Sinonasal NK/T-cell lymphomas in the United States

Sinonasal natural killer (NK)/T-cell lymphomas are common in Asia and areas of South and Central America but are rarely seen in the United States, where they have not been as well characterized. Fifteen cases diagnosed in Southern California were studied with respect to histologic features, immunophenotype, Epstein-Barr virus EBER in-situ hybridization (EBV EBER-ISH), and T-cell receptor gamma chain (TCR-gamma) gene rearrangement. Although ethnic background was available for only seven patients, six were of Asian or Hispanic descent with only one non-Hispanic white known. Twelve presented as sinonasal lesions, but three were limited to the oropharynx. Most cases (11 of 15) demonstrated both necrosis and an angiodestructive pattern. All cases demonstrated cytoplasmic CD3 positivity (15 of 15), and were positive for both TIA-1 and granzyme B (14 of 14). Perforin was positive in 5 of 14. CD56 was expressed in 10 of 15 and CD8 in 3 of 15. EBV EBER-ISH was positive in 14 of 14 and TCR-gamma gene rearrangement was detected in 1 of 14 cases. None (0 of 14) were positive for CD16 or CD57. Although CD16-positive histiocytes were abundant, double-label EBER-ISH/IHC failed to identify CD16 expression on EBV-positive tumor cells. Three cases with pleomorphic large cell morphology showed focal CD30 positivity, raising the differential diagnosis of anaplastic large cell lymphoma, but all were ALK-1-negative and otherwise similar to the other cases of NK/T-cell lymphoma. Sinonasal NK/T-cell lymphomas in the United States most often occur in ethnic groups from areas of reported high frequency (Asia, Central and South America), although less commonly than in endemic populations, and are otherwise similar phenotypically. A combined approach, including immunohistochemistry, EBV EBER-ISH, and TCR gene rearrangement studies, is most helpful to arrive at the correct diagnosis.     

Epstein-Barr virus negative clonal plasma cell proliferations and lymphomas in peripheral T-cell lymphomas: a phenomenon with distinctive clinicopathologic features

Clonal B-cell populations have been described in peripheral T-cell lymphomas (PTCL) as secondary Epstein-Barr virus (EBV) driven B-cell expansions that may evolve to an overt B-cell lymphoma. EBV-negative B-cell proliferations associated with T-cell lymphomas are uncommon and not well characterized. We studied 15 patients who developed an EBV-negative B-cell proliferation or malignant lymphoma associated with PTCL. The T-cell tumors were 8 PTCL, not otherwise specified, 4 angioimmunoblastic T-cell lymphomas, and 3 cutaneous PTCL. The B-cell component was intermingled with the PTCL in all patients and it was classified as clonal/monotypic plasma cell proliferation in 8 lesions, clonal/monotypic large B-cell proliferation in 4 patients, and B-cell lymphoma with plasmacytic/plasmablastic differentiation in 3 patients. Two patients had 2 clonally unrelated plasma cell proliferations associated with the same PTCL. All cases showed cytoplasmic Ig light chain restriction. Clonal IgH and T-cell receptor rearrangements were detected in 11/12 and 11/13 cases examined, respectively. EBV, cytomegalovirus, and HHV-8 were not observed in any of the examined cases. Sequential samples in 7 patients showed persistence of the PTCL and the B-cell component in 4, the PTCL without the B-cell lymphoma in 2, and progression of the B-cell neoplasm in 1. Patients followed an aggressive clinical course similar to conventional PTCL. In conclusion, EBV-negative clonal or mononotypic B-cell proliferations in patients with PTCL present with a spectrum of lesions ranging from plasma cell proliferations to overt lymphomas with plasmacytic/plasmablastic features. The distinctive features of these patients suggest that these lesions represent a specific phenomenon in PTCL.     

Penile metastasis secondary to nasal NK/T-cell lymphoma

We report on a case of recurrent nasal NK/T-cell lymphoma in a patient who presented with a penile mass. No obvious other recurrent site except the penile lesion was noted. Metastatic penile lymphoma is extremely rare. We describe the image findings and clinical course of this case.     

Hepatosplenic alphabeta T-cell lymphomas: a report of 14 cases and comparison with hepatosplenic gammadelta T-cell lymphomas

Hepatosplenic gammadelta T-cell lymphoma is a distinct entity, characterized by occurrence in young adult males with hepatosplenomegaly, B-symptoms, peripheral blood cytopenias, and no lymphadenopathy; lymphomatous infiltrates in the splenic red pulp, hepatic sinusoids, and bone marrow sinuses; T-cell receptor (TCR) gammadelta chains and a cytotoxic T-cell phenotype; isochromosome 7q; and an aggressive clinical course. In comparison, this study describes the clinicopathologic features of 14 hepatosplenic T-cell lymphomas expressing TCR alphabeta chains. They occurred in 11 women and 3 men with a median age of 36 years. Clinical presentation was similar to that described previously for hepatosplenic gammadelta T-cell lymphomas, except for the female preponderance and age distribution (5 patients younger than 13 years of age and 5 patients older than 50 years of age). Disease distribution was primarily in the splenic red pulp and hepatic sinusoids, although liver infiltrates were largely periportal in four cases. Bone marrow involvement, observed in eight patients, was usually interstitial and/or within the sinuses. Lymph nodes were involved in five patients, although lymphadenopathy was demonstrable in only two. Ten cases were composed of intermediate-size tumor cells with round/oval nuclei, slightly dispersed chromatin, inconspicuous nucleoli, and scant to moderate amounts of cytoplasm. Four lymphomas contained primarily large cells with irregular nuclei, dispersed chromatin, discernible nucleoli, and moderate to abundant cytoplasm. Tumor cells in all 14 lymphomas were cytotoxic alphabeta T-cells; 13 co-expressed natural killer cell-associated antigens and showed T-cell clonality. Three lymphomas were associated with Epstein-Barr virus. Two of four cases had an isochromosome 7q. Eleven patients are dead, eight within a year of diagnosis, and two patients have maintained complete remissions after combination chemotherapy. These data show that hepatosplenic T-cell lymphomas include an alphabeta-subtype. This group, along with the previously recognized gammadelta group, should be recognized as phenotypically heterogeneous subtypes of the same disease entity.     

Peripheral T-cell lymphomas expressing CD30 and CD15

Coexpression of CD30 and CD15 is typically associated with classic Hodgkin's lymphoma (HL). Peripheral T-cell lymphomas (PTCLs) can often display histologic features that simulate classic HL. However, reports of PTCLs coexpressing both CD30 and CD15 have been infrequently described. We report 11 cases of PTCL in which at least a subset of the neoplastic cells coexpressed CD30 and CD15. The patients included 4 women and 7 men and age ranged from 43 to 83 years (median, 62 years). Nine of 10 patients had advanced stage III or IV disease at presentation. Nodal involvement predominated in 8 of 11 patients, whereas 2 patients presented primarily with skin involvement. Two distinct groups were identified based on morphologic and immunophenotypic features. The first group of 5 cases had histologic features mimicking classic HL with CD30+, CD15+ Reed-Sternberg (RS)-like cells in an inflammatory background of varied extent and composition. The background lymphoid cells showed minimal cytologic atypia. The RS-like cells were negative for CD20 and CD79a in all cases, and CD45 expression was absent in 4 of 5 cases. The RS-like cells expressed CD25 and at least one T-cell-associated marker in all cases. The background T-cell population showed convincing subset predominance in 4 of 5 cases and loss of T-cell-associated antigens in 3 of 5 cases and coexpression of CD30 and CD15 in one case. The second group of 6 cases had morphologic features more in keeping with PTCL than classic HL. The proportion of neoplastic cells coexpressing CD30 and CD15 varied. Loss of T-cell antigens was noted in all cases and CD4 predominated in 4 of 5 cases. Three of the 6 cases expressed CD45. PCR analysis revealed clonal T-cell receptor gamma (TCR-gamma) chain gene rearrangements in 9 of 11 cases, but no immunoglobulin heavy (IgH) chain gene rearrangements. In situ hybridization studies for Epstein-Barr virus were negative in all cases. In some PTCL cases, the overlap with classic HL can be striking, and combined immunophenotypic and molecular studies are often necessary to confirm the diagnosis.     

New biotherapies for the treatment of cutaneous T-cell lymphomas

Most cutaneous lymphomas are cutaneous T-cell lymphomas, and the most common form is mycosis fungoides. Sézary syndrome is a leukemic form of cutaneous T-cell lymphoma which is characterized by erythroderma and the presence of blood tumor cells. The only potential cure of cutaneous T-cell lymphomas remains allogeneic stem cell transplantation. However, monoclonal antibodies have led to a substantial progress in the treatment of advanced-stage cutaneous T-cell lymphomas. Some of them, such as mogamulizumab (anti-CCR4 monoclobal antibody) or brentuximab vedotin (anti-CD30 coupled to monomethylauristatin E, antibody drug conjugate) have shown efficacy in international randomized controlled studies. Lacutamab, an anti-KIR3DL2 monoclonal antibody, is currently tested in an international, prospective phase 2 trial in cutaneous T-cell lymphomas and peripheral T-cell lymphomas. Finally, immune checkpoint inhibitors have shown clinical benefit in open-label phase 2 studies in cutaneous T-cell lymphomas. This review focuses on the new biotherapies currently used in cutaneous T-cell lymphomas.     

IG/MYC rearrangements are the main cytogenetic alteration in plasmablastic lymphomas

Plasmablastic lymphoma (PBL) is an aggressive lymphoma characterized by a terminally differentiated B-cell phenotype that usually occurs in the immunocompromised or elderly patients. Although the clinical and pathologic characteristics of these tumors have been defined, the genetic alterations involved in their pathogenesis are not well known. In this study, we have investigated the chromosomal alterations of MYC, BCL2, BCL6, MALT1, PAX5, and IGH loci using fluorescence in situ hybridization in 42 PBL and 3 extracavitary primary effusion lymphomas. MYC rearrangements were identified in 20 of 41 (49%) PBL and the immunoglobulin (IG) genes were the partners in most tumors. MYC rearrangements were more common in Epstein-Barr virus (EBV)-positive (14 of 19, 74%) than EBV-negative (9 of 21, 43%) tumors (P<0.05). No rearrangements of BCL2, BCL6, MALT1, or PAX5 were detected in any PBL but gains of these loci were observed in 31% to 41% of the cases examined. Twelve of the 40 PBL in which 3 or more loci could be investigated had multiple simultaneous gains in 3 or more loci. No differences in the survival of the patients according to MYC were observed but the 4 patients with the longest survival (>50?mo) had no or low number of gains (<3). No rearrangements of any of these loci were seen in the primary effusion lymphomas. In conclusion, PBL are genetically characterized by frequent IG/MYC translocations and gains in multiple chromosomal loci. The oncogenic activation of MYC in these lymphomas may be an important pathogenetic element associated with EBV infection.     

Sublabial approach to the nasal and nasopharyngeal cavities.

A sublabial transnasal degloving approach to the mid-face, nasal cavity, septum, paranasal sinuses, and nasopharynx is described. This approach provides adequate exposure and ample facility for management of tumors in these areas. The pterygomaxillary space and infratemporal fossa ard readily accessible for hemostasis and management of tumor extensions. Children, adolescents, and women with benign and low-grade malignant tumors of these areas are the ideal candidates for this procedure. Twenty-six patients have been managed in this fashion, with no major complication. The cosmetic results have been excellent. This approach to the mid-third of the face, nasal, paranasal, and nasopharyngeal cavities should receive more attention and use.     

Most Pancreatic Cancer Resections are R1 Resections

Background Curative resection has been shown to be one of the key factors influencing survival of pancreatic ductal adenocarcinoma (PDAC) patients. Although general guidelines for the processing of pancreatic specimens have been established, there is currently no widely accepted standardized protocol for pathological examination, especially with respect to resection margins. Methods Here we present a single-center experience with 111 consecutive macroscopic complete pancreatic head resections for PDAC carried out between 2005 and 2006 by using standardized pathological processing and reporting. The pancreatic transection margin, as well as the bile duct and stomach/duodenum margins and the circumferential soft tissue margins (medial, anterior surface, superior, and posterior), were inked and analyzed. R1 was defined as a distance of the tumor from the resection margin of ≤1 mm. Results One hundred eighty-eight consecutive macroscopic complete pancreatic head resections carried out for PDAC without a standardized protocol between 2002 and 2004 were used as a control group. The R1 rate for resections carried out with the standardized protocol was 76%. The medial (68%) and the posterior (47%) margins were most commonly involved, and in 32% of the cases, more than one margin was affected. The R1 resection rate in the period without standardized pathological reporting was 14%. Conclusions This study highlights the importance of pathological reporting and suggests that tumor growth patterns and thorough examination but not surgical technique determine R1 resection rates in PDAC. Presented at the 5th International Postgraduate Course Frontiers in HPB Diseases, Athens, Greece, March 2007; at the EHPBA meeting 2007, Verona, Italy, June 2007; and at the 16th Billroth Symposium, Binz, Germany, October 2007.     

Nonsquamous cell malignant neoplasms of the nasal cavities and paranasal sinuses

Background. Nonsquamous cell malignant tumors of the nasal cavity and paranasal sinuses are an uncommon and diverse group of neoplasms. Our goal was to define the relative frequency and distribution of these neoplasms, as well as treatment and outcome. Methods.This retrospective study analyzed 106 patients with nonsquamous cell malignant neoplasms of the nasal cavity and paranasal sinuses treated at our institution between 1966 and 1982. Results. Pathology included: salivary type carcinoma (33 patients); sarcoma (25 patients); melanoma (18 patients); esthesioneuroblastoma (11 patients); lymphoma (11 patients); and anaplastic cancer (9 patients). Most tumors arose in the nasal cavity (50%), followed by the antrum (39%), ethmoidsinus (9%), and frontal sinus (2%). Fifty-four percent of all patients were treated with surgery alone. Determinate 5-year and 10-year cure rates were: esthesioneuroblastoma, 70% and 50%; lymphoma, 45% and 30%; anaplastic, 33% and 25%; salivary, 31% and 18%; sarcoma, 25% and 21%; and melanoma, 19% and 0%. Conclusions. Overall survival for patients with nonsquamous cell malignant neoplasms of the nasal cavity and paranasal sinuses is poor, particularly with follow-up extended to 10 years. Local recurrence is the major source of treatment failure. We were unable to demonstrate any survival advantage in the group of patients who received surgery and radiotherapy in combination. © 1995 Jons Wiley & Sons, Inc.     

Clonal T-cell populations and increased risk for cytotoxic T-cell lymphomas in B-CLL patients: clinicopathologic observations and molecular analysis

Chronic lymphocytic leukemia (CLL) is associated with increased risk of malignancy, but the occurrence of other lymphomas, in particular T-cell lymphomas, is rare. We identified 7 cases of peripheral T-cell malignancy associated with B-cell-derived CLL from the files of two institutions over a 20-year period. The presence of both B and T lymphoproliferative disorders was confirmed in all cases by immunophenotype and in 6 cases by gene rearrangements. Six patients developed peripheral T-cell lymphoma (PTCL), unspecified, during the course of CLL (10-168 months). In all 5 evaluable cases, the cells had a cytotoxic T-cell phenotype; the sixth case was CD56+, but TIA-1 and Granzyme B could not be studied. A seventh patient with CLL developed mycosis fungoides, and an aggressive NK cell leukemia. To investigate possible risk factors for the development of PTCL, we screened 100 unselected peripheral blood samples from newly diagnosed CLL patients by PCR for the presence of clonal T cell populations. We found evidence of clonal T-cell expansion in 8 patients and increased lymphocytes with large granular lymphocyte morphology in 7 of 8 cases. The immunophenotype was assessed by multicolor flow cytometry and in 4 cases the T-cell expansion was composed of either CD3+/CD8+ or CD3+/CD4-/CD8- cells. The cytotoxic nature of the clonal T-cell expansions in the peripheral blood correlates with the cytotoxic nature of the PTCLs, but their role in the subsequent development of T-cell lymphomas is still unclear. PTCL following CLL should be distinguished from typical Richter syndrome, which it can mimic clinically.     

Chemokine receptor expression in cutaneous T cell and NK/T-cell lymphomas: immunohistochemical staining and in vitro chemotactic assay

Interactions between chemokines and chemokine receptors are involved in migration and invasion of lymphoma cells. We investigated expression profiles of CXCR3 and CCR4 by immunohistochemistry and flow cytometry, and their biologic behaviors by real-time horizontal chemotaxis assay in cutaneous T cell and NK/T-cell lymphomas (TCLs). Tumor cells in mycosis fungoides (MF) constantly expressed CXCR3 at the patch stage, and expressed CCR4 at the tumor stage and in the folliculotropic variant of MF. Neoplastic cells at the plaque stage expressed CXCR3 and/or CCR4. Sezary cells in the dermis and circulation were positive for CCR4. Epidermotropic atypical cells in pagetoid reticulosis expressed CXCR3. CD30 cells exclusively expressed CCR4 in anaplastic large-cell lymphoma, and CXCR3 and/or CCR4 in lymphomatoid papulosis. In CD8TCL and extranodal NK/TCL characterized by extensive epidermotropism, tumor cells were positive for CXCR3. These data demonstrated preferential expression of CXCR3 in epidermotropic tumor cells, and of CCR4 in dermis-based lymphomas. In chemotaxis assays, CCR4 tumor cells in MF and CXCR3 tumor cells in CD8TCL migrated to thymus and activation-regulated chemokine and inducible protein-10, respectively. Therefore, spatial and temporal interactions between chemokine receptors and their ligands seem to dictate recruitment and retention of lymphoma cells in the skin.