Alexandra Stefanovic

Extranodal marginal zone lymphoma of the ocular adnexa

Lymphomas of the ocular adnexa are a heterogeneous group of malignancies, composing approximately 1% to 2% of non-Hodgkin lymphomas (NHLs) and 8% of extranodal lymphomas. The most common subtype, accounting for up to 80% of cases of primary ocular adnexal lymphoma, is marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) type. In the recent past, there have been significant advances in our understanding of the clinical characteristics, morphology and phenotype, etiology, pathogenesis, diagnosis, natural history, treatment approaches, outcome, and prognostic factors of this disease entity. Novel immunologic and molecular techniques have aided in the distinction between MALT lymphoma and other lymphoproliferative disorders and led to the identification of tissue markers of prognostic significance. Modern imaging modalities provide invaluable tools for accurate staging and treatment planning. Besides radiotherapy and chemotherapy, a variety of new treatment options have emerged in the management of patients with ocular adnexal MALT lymphoma, especially monoclonal antibody therapy and antibiotic therapy against Chlamydia psittaci, which has been associated with the pathogenesis of ocular adnexal lymphomas in some parts of the world. In this review, we present a state-of-the-art summary of ocular adnexal MALT lymphomas.

Oral and Extraoral Plasmablastic Lymphoma: Similarities and Differences in Clinicopathologic Characteristics

Plasmablastic lymphoma (PBL), initially characterized as an aggressive lymphoma arising in the jaw and oral mucosa in HIV-infected patients, was recently reported to occur with extraoral manifestations, heterogeneous histologic findings, and variable association with immunodeficiency states. We reviewed clinical, morphologic, and immunophenotypic features of 13 cases of PBL to determine whether these different subtypes represent distinct morphologic and clinical entities. Two distinct subtypes of PBL were identified and classified as oral and extraoral PBL. The oral PBLs were strongly associated with HIV infection and commonly demonstrated plasmablastic morphologic features without plasmacytic differentiation. Extraoral PBLs tended to occur in patients with underlying non-HIV-related immunosuppression and universally demonstrated plasmacytic differentiation. The patients with oral PBL demonstrated better overall survival compared with patients with extraoral PBL (P = .02). Our findings suggest that PBL with oral and extraoral manifestation represent 2 distinct clinicopathologic entities.

Oral and Extraoral Plasmablastic LymphomaSimilarities and Differences in Clinicopathologic Characteristics

Plasmablastic lymphoma (PBL), initially characterized as an aggressive lymphoma arising in the jaw and oral mucosa in HIV-infected patients, was recently reported to occur with extraoral manifestations, heterogeneous histologic findings, and variable association with immunodeficiency states. We reviewed clinical, morphologic, and immunophenotypic features of 13 cases of PBL to determine whether these different subtypes represent distinct morphologic and clinical entities. Two distinct subtypes of PBL were identified and classified as oral and extraoral PBL. The oral PBLs were strongly associated with HIV infection and commonly demonstrated plasmablastic morphologic features without plasmacytic differentiation. Extraoral PBLs tended to occur in patients with underlying non-HIV-related immunosuppression and universally demonstrated plasmacytic differentiation. The patients with oral PBL demonstrated better overall survival compared with patients with extraoral PBL (P = .02). Our findings suggest that PBL with oral and extraoral manifestation represent 2 distinct clinicopathologic entities.

Primary ocular adnexal mucosa‐associated lymphoid tissue lymphoma (MALT): single institution experience in a large cohort of patients

Extranodal marginal zone B‐cell lymphoma is the most common orbital tumour. We conducted a retrospective analysis to examine: (i) the impact of initial presentation and staging on outcome and (ii) response to various treatment modalities and the effect of the latter on recurrence. Ninety patients with primary ocular adnexal marginal zone lymphoma (POAML) diagnosed at our institution between 1984 and 2009 were studied. POAML was associated with monoclonal gammopathy (13%) at presentation. Most POAML patients (86%) presented with Ann‐Arbor stage I disease. Radiotherapy led to excellent local control, but relapses occurred in 18% of Ann‐Arbor stage I patients during a median follow‐up of 5 years. Local relapses, including secondary central nervous system (CNS) involvement, were observed in patients receiving radiation doses <30·6 Gy. No differences in relapse rate and survival were observed between patients who did or did not undergo staging bone marrow biopsy. Ann‐Arbor stage II–IV disease and high lactate dehydrogenase levels were associated with shorter freedom from progression. In conclusion, POAML is an indolent lymphoma with continuous risk for relapse. Radiation doses of at least 30·6 Gy should be given in Ann‐Arbor stage I disease, since lower doses may be more frequently associated with relapses, including CNS relapses.

Pulmonary marginal zone lymphoma: A single centre experience and review of the SEER database

Pulmonary marginal zone lymphoma is a rare disease arising from bronchial-associated lymphoid tissue (BALT). There is limited information on clinical presentation, natural history and treatment of this type of lymphoma. We conducted a retrospective review of patients with biopsy-proven BALT lymphoma treated at our institution and patients from the surveillance epidemiology and end results (SEER) database. Twenty-one patients (median age 57) with disease stage IE (n = 10) and IV (n = 11), were treated at our institution. Initial management included observation (n = 4), surgery (n = 5), combination chemotherapy (n = 7), single-agent rituximab (n = 3) and radioimmunotherapy (n = 2). Complete remission was observed in 10, partial remission in 3, stable disease in 7, and disease progression in 1 patient. With a median follow-up of 20 months, Kaplan–Meier estimates for progression-free and overall survival (OS) at 80 months were 90% and 95%, respectively. We identified 326 patients (59% females and 41% males; median age 68 [30 to 85) with BALT lymphoma in the SEER database. Fifty-five per cent had stage IE, 10% stage IIE, 3% stage IIIE, and 22% stage IV disease. After a median follow-up of 35 months, median OS was 112 months, and disease-specific median survival was not reached. At 90 months, disease-specific survival was 85% (CI 77-92) with no significant differences in outcome between patients presenting with different stages. Our single institution experience and review of the SEER database, confirm the indolent features and favourable outcome of this rare disease.

Treatment of isolated primary intraocular lymphoma with high-dose methotrexate-based chemotherapy and binocular radiation therapy: a single-institution experience.

Primary intraocular lymphoma (PIOL) is a rare, aggressive malignancy involving the retina, vitreous or optic nerve head, without (isolated PIOL) or with central nervous system (CNS) involvement. While isolated PIOL may initially manifest unilaterally, the majority (80–90%) of patients eventually develop bilateral disease, and 60–85% progress in the CNS within 2–3 years of initial diagnosis, limiting median survival to only 3 years (Freeman et al, 1987). The optimal treatment for PIOL is controversial and data on the therapy and outcome of isolated PIOL is limited to retrospective case reports or mostly small series with heterogeneous patient populations and treatment approaches (Akpek et al, 1999, Grimm et al, 2007, Hoffman et al, 2003, Jahnke et al, 2006). In November 2005, the University of Miami Sylvester Comprehensive Cancer Center lymphoma programme team decided to use a combination of binocular external beam radiation therapy and systemic chemotherapy containing high-dose methotrexate (modified de Angelis regimen) (Abrey et al, 2000) in all patients with newly diagnosed isolated PIOL. Our design aimed to eliminate ocular disease by binocular radiation, and to use concomitant/sequential chemotherapy to eradicate potential microscopic brain disease, which may be responsible for later relapse. Patients were not enrolled in a clinical trial, but were followed and data collected prospectively. This report presents our experience using this approach. All patients underwent diagnostic pars plana vitrectomy with cytology, immunocytochemistry, flow cytometry and gene rearrangement studies. Staging evaluation, which included computerized tomography scans of chest, abdomen and pelvis, brain magnetic resonance imaging (MRI) scan, lumbar puncture, bone marrow biopsy and aspiration, showed no systemic lymphoma. Radiation therapy of 30–40 (median 36) Gy was given at 1.8–2.0 Gy per fraction to both eyes and orbits including the optic nerve and conus. Chemotherapy consisted of methotrexate 3.5 g/m2 i.v. over 4 h, followed by Leucovorin rescue (15 mg i.v. every 8 h), Vincristine 2 mg i.v. push and Procarbazine 100 mg/m2/day p.o. for 7 days (odd cycles only), given every 2 weeks for 6 cycles. Patients underwent follow-up evaluation every 3–6 months and annual surveillance brain MRI. Complete response was defined as complete disappearance of lymphomatous infiltrates on post-treatment ophthalmological examination. Overall survival (OS) was calculated from pathological diagnosis until date of death from any cause or last follow-up. Kaplan Meier survival curves were constructed, censoring patients at the time of death or last follow-up. This study was approved by our institutional review board, in accordance with the declaration of Helsinki. Patient characteristics, clinical and pathological findings, treatment and follow-up data are summarized in Table I. As illustrated in Figure 1a, five patients initially received radiation therapy, followed by chemotherapy, with partial overlap in 3 patients. One patient was first treated with chemotherapy due to personal preference, but thereafter completed a course of ocular radiation therapy. All six patients (4 male, 2 female, median age 61.5 years) completed therapy without major interruptions, delays or side effects and achieved a complete remission (CR). We did not observe any adverse ocular effects during concomitant administration of chemo- and radiotherapy. During median follow-up of 44 (range 10–51) months, one patient developed parenchymal brain relapse and died 21 months after initial diagnosis (Figure 1b), while the remaining 5 patients have maintained CR for a median of 40 months (range 5–47 months). Three patients developed radiation-induced cataract and vascular retinopathy with median latency of 11.5 months (range 5–16 months) after radiation therapy. No other treatment-related long-term side effects have been observed. Figure 1 Treatment and outcome of PIOL patients. (A) Treatment sequence of radiation therapy (XRT) and chemotherapy in 6 patients with PIOL; (B) Overall Survival of 6 patients with isolated PIOL treated with a combination of binocular external beam radiation therapy ... Table I Clinical features, treatment, and outcome of 6 patients with primary intraocular lymphoma (PIOL) Historically, binocular radiation therapy of 30–45 Gy has been the mainstay of treatment for PIOL, yielding response rates of 60–97%, with frequent complete remissions and long-term local control. However, this treatment modality has only minimal impact on OS (Margolis et al, 1980), because CNS relapse occurs in almost all patients after a median of 37 (11 to 84) months, with median survival of 12 to 20 months, thus limiting 5-year OS after radiotherapy to 10 to 29% (Peterson et al, 1993). Systemic chemotherapy offers the possibility of preventing CNS recurrence and potentially treating the intraocular disease. However, the latter may be difficult, since high-dose intravenous methotrexate, the single most effective agent in the treatment of PCNSL, has been shown to achieve therapeutic, albeit lower concentrations in the vitreous (median 3.4 μM) than in the aqueous humor and cerebrospinal fluid 4 h after administration of 8 g/m2 as a 4-h infusion – a very high dose with significant risk for potentially serious side effects (Batchelor et al, 2003). Moreover, only seven of nine patients with therapeutic drug levels (1 μM or greater) responded to therapy and intraocular relapse occurred in three patients, indicating that chemotherapy with high-dose methotrexate as a single modality may not be sufficient for the treatment of PIOL. We also observed persistence of PIOL in one of our patients (Patient 6) who was first treated with chemotherapy, but subsequently received ocular radiation, resulting in CR. In a retrospective study from the Memorial Sloan Kettering Cancer Center (Hormigo et al, 2004), eight patients with isolated PIOL were treated with different systemic chemotherapy regimens – most containing either high-dose methotrexate at 3.5 g/m2 and/or high-dose cytarabine at 3 g/m2 or higher - and ocular radiation therapy. Six of eight patients (75%) achieved a CR. Five of eight patients (63%) developed progressive disease in the CNS after a median of 10 months (range 8–25 months), while the other 3 patients remained in CR for a median of 44 months (range 6–47 months). While this approach was similar to ours, it produced inferior results. The total dose, fractionation and sequencing of radiation therapy with chemotherapy that was not uniform, were not specified and may account for the observed difference in outcome compared to our patients. However, considering the small patient numbers, it is possible that these differences are due to chance. To our knowledge, we present the first report in the literature using a uniform and highly effective treatment approach in a series of patients with isolated PIOL. Further studies of this promising combination regimen in larger cohorts of patients with isolated PIOL are needed.

[18F]-fluorodeoxyglucose positron emission tomography combined with computed tomography detection of asymptomatic late pulmonary toxicity in patients with non-Hodgkin lymphoma treated with rituximab-containing chemotherapy.

Rituximab is a chimeric anti-CD20 monoclonal antibody widely used in the treatment of B-cell non-Hodgkin lymphomas (NHL). Most adverse effects are due to infusion-related reactions, and severe respiratory complications are rare. We retrospectively reviewed clinical data and serial imaging studies of five patients with NHL treated with rituximab-containing chemotherapy who developed new pulmonary abnormalities on routine follow-up FDG-PET/CT imaging. None of the patients had pulmonary lymphoma or other pulmonary disease before therapy and all remained asymptomatic during follow-up. New pulmonary interstitial FDG-uptake was detected on follow-up FDG-PET/CT between 1 and 3 months post-treatment, preceded computed tomography abnormalities in one case, and persisted for several months. FDG uptake was linear, subpleural with maximum Standardized uptake value (SUV) from 2.0 to 5.84. Rituximab-containing chemotherapy for NHL may be associated with asymptomatic late pulmonary toxicity characterised by a distinct FDG uptake pattern. Awareness of this finding is important and should not be confused with lymphoma.

Autologous transplantation for relapsed non-Hodgkin's lymphoma using intravenous busulfan and cyclophosphamide as conditioning regimen: a single center experience

High-dose chemotherapy with autologous SCT has become standard of care for patients with relapsed aggressive non-Hodgkins lymphoma (NHL). To improve safety and efficacy of this treatment, new conditioning regimens are being developed. We retrospectively reviewed clinical data of patients with relapsed NHL treated at our institution with i.v. BU and CY (BU/CY) as conditioning regimen for autologous SCT between January 2000 and April 2005. We identified 43 patients (24 men, 19 women, median age 50) with diffuse large B-cell lymphoma (n=28), follicular lymphoma (n=8), mantle cell lymphoma (n=4) and peripheral T-cell lymphoma (n=3). Following salvage chemotherapy, there were 26 complete responses, 13 partial responses and 4 stable diseases. Median time to neutrophil and platelet recovery was 11 and 13.5 days, respectively. Treatment-related toxicities included nausea/vomiting, diarrhea and mucositis. The 100-day mortality was 9%: sepsis (n=1), pneumonia (n=1) and hepatic veno-occlusive disease (n=2). Twenty-one patients were followed until death and twenty-one surviving patients were followed for a median of 29 months (range 0.4–76). Three-year estimates of event-free survival, progression-free survival and overall survival were 35, 39 and 43%, respectively. We conclude that i.v. BU/CY is a safe and effective conditioning regimen for autologous SCT in relapsed NHL.

Post-transplant lymphoproliferative disorder presented as small bowel intussusception in adult liver transplant patient.

Intestinal obstruction after liver transplant is a rare complication, with diverse clinical manifestations. Intestinal adhesion is the most common cause. However, internal hernia, abdominal wall hernia, and neoplasm are also reported. Intussusception is another rare cause of intestinal obstruction, which has been reported primarily in pediatric patients. Herein, we report a case of intestinal obstruction from intussusception in an adult liver transplant patient associated with post-transplant lymphoproliferative disorder.

Sunitinib-induced microangiopathic hemolytic anemia with fatal outcome.

Sunitinib, a new vascular endothelial growth factor receptor inhibitor, has demonstrated activity in renal cell carcinoma and is now widely used in the palliative treatment of patients with metastatic renal cell carcinoma. It is generally well tolerated but has been associated with a low incidence of grade 3 and 4 toxicities including fatigue, diarrhea, anorexia, mucositis, skin toxicity, immune thrombocytopenic purpura, hypertension, hypothyroidism, cytopenias, and decreased cardiac ejection fraction. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is a rare condition that is severe and may be fatal. Several medications have been implicated in causing TTP-HUS including clopidogrel, mitomycin C, cisplatin. In this report, we describe a case of atypical HUS-microangiopathic hemolytic anemia during treatment with sunitinib in a patient with metastatic renal cell carcinoma. To our knowledge, this is the fourth case of microangiopathic hemolytic anemia associated with sunitinib described in the literature and the first case with fatal outcome despite treatment with plasmapheresis, dialysis, and withdrawal of sunitinib.