D, EZH2, and EP300), and proliferation index to classify cutaneous FL specimens based on the likelihood of concurrent or future systemic spread.
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http://dx.doi.org/10.1182/bloodadvances.2020002469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876877PMC
February 2021

Imaging of IgG4-Related Disease in the Head and Neck: A Systematic Review, Case Series, and Pathophysiology Update.

J Neuroradiol 2021 Jan 28. Epub 2021 Jan 28.

Division of Neuroradiology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Electronic address:

This systematic review aims to clarify and comprehensively detail the sometimes variable published imaging features as well as the pathogenesis, clinical diagnostic criteria, and treatment options of IgG4-Related Diseases (IgG4-RD) in the head and neck to aid the radiologist in diagnosing relapse and new sites of disease. A literature search in PubMed and EMBASE for reported cases of IgG4-RD was performed in December 2019. Case reports or series of IgG4-RD in the head and neck in adults that included sufficient imaging and pathology findings were included. This yielded 50 reports. IgG4-RD locations included the orbits, thyroid, pituitary gland, paranasal sinuses, salivary and parotid glands, larynx, pharynx, cervical lymph nodes, meninges, and skull base. Most lesions demonstrated non-specific homogenous CT attenuation, diffuse enhancement, isointense/low T2 signal intensity, and low T1 signal intensity. 6 cases from our institution followed previously reported imaging patterns.
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http://dx.doi.org/10.1016/j.neurad.2021.01.006DOI Listing
January 2021

Cohesin mutations alter DNA damage repair and chromatin structure and create therapeutic vulnerabilities in MDS/AML.

JCI Insight 2021 Feb 8;6(3). Epub 2021 Feb 8.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

The cohesin complex plays an essential role in chromosome maintenance and transcriptional regulation. Recurrent somatic mutations in the cohesin complex are frequent genetic drivers in cancer, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Here, using genetic dependency screens of stromal antigen 2-mutant (STAG2-mutant) AML, we identified DNA damage repair and replication as genetic dependencies in cohesin-mutant cells. We demonstrated increased levels of DNA damage and sensitivity of cohesin-mutant cells to poly(ADP-ribose) polymerase (PARP) inhibition. We developed a mouse model of MDS in which Stag2 mutations arose as clonal secondary lesions in the background of clonal hematopoiesis driven by tet methylcytosine dioxygenase 2 (Tet2) mutations and demonstrated selective depletion of cohesin-mutant cells with PARP inhibition in vivo. Finally, we demonstrated a shift from STAG2- to STAG1-containing cohesin complexes in cohesin-mutant cells, which was associated with longer DNA loop extrusion, more intermixing of chromatin compartments, and increased interaction with PARP and replication protein A complex. Our findings inform the biology and therapeutic opportunities for cohesin-mutant malignancies.
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http://dx.doi.org/10.1172/jci.insight.142149DOI Listing
February 2021

Contribution of clonal hematopoiesis to adult-onset hemophagocytic lymphohistiocytosis.

Blood 2020 Dec;136(26):3051-3055

Department of Medical Oncology, Dana-Farber Cancer Institute.

Adult-onset hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disease of immune hyperactivation. Unlike pediatric HLH, adult HLH is rarely driven by germline genetic variants. Although numerous precipitating etiologies have been identified, the reason that HLH occurs in only a subset of individuals and how other factors contribute to the disease remains unknown. We hypothesized that clonal hematopoiesis (CH), a state in which somatic mutations in blood cells cause an expanded population of mutant hematopoietic cells and drive an aberrant inflammatory state, could contribute to adult-onset HLH. In a highly annotated cohort of older adults with HLH we found that CH was more prevalent than in control cohorts. Using the adult-onset HLH mouse model in which repeated treatments of the TLR9 agonist, ODN1826, was delivered to the mouse, we observed that macrophages carrying mutations in Tet2, one of the most commonly mutated genes in CH, have an enhanced inflammatory response to TLR9 agonism. Finally, mice carrying Tet2 mutations in the hematopoietic compartment (a common model for CH) displayed an exaggerated response to TLR9 agonism, including worse splenomegaly and anemia. Our data suggest that CH is more common in individuals with adult-onset HLH and can contribute to the pathophysiology of this disease.
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http://dx.doi.org/10.1182/blood.2020008206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770567PMC
December 2020

Harmonization of the Essentials: Matching Diagnostics to Treatments for Global Oncology.

JCO Glob Oncol 2020 08;6:1352-1356

Center for Global Health, American Society for Clinical Pathology, Chicago, IL.

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http://dx.doi.org/10.1200/GO.20.00338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529511PMC
August 2020

Why "good enough" is not good enough: scientific data, not supply chain deficiencies, should be driving Centers for Disease Control and Prevention recommendations.

Am J Obstet Gynecol MFM 2020 Aug 25;2(3):100165. Epub 2020 Jun 25.

Department of Maternal-Fetal Medicine, Baystate Medical Center, Springfield, MA.

Obstetricians and clinicians previously requested clarification from the Centers for Disease Control and Prevention on the need for full personal protective equipment including N95 respirators during the second stage of labor. The Centers for Disease Control and Prevention responded with new guidance excluding the second stage of labor from its list of aerosol-generating procedures based on research from which experience on labor and delivery units was notably absent. Additional literature that explores other modes of aerosol generation, such as coughing, vomiting, passing flatus, and loud vocalization, all of which are prevalent during the labor course, was notably omitted. It is clear that the Centers for Disease Control and Prevention based their guidance not from the application of scientific principles but from pragmatism owing to the lack of equipment, and our colleagues were urged to follow suit. If we replace recommendations based on scientific principles with recommendations based on supply chain deficiencies, we become complacent with that which is "good enough under the circumstances." This is a dangerous precedent on which to base our professional society guidelines. We should continue to address these inadequate responses even as Centers for Disease Control and Prevention guidelines evolve and the pandemic winds down. We will certainly face similar conflict again, whether during a fall resurgence of the current pandemic or a future infectious disease outbreak.
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http://dx.doi.org/10.1016/j.ajogmf.2020.100165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315143PMC
August 2020

LIM domain only 2 (LMO2) expression distinguishes T-lymphoblastic leukemia/lymphoma from indolent T-lymphoblastic proliferations.

Histopathology 2020 Dec 24;77(6):984-988. Epub 2020 Sep 24.

Department of Pathology, University of California San Francisco, San Francisco, CA, USA.

Aims: An indolent T-lymphoblastic proliferation (iT-LBP) is a benign, reactive expansion of immature terminal deoxynucleotidyl transferase (TdT)-positive T cells found in extrathymic tissues. iT-LBP can be challenging to distinguish from malignant processes, specifically T-lymphoblastic lymphoma (T-LBL), given the overlapping clinical and histological features. Recently, it has been shown that LIM domain only 2 (LMO2) is overexpressed in T-LBL but not in reactive immature TdT+ T cells in the thymus. On the basis of these findings, the aim of this study was to investigate the expression of LMO2 by using immunohistochemistry and its role in differentiating iT-LBPs from T-LBLs.

Methods And Results: We retrospectively identified cases of iT-LBP and T-LBL from the pathology archives of four institutions. Seven iT-LBP cases (including five new cases that have not been reported in the literature) and 13 T-LBL cases were analysed. Clinical, morphological, immunophenotypic and molecular data were analysed. Immunohistochemical staining with LMO2 was performed on all iT-LBP and T-LBL cases. A review of five new iT-LBP cases showed similar morphological, immunophenotypic and molecular features to those of previously reported cases. All iT-LBP cases were negative for LMO2 (0/7), whereas 92% of T-LBL cases (12/13) expressed LMO2; the sensitivity was 92% (confidence interval 64-100%) and the specificity was 100% (confidence interval 59-100%).

Conclusion: We confirm previously published findings that iT-LBP cases show highly overlapping morphological and immunophenotypic features with T-LBL. Importantly, LMO2 expression is a sensitive and specific marker with which to rule out iT-LBP.
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http://dx.doi.org/10.1111/his.14176DOI Listing
December 2020

Genomic Profiling of Smoldering Multiple Myeloma Identifies Patients at a High Risk of Disease Progression.

J Clin Oncol 2020 07 22;38(21):2380-2389. Epub 2020 May 22.

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Purpose: Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with a 10% annual risk of progression. Various prognostic models exist for risk stratification; however, those are based on solely clinical metrics. The discovery of genomic alterations that underlie disease progression to MM could improve current risk models.

Methods: We used next-generation sequencing to study 214 patients with SMM. We performed whole-exome sequencing on 166 tumors, including 5 with serial samples, and deep targeted sequencing on 48 tumors.

Results: We observed that most of the genetic alterations necessary for progression have already been acquired by the diagnosis of SMM. Particularly, we found that alterations of the mitogen-activated protein kinase pathway ( and single nucleotide variants [SNVs]), the DNA repair pathway (deletion 17p, , and SNVs), and (translocations or copy number variations) were all independent risk factors of progression after accounting for clinical risk staging. We validated these findings in an external SMM cohort by showing that patients who have any of these three features have a higher risk of progressing to MM. Moreover, APOBEC associated mutations were enriched in patients who progressed and were associated with a shorter time to progression in our cohort.

Conclusion: SMM is a genetically mature entity whereby most driver genetic alterations have already occurred, which suggests the existence of a right-skewed model of genetic evolution from monoclonal gammopathy of undetermined significance to MM. We identified and externally validated genomic predictors of progression that could distinguish patients at high risk of progression to MM and, thus, improve on the precision of current clinical models.
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http://dx.doi.org/10.1200/JCO.20.00437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367550PMC
July 2020

Comprehensive metagenomic analysis of blastic plasmacytoid dendritic cell neoplasm.

Blood Adv 2020 03;4(6):1006-1011

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a hematologic malignancy believed to originate from plasmacytoid dendritic cells (pDCs), the immune cells responsible for producing type 1 interferons during infection. Nearly all patients with BPDCN have prominent skin involvement, with cutaneous infiltration occupying the dermis and subcutis. One half of patients present with BPDCN cells only in the skin, with no evidence of disease elsewhere. Because normal pDCs are rare or absent in cutaneous sites, and they only traffic to the skin after activation by pathogen or inflammation, our aim was to determine if a microorganism is associated with BPDCN. We performed RNA sequencing in BPDCN skin and bone marrow, with cutaneous T-cell lymphoma (CTCL) and normal skin as controls. GATK-PathSeq was used to identify known microbial sequences. Bacterial reads in BPDCN skin were components of normal flora and did not distinguish BPDCN from controls. We then developed a new computational tool, virID (Viral Identification and Discovery; https://github.com/jnoms/virID), for identification of microbial-associated reads remaining unassigned after GATK-PathSeq. We found no evidence for a known or novel virus in BPDCN skin or bone marrow, despite confirming that virID could identify Merkel cell polyomavirus in Merkel cell carcinoma, human papillomavirus in head and neck squamous cell carcinoma, and Kaposi's sarcoma herpesvirus in Kaposi's sarcoma in a blinded fashion. Thus, at the level of sensitivity used here, we found no clear pathogen linked to BPDCN.
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http://dx.doi.org/10.1182/bloodadvances.2019001260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094006PMC
March 2020

Detection of the KIT mutation in myelodysplastic and/or myeloproliferative neoplasms and acute myeloid leukemia with myelodysplasia-related changes predicts concurrent systemic mastocytosis.

Mod Pathol 2020 06 2;33(6):1135-1145. Epub 2020 Jan 2.

Harvard Medical School, Boston, MA, USA.

Greater than 90% of cases of systemic mastocytosis (SM) harbor pathogenic KIT mutations, particularly KIT. Prognostically-significant pathogenic KIT mutations also occur in 30-40% of core binding factor-associated acute myeloid leukemia (CBF-AML), but are uncommonly associated with concurrent SM. By comparison, the occurrence of SM in other myeloid neoplasms bearing pathogenic KIT mutations, particularly those with a chronic course, is poorly understood. Review of clinical next-generation sequencing (NGS) performed at our institutions in patients with known or suspected hematologic malignancies over an 8-year period revealed 64 patients with both a pathogenic KIT mutation detected at one or more timepoints and available bone marrow biopsy materials. Patients with KIT-mutated myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), or overlap MDS/MPN (n = 22) accounted for approximately one-third of our cohort (34%). Comprehensive morphologic and immunophenotypic characterization revealed that nearly all cases (n = 20, 91%) exhibited concurrent SM. In contrast, of the 18 patients (28%) with AML and KIT, only eight (44%) showed evidence of SM at any point in their disease course (p = 0.0021); of these eight, the AML component was characterized as AML with myelodysplasia-related changes (AML-MRC) in all but one instance (n = 7, 87%). Twelve patients (19%) had pathogenic KIT mutations other than p.D816V, all in the setting of AML (CFB-AML, n = 7; AML, not otherwise specified, n = 2; AML-MRC, n = 1; acute promyelocytic leukemia, n = 1); only two of these patients (17%), both with CBF-AML, exhibited concurrent SM. The remaining 12 patients (19%) had SM without evidence of an associated hematological neoplasm (AHN). For nearly one-third of the 30 SM-AHN patients in our cohort (n = 9, 30%), the SM component of their disease was not initially clinicopathologically recognized. We propose that identification of the KIT mutation in patients diagnosed with MDS, MPN, MDS/MPN, or AML-MRC should trigger reflex testing for SM.
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http://dx.doi.org/10.1038/s41379-019-0447-xDOI Listing
June 2020

Proapoptotic protein BIM as a novel prognostic marker in mantle cell lymphoma.

Hum Pathol 2019 11 16;93:54-64. Epub 2019 Aug 16.

Department of Pathology, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT 06510. Electronic address:

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma. Numerous studies have demonstrated many genetic aberrations in MCL in addition to the characteristic t(11:14), including frequent biallelic deletions of Bim, a proapoptotic member of the BCL-2 family. In mice, Bim deletion coupled with cyclin D1 overexpression generates pathologic and molecular features of human MCL. Since the regulation of apoptosis is crucial in MCL pathogenesis, we hypothesize that BIM expression may be associated with tumor cell survival. Clinical data and tissue from 100 nodal MCL cases between 1988 and 2009 were collected from three large academic medical centers. The average patient age of our MCL cohort was 65.5 years old (range, 42-97) with a 2:1 male to female ratio. Immunohistochemistry was performed with a validated anti-BIM antibody. Patients were separated into low and high BIM-expressing categories with a cutoff of 80%. As expected for a proapoptotic tumor suppressor, patients with high BIM expression were less likely to have progressive disease and more likely to have a complete response (P = .022). In addition, high BIM-expressing MCL tumors revealed a trend toward increased overall survival with this trend persisting in sub-analysis of Ann Arbor stages III and IV. No correlation between BIM expression, Ki-67 index, and MIPI score was observed, suggesting a role for BIM as a novel independent prognostic factor. While BIM is only one member of a complex family of apoptosis-regulating proteins, these findings may yield clinically relevant information for the prognosis and therapeutic susceptibility of MCL.
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http://dx.doi.org/10.1016/j.humpath.2019.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038910PMC
November 2019

Targeted inhibition of CD47-SIRPα requires Fc-FcγR interactions to maximize activity in T-cell lymphomas.

Blood 2019 10;134(17):1430-1440

Harvard Medical School, Boston, MA.

Antibodies that bind CD47 on tumor cells and prevent interaction with SIRPα on phagocytes are active against multiple cancer types including T-cell lymphoma (TCL). Here we demonstrate that surface CD47 is heterogeneously expressed across primary TCLs, whereas major histocompatibility complex (MHC) class I, which can also suppress phagocytosis, is ubiquitous. Multiple monoclonal antibodies (mAbs) that block CD47-SIRPα interaction promoted phagocytosis of TCL cells, which was enhanced by cotreatment with antibodies targeting MHC class I. Expression levels of surface CD47 and genes that modulate CD47 pyroglutamation did not correlate with the extent of phagocytosis induced by CD47 blockade in TCL lines. In vivo treatment of multiple human TCL patient-derived xenografts or an immunocompetent murine TCL model with a short course of anti-CD47 mAb markedly reduced lymphoma burden and extended survival. Depletion of macrophages reduced efficacy in vivo, whereas depletion of neutrophils had no effect. F(ab')2-only fragments of anti-CD47 antibodies failed to induce phagocytosis by human macrophages, indicating a requirement for Fc-Fcγ receptor interactions. In contrast, F(ab')2-only fragments increased phagocytosis by murine macrophages independent of SLAMF7-Mac-1 interaction. Full-length anti-CD47 mAbs also induced phagocytosis by Fcγ receptor-deficient murine macrophages. An immunoglobulin G1 anti-CD47 mAb induced phagocytosis and natural killer cell-mediated cytotoxicity of TCL cells that was augmented by cotreatment with mogamulizumab, an anti-CCR4 mAb, or a mAb blocking MHC class I. These studies help explain the disparate activity of monotherapy with agents that block CD47 in murine models compared with patients. They also have direct translational implications for the deployment of anti-CD47 mAbs alone or in combination.
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http://dx.doi.org/10.1182/blood.2019001744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839960PMC
October 2019

The effect of placental location in cases of placenta accreta spectrum.

Am J Obstet Gynecol 2019 10 22;221(4):357.e1-357.e5. Epub 2019 Jul 22.

Minnesota Perinatal Physicians, Allina Health, Minnesota, MN.

Background: Placenta accreta spectrum affects approximately 3 in 1000 pregnancies. There is a paucity of data evaluating the effect of placental location on diagnosis, risk factors, and resultant outcomes in cases of placenta accreta spectrum.

Objective: We analyzed placenta accreta spectrum cases to assess whether risk factors or maternal outcomes varied based on placental location.

Materials And Methods: We performed a retrospective chart review of pathology-confirmed cases of placenta accreta spectrum from patients delivering at 2 large urban hospitals in the same healthcare system from 2007 to 2017. Placental location was defined by ultrasound images and confirmed by pathology reports. Location was categorized as anterior, posterior, or anterior/posterior for those with placental location at both sites. Fisher exact tests and analysis of variance were used to examine associations with measures of diagnosis, risk factors, and maternal outcomes.

Results: A total of 86 pathology-confirmed placenta accreta spectrum cases were reviewed. The distribution of placental location on ultrasound was as follows: 19% posterior, 59% anterior, and 22% anterior/posterior. We found that prior cesarean delivery was lower with posterior placenta accreta spectrum (63% vs 94% vs 84% in the anterior and anterior/posterior groups respectively; (P = .007); however, in vitro fertilization rates were significantly higher (38% vs 2% vs 5% in the anterior and anterior/posterior groups respectively; P = .001). There was also lower incidence of percreta with posterior placenta accreta spectrum compared to the anterior and anterior/posterior groups (19% vs 47% vs 58% respectively; P = .055). Posterior cases were less likely to have placenta accreta spectrum suspected prenatally (50%) compared to anterior (80%) and anterior/posterior (89%) cases (P = .019). Despite late diagnosis, ureteral injury was the only surgical complication that was more common in patients with posterior placenta accreta spectrum (13% vs 0% vs 5% for anterior and anterior/posterior groups respectively; P = .037).

Conclusion: Placenta accreta spectrum with posterior placental location is associated with delayed diagnosis, surgical complications, assisted reproductive technology, and lower numbers of prior cesarean deliveries relative to anterior location. These differences in outcomes and risk factors based on placental location may allow for heightened clinical awareness, and improved diagnosis and management.
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http://dx.doi.org/10.1016/j.ajog.2019.07.028DOI Listing
October 2019

Recurrent genetic HLA loss in AML relapsed after matched unrelated allogeneic hematopoietic cell transplantation.

Blood Adv 2019 07;3(14):2199-2204

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Immune evasion is a hallmark of cancer and a central mechanism underlying acquired resistance to immune therapy. In allogeneic hematopoietic cell transplantation (alloHCT), late relapses can arise after prolonged alloreactive T-cell control, but the molecular mechanisms of immune escape remain unclear. To identify mechanisms of immune evasion, we performed a genetic analysis of serial samples from 25 patients with myeloid malignancies who relapsed ≥1 year after alloHCT. Using targeted sequencing and microarray analysis to determine HLA allele-specific copy number, we identified copy-neutral loss of heterozygosity events and focal deletions spanning class 1 HLA genes in 2 of 12 recipients of matched unrelated-donor HCT and in 1 of 4 recipients of mismatched unrelated-donor HCT. Relapsed clones, although highly related to their antecedent pretransplantation malignancies, frequently acquired additional mutations in transcription factors and mitogenic signaling genes. Previously, the study of relapse after haploidentical HCT established the paradigm of immune evasion via loss of mismatched HLA. Here, in the context of matched unrelated-donor HCT, HLA loss provides genetic evidence that allogeneic immune recognition may be mediated by minor histocompatibility antigens and suggests opportunities for novel immunologic approaches for relapse prevention.
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http://dx.doi.org/10.1182/bloodadvances.2019000445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650729PMC
July 2019

Variable loss of CD30 expression by immunohistochemistry in recurrent cutaneous CD30+ lymphoid neoplasms treated with brentuximab vedotin.

J Cutan Pathol 2019 Nov 2;46(11):823-829. Epub 2019 Aug 2.

Dermatopathology Unit, Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.

Aims: Brentuximab vedotin is a monoclonal anti-CD30 antibody-drug conjugate that has been used to treat a variety of CD30+ neoplasms. The phenomenon of antigen loss has been observed in patients treated with the anti-CD20 antibody rituximab. This study seeks to assess for antigen loss in the setting of recurrent CD30+ neoplasms treated with brentuximab vedotin.

Methods: We report nine cases of persistent/recurrent cutaneous CD30+ lymphoid neoplasms that demonstrated variable CD30 expression after treatment with brentuximab vedotin. Cases include MF (n = 6), cutaneous T-cell lymphoma, not otherwise specified (n = 1), and anaplastic large cell lymphoma (ALCL), both primary (n = 1) and systemic (n = 1).

Results: Immunohistochemical staining revealed decreased CD30 expression following brentuximab vedotin therapy in seven of nine cases. In these seven cases, the pre-treatment percent of tumor cells staining for CD30 ranged from 10% to 100% (mean 50.0%, SD 27.8%), compared to 5% to 50% (mean 14.5%, SD 14.8%, P = 0.003) at recurrence.

Conclusions: This case series highlights the finding that CD30 positivity can be variable in recurrences after treatment with anti-CD30 antibodies. This serves to raise awareness of the phenomenon of antigen loss after treatment with brentuximab vedotin and underscores the utility of performing multiple biopsies and/or employing molecular diagnostic techniques in patients with recurrent/persistent disease.
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http://dx.doi.org/10.1111/cup.13545DOI Listing
November 2019

Genetic Testing in the Diagnosis and Biology of Myeloid Neoplasms (Excluding Acute Leukemias).

Am J Clin Pathol 2019 08;152(3):302-321

Department of Pathology and Neuropathology.

Objectives: The 2017 Workshop of the Society for Hematopathology/European Association for Haematopathology reviewed the role of genetic testing in the diagnosis of hematopoietic neoplasms, including non-acute leukemia myeloid malignancies.

Methods: The workshop panel assigned 98 submitted cases to the category of non-acute leukemia myeloid neoplasms, of which 13 were selected for oral presentation.

Results: Data from both conventional karyotyping and genetic sequencing had important impact on diagnosis, classification, and prognostication. However, some cases had genetic results that appeared discordant from the morphology and/or clinical features. Thus, the workshop underscored the need for careful management of genetic data by the pathologist and clinician, in the context of other findings.

Conclusions: The workshop cases highlighted the significance of genetic aberrations in the diagnosis and treatment of non-acute leukemia myeloid neoplasms. Many genetic data have already been incorporated in the most recent World Health Organization classification, and undoubtedly they will factor increasingly in future classifications.
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http://dx.doi.org/10.1093/ajcp/aqz069DOI Listing
August 2019

Clinicopathologic and genetic characterization of nonacute -mutated myeloid neoplasms.

Blood Adv 2019 05;3(9):1540-1545

Department of Pathology, Brigham and Women's Hospital, Boston, MA.

-mutated myeloid neoplasms ( MNs) with <20% blood or bone marrow blasts are rare and have been previously shown in limited case series to exhibit an aggressive clinical course. We assembled the largest cohort of MN cases to date (n = 45) and compared it with MN (n = 95) and de novo acute myeloid leukemia (AML; n = 119) patients. Compared with MN, MN were associated with younger age ( = .007), a normal karyotype ( < .0001), more frequent mutations involving ( = .01) and ( = .03), and fewer involving ( = .003), ( = .0004), and ( = .02). Mutations involving or () ( = .007) and (internal tandem duplication, < .0001; noninternal tandem duplication, = .01) were less frequent in MN than in AML. In multivariable analyses performed in patients with myelodysplastic syndrome only, total mutation count (hazard ratio [HR], 1.3; = .05), mutation (HR, 3.6; = .02), mutation (HR, 5.2; = .01), and higher International Prognostic Scoring System-R score (HR, 1.7; = .0003) were independently associated with shorter overall survival, whereas stem cell transplant conferred a favorable effect (HR, 0.1; < .0001). These data suggest that MN are biologically distinct from MN. Similar to AML, patients with -mutated myelodysplastic syndrome may benefit from more intensive therapeutic regimens.
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http://dx.doi.org/10.1182/bloodadvances.2019000090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517660PMC
May 2019

Mechanisms of Lymphoma Clearance Induced by High-Dose Alkylating Agents.

Cancer Discov 2019 07 30;9(7):944-961. Epub 2019 Apr 30.

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

The extraordinary activity of high-dose cyclophosphamide against some high-grade lymphomas was described nearly 60 years ago. Here we address mechanisms that mediate cyclophosphamide activity in bona fide human double-hit lymphoma. We show that antibody resistance within the bone marrow (BM) is not present upon early engraftment but develops during lymphoma progression. This resistance required a high tumor:macrophage ratio, was recapitulated in spleen by partial macrophage depletion, and was overcome by multiple, high-dose alkylating agents. Cyclophosphamide induced endoplasmic reticulum (ER) stress in BM-resident lymphoma cells that resulted in ATF4-mediated paracrine secretion of VEGFA, massive macrophage infiltration, and clearance of alemtuzumab-opsonized cells. BM macrophages isolated after cyclophosphamide treatment had increased phagocytic capacity that was reversed by VEGFA blockade or SYK inhibition. Single-cell RNA sequencing of these macrophages identified a "super-phagocytic" subset that expressed CD36/FCGR4. Together, these findings define a novel mechanism through which high-dose alkylating agents promote macrophage-dependent lymphoma clearance. SIGNIFICANCE: mAbs are effective against only a small subset of cancers. Herein, we recapitulate compartment-specific antibody resistance and define an ER stress-dependent mechanism induced by high-dose alkylating agents that promotes phagocytosis of opsonized tumor cells. This approach induces synergistic effects with mAbs and merits testing across additional tumor types...
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http://dx.doi.org/10.1158/2159-8290.CD-18-1393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606344PMC
July 2019

Intergenerational epigenetic inheritance of cancer susceptibility in mammals.

Elife 2019 04 9;8. Epub 2019 Apr 9.

Whitehead Institute, Cambridge, United States.

Susceptibility to cancer is heritable, but much of this heritability remains unexplained. Some 'missing' heritability may be mediated by epigenetic changes in the parental germ line that do not involve transmission of genetic variants from parent to offspring. We report that deletion of the chromatin regulator () in the paternal germ line results in elevated tumor incidence in genetically wild type mice. This effect increases following passage through two successive generations of male germline deletion, but is lost following passage through a wild type germ line. The H3K27me3 mark is redistributed in sperm of mutants, and we define approximately 200 H3K27me3-marked regions that exhibit increased DNA methylation, both in sperm of mutants and in somatic tissue of progeny. Hypermethylated regions in enhancers may alter regulation of genes involved in cancer initiation or progression. Epigenetic changes in male gametes may therefore impact cancer susceptibility in adult offspring.
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http://dx.doi.org/10.7554/eLife.39380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456297PMC
April 2019

A Comparison of Outcomes and Prognostic Features for Radiation-Associated Angiosarcoma of the Breast and Other Radiation-Associated Sarcomas.

Int J Radiat Oncol Biol Phys 2019 06 29;104(2):425-435. Epub 2019 Jan 29.

Department of Pathology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts. Electronic address:

Purpose: Radiation-associated sarcomas (RAS) are considered to have a poor prognosis. Although the incidence is anticipated to rise, contemporary data regarding predictors of outcomes are few. We performed a retrospective analysis to identify RAS prognostic factors and subset analyses for radiation-associated angiosarcoma arising after treatment for breast cancer (RAAB) and other RAS subtypes (other-RAS).

Methods And Materials: Patients with localized RAS evaluated at an institutional multidisciplinary sarcoma clinic were identified. Clinical and histologic review was performed, and outcomes were assessed to identify prognostic features. A subset of cases underwent molecular analysis by next-generation sequencing.

Results: Among 176 patients, histologic subtypes of RAS included angiosarcoma (41%), undifferentiated/unclassified sarcoma (40%), leiomyosarcoma (8%), malignant peripheral nerve sheath tumor (6%), and osteosarcoma (2%). Sixty-seven patients (38%) had RAAB, and 109 (62%) had other-RAS. RAAB had significantly shorter latency from time of initial radiation compared with other-RAS (8 vs. 15 years; P < .001). Treatment approaches included surgery (91%), chemotherapy (44%), and radiation therapy (27%). Median follow-up was 3.2 years; 3-year overall survival (OS) was 74%. On multivariate analysis, positive margins (P < .0001), deep tumor location (intrathoracic/intra-abdominal, P = .002), and high grade (P < .0001) were associated with worse OS. In particular, 3-year OS with negative versus positive margins was 90% versus 66%. Patients with RAAB versus other-RAS showed a trend for higher 3-year OS (84% vs 68%; P = .09), significantly higher 3-year metastasis-free survival (82% vs 67%; P = .001), but similar 3-year local recurrence-free survival (54% vs 61%; P = .28). Next-generation sequencing identified overall low tumor mutational burden, recurrent MYC amplification in RAAB, and few clinically actionable mutations.

Conclusions: Margin negative excision, superficial tumor location, and low tumor grade are determinants of improved OS for RAS, suggesting that complete surgical excision, when possible, is an optimal component of treatment. RAAB is a clinicopathologically distinct type of RAS with shorter latency from initial RT, different recurrence patterns, and when aggressively managed has potentially better outcomes compared with other-RAS.
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http://dx.doi.org/10.1016/j.ijrobp.2019.01.082DOI Listing
June 2019

Milton T Edgerton, MD: A Pioneer of Surgery of the Hand.

J Craniofac Surg 2019 Mar/Apr;30(2):303-305

Department of Plastic Surgery, University of Virginia, Charlottesville, VA.

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http://dx.doi.org/10.1097/SCS.0000000000005063DOI Listing
January 2019

Concomitant classic Hodgkin lymphoma and schistosomiasis.

Am J Hematol 2019 07 25;94(7):840-841. Epub 2018 Nov 25.

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1002/ajh.25316DOI Listing
July 2019

NK-Cell Enteropathy and Similar Indolent Lymphoproliferative Disorders: A Case Series With Literature Review.

Am J Clin Pathol 2019 01;151(1):75-85

The James Homer Wright Pathology Laboratories of the Massachusetts General Hospital, Boston.

Objectives: We report four new cases of natural killer-cell enteropathy (NKCE) and similar lymphoproliferative disorders (LPDs), as well as review the literature concerning indolent natural killer (NK)-cell LPDs of the gastrointestinal tract.

Methods: Pathologic and clinical data were obtained from institutional/referral records.

Results: Patient 1 (45-year-old man) had anemia; a small intestinal lesion was endoscopically biopsied. Patient 2 (65-year-old woman) had biliary colic, treated with cholecystectomy. Patient 3 (62-year-old man) had a small colonic polyp, biopsied on routine colonoscopy. Patient 4 (68-year-old man) had presumed Crohn disease; multiple biopsies were performed over more than 10 years. Diagnostic specimens showed atypical infiltrates of Epstein-Barr virus-negative lymphocytes with immunophenotypes suggestive of NK cells. In all cases, there was distortion of glandular architecture but no marked intraepithelial lymphocytosis or necrosis. The patients did not receive therapy for lymphoma and were well on follow-up.

Conclusions: These cases support the indolent nature of NKCE and similar LPDs, and they indicate that involvement outside the alimentary canal may occur.
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http://dx.doi.org/10.1093/ajcp/aqy108DOI Listing
January 2019

Many faces of the same myeloid neoplasm: a case of leukaemia cutis with mixed histiocytic and Langerhans cell differentiation.

J Clin Pathol 2019 01 9;72(1):93-96. Epub 2018 Aug 9.

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

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http://dx.doi.org/10.1136/jclinpath-2018-205161DOI Listing
January 2019

Genomic Analyses Identify Recurrent Alterations in Immune Evasion Genes in Diffuse Large B-Cell Lymphoma, Leg Type.

J Invest Dermatol 2018 11 30;138(11):2365-2376. Epub 2018 May 30.

Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA; Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA. Electronic address:

Cutaneous diffuse large B-cell lymphomas (DLBCLs) are aggressive lymphomas with a poor prognosis. To elucidate their genetic bases, we analyzed exome sequencing of 37 cutaneous DLBCLs, including 31 DLBCLs, leg type (DLBCL-LT) and 6 cutaneous DLBCLs-not otherwise specified (DLBCL-NOS). As reported previously, 77% of DLBCL-LT harbor NF-κB-activating MYD88 mutations. In nearly all MYD88-wild-type DLBCL-LT, we found cancer-promoting mutations that either activate the NF-κB pathway through alternative genes (NFKBIE or REL) or activate other canonical cancer pathways (BRAF, MED12, PIK3R1, and STAT3). After NF-κB, the second most commonly mutated pathway putatively enables immune evasion via mutations predicted to downregulate antigen processing (B2M, CIITA, HLA) or T-cell co-stimulation (CD58). DLBCL-LT have little genetic overlap with the genetically heterogeneous DLBCL-NOS. Instead, they resemble primary central nervous system and testicular large B-cell lymphomas (primary central nervous system lymphomas and primary testicular lymphomas). Like primary central nervous system lymphomas/primary testicular lymphomas, 40% of DLBCL-LT (vs. 0% of DLBCLs-not otherwise specified) harbored PDL1/PDL2 translocations, which lead to overexpression of PD-L1 or PD-L2 in 50% of the cases. Collectively, these data broaden our understanding of cutaneous DLBCLs and suggest novel therapeutic approaches (e.g., BRAF or PI3K inhibitors). Additionally, they suggest novel treatment paradigms, wherein DLBCL-LT can be targeted with strategies (e.g., immune checkpoint blockers) currently being developed for genomically similar primary central nervous system lymphomas/primary testicular lymphomas.
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http://dx.doi.org/10.1016/j.jid.2018.04.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200585PMC
November 2018