Anaplastic Large Cell Transformation of Mycosis Fungoides: Case Report and Review of the Literature.

ABSTRACT: We report a 48-year-old man with CD30+ large cell transformation of mycosis fungoides (tMF) with distinctive anaplastic morphology. The patient initially presented with folliculotropic and syringotropic mycosis fungoides (MF) manifested as occipital scalp plaque and trunk and extremities patches. Six years later, he progressed to the tumor stage from his scalp lesion and developed cervical lymphadenopathy. Lymph node and scalp biopsies showed diffuse infiltration of CD30+ anaplastic cells with multinucleated, hallmark-like, Hodgkin-Reed-Sternberg-like, histiocytoid forms, indistinguishable from anaplastic large cell lymphoma (ALCL). T-cell receptor gamma gene (TCRg) rearrangement studies revealed identical clones in the initial MF scalp lesion and nodal anaplastic lesion, confirming the transformation. Ancillary studies showed absence of IRF4/DUSP22 and ALK rearrangements and positive RB1, SMARCA4, SOCS1, and TP53 mutations. The patient achieved partial response with systemic chemotherapy. Our case is an example of tMF presenting as the morphology and phenotype of ALCL. Because clinical behavior and therapeutic options of tMF and primary cutaneous ALCL may be different, it is clinically relevant to differentiate these 2 entities. The proof of clonal relationship may be useful in diagnostically challenging cases with features overlapping between tMF and primary cutaneous ALCL.

Apixaban Discontinuation for Invasive Or major Surgical procedures (ADIOS): A prospective cohort study.

Background: Apixaban pharmacokinetic properties and some clinical reports suggest cessation 48 hours prior to surgery is safe, but this has not been demonstrated in a naturalistic setting. We sought to measure the residual apixaban exposure in patients who had apixaban held as part of standard of care perioperative management. Methods: This was a prospective, observational study of patients in whom apixaban plasma concentration and anti-Xa activity were measured while at steady state apixaban dosing and again immediately prior to surgery. Clinical management of cessation and resumption of apixaban was at the discretion of the treating physician. Results: Paired blood samples were provided by 111 patients. Ninety-four percent (104/111) of patients had measured apixaban concentrations of ⩽ 30 ng/mL. Only one patient had a value > 50 ng/mL. The median time between the self-reported last dose and presurgery blood sampling was 76 hours (range 32-158) for those who achieved concentrations ⩽ 30 ng/mL and 59 hours (range 49-86) for those > 30 ng/mL. Measured anti-Xa activity correlated well with apixaban exposure. Clinically significant nonmajor bleeding was reported in one patient at 1 week postsurgery. There was one venous thromboembolic event and one stroke in the perioperative period. Conclusion: In a naturalistic setting with a heterogeneous patient population, apixaban discontinuation for at least 48 hours before a procedure resulted in a clinically insignificant degree of anticoagulation prior to a surgical procedure. ClinicalTrials.gov Identifier: NCT02935751.

Brentuximab vedotin in the treatment of CD30+ PTCL.

The development of brentuximab vedotin has opened a new era in the management of peripheral T-cell lymphomas (PTCLs). The improved outcomes with brentuximab vedotin (BV) in combination with cyclophosphamide, doxorubicin, and prednisone (BV-CHP) vs cyclophosphamide, doxorubicin, vincristine, and prednisone in the ECHELON-2 trial are practice changing for common nodal CD30+ PTCLs. Questions regarding the optimal cutoff of CD30 expression for BV-CHP therapy and the efficacy and safety of BV-CHP in less common subtypes of CD30+ PTCL subtypes await clarification.

Comparison of Chromogenic In Situ Hybridization and Fluorescence In Situ Hybridization for the Evaluation of MDM2 Amplification in Adipocytic Tumors.

BACKGROUND: Atypical lipomatous tumor/well-differentiated liposarcoma (ALT-WDLPS) and dedifferentiated liposarcoma (DDLPS) are characterized cytogenetically by a 12q13-15 amplification involving the mouse double minute 2 (MDM2) oncogene. Fluorescence in situ hybridization (FISH) is used frequently to detect this amplification and aid with the diagnosis of these entities, which is difficult by morphology alone. Recently, bright-field in situ hybridization techniques such as chromogenic in situ hybridization (CISH) have been introduced for the determination of MDM2 amplification status. METHODS: The present study compared the results of FISH and CISH for detecting MDM2 amplification in 41 cases of adipocytic tumors. Amplification was defined in both techniques as a MDM2/CEN12 ratio of 2 or greater. RESULTS: Eleven cases showed amplification with both FISH and CISH, and 26 cases showed no amplification with both methods. Two cases had discordant results between CISH and FISH, and two cases were not interpretable by CISH. CONCLUSION: CISH is advantageous for allowing pathologists to evaluate the histologic and molecular alterations occurring simultaneously in a specimen. Moreover, CISH is found to be more cost- and time-efficient when used with automation, and the signals do not quench over time. CISH technique is a reliable alternative to FISH in the evaluation of adipocytic tumors for MDM2 amplification.

Optimization of laboratory diagnosis of heparin-induced thrombocytopenia using HemosIL-AcuStar-HIT-IgG assay.

OBJECTIVE: The aim of this study was to determine an optimal cutoff value for the newly available HemosIL-AcuStar-HIT-IgG assay (AcuStar) for the diagnosis of heparin-induced thrombocytopenia (HIT). METHOD: We evaluated the performance of AcuStar using serotonin release assay (SRA) as the gold standard and incorporated 4T score calculation in a cohort of suspected HIT cases. Statistical analysis was performed to determine optimal cutoff value for the diagnosis of HIT. RESULT: A diagnosis of HIT can be excluded with a platelet factor 4 (PF4) value of <0.4 U/mL by AcuStar and 4T score in the low-risk category (≤3). All other cases will require confirmation with a functional test. CONCLUSION: Our study resulted in the implementation of a diagnostic algorithm for laboratory diagnosis of HIT, which incorporates pretest calculation of 4T score and AcuStar as a screening test, with reflex confirmation by SRA. This new algorithm resulted in extended hours of test availability and a more rapid turnaround time in reporting PF4 results.

Upregulation of Enhancer of Zeste Homolog 2 (EZH2) with Associated pERK Co-Expression and PRC2 Complex Protein SUZ12 Correlation in Adult T-Cell Leukemia/Lymphoma.

EZH2, a subunit of the polycomb repressive complex 2 (PRC2), is an important methyltransferase that catalyzes the trimethylation of histone H3 at lysine 27 (H3K27me3). EZH2 is overexpressed in various malignancies. Here, we investigated EZH2 expression and potential signaling molecules that correlate with EZH2 expression in ATLL and other T-cell neoplasms. Immunohistochemical staining (IHC) was performed for EZH2, pERK, MYC, and pSTAT3 on 43 ATLL cases and 104 cases of other T-cell neoplasms. Further IHC studies were conducted for Ki-67, SUZ12, and H3K27me3 on ATLL cases. All ATLL cases showed EZH2 overexpression. In other T-cell neoplasms, a high prevalence of EZH2 overexpression was identified (86%), except for T-PLL (33%). In ATLL, EZH2 overexpression correlated with pERK co-expression (86%), while only a small subset of cases showed MYC (7%) or pSTAT3 (14%) co-expression. In the other T-cell neoplasms, there was a variable, but higher, co-expression of EZH2 with pERK, MYC, and pSTAT3. In ATLL, enhanced EZH2 expression correlated with higher Ki-67 staining, SUZ12 (another PRC2 subunit), and H3K27me3 co-expression. In conclusion, EZH2 is overexpressed in ATLL and is associated with pERK expression. It correlates with an increased proliferation index, indicating an aggressive clinical course. EZH2 also correlates with SUZ12 and H3K27me3 co-expression, suggesting its PRC2-dependent catalytic activity through trimethylation. Additionally, EZH2 is overexpressed in most T-cell neoplasms, suggesting that EZH2 could function as an oncogenic protein in T-cell tumorigenesis. EZH2 and pERK could serve as potential therapeutic targets for treating aggressive ATLL. EZH2 could also be targeted in other T-cell neoplasms.

Alpha- and beta-synucleins are new diagnostic tools for acute erythroid leukemia and acute megakaryoblastic leukemia.

α-Synuclein is a key component of the Lewy body, a large globular protein complex that forms in the nervous system of patients with Parkinson disease and other dementias [1-3]. Since α-synuclein also occurs in megakaryocytic and erythroid lineages [4-7], we wondered what role synucleins had in the hematopoietic system. Therefore, we studied the expression of α-, ß-, and γ-synucleins in a comprehensive panel of patient bone marrows and leukemic cell lines. We observed under expression of α-synuclein in the megakaryocytes of myeloproliferative neoplasm (MPN), but not normal reactive marrow (NRM) or myelodysplastic syndrome (MDS). Conversely, we observed over expression of ß-synuclein in the blasts of megakaryoblastic leukemias (MegL), but not acute myeloid leukemia (AML) or erythroleukemia (EryL), suggesting that α- and ß-synucleins could be useful adjunct markers for the early detection of MDS and the differential diagnosis of EryL and MegL from other AMLs.

A phase II study of amifostine in children with myelodysplastic syndrome: a report from the Children's Oncology Group study (AAML0121).

Based on its potential role in adult myelodysplastic syndrome (MDS), the Children's Oncology Group (COG) embarked on a phase II study using amifostine in pediatric MDS (WHO 2001 criteria) patients. Responses were evaluated after two cycles. Ten patients were enrolled; five were deemed ineligible, and four withdrew after the first course. Only one patient completed two courses, and was found to be in complete remission. The study was closed after being open for 2 years due to slow accrual. Studying a rare disease like MDS may pose insurmountable obstacles even in a large clinical trials group such as COG, in part because of the changing definitions of MDS and the rarity of adult type MDS in children. The role of amifostine in pediatric MDS was not known at the time of study.

Bleeding and Thrombotic Adverse Events in Hospitalized Patients Under Empiric Treatment for Suspected Heparin-Induced Thrombocytopenia While Awaiting Confirmatory Testing.

Empiric management in suspected heparin-induced thrombocytopenia (HIT) is challenging due to imperfect prediction models, latency while awaiting test results and risks of empiric therapies. When there is high clinical suspicion for HIT, cessation of heparin and empiric non-heparin anticoagulation with FDA-approved argatroban is recommended. Alternatively off-label fondaparinux or watchful waiting have been utilized in clinical practice. Outcomes of patients empirically managed for HIT have not been compared directly in clinical trials and patients that ultimately do not have HIT are often overlooked. Clinicians need studies investigating empiric management to guide decision making in suspected HIT. In this study, adverse events (AE) were categorized and compared in patients being evaluated for HIT while undergoing empiric management by non-heparin anticoagulation with argatroban or fondaparinux, both at therapeutic or reduced doses, or watchful waiting with or without heparin. AE were defined as new thrombosis confirmed on imaging or new bleeding event after HIT was first suspected. A retrospective chart review of 312 patients tested for HIT at an academic hospital was conducted. 170 patients met inclusion criteria. Patients were excluded if the 4Ts score was < 4. The 4Ts score is a pretest probability for HIT based on thrombocytopenia degree, timing, alternative causes and presence of thrombosis. Included patients were divided according to management groups and compared with logistic regression analysis. Bleeding risk significantly differed between management groups (p = 0.002). Despite adjustment for bleeding risk, fondaparinux was associated with increased AE, (p = 0.03, OR = 5.81), while argatroban was not. There was no difference in AE based on time to initiation of empiric treatment and no advantage to reduced dosing with either anticoagulant. These findings challenge assumptions surrounding empiric HIT management.

Differentiating Primary Pancreatic Lymphoma Versus Primary Splenic Lymphoma: A Case Report.

Background: Both primary pancreatic lymphoma (PPL) and primary splenic lymphoma (PSL) represent rare entities. PPL typically arises in the head of the pancreas but may arise in other locations also. PSL usually presents with nonspecific symptoms, including left upper quadrant pain, weight loss, and fever. This report describes a patient with a large left upper quadrant mass, which initially was believed to be a primary pancreatic mass, but which on final pathology appeared to be consistent with a PSL. Presentation: The patient is a 64-year-old woman who initially presented with symptoms of left upper quadrant abdominal pain and distension; she subsequently was found to have an 18 cm heterogeneous mass arising from the pancreatic tail. She underwent a distal pancreatectomy with splenectomy. Final pathology confirmed a diffuse large B cell lymphoma arising from the splenic parenchyma. Conclusions: Both PPL and PSL are rare causes of left upper quadrant masses. In this case, we describe a large lymphoma that appeared to arise from the tail of the pancreas, but on final pathology was found to be splenic in origin. Differentiating these two clinical entities is important for prognostication and treatment. A multimodal approach with surgical resection followed by chemotherapy is preferred.

Durable Response to Brentuximab Vedotin Plus Cyclophosphamide, Doxorubicin, and Prednisone (BV-CHP) in a Patient with CD30-Positive PTCL Arising as a Post-Transplant Lymphoproliferative Disorder (PTLD).

T-cell PTLDs are lymphoid proliferations that develop in recipients of SOT or allogeneic HSCT. They carry an extremely poor prognosis with a reported median survival of only 6 months. The infrequency with which they are encountered makes treatment a challenge due to the lack of prospective trials to guide management. The significantly higher risk of morbidity and mortality in T-cell PTLD, compared to B-cell PTLD, underscores the challenge of treating these patients and the need for new therapeutic options. Brentuximab vedotin, an ADC targeting CD30, is FDA-approved in combination with CHP as front-line treatment for patients with CD30 expressing PTCL. Herein we report a case of CD30-positive T-cell PTLD that was successfully treated with BV-CHP, suggesting the added value of the addition of BV to chemotherapy, contributing to our patient's long and ongoing progression-free survival. To our knowledge, this is the first documented case of successful treatment using BV-CHP for a CD30-positive, EBV-negative, late T-cell PTLD.

Mantle Cell Lymphoma With Hodgkin and Reed-Sternberg Cells: Review With Illustrative Case.

Non-Hodgkin lymphoma may occasionally contain large transformed cells resembling Hodgkin and Reed-Sternberg cells (HRS cells). We report a 63-year-old man with HRS cells in a recurrent mantle cell lymphoma (MCL). The patient initially presented with orbital MCL and recurred after 8 years with widespread involvement. The HRS cells were present in the recurrent disease but not in the initial orbital lesions, suggesting a transformed event after a prolonged disease course. Morphologically, the HRS cells were single cells and small clusters among the MCL cells and were frequently accompanied by histiocytes but without eosinophils or other inflammatory cells. The HRS cells showed a phenotype of classic Hodgkin lymphoma (cHL). The HRS cells were clonally related to the MCL, which was demonstrated by the presence of identical t(11;14) that resulted in productive cyclin D1 expression in both cell types. Review of the literature identified 7 additional MCL cases that showed a spectrum of clinical and pathologic features ranging from scattered HRS cells to true composite MCL and cHL. The HRS cells were clonally related to MCL in 4 cases (including the current case) and unrelated in 2 cases. These findings suggest MCL with HRS cells is a heterogeneous group that may represent a spectrum of transformation at the various stages. Proof of clonal relationship between HRS cells and MCL is useful to distinguish these cases from true composite MCL and cHL.

Mediastinal adenopathy, lung infiltrates, and hemophagocytosis: unusual manifestation of pediatric anaplastic large cell lymphoma: report of two cases.

To date, only 1 report describes an anaplastic large cell lymphoma (ALCL) associated with hemophagocytosis in the pediatric population. To better characterize this unusual manifestation of ALCL, we identified 2 additional cases. Both patients had fever, cytopenia, decreased fibrinogen level, mediastinal or hilar adenopathy, minimal to no peripheral adenopathy, and lung infiltrates. Bone marrow biopsies and aspirates revealed striking hemophagocytosis but no ALCL. One patient fulfilled the criteria for hemophagocytic syndrome, but the other lacked 1 criterion. Both patients were initially given a misdiagnosis of infection-associated hemophagocytosis. Definitive diagnosis required lymph node biopsies that showed CD30+, anaplastic lymphoma kinase-l+ ALCL. Both tumors responded to standard lymphoma chemotherapy. One patient achieved complete remission, whereas the other patient died of complications after 2 cycles of therapy. These findings are similar to the first reported case and indicate that pediatric ALCL can manifest with an unusual constellation of symptoms consisting of hemophagocytosis, mediastinal or hilar adenopathy, and lung infiltrates.

Clinicopathologic findings in high-grade B-cell lymphomas with typical Burkitt morphologic features but lacking the MYC translocation.

In the World Health Organization classification, cases with classical Burkitt morphologic features and a very high proliferation fraction but without the MYC translocation are not clearly designated as a separate entity and are usually categorized as diffuse large B-cell lymphoma (DLBCL). We identified from our records 33 cases of highly aggressive mature B-cell neoplasms from 8 children and 25 adults with typical Burkitt cytomorphologic, histologic, and immunophenotypic (CD20+/CD10+ and surface immunoglobulin-positive) features. Rearrangement of MYC (MYC+) was present in only 18 of 33 cases, but the proliferation fraction was more than 90% in all MYC-cases (no MYC rearrangement). The immunophenotype of the lymphoma cells in the 2 groups was similar. Although children with MYC+ and MYC- neoplasms were treated with chemotherapy regimens appropriate for Burkitt lymphoma, adults with MYC- lymphomas received less aggressive therapy usually given for DLBCL. Survival analysis showed that adults in the MYC- group had an inferior outcome compared with adults with MYC+ disease. Provisional identification of MYC- lymphomas with typical Burkitt morphologic features as an entity separate from DLBCL will facilitate further studies and possible categorization as a separate entity.

Non-Hodgkin and Hodgkin Lymphomas Select for Overexpression of BCLW.

Purpose: B-cell lymphomas must acquire resistance to apoptosis during their development. We recently discovered BCLW, an antiapoptotic BCL2 family member thought only to contribute to spermatogenesis, was overexpressed in diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma. To gain insight into the contribution of BCLW to B-cell lymphomas and its potential to confer resistance to BCL2 inhibitors, we investigated the expression of BCLW and the other antiapoptotic BCL2 family members in six different B-cell lymphomas.Experimental Design: We performed a large-scale gene expression analysis of datasets comprising approximately 2,300 lymphoma patient samples, including non-Hodgkin and Hodgkin lymphomas as well as indolent and aggressive lymphomas. Data were validated experimentally with qRT-PCR and IHC.Results: We report BCLW is significantly overexpressed in aggressive and indolent lymphomas, including DLBCL, Burkitt, follicular, mantle cell, marginal zone, and Hodgkin lymphomas. Notably, BCLW was preferentially overexpressed over that of BCL2 and negatively correlated with BCL2 in specific lymphomas. Unexpectedly, BCLW was overexpressed as frequently as BCL2 in follicular lymphoma. Evaluation of all five antiapoptotic BCL2 family members in six types of B-cell lymphoma revealed that BCL2, BCLW, and BCLX were consistently overexpressed, whereas MCL1 and A1 were not. In addition, individual lymphomas frequently overexpressed more than one antiapoptotic BCL2 family member.Conclusions: Our comprehensive analysis indicates B-cell lymphomas commonly select for BCLW overexpression in combination with or instead of other antiapoptotic BCL2 family members. Our results suggest BCLW may be equally as important in lymphomagenesis as BCL2 and that targeting BCLW in lymphomas should be considered. Clin Cancer Res; 23(22); 7119-29. ©2017 AACR.

BCL-W has a fundamental role in B cell survival and lymphomagenesis.

Compromised apoptotic signaling is a prerequisite for tumorigenesis. The design of effective therapies for cancer treatment depends on a comprehensive understanding of the mechanisms that govern cell survival. The antiapoptotic proteins of the BCL-2 family are key regulators of cell survival and are frequently overexpressed in malignancies, leading to increased cancer cell survival. Unlike BCL-2 and BCL-XL, the closest antiapoptotic relative BCL-W is required for spermatogenesis, but was considered dispensable for all other cell types. Here, however, we have exposed a critical role for BCL-W in B cell survival and lymphomagenesis. Loss of Bcl-w conferred sensitivity to growth factor deprivation-induced B cell apoptosis. Moreover, Bcl-w loss profoundly delayed MYC-mediated B cell lymphoma development due to increased MYC-induced B cell apoptosis. We also determined that MYC regulates BCL-W expression through its transcriptional regulation of specific miR. BCL-W expression was highly selected for in patient samples of Burkitt lymphoma (BL), with 88.5% expressing BCL-W. BCL-W knockdown in BL cell lines induced apoptosis, and its overexpression conferred resistance to BCL-2 family-targeting BH3 mimetics. Additionally, BCL-W was overexpressed in diffuse large B cell lymphoma and correlated with decreased patient survival. Collectively, our results reveal that BCL-W profoundly contributes to B cell lymphoma, and its expression could serve as a biomarker for diagnosis and aid in the development of better targeted therapies.

EBV-associated Peripheral T-Cell Lymphoma of Gastrointestinal Tract Presented With Widespread Chronic Inflammation: A Case Report.

We report a case of Epstein-Barr virus (EBV)-associated T-cell lymphoma of gastrointestinal (GI) tract from a 70-year-old white woman who initially presented with a widespread GI inflammation and gastric obstruction. Initial biopsies of the GI tract showed severe chronic inflammation in the esophagus, stomach, and the small intestine. Celiac disease and inflammatory bowel disease were ruled out. The patient was treated with partial gastrectomy. Histology showed gastric wall thickening with EBV-positive, mixed lymphocytic and plasma cell infiltration in the mucosa, and thickening and fibrosis of the submucosa. She developed EBV-associated T-cell lymphoma of the GI tract one and a half years later and expired due to multiorgan failure. The T-cell lymphoma diffusely infiltrated the GI wall without forming a mass lesion. The lymphoma expressed EBV and cytotoxic molecules but lacked common features of extranodal natural killer/T-cell lymphoma nasal type, such as angioinvasion/angiodestruction, necrosis, or CD56 expression. Immunoglobulin heavy chain (IGH) gene and T-cell receptor-γ gene rearrangements and EBV-positive cells were detected at the early stage of the disease. While IGH clones were transient, T-cell clones and EBV-positive cells progressively increased over the disease course. We conclude that this case is best classified as EBV-associated peripheral T-cell lymphoma of GI tract. Age-related immune senescence may have contributed to the uncontrolled GI inflammation and subsequent transformation to T-cell lymphoma.

Posttransplant lymphoproliferative disorder after umbilical cord blood transplantation in children.

Reported are 7 cases of posttransplant lymphoproliferative disorder (PTLD) arising in children who received umbilical cord blood transplantation (UCBT). There were 4 females and 3 males with a median age of 3 years (range, 1-16 years). All 7 patients received UCBT, including 1 patient who received multiple units and 1 transplanted under nonmyeloablative condition. The time interval from UCBT to PTLD averaged 4 months (range, 2 weeks to 9 months). Patients typically presented with high-stage disease with visceral organ involvement. Histology of the PTLDs showed monomorphic morphology in 5 cases and polymorphic morphology in the remaining 2 cases. Bone marrow biopsies were performed in 3 cases and were negative for PTLD. Epstein-Barr virus (EBV) was detected in the PTLD in all 7 patients by in situ hybridization. Evidence of past EBV infection was found in the recipients, but the EBV genome was not detected in the donor cord blood samples, suggesting that donor cord blood was not the source of EBV infection. The origin of the PTLD was investigated in 5 cases. PTLD was of host origin in 2 patients who failed engraftment and of donor origin in the remaining 3 patients who had complete engraftment. Four of 5 patients with monomorphic PTLD failed to demonstrate significant responses to rituximab and/or reduction of immunosuppression and died within 1 month after diagnosis. The remaining 2 patients with polymorphic PTLD showed complete response to therapy. One patient was alive 35 months after transplant, and the other patient died of infection 6 months after transplant. It is concluded that PTLD arising after UCBT in children occurs early after transplant and represents a serious EBV-related complication. PTLD may be of donor or recipient origin depending on engraftment status. Both monomorphic and polymorphic histology may be seen, and monomorphic histology appears to predict an unfavorable prognosis.