OBJECTIVES:To evaluate the utilization of hematopathology resources within our enterprise on axillary lymph node core biopsy (AxLNCB) specimens, particularly those obtained in the context of breast cancer screening. METHODS:The utilization of hematopathology resources was determined for all AxLNCB specimens over a 30-month period from across our enterprise, and chart review was performed for select patient demographics and radiographic features. The AxLNCB cases with benign histology were reviewed for subtyping of histologic patterns. RESULTS:Of the total 594 AxLNCB specimens, 61.6% were benign and 38.6% malignant. Of malignant cases, only 9.3% contained any hematologic malignancy, yet 94% of all cases received tissue triage for lymphoma, and 81% were reviewed at least in part by a hematopathologist. Six clinical parameters were found to independently predict risk of hematologic malignancy: male sex (P = .041), bilateral lymphadenopathy (P = .004), diffuse cortical thickening (P = .005), lack of breast cancer (P = .001), older age (P < .001), and history of hematologic malignancy (P < .001). CONCLUSIONS:Our enterprise overused hematopathology resources in the evaluation of AxLNCB performed in the study period. Our process could improve from the application of a simple tool generated from this cohort to predict percent risk of the specimen containing hematologic malignancy using patient characteristics easily found via routine chart review.

BACKGROUND Castleman disease was first described in 1956 as mediastinal masses composed of benign lymphoid hyperplasia with germinal center formation and capillary proliferation closely resembling thymomas. It has been linked with many multi-system disorders, including myasthenia gravis. Cases of Castleman disease with corresponding myasthenia gravis have higher rates of postoperative myasthenic crisis, which are reported as high as 37.5%. We encountered a case of Castleman disease with myasthenia gravis that was discovered early and managed successfully with complete surgical resection and no postoperative myasthenic crisis. CASE REPORT A 25-year-old woman with an uncomplicated history presented with shortness of breath, numbness in hands, tiring with chewing, and fatigue. Myasthenia gravis was diagnosed with serology test results, and a 7.5×7.0-cm mediastinal mass was discovered in addition to the incidental finding of a persistent left superior vena cava, closely abutting the mass. Biopsy showed lymphoid proliferation, regressed germinal centers surrounded by small lymphocytes, and vascular proliferation, consistent with unicentric Castleman disease, hyaline-vascular type. The patient was successfully treated for Castleman disease with myasthenia gravis, and no postoperative myasthenic crisis occurred. CONCLUSIONS Castleman disease associated with myasthenia gravis can dramatically increase the risk of postoperative myasthenic crisis. Our literature review of all 16 cases of Castleman disease with myasthenia gravis since 1973 revealed that 18.75% of cases were associated with a postoperative myasthenic crisis. This association elicits the importance of prompt diagnosis of myasthenia gravis when evaluating mediastinal masses and the value of having neurology and anesthesiology staff aware of the increased risk of crisis.

Purpose: The purpose of this study was to evaluate various morphologic features of axillary nodes on ultrasound (US) in predicting malignancy and estimate the incidence of malignancy in axillary nodes based on their imaging mode of detection. Methods and materials: A retrospective review of all percutaneous US-guided biopsies on axillary nodes performed at our institution between 1/1/2019-09/30/2021 was performed. Sonographic morphologic features of the biopsied node, imaging mode of detection and size of primary breast malignancy were correlated with malignancy. Results: There were 224 malignancies detected in a total of 594 patients who underwent an axillary node biopsy. The positive predictive value (PPV) was significantly associated with the extent of nodal cortical thickening (p < 0.0001). The PPV of malignancy was significantly higher in nodes which lacked a normal hilum (0.61 vs 0.23). The PPV of malignancy in nodes detected on screening mammography (18.8%) or MRI (15.8%) was much lower than those detected on diagnostic imaging, by palpation or on CT/PET (48.4%, 43.8% and 65.3% respectively). Of all screening detected nodes in patients with no history of malignancy and mild cortical thickening, only 2 (4.3%) demonstrated malignancy. Conclusions: Morphology of axillary nodes on sonography is vital in predicting nodal metastasis. Cortical thickness > 5 mm and/or absence of a normal hilum had the highest PPV for metastatic disease. Using clinical history in conjunction with imaging findings will help improve accuracy of axillary nodal biopsies, especially for incidental nodes detected on screening.

A previously healthy 12-year-old boy presented with a 3-month history of nasal obstruction, progressive dysphonia, recurrent deep neck abscesses, and tender, bulky cervical lymphadenopathy. What is your diagnosis?

Mice with a functional human immune system serve as an invaluable tool to study the development and function of the human immune system in vivo. A major technological limitation of all current humanized mouse models is the lack of mature and functional human neutrophils in circulation and tissues. To overcome this, we generated a humanized mouse model named MISTRGGR, in which the mouse granulocyte colony-stimulating factor (G-CSF) was replaced with human G-CSF and the mouse G-CSF receptor gene was deleted in existing MISTRG mice. By targeting the G-CSF cytokine-receptor axis, we dramatically improved the reconstitution of mature circulating and tissue-infiltrating human neutrophils in MISTRGGR mice. Moreover, these functional human neutrophils in MISTRGGR are recruited upon inflammatory and infectious challenges and help reduce bacterial burden. MISTRGGR mice represent a unique mouse model that finally permits the study of human neutrophils in health and disease.

Donor cell leukemia is a rare complication following hematopoietic stem cell transplant (HSCT). There are currently few reports in children and only rare, reported cases of donor-derived myelodysplastic syndrome/acute myeloid leukemia in patients with an underlying germline GATA2 mutation. Most reported cases are myeloid in origin and occur following related HSCT. We present a 3-year-old female who developed a donor-derived B-cell acute lymphoblastic leukemia 2 years post unrelated HSCT for GATA2 germline mutation.

Copper deficiency is a rare nutritional deficiency with hematological manifestations that mimic those found in myelodysplastic syndrome, a hematological malignancy incurable without allogeneic hematopoietic stem cell transplantation. Bone marrow biopsy findings and peripheral blood counts are oftentimes insufficient to differentiate the two conditions. Moreover, the symptoms of copper deficiency can arise years after the surgery, making diagnosis a challenge. In patients with new-onset pancytopenia, copper deficiency must be considered on the differential, especially in the setting of known risk factors such as bariatric surgery, zinc supplementation, and celiac disease. Herein, we present a case of a 61-year-old female with a remote history of gastric bypass being evaluated for MDS in the context of progressive pancytopenia and new-onset paresthesias. The patient was found to have low serum copper and ceruloplasmin. Copper supplementation largely resolved the hematological abnormalities, but the limb paresthesias remain. This case highlights the need to identify copper deficiency early and distinguish it from MDS in order to prevent permanent neurological deficits and catastrophic response should the patient undergo hematopoietic stem cell transplantation.

Classical Hodgkin lymphoma (cHL) is a highly-curable disease; however, the subset of relapsed patients progressing after autologous haematopoietic cell transplantation (autoHCT) and failing novel agents [such as brentuximab vedotin (Bv) and check-point inhibitors (CPIs)] have poor outcomes.1, 2 Innovative strategies are needed to improve outcomes for this subset of high risk patients. Ibrutinib is an oral, small molecule Bruton's tyrosine kinase (BTK) inhibitor approved for patients with chronic lymphocytic leukaemia (CLL), mantle cell lymphoma and Waldenstrom macroglobulinemia.3-5 Preclinical studies suggest activity of ibrutinib in cHL. Fernández-Vega et al.6 demonstrated increased BTK expression on Reed-Sternberg cells of a subset of cHL cases (22%). We previously reported responses to ibrutinib in two heavily-pretreated cHL patients.7 In this study, we update our experience in a larger cohort of relapsed refractory (RR) cHL patients who received single agent ibrutinib. Seven consecutive adult (≥18 years) biopsy-proven RR cHL patients who progressed on standard-of-care therapies and received single agent ibrutinib at a dose of 420 to 560 mg once daily (based on haematological parameters) were included in this cohort analysis. Responses were assessed by standard criteria.8 Duration of response (DOR) was calculated from the time of documented response until progression or last follow up. This retrospective study was approved by the Institutional Review Board. Patient characteristics, therapies prior to ibrutinib start and response to ibrutinib are summarised in Table 1. Median age of patients was 35 years (range, 26–72). Six out of seven patients (86%) had primary refractory disease. The median number of therapies prior to ibrutinib was eight (range, 4–12). Five out of seven patients (71%) had an autoHCT or alloHCT prior to ibrutinib. Among five patients who had a prior alloHCT, one patient had active mild chronic graft versus host disease (GVHD) and one patient had history of steroid refractory acute GVHD, predating cHL relapse and ibrutinib initiation (in both patients). Four of the five post-alloHCT patients had repeat biopsy confirmation of post-transplantation relapse. All patients with prior alloHCT were either off immunosuppressive therapy (IST) before relapse or IST was tapered off before initiation of ibrutinib, without any disease response attributable to IST taper. Ibrutinib therapy had no impact of GVHD. Median time between alloHCT and ibrutinib initiation was 12 months (range, 3–38). Three patients received ibrutinib at a dose of 420 mg once daily (OD) and the remaining patients received a dose of 560 mg once daily. Four patients (57%) responded [three complete remissions (CR), one partial remission (PR)] (Fig 1). The median time to response was 2·9 months. The DOR in two patients who eventually progressed was 2 and 5·5 months. The remaining two responding patients had ongoing CR (15+ and 3+ months). Among the two patients with no history of undergoing an alloHCT, one patient did not respond and the other died due to respiratory failure prior to response assessment. Overall, ibrutinib was well-tolerated and none of the patients required discontinuation due to adverse events. To investigate whether BTK expression on cHL predicted response to ibrutinib in our series, BTK staining (BTK clone EPR20445, catalog ab208937, 1:1500, Dako En VisionTM) was performed on patients (#1, #2, #3 and #5) with available archival tissue. BTK positivity was determined using a 10% cutoff in Reed-Sternberg cells. Among these, patient #1 was positive for BTK expression and was among the responders. Remaining patients #2, #3 and #5 were negative for BTK expression by immunohistochemistry (Fig S1). Patient #3 had a progressive disease and #2 and #5 achieved CR after ibrutinib. Demonstrates PET scan images (A) before and (B) after ibrutinib in responding patient #1 and patient #4. A similar version of figure for patient #1 previously appeared in Hamadani et al., N Engl J Med. 2015; 373(14):1381–2. The mechanism of ibrutinib's activity in cHL is not known. In our prior report, BTK expression was seen in one responding patient, along with evidence of Th1 cell polarisation.7 In our current series, none of the patients without prior history of alloHCT responded (n = 2). Among the four responding post-alloHCT patients, archival tissue was available on three patients to examine BTK expression and only one subject (patient #1, reported previously)7 demonstrated BTK expression on Reed-Sternberg cells. The absence of BTK expression on two responding post-alloHCT patients (patient #2 & #5) suggests a non-BTK-dependent mechanism for ibrutinib's activity in this setting. In patients #2 and #5, tapering of immunosuppression or development of new or worsening GVHD do not appear to be likely explanations of disease responses (details in Table 1). Ibrutinib-mediated inhibition of interleukin-2-inducible kinase (ITK) and resultant Th1-polarisation in T lymphocytes9 is a potential mechanism of ibrutinib activity in post-alloHCT relapses (i.e., via augmentation of graft-versus-lymphoma effects). In addition, ibrutinib has been shown to increase persistence of activated CD4+ and CD8+ T cells, reduce the regulatory/conventional CD4+ T cell ratio and diminish the immune-suppressive properties of tumour cells by reducing PD1 and CTLA-4 expression.10 These immune-activating properties may be responsible for ibrutinib's activity in post-alloHCT relapsed cHL patients in our series.10, 11 We acknowledge the limitation of our study, which involved a small number of patients with available BTK staining and, as such, a BTK-dependent mode of action cannot be ruled out based on our analysis. In conclusion, we report that single agent activity of ibrutinib in cHL relapsing after alloHCT appears to be independent of BTK expression on tumour cells. A phase II study is underway to evaluate effectiveness of ibrutinib in RR cHL patients (NCT02824029). The trial has completed accrual, but it is not specific to the post-alloHCT relapsed cHL. We think that ibrutinib can augment immune responses and could have a potential role as a disease-agnostic relapse prevention strategy after allografting. T.B. helped in study design, methodology and wrote the original manuscript draft. I.K.K reviewed the literature. P.H. contributed patients and helped in data curation. K.Z. contributed patients. J.A. helped in data curation. M.H. helped in study design, methodology, contributed patients and manuscript editing. M.H. reports research support/funding from Takeda Pharmaceutical Company, Spectrum Pharmaceuticals and Astellas Pharma; consultancy for Janssen, Incyte Corporation, ADC Therapeutics, Celgene Corporation, Pharmacyclics, Magenta Therapeutics, Omeros, AbGenomics, Verastem and TeneoBio; speaker's bureau from Sanofi Genzyme and AstraZeneca. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Abstract Background Peripheral T-cell lymphomas (PTCLs) are heterogenous, mature T-cell neoplasms that are a diagnostic challenge, requiring a combination of morphologic assessment and ancillary studies. Flow cytometry (FC) is a tool used routinely in lymphoma diagnosis; however, most analyses are limited to B-cell evaluation and pathologists generally lack experience evaluating for PTCL. We aimed to describe the immunophenotypic aberrancies observed by FC in PTCL. Design PTCLs with FC were collected, excluding primary leukemic processes. Four- and eight-color FC data were reanalyzed with the following antigens (when available): CD2, CD3, CD4, CD5, CD7, CD8, CD30, CD45, CD45RO, CD56, and CD57. Lymphoma cells were compared to normal T cells and an isotype control. Antigen expression was defined as >20%. Results Thirty-eight cases were analyzed (29 males, 9 females, 6-86 years, median 62 years), including 29 PTCLs NOS, 4 angioimmunoblastic T-cell lymphomas (AITLs), 3 anaplastic large cell lymphomas, 1 δγ-TCL, and 1 hepatosplenic TCL from 15 bone marrows, 14 lymph nodes, 6 bloods, 2 fluids, and 1 skin. Twenty cases were CD4+, 4 were CD8+, 3 were dual +, and 10 were dual –. Thirty-seven cases (97%) showed global aberrant antigen patterns, median 4 aberrancies/case (1-8). Lymphoma cells accounted for 0.07% to 68% (median 2.6%) of total events. Aberrant CD7 expression was present in 34 of 38 (89%) and was underexpressed in 22 of 34 (65%). CD3 and CD5 were aberrant in 79% of cases each, with two-thirds showing underexpression. CD2 and CD45RO were aberrant in two-thirds of PTCLs, with overexpression in 61% and 92% of those cases, respectively. One AITL showed no aberrancies. Conclusions Nearly all PTCLs show immunophenotypic aberrancy compared to normal T cells. Most commonly, PTCL showed aberrant underexpression of CD7, CD3, and CD5 and overexpression of CD2 and CD45RO. Our data support FC panels with CD2, CD3, CD4, CD5, CD7, CD8, and CD45RO to optimize recovery of aberrant T cells.

Background: COO subtyping is required at diagnosis of DLBCL by the 2016 WHO classification.This is most commonly performed by the Hans algorithm, which utilizes immunohistochemistry (IHC).Some laboratories routinely use flow cytometry (FC) for assessment of CD10 expression, but this method has not been formally validated as a surrogate technique for the purposes of COO subtyping.Design: Diagnostic DLBCL cases with accompanying FC studies were retreived over a 10 year period, yielding 111 cases.These were evaluated by either 4-(26 cases) or 8-color (85 cases) FC using antibodies to CD5, CD10, CD19, CD20, CD23, CD38, FMC-7, and surface immunoglobulin in most cases.CD10 expression was assessed as the percentage of events exceeding a 2% isotypic control threshold.CD10 expression by IHC was assessed as the percentage of positive staining cells.Per the Hans algorithm, cases with at least Conclusions: Our findings demonstrate that CD10 assessment by FC and IHC are strongly correlated in DLBCL.However, using an optimized FC cutoff, 12% of cases were discordant.Laboratories that routinely employ FC in lieu of IHC for assessment of CD10 should be aware that these methods are not entirely comparable for the purposes of COO subtyping.

The 2016 revision to the World Health Organization (WHO) classification of Tumors of Hematopoietic and Lymphoid Tissues has identified a new provisional entity to be included under the category of ...

In a recent audit of our orderables, we found a discrepancy between the Electronic Medical Record orderable “Manual Diff also order CBC” and the linked Laboratory Information System (LIS) translation “Physician requested manual smear review” (PRMSR). With this orderable, our providers believe they are ordering a manual differential (MD); however, our internal laboratory process has been to perform a smear review, assess the accuracy of the automated differential (AD), and evaluate instrument flags. We evaluated the ordering practice for the MD and its impact on our laboratory workflow over a 4-month period. Institutional databases were queried for the number of PRMSRs received monthly in 2017. Detailed information was collected on the PRMSR requests over a 4-month period using our LIS and Sysmex’s WAM. A total of 1,548 PRMSRs were ordered in 2017, ranging from 116 to 145 monthly requests (mean 129), including 629 PRMSRs during the study period. Patients’ ages ranged from newborn to 93 years old (mean 49). The requests were received from inpatients (n = 385), cancer center outpatients (210), and outside clients (34). In total, 263 providers requested PRMSRs, including 44.5% residents/fellows, 25.5% physician faculty, and 18.3% APPs (28% from internal medicine). MDs were performed on 590/629 requests (93.8%) and ADs on 39. WAM OP Alerts occurred in 385/629 PRMSRs (61%), requiring manual review. In specimens without OP Alerts (244 PRMSRs), MDs were performed in 210, and the AD correlated with the MD in 205 cases (98%). Five showed significant disagreement between the AD and MD, requiring an MD report. Thirty-five PRMSRs met criteria for hematopathology review, 34 of which had OP alerts. In 2/3 of PRMSRs, instrument flags are necessitating manual review of the blood film. In the majority without flags, the MD correlates well with the AD results; therefore, this orderable should be discontinued at our institution.