Ahmed Ali Elsayed

T-cell receptor (TCR) phenotype of nodal Epstein-Barr virus (EBV)-positive cytotoxic T-cell lymphoma (CTL): a clinicopathologic study of 39 cases.

Among Epstein-Barr virus (EBV)-positive cytotoxic T/NK-cell lymphoma, there are only a few reports on the clinicopathologic features of patients with primary nodal presentation (nodal EBV+ cytotoxic T-cell lymphoma [CTL]). Here, we compared the clinicopathologic profiles of 39 patients with nodal EBV+ CTL with those of 27 cases of “extranasal” NK/T-cell lymphoma of nasal type (ENKTL), especially addressing their T-cell receptor (TCR) phenotype. Histologically, 22 of 39 nodal EBV+ CTL cases (56%) were unique in having centroblastoid appearance, which was contrasted with the lower incidence of this feature in ENKTL (15%, P=0.001). In contrast, pleomorphic appearance was more frequently seen in ENKTL than in nodal EBV+ CTL (67% vs. 23%, P=0.001). Thirty-three of 39 nodal EBV+ CTL cases (85%) were of T-cell lineage on the basis of TCR expression and/or TCR&ggr; gene rearrangement; in detail, 18 cases (46%) were TCR&bgr; positive (&agr;&bgr; T), 5 (13%) were TCR&ggr; and/or &dgr; positive (&ggr;&dgr; T), and 10 (26%) were TCR-silent type with clonal TCR&ggr; gene rearrangement but no expression of TCR&bgr;, &ggr;, or &dgr;. These results were clearly contrasted by a lower incidence of T-cell lineage in ENKTL (7 cases, 26%, P<0.001). Notably, the survival time of the 5 nodal lymphoma patients with &ggr;&dgr; T-cell phenotype was within 3 months, which was inferior to those of &agr;&bgr; T and TCR-silent types (P=0.003), and 3 of those with available clinical information were all found to be associated with autoimmune diseases. These data suggest that nodal EBV+ CTL is distinct from ENKTL.

Epstein-Barr Virus (EBV)-positive Sporadic Burkitt Lymphoma An Age-related Lymphoproliferative Disorder?

Epstein-Barr virus (EBV) is detected in 20% to 30% of sporadic Burkitt lymphoma (sBL). However, only a few studies of EBV-positive (EBV+) sBL have been reported, and its characteristics still remain controversial. To highlight the features of EBV+ sBL, we compared the clinicopathologic characteristics of 33 cases of EBV+ and 117 cases of EBV-negative (EBV−) sBL in Japan. EBV+ sBL showed significantly higher age distribution (median, 42 vs. 13 y; P<0.0001) and higher frequency of patients older than 50 years (48% vs. 16%, P<0.0001). We also revealed the difference of the involved sites. The EBV+ group showed significantly higher incidence of involvement of tonsil (P=0.027), adrenal gland (P=0.011), and cervical lymph node (P=0.040). In addition, the EBV+ group tended to have higher incidence of nodal involvement (P=0.078) and involvement of para-aorta lymph node (P=0.084) and heart (P=0.050). In contrast, the gastrointestinal tract was less frequently affected in EBV+ sBL (P=0.024). In addition, the less positivity for MUM1 (P=0.020) of EBV+ sBL was highlighted. These results indicate that biological behavior and pathogenesis of EBV+ sBL might be different from those of EBV− sBL. Our results demonstrate that EBV+ sBL has an aspect of age-related disease and is a distinct clinicopathologic subtype, which should be distinguished from EBV− sBL.

Epstein-Barr virus–positive cytotoxic T-cell lymphoma followed by chronic active Epstein-Barr virus infection–associated T/NK-cell lymphoproliferative disorder: a case report

A 30-year-old female patient presented with intestinal Epstein-Barr virus (EBV)-positive cytotoxic T-cell lymphoma (EBV+ CTL), which was surgically resected. Fourteen years later, she returned to our hospital with hypersensitivity to mosquito bites and was diagnosed with chronic active EBV infection-associated T/NK-cell lymphoproliferative disorder (CAEBV/TNK-LPD). She developed systemic EBV+ CTL at age 47 years during the 2.5-year clinical course of CAEBV/TNK-LPD, despite multiagent chemotherapy and allogeneic stem cell transplantation. Afterward, she had a rapidly deteriorating clinical course and died at age 48 years. The immunophenotype of the EBV+ CTL was consistently a CD3, CD8, and cytotoxic molecule-positive type with the same clonality in polymerase chain reaction analysis of T-cell receptor-γ chain gene rearrangement. This is the first reported case of EBV+ CTL preceding the clinical presentation of CAEBV/TNK-LPD. The present case was unique in suggesting a close relationship between EBV+ CTL and chronic active EBV infection.

Epstein-Barr virus–positive mucocutaneous ulcer arising in a post–hematopoietic cell transplant patient followed by polymorphic posttransplant lymphoproliferative disorder and cytomegalovirus colitis

Epstein-Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) is a newly described entity occurring in elderly or iatrogenically immunocompromised patients. We describe a case of EBVMCU arising in a post-hematopoietic cell transplant patient and followed by EBV-positive polymorphic posttransplant lymphoproliferative disorder (EBV+ polymorphic PTLD). The patient, a 52-year-old woman, received chemotherapy and autologous peripheral blood stem cell transplantation for relapsed diffuse large B-cell lymphoma (DLBCL). She achieved complete remission and was followed up in an outpatient clinic after discharge. One year later, EBVMCU appeared in the tongue and exhibited spontaneous regression. Six months after the regression of the EBVMCU, she had EBV+ polymorphic PTLD, analogous to EBV+ polymorphic DLBCL. The therapy for PTLD was not effective, and the patient finally died of disease progression. This was the first case of EBVMCU characterized by both an association with autologous peripheral blood stem cell transplantation and subsequent emergence of malignant lymphoma in a patient with relapsed DLBCL.

Clinicopathologic Spectrum of Gastrointestinal T-cell Lymphoma: Reappraisal Based on T-cell Receptor Immunophenotypes.

The differential diagnosis of primary gastrointestinal EBV− T-cell lymphoma (GITCL) includes enteropathy-associated T-cell lymphoma (EATL), peripheral T-cell lymphoma, not otherwise specified, adult T-cell leukemia/lymphoma, and anaplastic large cell lymphoma. Type II EATL is considered to be a tumor of intraepithelial lymphocytes. However, the evaluation of intraepithelial lymphocytosis by biopsy specimens is challenging, which poses a diagnostic problem between the EATL and peripheral T-cell lymphoma, not otherwise specified. This situation requested us to establish a pragmatic diagnostic approach for the classification of GITCL. We identified 42 cases of GITCL and analyzed clinicopathologic features, especially addressing their T-cell receptor (TCR) phenotype. Nine (21%) of 42 GITCL cases were positive for TCR&ggr; protein expression. Among these TCR&ggr;+ cases, TCR&bgr; expression or not was detected in 5 and 4, respectively, but resulted in no further clinicopathologic differences. TCR&bgr; positivity without TCR&ggr; expression (&bgr;+&ggr;−) was seen in 9 GITCL patients (21%). Twenty-four patients (57%) were negative for TCR&bgr; and &ggr; expression (&bgr;−&ggr;−). Compared with TCR&bgr;+&ggr;− or &bgr;−&ggr;− type, TCR&ggr;+ cases were characterized by exclusive involvement of intestinal sites (100% vs. 11%, P<0.001; 100% vs. 58%, P=0.032, respectively), but not of stomach (0% vs. 78%, P=0.002; 0% vs. 38%, P=0.039, respectively). Notably, TCR&ggr; positivity was an independent unfavorable prognostic factor among our GITCL patients (P<0.001). Considering our results, TCR&ggr;+ GITCL, that is, intestinal &ggr;&dgr; T-cell lymphoma, appears to constitute a distinct disease entity.

FoxP3-positive T cell lymphoma arising in non-HTLV1 carrier: clinicopathological analysis of 11 cases of PTCL-NOS and 2 cases of mycosis fungoides.

Forkhead box protein 3‐positive (FoxP3+) T cell lymphoma, in the absence of human T cell lymphotrophic virus type 1 (HTLV‐1) infection, is rare and its clinicopathological characteristics still remain unclear. The aim of this study was to elucidate its characteristics.

Prognostic significance of CD20 expression and Epstein-Barr virus (EBV) association in classical Hodgkin lymphoma in Japan: A clinicopathologic study

To investigate the clinicopathological significance of CD20 expression and Epstein‐Barr virus (EBV) association in Hodgkin and Reed–Sterberg cells of classical Hodgkin lymphoma (CHL), CD20 expression and EBV positivity (by EBER in situ hybridization) were investigated in 389 CHL patients in Japan. They included 74 CD20‐positive cases (19%) and 315 CD20‐negative cases (81%). CD20‐positive cases showed significantly older age at onset (P = 0.018) and higher association with EBV (P = 0.002). Multivariate analysis identified EBV‐positivity (but not CD20‐positivity), presence of B symptoms, thrombocytopenia, elevated serum lactate dehydrogenase and performance status >1 as poor prognostic factors for overall survival (OS). We constructed a new prognostic model with these five factors classifying patients into three groups: low risk, 0–1 adverse factor; intermediate risk, 2–3 factors; high risk, 4–5 factors. This prognostic model could stratify the prognosis of CHL patients (P < 0.0001). For 144 patients (58%) classified into the low‐risk group, the 5‐year OS was 91%. For 92 patients (37%) in the intermediate group, the 5‐year OS was 66%; for 11 patients (5%) in the high‐risk group, the 5‐year OS was 36%. In conclusion, EBV is identified as an independent poor prognostic factor for CHL patients. Therefore, examination of EBV association in CHL is recommended as routine pathologic practice especially in countries where EBV infection prevails.

Clinicopathological Study of 30 Cases of Peripheral T-cell Lymphoma with Hodgkin and Reed-Sternberg-like B-cells from Japan.

The presence of Hodgkin and Reed-Sternberg (HRS)-like B-cells in peripheral T-cell lymphoma (PTCL) is rare and its clinicopathological features still remain unclear. Here, we describe 30 cases of PTCL with HRS-like B-cells from Japan. Twenty-three cases (77%) presented evidence of follicular T-helper phenotype (TFH) derivation: 12 were angioimmunoblastic T-cell lymphoma and 11 PTCL with TFH phenotype (PTCL-TFH). The remaining seven cases were diagnosed as PTCL, not otherwise specified (PTCL-NOS). Epstein-Barr virus (EBV) reactivation was detected in 25 cases (83%), but HRS-like B-cells were EBER+ in only 20 cases (67%). The median age at diagnosis was 77 years (range, 39-91 y), including 24 patients (80%) were older than 60 years of age. Most of the patients presented at an advanced clinical stage and were associated with higher risk according to the International Prognostic Index. The 3-year overall and progression-free survival rates were 44% and 27%, respectively. No significant clinicopathological differences were detected between PTCL-TFH, PTCL-NOS and the angioimmunoblastic cases. Cases with EBER+ HRS-like B-cells were associated with inferior overall and progression-free survival compared to those with EBER− HRS-like B-cells, but the difference was not significant. In conclusion, HRS-like B-cells were found in a subset of T-cell lymphomas, especially in association with the TFH phenotype and EBV reactivation. These cells have a tendency to affect elderly patients and to be associated with advanced clinical stages and dismal prognosis. The EBV status of HRS-like B-cells does not seem to affect the clinicopathological features of this group of PTCLs.

Prognostic Impact of MUM1/IRF4 Expression in Burkitt Lymphoma (BL): A Reappraisal of 88 BL Patients in Japan.

MUM1/IRF4 expression is detected in 18% to 41% of Burkitt lymphoma (BL). However, only a few studies of MUM1-positive (MUM1+) BL have been reported, and its characteristics still remain controversial. To highlight the features of MUM1+ BL, we compared the clinicopathologic characteristics of 37 cases of MUM1+ and 51 cases of MUM1-negative (MUM1−) BL in Japan. Compared with MUM1− BL, patients with MUM1+ BL showed significantly younger onset (P=0.0062) and a higher ratio of females (P=0.013). We have also revealed the difference in the involved sites. The MUM1+ group showed lower incidences of involvement of stomach (P=0.012) and tonsil (P=0.069). There was a more tendency in MUM1+ group to involve colon (P=0.072), breast (P=0.073), and kidney (P=0.073). Regarding the prognosis, a trend toward a lower overall survival for MUM1+ group was noted (P=0.089). Notably, comparing MUM1+ and MUM1− BL cases of adults (age16 y old and above), the former showed significantly worse prognosis (P=0.041). Among the BL patients treated with the intensive chemotherapy, a standard therapy for BL, MUM1+ cases showed worse prognosis (P=0.056). In conclusion, MUM1+ BL showed worse prognosis, particularly in adult cases, compared with MUM1− BL. In addition, the difference of the onset age, sex ratio, and involved sites between the 2 groups was noted. Our results demonstrate that MUM1 expression might predict worse prognosis of BL, and MUM1+ BL should be distinguished from MUM1− BL.

Primary cutaneous NK/T-cell lymphoma of nasal type: an age-related lymphoproliferative disease?

Among extranodal NK/T-cell lymphoma of nasal type (NKTL), the extranasal variant (ENKTL) is known to have a worse prognosis with advanced clinical stage than the nasal variant of NKTL. However, detailed clinicopathological features of the localized extranasal disease have not been well documented in English literature. Here, we described the clinicopathological profiles of 14 patients with stage I ENKTL, including 7 in the skin, 5 in the gastrointestinal tract, and 2 in the central nervous system, highlighting the distinctiveness of the first. The 7 primary cutaneous (PCNKTL) cases were characterized by an older onset age (median, 76 versus 53 years, P=.012) and a more favorable clinical course (P=.041) compared with 17 patients with stages II-IV ENKTL that showed cutaneous involvement. The skin lesions in the PCNKTL group were distributed in the face or neck (n=4) and limbs (n=3) but not the trunk, which was most frequently affected (60%, P=.017) in the latter group. Furthermore, the stage I cutaneous disease showed a female predominance (male-female, 2:5 versus 7:0; P=.021) and a significantly more favorable survival compared with the noncutaneous stage I ENKTL (P=.037). These results suggest that PCNKTL constitute a distinct subgroup in the nasal-type lymphoma spectrum.