Lack of a Prognostic Impact of the MyD88 L265P Mutation for Diffuse Large B Cell Lymphoma Patients Undergoing Autologous Stem Cell Transplantation.

Cell-of-origin determination has emerged as an important prognostic factor for patients initially diagnosed with diffuse large B cell lymphoma (DLBCL). Specifically, the nongerminal center B cell-like (non-GCB) subtype, composed predominantly of the activated B cell-like (ABC) molecular subtype, has been shown to portend poor prognosis because of its more aggressive nature and resistance to standard cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone (CHOP)-like chemotherapy compared with the GCB subtype. The recurrent MyD88 L265P mutation, present in 29% of ABC DLBCL, was reported as an independent poor prognostic factor for patients with newly diagnosed DLBCL. For patients whose disease relapses or is refractory to first-line chemotherapy, high-dose chemotherapy with autologous stem cell transplantation (ASCT) is frequently offered as salvage therapy. However, the impact of MyD88 mutation status on post-ASCT outcome has not been reported. Here, we retrospectively analyzed, with up to 20 years of follow-up, 165 patients who underwent ASCT for relapsed/refractory DLBCL at our institution. We found that MyD88 mutation status did not correlate with overall survival (OS), post-ASCT OS, or progression-free survival (PFS). Patients with non-GCB subtype had significantly worse OS from initial diagnosis and after ASCT. Notably, high International Prognostic Index score was predictive of poor pre- and post-transplant PFS and post-transplant OS.

CD4-positive diffuse large B-cell lymphoma: A variant with aggressive clinical potential.

CD4 expression is rare in diffuse large B-cell lymphoma (DLBCL), with 4 previously reported cases. Its significance is uncertain. We report five patients with CD4(+) DLBCL and one CD4(+) primary mediastinal large B-cell lymphoma. Cases were identified by searching the electronic database of the department; each was reviewed. Average age was 56 years. Neoplastic cells expressed CD20 (5/6 tested cases). BCL2/BCL6 expression were seen in 3/3 tested cases, suggesting a germinal center origin. Additionally, expression of T-cell antigens CD2 and CD5 was noted in 2/2 and CD7 in 1/1 tested case. CD3 was negative in all. Lymph nodes were commonly involved (67%). Patients received chemotherapy +/- radiation (6/6) and bone marrow transplant (2/6). Average survival was 44.2 mo. CD4 expression in DLBCL raises questions of lineage commitment. CD4(+) DLBCL is rare; care should be exercised not to diagnose these as T-cell lymphomas. A subset behaves aggressively.

Hematolymphoid Lesions of the Sinonasal Tract.

Hematolymphoid neoplasms of the sinonasal tract are rare and the majority represents non-Hodgkin lymphomas. This review will focus on morphologic, immunophenotypic, and genetic characteristics of the most common types of non-Hodgkin lymphoma, namely diffuse large B cell lymphoma and extranodal natural killer/T-cell lymphoma, nasal type, but also include the discussion of less frequent other hematolymphoid entities, such as extranodal plasmacytomas and Rosai-Dorfman disease.

Expression of TIA1 and PAX5 in Classical Hodgkin Lymphoma at Initial Diagnosis May Predict Clinical Outcome.

Although the expression of T-cell antigens and proteins associated with tumor-infiltrating T-lymphocytes (TILs), regulatory T cells (T-regs), and B-cell development have been evaluated in classical Hodgkin lymphoma (cHL), few studies correlate these proteins' expression patterns with clinical outcome. The purpose of this study was to evaluate proteins expressed in the Reed-Sternberg cells (RSCs) and TILs of cHLs at initial diagnosis to determine their prognostic significance. The expression of 12 proteins in RSCs and TILs from 88 diagnostic cHL biopsies was quantitated and correlated to overall survival (OS) and progression-free survival (PFS). CD2, CD3, CD4, CD5, CD7, CD25, PD1, TIA1, MUM1, and ZAP70 expression in RSCs did not correlate with OS or PFS, nor did programmed death 1 (PD1) expression in TILs. High numbers of TIA1-positive TILs (≥50%) correlated with OS (P=0.027), but not PFS (P=0.993) in univariate analysis. Expression of CD2, CD3, CD4, CD5, and/or TIA1 (6%) in RSCs was associated with lymphocyte-rich/mixed-cellularity subtype (P=0.032). High International Prognostic Score (IPS; P=0.036), and high stage (P=0.046) were independent predictors of worse PFS in univariate analysis. Low IPS (P=0.003) and nodular sclerosing subtype (P=0.022) were associated with better OS in univariate analysis. Only the IPS predicted OS in multivariate (P=0.009) analysis. High TIA1+ TILs correlated with worse clinical outcomes for cHLs, as did PAX5-RSCs (P=0.024), although only 2/74 cases were shown to be negative for this marker, suggesting that the tumor microenvironment and a transcription factor crucial for B-cell development are critical biological determinants of the disease course.

T-cell prolymphocytic leukemia frequently shows cutaneous involvement and is associated with gains of MYC, loss of ATM, and TCL1A rearrangement.

T-cell prolymphocytic leukemia (T-PLL) is a rare aggressive mature T-cell leukemia with frequent cutaneous presentation, which has not been well characterized. Among the 25 T-PLLs diagnosed between 1990 and 2013 at our institution, 32% (8/25) showed cutaneous manifestations, presenting as rash, purpura, papules, and ulcers. The skin biopsies showed leukemia cutis with perivascular and periadnexal irregular, small to medium-sized lymphoid infiltrates without epidermotropism. The lymphoid infiltrates were composed of mature CD4+ T cells expressing other T-cell antigens, and a subset (48%) showed dual CD4+/CD8+ coexpression. Higher median absolute peripheral blood lymphocyte count (43.0 vs. 13.0 k/mm; P=0.031) and elevated lactate dehydrogenase levels (P=0.00018) at the time of diagnosis were significantly associated with T-PLLs with skin involvement compared with those without. The extent of bone marrow involvement (P=0.849) and overall survival (P=0.144) was similar in the 2 groups. Fluorescence in situ hybridization or karyotype revealed frequent gains of MYC (67%; n=9), loss of ATM (64%; n=11), and TCL1A rearrangement or inversion 14q (75%; n=12). Gains of TCL1A was also seen (78%; n=9), including in some cases that had concurrent TCL1A rearrangement, whereas TP53 loss was less common (30%; n=10). No correlation was seen between the immunophenotype and morphology versus the presence or absence of skin involvement. These data suggest that cutaneous involvement by T-PLL is relatively common and often associated with significant peripheral blood involvement. The frequent MYC, ATM, and TCL1A alterations identified support that these genes are integral to the pathogenesis of T-PLL.

Mast cell leukemia with prolonged survival on PKC412/midostaurin.

Mast cell leukemia (MCL) is a rare and aggressive form of systemic mastocytosis. There are approximately 50 reported cases since 1950s. MCL is refractory to cytoreduction chemotherapy and the average survival is only six months. We report a MCL case in a 71 year-old woman with high tumor load at the initial presentation in 2005, who did not respond to either interleukin-2 or dasatinib therapy. After enrolled in a clinical trial of PKC412 (or Midostaurin) with a daily dose of 100 mg, the patient responded well to PKC412 and became transfusion independent in three months. Since then, her disease had been stably controlled. This is the first report of a high-tumor-load MCL case which achieved prolonged survival (101 months) by PKC 412. The 101-month overall survival is the longest among reported MCL cases in the English literature.

Clinicopathologic features of adult T-cell leukemias/lymphomas at a North American tertiary care medical center: infrequent involvement of the central nervous system.

Human T-cell lymphotropic virus type 1 is associated with adult T-cell leukemia/lymphoma (ATLL). Published series of ATLLs seen at a United States medical institution are rare. We present the features of 4 ATLLs diagnosed at our North American tertiary care medical center from 1990 to 2012. Despite the absence of a history of origin from an endemic region, all our ATLLs demonstrated evidence of human T-cell lymphotropic virus type 1 infection. Central nervous system (CNS) involvement by ATLL was uncommon in our series, and represented only 1.6% (1/64) of all CNS B-cell or T-cell lymphomas diagnosed over a 20+ year period at our institution. Review of the medical literature reveals that the majority of CNS-involved ATLLs present with the lymphoma or acute subtype, and complete remission is difficult to achieve in these cases. CNS involvement frequently occurs with a systemic disease, which carries an aggressive clinical course with poor prognosis. In addition, CNS involvement by ATLL can be the initial presentation or seen with relapsed disease, can be the only site or be associated with other tissue sites of involvement, and may manifest with variable clinical signs/symptoms. Our retrospective study reveals that ATLLs are rare mature T-cell lymphomas in a native North American population, but the clinical and histopathologic features of ATLLs from this nonendemic region are similar to those seen from other endemic regions. Early recognition of these rare ATLLs involving uncommon sites, such as the CNS, will help optimize treatment for these infrequent mature T-cell lymphomas.

Assessment of cellular proliferation in tumors by PET using 18F-ISO-1.

UNLABELLED: This first study in humans was designed to evaluate the safety and dosimetry of a cellular proliferative marker, N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-2-(2-(18)F-fluoroethoxy)-5-methylbenzamide ((18)F-ISO-1), and evaluate the feasibility of imaging tumor proliferation by PET in patients with newly diagnosed malignant neoplasms. METHODS: Patients with biopsy-proven lymphoma, breast cancer, or head and neck cancer underwent (18)F-ISO-1 PET. Tumor (18)F-ISO-1 uptake was assessed semiquantitatively by maximum standardized uptake value, ratios of tumor to normal tissue and tumor to muscle, and relative distribution volume ratio. The PET results were correlated with tumor Ki-67 and mitotic index, from in vitro assays of the tumor tissue. The biodistribution of (18)F-ISO-1 and human dosimetry were evaluated. RESULTS: Thirty patients with primary breast cancer (n = 13), head and neck cancer (n = 10), and lymphoma (n = 7) were evaluated. In the entire group, tumor maximum standardized uptake value and tumor-to-muscle ratio correlated significantly with Ki-67 (τ = 0.27, P = 0.04, and τ = 0.38, P = 0.003, respectively), but no significant correlation was observed between Ki-67 and tumor-to-normal-tissue ratio (τ = 0.07, P = 0.56) or distribution volume ratio (τ = 0.26, P = 0.14). On the basis of whole-body PET data, the gallbladder is the dose-limiting organ, with an average radiation dose of 0.091 mGy/MBq. The whole-body and effective doses were 0.012 mGy/MBq and 0.016 mSv/MBq, respectively. No adverse effects of (18)F-ISO-1 were encountered. CONCLUSION: The presence of a significant correlation between (18)F-ISO-1 and Ki-67 makes this agent promising for evaluation of the proliferative status of solid tumors. The relatively small absorbed doses to normal organs allow for the safe administration of up to 550 MBq, which is sufficient for PET imaging in clinical trials.

Cutaneous myeloid sarcoma: natural history and biology of an uncommon manifestation of acute myeloid leukemia.

We conducted a retrospective study of patients with cutaneous myeloid sarcoma, from 2 tertiary care institutions. Eighty-three patients presented, with a mean age of 52 years. Diagnosis of myeloid sarcoma in the skin was difficult due to the low frequency of myeloperoxidase and/or CD34+ cases (56% and 19% of tested cases, respectively). Seventy-one of the 83 patients (86%) had ≥ 1 bone marrow biopsy. Twenty-eight (39%) had acute myeloid leukemia with monocytic differentiation. Twenty-three had other de novo acute myeloid leukemia subtypes. Thirteen patients had other myeloid neoplasms, of which 4 ultimately progressed to an acute myeloid leukemia. Seven had no bone marrow malignancy. Ninety-eight percent of the patients received chemotherapy, and approximately 89% died of causes related to their disease. Cutaneous myeloid sarcoma in most cases represents an aggressive manifestation of acute myeloid leukemia. Diagnosis can be challenging due to lack of myeloblast-associated antigen expression in many cases, and difficulty in distinguishing monocyte-lineage blasts from neoplastic and non-neoplastic mature monocytes.

Use of classic and novel immunohistochemical markers in the diagnosis of cutaneous myeloid sarcoma.

Cutaneous myeloid sarcoma is often challenging to diagnose based solely upon histopathological features. Although immunohistochemistry can aid in its diagnosis, specific markers have not been clearly identified. We evaluated the utility of immunohistochemical markers in 57 cutaneous myeloid sarcoma cases. In addition to classical markers (CD117, CD163, CD34, myeloperoxidase and lysozyme), we used CD33 and CD14, recently described markers in paraffin-embedded tissue samples, and Kruppel-like factor 4 (KLF-4), a novel monocytic marker. Our results show that lysozyme was expressed in 91%, CD33 in 60%, myeloperoxidase in 54%, CD34 in 39% and CD117 in 36% of cases. An antibody panel that included lysozyme, CD117 and CD33 identified all cases. The monocytic markers CD14, KLF-4 and CD163 were expressed in 60, 58 and 40% of all cases, respectively. CD14 and KLF-4 expression was significantly more common in cases with monocytic differentiation. CD14 is the single most sensitive and specific marker for monocytic differentiation (79 and 80%). Although KLF-4 in isolation is relatively insensitive (50 and 87%), it enhances sensitivity in detecting monocytic cutaneous myeloid sarcoma when combined with CD14. Our results indicate that in addition to classical immunohistochemical markers, targeted use of newer antibodies, including CD33, CD14 and KLF-4 is useful in the diagnosis of cutaneous myeloid sarcoma and in the detection of monocytic differentiation.

Immunohistochemical analysis of monocytic leukemias: usefulness of CD14 and Kruppel-like factor 4, a novel monocyte marker.

Detection of monocytic differentiation in myeloid neoplasms by immunohistochemical analysis is challenging owing to a lack of sensitive and/or specific antibodies. We tested the usefulness of immunohistochemical analysis for CD14, an antigen commonly detected by flow cytometry, and Krüppel-like factor 4 (KLF4), a potentially novel marker of monocytic differentiation, in a series of myeloid leukemias, including 53 acute myeloid leukemias with monocytic differentiation. These findings were compared with immunohistochemical findings for CD68 (KP-1), CD34, and CD163 and were also correlated with flow cytometric and enzyme cytochemical results. CD163 and CD14 are the most specific markers of monocytic differentiation, followed by KLF4. CD68, in contrast, is the most sensitive monocytic marker, and KLF4 is also significantly more sensitive than CD14 and CD163. These studies show that KLF4 is another marker of monocytic differentiation and that the combination of CD14 and CD163 can increase the diagnostic sensitivity for monocytic neoplasms.

Cystic lymphoid hyperplasia of the parotid gland in HIV-positive and HIV-negative patients: quantitative immunopathology.

BACKGROUND: Benign lymphoepithelial lesions of the parotid include a spectrum of disorders ranging from lymphoepithelial sialadenitis (LESA) of Sjögren syndrome to lymphoepithelial cysts (LEC) and both human immunodeficiency virus (HIV)-related and -unrelated cystic lymphoid hyperplasia (CLH). They share a common microscopic appearance characterized by epimyoepithelial islands and/or epithelial lined cysts in a lymphoid stroma. However, they differ greatly regarding their etiology, clinical presentation, and management. OBJECTIVE: The purpose of this study was to establish specific immunophenotypic profiles for these diverse disease entities. STUDY DESIGN: Four cases of HIV+ CLH, 5 cases of HIV- CLH, 3 cases of LESA of Sjögren syndrome, and 3 cases of sporadic LEC were quantitatively analyzed for distribution of lymphoreticular cell subpopulations, using antibodies against CD20, CD45RO, CD4, CD8, CD57, and CD68. RESULTS: The cystic lesions in both the HIV+ and HIV- cases were microscopically analogous. However, a marked decrease in the interfollicular CD4:CD8 ratio was observed in all HIV+ CLH cases, which was statistically significant when compared with the HIV- cases (P = .02) and cases of LESA of Sjögren syndrome (P = .03). No significant differences regarding the distribution of CD20+ B lymphocytes in epithelial cyst lining or the interfollicular or follicular distribution of CD20+, CD45RO+, CD57+, and CD68+ cells were present among the different groups. CONCLUSION: Analysis of the interfollicular CD4:CD8 ratio may offer a simple immunophenotypic approach in the distinction of HIV+ from other lymphoepithelial lesions of the parotid gland, when HIV status is unknown and p24 immunohistochemistry is not readily available.

Molecular pathology of myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPNs; formerly chronic myeloproliferative disorders) are a class of myeloid hematologic malignancies that represent a stem cell-derived expansion of 1 or more hematopoietic cell lineages. The current 2008 World Health Organization system recognizes 8 types of MPN: chronic myelogenous leukemia, chronic neutrophilic leukemia, polycythemia vera, primary myelofibrosis, essential thrombocythemia, chronic eosinophilic leukemia, mastocytosis, and myeloproliferative neoplasm, unclassifiable. This review summarizes the salient characteristics of the MPNs, with emphasis on recent developments in the molecular pathophysiology and therapeutic monitoring of these disorders.

Bone marrow biopsy in patients with hepatitis C virus infection: spectrum of findings and diagnostic utility.

Patients with hepatitis C virus (HCV) infection develop a number of hematologic disorders, with benign and malignant B-cell proliferations being the most common. HCV-infected patients are also prone to developing peripheral cytopenias, the etiologies of which are multifactorial and include hypersplenism and/or antiviral medications. Some of these patients may undergo bone marrow biopsy but no study has systematically recorded the bone marrow findings in this patient group. Here, we report on the range of bone marrow findings in 47 adult HCV-infected patients. These patients, who lacked concurrent human immunodefiency virus (HIV) infection, most commonly presented for a bone marrow biopsy due to abnormal peripheral cell counts. The bone marrow biopsies displayed a range of findings. Dyserythropoiesis, present in 19% of the cases, was the most common finding. Patients with pancytopenia(n = 6), as defined by current World Health Organization standards, were the most likely to have bone marrow abnormalities; two pancytopenic patients had acute myeloid leukemia, and one patient had a primary myelodysplastic syndrome. There was no correlation in bone marrow findings and antiviral medications, MELD score, cirrhosis or splenomegaly, suggesting that the degree of bone marrow dysfunction is independent of stage of HCV. The results of this study suggest that bone marrow biopsy in HCV-infected patients, even those with features of hypersplenism and/or documented antiviral therapy, can be a valid test for hematologic evaluation, especially for patients with severe pancytopenia and/or sudden alterations in peripheral cell counts.

Pathologic and clinical features of Hodgkin lymphoma--like posttransplant lymphoproliferative disease.

Because of its rarity, pathologic and clinical features of Hodgkin lymphoma-like posttransplant lymphoproliferative disorder (HL-like PTLD) are not well understood, and it is unclear whether its biological behavior is more closely related to classical Hodgkin disease or to monomorphic B-cell PTLD. The authors compared 6 cases of HL-like PTLD with 5 cases of monomorphic B-cell PTLD for differences in histology, immunophenotype, and clinical behavior. Histologically, all cases of HL-like PTLD resembled classical HL with typical Reed-Sternberg (RS) cells and a cellular background mimicking mixed cellularity subtype. CD45 was absent on RS-like cells, but the expression pattern of B-cell-associated markers Oct-2 and BOB.1 resembled monomorphic B-cell PTLD. Whereas Epstein-Barr virus early RNA expression is normally restricted to RS cells of classical HL, it was expressed in both RS-like cells and background lymphocytes in HL-like PTLD. Although all patients diagnosed with monomorphic B-cell PTLD show no evidence of disease following treatment, half of the patients with HL-like PTLD relapsed or died, indicating a more aggressive clinical behavior. The findings suggest that HL-like PTLD represents a distinct clinicopathologic entity with an aggressive clinical course.

Cutting edge: Acute lung allograft rejection is independent of secondary lymphoid organs.

It is the prevailing view that adaptive immune responses are initiated in secondary lymphoid organs. Studies using alymphoplastic mice have shown that secondary lymphoid organs are essential to initiate allograft rejection of skin, heart, and small bowel. The high immunogenicity of lungs is well recognized and allograft rejection remains a major contributing factor to poor outcomes after lung transplantation. We show in this study that alloreactive T cells are initially primed within lung allografts and not in secondary lymphoid organs following transplantation. In contrast to other organs, lungs are acutely rejected in the absence of secondary lymphoid organs. Two-photon microscopy revealed that recipient T cells cluster predominantly around lung-resident, donor-derived CD11c(+) cells early after engraftment. These findings demonstrate for the first time that alloimmune responses following lung transplantation are initiated in the graft itself and therefore identify a novel, potentially clinically relevant mechanism of lung allograft rejection.

The spectrum of adult B-lymphoid leukemias with BCR-ABL: molecular diagnostic, cytogenetic, and clinical laboratory perspectives.

The Philadelphia (Ph) chromosome is characteristic of chronic myelogenous leukemia (CML), but it is also the most frequent cytogenetic abnormality in precursor B-lymphoblastic leukemia (ALL) of adults. The vast majority of CML patients have a BCR-ABL translocation that yields a 210 kD (p210) oncoprotein, whereas adult Ph-positive ALL cases can present with either a p190 or a p210 oncoprotein, or both. Considering that 30% of the patients with CML that progress to blast crisis will have a lymphoblastic presentation, adults presenting with a p210 ALL may have either a de novo ALL or CML presenting for the first time in lymphoblastic phase. To identify the distinguishing features, cases of p190-ALL, p210-ALL, and lymphoblastic CML were compared. In spite of significant overlap between the three entities, a number of features were found to aid in their differentiation. p210-ALL patients present at a younger age with blasts that frequently show loss of expression of CD34, whereas p190-ALL patients present with marked increase in peripheral blast percentage. Interestingly, bone marrow findings characteristic of a myeloproliferative disorder are specific, but are not sensitive for lymphoblastic CML. This study suggests that despite the similarities between these leukemias, p190-ALL, p210-ALL, and lymphoblastic phase CML likely represent three distinct diseases.

CD4+ T lymphocytes are not necessary for the acute rejection of vascularized mouse lung transplants.

Acute rejection continues to present a major obstacle to successful lung transplantation. Although CD4(+) T lymphocytes are critical for the rejection of some solid organ grafts, the role of CD4(+) T cells in the rejection of lung allografts is largely unknown. In this study, we demonstrate in a novel model of orthotopic vascularized mouse lung transplantation that acute rejection of lung allografts is independent of CD4(+) T cell-mediated allorecognition pathways. CD4(+) T cell-independent rejection occurs in the absence of donor-derived graft-resident hematopoietic APCs. Furthermore, blockade of the CD28/B7 costimulatory pathways attenuates acute lung allograft rejection in the absence of CD4(+) T cells, but does not delay acute rejection when CD4(+) T cells are present. Our results provide new mechanistic insight into the acute rejection of lung allografts and highlight the importance of identifying differences in pathways that regulate the rejection of various organs.

Secondary lymphoma involving metastatic follicular thyroid carcinoma to the skull: a unique example of tumor-to-tumor metastasis.

Tumor-to-tumor metastases to the skull, presenting as a scalp mass, and thyroid follicular carcinoma presenting in that location are extremely rare. We present the case of a patient with recently diagnosed retroperitoneal diffuse large B-cell lymphoma and an 8-year history of a non-tender large scalp-based mass. The scalp mass was an osteolytic enhancing lesion on imaging studies and diagnosed as metastatic thyroid carcinoma to the skull. The patient had no pre-existing history of thyroid cancer. This metastatic carcinoma was also secondarily involved with diffuse large B-cell lymphoma. This case illustrates a unique and previously unreported example of tumor-to-tumor metastasis in which both malignancies represent metastatic tumors to the skull with soft tissue extension presenting as a large scalp mass.