Spontaneous splenic rupture in two patients with a blastoid variant of mantle cell lymphoma

 Spontaneous rupture of the spleen is a rare complication of hematological malignancies, occurring most commonly in patients with acute leukemia, but it has been documented in chronic leukemias and also in lymphomas. We report two patients with histologically and immunohistochemically confirmed mantle cell lymphoma (MCL) who experienced a spontaneous splenic rupture. An 80-year-old woman and a 51-year-old man had a blastoid variant of MCL and responded poorly to conventional treatment. Both patients recovered after splenectomy. The woman died of progressive lymphoma 2 months later. An allogeneic bone marrow transplantation was performed in the man with a good initial result, but an aggressive relapse was seen only 6 months later and he died of progressive lymphoma. In view of our data, we suggest special caution when MCL is complicated by rapid progression and severe splenomegaly. Although it is a rare phenomenon, the risk of splenic rupture should be kept in mind. Received: 2 September 1996 / Accepted: 16 October 1996     

Intraocular involvement of Mantle cell lymphoma: A case report and literature review

Lymphomatous involvement of the ocular adnexal region (OAR) is generally rare; however, it constitutes the most common ocular malignancy. Most cases of ocular adnexal lymphomas are extra nodal marginal zone B cell lymphomas. Mantle cell lymphoma involvement (MCL) of the OAR is a less common presentation compared with other lymphomas and it has been reported anecdotally. Studies have suggested an association of OAR involvement with poor prognosis. Here, we report the case of a 61 year old man who started experiencing conjunctival erythema which was followed by development of bilateral proptosis. The diagnosis of Stage IV Mantle cell lymphoma with OAR involvement was confirmed 5 months after patient onset of symptomatology. He underwent treatment with systemic chemotherapy, which was followed by high-dose chemotherapy and autologous hematopoietic cell transplant. He is currently day +100 from his transplant and is in complete remission. A review of the literature regarding ocular involvement of MCL is also summarized.     

Epstein-Barr Virus-Positive Blastoid Variant of Mantle Cell Lymphoma in an Adult with Recurrent Infectious Mononucleosis-Like Symptoms: A Case Report

Epstein-Barr virus (EBV) is closely associated with several lymphomas, such as Burkitt lymphoma, natural killer/T-cell lymphoma, peripheral T-cell lymphoma, and Hodgkin's lymphoma; however, whether EBV is implicated in mantle cell lymphoma (MCL) has not been established. We report the case of an adult with recurrent infectious mononucleosis (IM)-like symptoms who developed an EBV-positive blastoid variant of MCL. A 54-year-old Japanese man presented with fever, swelling of the oral mucosa and tongue, dispersed pulmonary infiltrations, systemic lymphadenopathy, and splenomegaly. He had a history of recurrent IM-like symptoms (prolonged fever and cervical lymphadenopathy) for at least 1 year. MCL was diagnosed by biopsy of the cervical lymph node. The anti-EBV antibody titer indicated a reactivation of chronic infection with this virus. EBV was detected in most of the lymphoma cells and in the peripheral blood. EBV might have played some role in the tumorigenesis of blastoid MCL.     

Primary cutaneous marginal center lymphoma – complete remission induced by interferon α2a

Marginal zone lymphoma (MZL) is a distinct entity among B-cell lymphomas. We report on a 53-year-old woman who developed disseminated primary cutaneous MZL with secondary lymph node involvement and perinodular spreading. The tumor cell phenotype was characterized as CD20/CD79a/κ/λ+/bcl-2-positive, CD3/5/15/39/bcl-1-negative. Ki-67 was expressed by 20–35% of tumor cells. There was no evidence of systemic (including bone marrow) involvement. The diagnosis of MZL with plasmacellular differentiation (Stage IVa) was made. The patient was treated with interferon α2a injected s.c. at 9 × 10⁶ U 3 days a week for 1 year. During this time the skin lesions completely disappeared. No evidence of lymph node or extracutaneous disease was found. The patient remains in complete remission. Side effects were only of grade I (WHO); the Karnovsky index was 90%. As shown for other types of primary cutaneous B-cell lymphoma, prolonged interferon α monotherapy may be effective in controlling the disease and/or inducing complete remission in MZL. Received: 11 December 1998 / Accepted: 13 January 1999     

How I manage mantle cell lymphoma: indolent versus aggressive disease

Mantle cell lymphoma (MCL) is a mature B-cell lymphoma with a variable clinical course and historically poor prognosis. Management is challenging in part due to the heterogeneity of the disease course, with indolent and aggressive subtypes now well recognised. Indolent MCL is often characterised by a leukaemic presentation, SOX11 negativity and low proliferation index (Ki-67). Aggressive MCL is characterised by rapid onset widespread lymphadenopathy, extra-nodal involvement, blastoid or pleomorphic histology and high Ki-67. Tumour protein p53 (TP53) aberrations in aggressive MCL are recognised with clear negative impact on survival. Until recently, trials have not addressed these specific subtypes separately. With the increasing availability of targeted novel agents and cellular therapies, the treatment landscape is constantly evolving. In this review, we describe the clinical presentation, biological factors, and specific management considerations of both indolent and aggressive MCL and discuss current and potential future evidence which may help move to a more personalised approach.     

Outcomes in 370 patients with mantle cell lymphoma treated with ibrutinib: a pooled analysis from three open‐label studies

Ibrutinib is highly active in treating mantle cell lymphoma (MCL), an aggressive B‐cell lymphoma. We pooled data from three ibrutinib studies to explore the impact of baseline patient characteristics on treatment response. Patients with relapsed/refractory MCL (n = 370) treated with ibrutinib had an objective response rate (ORR) of 66% (20% complete response; 46% partial response); median duration of response (DOR), progression‐free survival (PFS) and overall survival (OS) were 18·6, 12·8 and 25·0 months, respectively. Univariate analyses showed patients with one versus >one prior line of therapy had longer OS. Multivariate analyses identified that one prior line of therapy affected PFS; Eastern Cooperative Oncology Group (ECOG) performance status, simplified MCL international prognostic index (sMIPI) score, bulky disease, and blastoid histology affected OS and PFS. Patients with blastoid versus non‐blastoid histology had similar time to best response, but lower ORR, DOR, PFS and OS. OS and PFS were longer in patients with better sMIPI, patients with ECOG performance status 0–1, non‐bulky disease and non‐blastoid histology. Additionally, the proportion of patients with poor prognostic factors increased with increasing lines of therapy. Together, results suggest that patient outcomes following treatment failure with ibrutinib are related to the natural biological evolution of the disease.     

BCL6 rearrangement in a patient with mantle cell lymphoma

 We describe a patient with mantle cell lymphoma (MCL) associated with BCL6 gene rearrangement. MCL is a distinct subtype of non-Hodgkin's lymphoma characterized by CD5+, CD10–, CD20+, t(11;14)(q13;q32) and PRAD1/cyclin D1 overexpression. Although rearrangement of the BCL6 gene is the most frequent genetic change among diffuse lymphomas and some follicular lymphomas this is the first report of a patient with MCL associated with BCL6 rearrangement. Received: 6 January 1997 / Accepted: 17 February 1997     

Presence of a high-grade component in gastric mucosa-associated lymphoid tissue (MALT) lymphoma is not associated with an adverse prognosis

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B cell lymphoma (DLBCL) show a spectrum of disease characterized by varying proportions of low-grade and high-grade components. While the natural history and optimum treatment for low-grade gastric MALT lymphoma and DLBCL is well established, the prognosis and optimal treatment of patients with both low- and high-grade components is not well established. The purpose of our study was to evaluate the clinical characteristics, survival outcomes, and prognostic factors of patients with gastric MALT lymphoma and gastric DLBCL. A retrospective review of patients with gastric MALT lymphoma, gastric DLBCL, or MALT lymphoma with a high-grade component treated at our centers from 1994 to 2006 was performed. Patients were divided into three categories: “pure MALT lymphoma,” “MALT lymphoma with high-grade component” (mixed), and “pure DLBCL.” Seventy-six patients were included in our study—26 with pure MALT, 22 with MALT with high-grade component (“mixed”), and 28 with pure DLBCL. Pure MALT lymphoma and mixed lymphoma patients had similar clinical characteristics, whereas pure DLBCL patients had less favorable disease characteristics with significantly poorer performance status, higher number of extranodal sites of disease, higher stage, and larger proportion of bone marrow involvement and international prognostic index (IPI) scores compared with mixed lymphoma. The majority of mixed lymphoma (72.7%) and DLBCL patients (71.4%) were treated with chemotherapy. Of patients receiving chemotherapy, a higher proportion of mixed lymphoma and DLBCL patients received anthracycline-based combination chemotherapy regimens compared with MALT lymphoma (73% vs 71% vs 8%) whereas the proportion of mixed lymphoma and DLBCL patients was similar (p = 0.919). At a median follow-up of 37 months, the 5-year overall survival was 66.9%. The 5-year overall survival was 78% for MALT lymphoma, 84% for mixed lymphoma, and 45% for DLBCL. On univariate analysis, DLBCL histology, age, performance status, serum albumin, lactate dehydrogenase, bone marrow, number of extranodal sites, stage, and IPI score were prognostic for inferior survival. On multivariate analysis, DLBCL histology remained significantly prognostic for inferior survival, independent of chemotherapy regimen (hazard ratio (HR) 6.66, 95% confidence interval (CI) 2.01–21.41, p = 0.001). Mixed histology was not prognostic for inferior survival (HR 1.13, 95% CI 0.28–4.54, p = 0.868). Other factors prognostic for inferior survival were serum albumin <37 g/L (HR 3.22, 95% CI 1.11–13.22, p = 0.034) and treatment with non-cyclophosphamide, doxorubicin, vincristine, and prednisolone chemotherapy (HR 4.89, 95% CI 1.67–14.36, p = 0.004). In conclusion, the clinical characteristics of mixed histology MALT lymphoma are similar to low-grade MALT lymphoma and significantly different from pure DLBCL. The prognosis of mixed histology MALT lymphoma is significantly better than pure DLBCL, independent of IPI and chemotherapy regimen, and pure DLBCL histology is independently prognostic of inferior survival outcome.     

Mantle cell lymphoma with central nervous system involvement: frequency and clinical features

Reported rates of central nervous system (CNS) involvement in mantle cell lymphoma (MCL) are highly variable but substantial (4–26%). Data is lacking regarding risk factors for CNS relapse, and for those patients in whom CNS prophylaxis could be beneficial. We present single institution retrospective analysis of data of baseline features, clinical course, rate of CNS disease and putative risk factors in 62 patients with MCL (18 female, 44 male). CNS disease (all cases were symptomatic) occurred in four patients at a median of 12 months (range 1–58) from diagnosis, with a crude incidence of 6·5% and 5-year actuarial incidence of 5 ± 3%. Two cases had blastic MCL at diagnosis. Survival after CNS relapse ranged from 2–9 months. Patients who developed CNS disease had a significantly shorter survival from diagnosis than those who did not ( P  = 0·0024). Symptomatic CNS disease in patients with MCL either at presentation or relapse is an uncommon but devastating complication. In younger patients, more aggressive immuno-chemotherapy regimens containing CNS-penetrating agents may reduce the incidence of CNS disease. While not routinely justified for all patients, CNS prophylaxis may particularly benefit patients with blastic histology at diagnosis, or those with systemic relapse after first-line treatment.     

The hyper-CVAD–rituximab chemotherapy programme followed by high-dose busulfan,melphalan and autologous stem cell transplantation produces excellent event-free survival in patients with previously untreated mantle cell lymphoma

The hyper-CVAD + rituximab (R) programme consists of fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone + R alternating with high-dose methotrexate + cytarabine (HD MTX/ARA-C) + R. This regimen, when used as initial therapy for patients under 65 years of age with previously untreated mantle cell lymphoma (MCL), results in remission rates of > 85% with a median event-free survival (EFS) of > 50 months, but with a pattern of continuous relapse out to 60 months. We performed a study of hyper-CVAD + R, followed by consolidative peripheral blood progenitor cells autograft [autologous stem cell transplant (AuSCT)] with high-dose busulfan and melphalan (Bu/Mel) conditioning, in patients with responsive disease. Thirteen patients with a median age of 54 (range = 33–61) were treated. Complete remission (CR) was achieved in 12 patients (92%) after hyper-CVAD + R and 12 completed AuSCT after Bu/Mel conditioning. One patient died during the autograft and another declined AuSCT after achieving a CR with hyper-CVAD + R. With a median follow-up from diagnosis of 36 months (range = 16–53 months), the observed 36 months overall survival and EFS are both 92% for the whole cohort. These data confirm the excellent CR rates achieved by the use of hyper-CVAD + R in patients with MCL and suggest that consolidation with Bu/Mel and AuSCT may improve durable disease control when compared to published outcomes of hyper-CVAD + R alone.     

Bilateral breast MALT lymphoma: a case report and review of the literature

 Breast lymphoma is a rare disease. Both primary and secondary breast involvement have been reported. Most primary breast lymphomas are high-grade malignant neoplasms, mainly large cell and Burkitt type. Low-grade lymphomas of the breast, particularly mucosa-associated lymphoid tissue (MALT) lymphomas, have been exceedingly rare. In this report we present a patient with bilateral breast involvement by MALT lymphoma. Our patient developed localized MALT lymphoma in both breasts in a sequential fashion. She was treated with bilateral lumpectomy, followed by radiation therapy to both breasts. The patient is alive and well more than 1 year after therapy with no recurrence. We believe this is the first such case described in detail in the literature. Received: March 10, 1999 / Accepted: July 6, 1999     

The clinical outcome of 65 cases of mantle cell lymphoma initially treated with non-intensive therapy by the British National Lymphoma Investigation Group

Mantle cell lymphoma (MCL) was first described as a distinct biological entity on the basis of its association with the t(11;14)(q13;q32) resulting in over-expression of the cyclin D1 gene. Recognition of the morphological, immunophenotypic and clinical characteristics of MCL has enabled the accurate diagnosis of this entity and appreciation of its poor prognosis. Most published series of patients with MCL have used anthracycline-containing regimens. In contrast the British National Lymphoma Investigation (BNLI) group have treated 65 patients with MCL with non-intensive 'low-grade lymphoma' therapy. The median overall survival of 57 months and progression-free survival of 24 months compares favourably with the more intensively treated series. Although the disease was generally more aggressive than other low-grade lymphomas, some patients were asymptomatic and had indolent disease. When compared to 1853 patients with non-MCL low-grade lymphomas entered on the BNLI database, patients were found on average to be older ( P  = 0.02), to have more extra-nodal disease ( P  < 0.00001), and a higher proportion to have a raised ESR ( P  = 0.02) and a low serum albumin ( P  = 0.002). Multivariate analysis of significant prognostic markers in all BNLI low-grade lymphomas failed to identify MCL as an independent prognostic factor.     

Bone marrow and blood involvement by non-Hodgkin's lymphoma: a study of clinicopathologic correlations and prognostic significance in relationship to the Working Formulation

In a series of 172 patients with non-Hodgkin's lymphoma (NHL) classified according to the Working Formulation (WF) the overall incidence of bone marrow infiltration (BM+) at diagnosis was 39%: 59% for low-grade (LGML), 30% for intermediate-grade (IGML), and 25% for high-grade malignant lymphomas (HGML). The features most significantly correlated with the presence of BM+ were a low grade of histological malignancy, the degree of splenomegaly and high values of LDH, while those correlated with the extent of BM+ were a non-focal pattern of BM disease, the presence of blood involvement at diagnosis, and the degree of BM fibrosis. Blood involvement was detected at diagnosis in 13% of patients, and a further 16% developed a leukemic phase during the course of the disease. Blood involvement correlated significantly with splenomegaly, bulky disease, advanced clinical stage, and extent of BM+. The presence of BM infiltration 'per se' at diagnosis did not significantly affect prognosis. However, the extent of BM disease was correlated with a poorer outcome in IGML and HGML patients. Regarding peripheral blood involvement, in LGML patients only late leukemic conversions were significantly associated with a worse prognosis. In patients with IGML and HGML, either initial or subsequent blood involvement was correlated with significantly poorer outcome.     

Primary gastric non-Hodgkin's lymphoma: a clinicopathological study of 41 patients

Pathological findings in 41 patients (male/female ratio: 1.3/1) with primary localized gastric non-Hodgkin's lymphoma (NHL) were retrospectively studied and correlated with survival. The median observation period after diagnosis was 32 (0–189) months. Nineteen patients were low-grade NHL, all but one B-cell lymphomas of the mucosa-associated lymphoid tissue (MALT) type. Twenty-two patients had primary (n-7) or secondary (n=15) high-grade lymphomas; Musshoff stage IE was found in 29 and II E in 12 cases. The median age at diagnosis was 61 years (range, 26–88 years), and proliferation, measured by the number of mitosis and Ki-67 antigen positivity (MIB-1), was high or moderately high in 24 cases and low in 17 cases. Follicular lymphatic hyperplasia could be found in 25 of 34 evaluable cases, more often in low-grade than in high-grade NHL. Most of the patients were treated by resective surgery and additional ratio- or chemotherapy. Thirteen patients (31%) died (median survival: 10 months), 5 of them within 3 months after surgery owing to postoperative complications. Survival was superior, though not statistically significant, in low-grade lymphomas. Our retrospective anlysis of heterogeneously treated gastric lymphomas reveals that gastric lymphomas, especially of the low-grade MALT type, often remain a localized disease with a good long-term prognosis. Our study confirms previous reports indicating that lymphomas of the MALT type represent a specific clinicopathological entity.     

Deletion of 14q in non-Hodgkin's lymphoma

6 patients with non-Hodgkin's lymphoma [3 with small cell lymphocytic lymphoma of B-cell type (SL), and 1 each with follicular centroblastic/centrocytic, centroblastic, and immunoblastic lymphoma] and with the acquired cytogenetic abnormalities del(14) (q22) or del(14) (q24) are described. An evaluation of these 6 cases and 41 other lymphatic neoplasms with 14q deletion known from the literature revealed that 37 had a breakpoint in bands q22 to q24. The deletions occur significantly more often in lymphomas of SL morphology and in the leukemic counterpart, chronic lymphocytic leukemia, than in other types of lymphatic malignancies (p less than 0.001).     

Splenic involvement by blastic mantle cell lymphoma (large cell/anaplastic variant) mimicking splenic marginal zone lymphoma

The most cases of splenic marginal zone lymphoma (SMZL) seem to respond favorably to splenectomy. The diagnosis of this lymphoma is mainly based on the recognition of a micronodular pattern of splenic involvement with marginal zone differentiation. However, it is possible to find so-called "marginal zone differentiation" in splenic involvement by other small B-cell lymphomas, particularly mantle cell lymphoma (MCL) and follicular lymphoma. We report a case of blastic MCL, large cell/anaplastic variant with a high level of clinical aggressiveness, showing biphasic cytology and a micronodular pattern which resembles SMZL. A single biopsy corresponding to this case shows two phases of tumoral progression in a MCL, a rare finding in MCL. In conclusion, the differential diagnosis of SMZL must take the possibility of a blastic MCL with biphasic cytology into account, as the case here.     

Primary and secondary central nervous system mature T- and NK-cell lymphomas

Primary central nervous system (CNS) mature T- and NK-cell lymphomas are rare, only comprising 2% to 3% of all primary CNS lymphomas. Among them, peripheral T-cell lymphoma, not otherwise specified, anaplastic large cell lymphoma (ALCL), and extranodal NK/T-cell lymphoma (ENKTL) are the commonly reported histological subtypes. Secondary CNS T-cell lymphoma generally affects about 5% of patients with T- or NK-cell lymphoma, with some exceptions. Acute and lymphomatous subtypes of adult T-cell leukemia/lymphoma (ATLL) have high risk of CNS progression, may affect up to 20% of patients; ALK-positive ALCL with extranodal involvement >1 also has high risk of CNS progression. However, the impact and the optimal methodology of CNS prophylaxis remain unclear in systemic T-cell lymphomas. There are little data on the treatment strategy of primary and secondary CNS T-cell lymphoma. Treatment strategy derived from B-cell CNS primary lymphoma is generally used; this includes induction therapy with high-dose methotrexate-based regimens, followed by high-dose chemotherapy with autologous stem cell transplant in fit patients. There are unmet needs for patients who are not fit for intensive chemotherapy. The prognosis after CNS progression in T-cell lymphoma is dismal with the median overall survival of less than 1 year. New agents targeting T-cell lymphomas are emerging and should be tested in patients with mature T- and NK-cell lymphoma who suffer from CNS involvement.     

IMPROVED TREATMENT RESULTS FOR LYMPHOBLASTIC LYMPHOMA IN ADOLESCENTS AND ADULTS USING A DOXORUBICIN-BASED (APO) PROTOCOL

A multi-drug chemotherapy (APO) protocol incorporating doxorubicin was used to treat 12 patients (median age 19 years) with lymphoblastic lymphoma. The APO protocol consisted of intensive induction and consolidation phases, prophylactic CNS treatment, and 24 months of maintenance therapy. Eleven patients had an anterior mediastinal mass, while T cell markers were found on the lymphoma cells in eight of the nine cases tested. Two patients had initial CNS involvement, with one also having bone marrow replacement. Complete remission was obtained in all patients, with no deaths due to treatment toxicity. There have been four relapses, one in the patient with initial CNS and leukemic disease, two in abdominal sites, and in the mediastinum in one patient. With a median follow-up time of 30 months from diagnosis, 67% of patients remain alive in first remission. These results indicate that the APO protocol provides a highly effective approach to the management of this high grade lymphoma in adolescents and adults.     

Systemic high-dose methotrexate plus ifosfamide is highly effective for central nervous system (CNS) involvement of lymphoma

Patients with malignant central nervous system (CNS) involvement of lymphoma have a poor prognosis with intrathecal chemotherapy and radiation. In this paper, we report the results we obtained in such patients by intravenous chemotherapy with high-dose methotrexate and ifosfamide (HDMTX/IFO). The study involved a review of all patients who received HDMTX/IFO for CNS involvement of malignant lymphoma at our hospital. Therapy consisted of 4 g/m² of MTX (4 h infusion on day 1) and 1.5–2 g/m²/day of IFO (3 h infusion on days 3–5). The study included 20 patients with a median age of 65 years (range, 30–83) and CNS relapse of a malignant lymphoma. Seventeen patients had been pretreated with up to two chemotherapy regimens. The objective response rate was 90% with 12 complete or unconfirmed complete (CR and CRu) and six partial remissions. All patients had at least stabilization of their neurological symptoms. Myelosuppression was the most common toxicity. The median follow-up time was 14.9 months. The median time to neurological progression was 8.9 months. Twelve patients received subsequent therapy, including high-dose chemotherapy with autologous stem cell transplantation in five cases. The median overall survival was not reached. Systemic chemotherapy with HDMTX/IFO is a feasible and promising treatment modality for CNS relapse of a malignant lymphoma.