Jan Paul de Boer

Anaplastic large-cell lymphoma in women with breast implants.

CONTEXT Recently, we identified 2 patients with anaplastic large T-cell lymphoma (ALCL) negative for tyrosine kinase anaplastic lymphoma kinase (ALK-negative) in the fibrous capsule of silicone breast prostheses, placed for cosmetic reasons. Similar cases have been reported in the literature. Although an increased risk of ALCL in patients with breast prostheses has been speculated, no studies have been conducted so far. OBJECTIVE To determine whether ALCL risk is associated with breast prostheses. DESIGN A search for all patients with lymphoma in the breast diagnosed in The Netherlands between 1990 and 2006 was performed through the population-based nationwide pathology database. Subsequently, we performed an individually matched case-control study. Conditional logistic regression analysis was performed to estimate the relative risk of ALCL associated with breast prostheses. SETTING AND PATIENTS Eleven patients with breast ALCL were identified in the registry. For each case patient with ALCL in the breast, we selected 1 to 5 controls with other lymphomas in the breast, matched on age and year of diagnosis. For all cases and controls (n = 35), pathological and clinical information was obtained with special emphasis on the presence of a breast prosthesis. MAIN OUTCOME MEASURE Association between breast implants and ALCL of the breast. RESULTS The 11 patients with ALCL of the breast were diagnosed between 1994 and 2006 at a median age of 40 years (range, 24-68 years). In 5 of these patients, bilateral silicone breast prostheses had been placed 1 to 23 years before diagnosis. All received prostheses for cosmetic reasons. Lymphoma classes of 35 eligible control patients were 12 diffuse large B-cell lymphomas, including 1 T-cell rich B-cell lymphoma; 5 Burkitt lymphomas; 10 mucosa-associated lymphoid tissue-type lymphoma; 3 follicular lymphomas; 3 peripheral T-cell lymphomas; and 2 indolent B-cell lymphomas, unclassified. One of 35 control patients had a breast implant placed before diagnosis of lymphoma. The odds ratio for ALCL associated with breast prostheses was 18.2 (95% confidence interval, 2.1-156.8). CONCLUSIONS These preliminary findings suggest an association between silicone breast prostheses and ALCL, although the absolute risk is exceedingly low due to the rare occurrence of ALCL of the breast (11 cases in The Netherlands in 17 years). These findings require confirmation in other studies.

Breast Implant–Associated Anaplastic Large-Cell Lymphoma: Long-Term Follow-Up of 60 Patients

PURPOSE Breast implant-associated anaplastic large-cell lymphoma (ALCL) is a recently described clinicopathologic entity that usually presents as an effusion-associated fibrous capsule surrounding an implant. Less frequently, it presents as a mass. The natural history of this disease and long-term outcomes are unknown. PATIENTS AND METHODS We reviewed the literature for all published cases of breast implant-associated ALCL from 1997 to December 2012 and contacted corresponding authors to update clinical follow-up. RESULTS The median overall survival (OS) for 60 patients was 12 years (median follow-up, 2 years; range, 0-14 years). Capsulectomy and implant removal was performed on 56 of 60 patients (93%). Therapeutic data were available for 55 patients: 39 patients (78%) received systemic chemotherapy, and of the 16 patients (28%) who did not receive chemotherapy, 12 patients opted for watchful waiting and four patients received radiation therapy alone. Thirty-nine (93%) of 42 patients with disease confined by the fibrous capsule achieved complete remission, compared with complete remission in 13 (72%) of 18 patients with a tumor mass. Patients with a breast mass had worse OS and progression-free survival (PFS; P = .052 and P = .03, respectively). The OS or PFS were similar between patients who received and did not receive chemotherapy (P = .44 and P = .28, respectively). CONCLUSION Most patients with breast implant-associated ALCL who had disease confined within the fibrous capsule achieved complete remission. Proper management for these patients may be limited to capsulectomy and implant removal. Patients who present with a mass have a more aggressive clinical course that may be fatal, justifying cytotoxic chemotherapy in addition to removal of implants.

Second Cancer Risk Up to 40 Years after Treatment for Hodgkin’s Lymphoma

BACKGROUND Survivors of Hodgkins lymphoma are at increased risk for treatment-related subsequent malignant neoplasms. The effect of less toxic treatments, introduced in the late 1980s, on the long-term risk of a second cancer remains unknown. METHODS We enrolled 3905 persons in the Netherlands who had survived for at least 5 years after the initiation of treatment for Hodgkins lymphoma. Patients had received treatment between 1965 and 2000, when they were 15 to 50 years of age. We compared the risk of a second cancer among these patients with the risk that was expected on the basis of cancer incidence in the general population. Treatment-specific risks were compared within the cohort. RESULTS With a median follow-up of 19.1 years, 1055 second cancers were diagnosed in 908 patients, resulting in a standardized incidence ratio (SIR) of 4.6 (95% confidence interval [CI], 4.3 to 4.9) in the study cohort as compared with the general population. The risk was still elevated 35 years or more after treatment (SIR, 3.9; 95% CI, 2.8 to 5.4), and the cumulative incidence of a second cancer in the study cohort at 40 years was 48.5% (95% CI, 45.4 to 51.5). The cumulative incidence of second solid cancers did not differ according to study period (1965-1976, 1977-1988, or 1989-2000) (P=0.71 for heterogeneity). Although the risk of breast cancer was lower among patients who were treated with supradiaphragmatic-field radiotherapy not including the axilla than among those who were exposed to mantle-field irradiation (hazard ratio, 0.37; 95% CI, 0.19 to 0.72), the risk of breast cancer was not lower among patients treated in the 1989-2000 study period than among those treated in the two earlier periods. A cumulative procarbazine dose of 4.3 g or more per square meter of body-surface area (which has been associated with premature menopause) was associated with a significantly lower risk of breast cancer (hazard ratio for the comparison with no chemotherapy, 0.57; 95% CI, 0.39 to 0.84) but a higher risk of gastrointestinal cancer (hazard ratio, 2.70; 95% CI, 1.69 to 4.30). CONCLUSIONS The risk of second solid cancers did not appear to be lower among patients treated in the most recent calendar period studied (1989-2000) than among those treated in earlier periods. The awareness of an increased risk of second cancer remains crucial for survivors of Hodgkins lymphoma. (Funded by the Dutch Cancer Society.).

Impact of the tumor microenvironment on prognosis in follicular lymphoma is dependent on specific treatment protocols

The clinical behavior of follicular lymphoma is largely determined by properties of the non-malignant tumor microenvironment. The results of this study suggest that characteristic properties of the microenvironment in follicular lymphoma influence the response to treatment. See related perspective article on page 16. Background The clinical behavior of follicular lymphoma is largely determined by properties of the non-malignant tumor microenvironment. The precise nature of the cell populations is still unclear and published data on their prognostic significance are highly conflicting. This may be partly due to heterogeneous composition and treatments. Design and Methods Pre-treatment biopsy samples of patients with follicular lymphoma treated in an EORTC/BNLI trial comparing fludarabine to cyclophosphamide, vincristine and prednisone (CVP) chemotherapy could be retrieved for 61 patients in five European countries. Immunohistochemical investigations were performed evaluate tumor cell characteristics, T-cell subsets, follicular dendritic cells and macrophages and associations with clinical outcome were studied. Results Some markers showed a homogeneous prognostic impact, while others had a different nd sometimes opposite effect in the treatment arms. CD69 expression on tumor cells was a poor prognostic sign and an interfollicular infiltrate of FoxP3-positive T cells was a good prognostic sign irrespective of the treatment arm. It is suggestive that a dense infiltrate of FoxP3-positive T cells, dense and interfollicular infiltrate of CD68-positive macrophages and complete follicular dendritic meshworks were associated with a favorable time to progression in CVP-treated patients, while being poor prognostic sign in fludarabine-treated patients. Conclusions Our results suggest that characteristic properties of the microenvironment in follicular lymphoma determines the responses to essentially different chemotherapeutic approaches. These data may provide an explanation for the highly conflicting results on immunohistochemical markers and the prognostic role of the microenvironment in follicular lymphoma reported thus far and lay the basis for the development of predictive assays to tailor treatment in patients with follicular lymphoma.

Intra-arterial versus intravenous chemoradiation for advanced head and neck cancer: Results of a randomized phase 3 trial

Chemoradiation is the preferred treatment for advanced stage IV head and neck cancer. Higher doses of chemotherapy yielded promising results in vitro and vivo, confirmed by intra‐arterial (IA) cisplatin‐based chemoradiation in phase 2 studies.

FIRST-YEAR QUALITY OF LIFE ASSESSMENT OF AN INTRA-ARTERIAL (RADPLAT) VERSUS INTRAVENOUS CHEMORADIATION PHASE III TRIAL

We report the results of a multicenter randomized phase III study, assessing quality of life (QOL) in intra‐arterial (IA) versus standard intravenous (IV) chemoradiation in advanced head and neck cancer.

Dissemination patterns in non-gastric MALT lymphoma

Primary extranodal non-gastric marginal zone MALT lymphoma frequently present with stage IV disease and multifocal disease, and a site-specific dissemination pattern. Extensive staging at diagnosis of fundamental importance. Background In contrast to gastric extranodal marginal zone mucosa associated lymphoid tissue (MALT) lymphomas, there is little consensus on the value and clinical consequences of extensive staging at diagnosis and during follow-up in non-gastric MALT lymphomas. Design and Methods Complete clinical information at presentation and during follow-up was collected for 72 patients with non-gastric MALT lymphoma treated at the Netherlands Cancer Institute between 1977 and 2005. Dissemination patterns at presentation were studied for nine primary dominant organ groups in our series of 72 patients and in a similar cohort treated at Vienna University (for a total of 106 patients). Results Twenty-three of our patients (32%) had more than one site of extranodal MALT lymphomatous disease, 13 patients (18%) had regional nodal involvement and 7 (10%) had bone marrow involvement. Site-specific dissemination was seen in paired organs (orbit, lung) and in the gastrointestinal tract (stomach, colon) and primary pulmonary MALT lymphoma was specifically related to gastric involvement (p<0.0001). These patterns of dissemination were retained during relapsed disease. Conclusions Primary extranodal non-gastric marginal zone MALT lymphoma frequently presents as stage IV disease (26%) and multifocal disease (32%) and with a site-specific dissemination pattern. After an extensive staging procedure at presentation, we recommend primary site-directed protocols during follow-up focused on the primary involved tract/organ system, regional lymph nodes and pulmonary and gastric relapses.

Cytolytic Virus Activation Therapy for Epstein-Barr Virus–Driven Tumors

Purpose: Nasopharyngeal carcinoma (NPC) is causally linked to Epstein–Barr virus (EBV) infection. Because all tumor cells carry EBV, the virus itself is a potential target for therapy. In these tumor cells, EBV hides in a latent state and expresses only a few non-immunogenic proteins for EBV maintenance and contributes to tumor growth. We developed a cytolytic virus activation (CLVA) therapy for NPC treatment, reactivating latent EBV, triggering immune recognition, and inducing susceptibility to antiviral therapy. Experimental Design: CLVA therapy combines gemcitabine (GCb) and valproic acid (VPA) for virus activation and tumor clearance with (val)ganciclovir (GCV) as the antiviral drug to block virus replication and kill proliferating virus-infected cells. CLVA treatment was optimized and validated in NPC cell lines and subsequently tested in 3 Dutch patients with NPC that was refractory to conventional treatment. Results: In NPC cell lines, both GCb and VPA can induce the lytic cycle of EBV. Their combination resulted in a strong synergistic effect. The addition of GCV resulted in higher cytotoxicity compared with chemotherapy alone, which was not observed in EBV-negative cells. CLVA therapy was analyzed in 3 patients with end-stage NPC. Patients developed increased levels of viral DNA in the circulation originating from apoptotic tumor cells, had disease stabilization, and experienced improved quality of life. Conclusions: Our results in the initial CLVA-treated patients indicate that the therapy had a biological effect and was well tolerated with only moderate transient toxicity. This new virus-specific therapy could open a generic approach for treatment of multiple EBV-associated malignancies. Clin Cancer Res; 18(18); 5061–70. ©2012 AACR.

Long-term results of stomach-conserving therapy in gastric MALT lymphoma

PURPOSE To evaluate long-term results of stomach-conserving therapy and to assess the value of histological probable minimal residual disease (pMRD) in predicting outcome in patients with gastric MALT lymphoma. MATERIALS AND METHODS We studied 115 patients with stage I-II(2) gastric MALT lymphoma treated between 1975 and 2002. Initially, first-line treatment consisted of radiotherapy only. Since 1994 most patients were primarily treated with Helicobacter pylori eradication; radiotherapy was used in case of eradication failure. To assess the value of pMRD, first follow-up biopsy samples classified as compete remission (CR) according to classical clinico-pathological criteria and biopsy samples 1 year after assessment of histological CR were reviewed; results were related to outcome. RESULTS Following radiotherapy only (n=56) 96% achieved a clinical CR; 10-year cancer-specific survival rate was 94%. Following H. pylori eradication only (n=35) CR-rate was 43% and after additional treatment 89%; 5-year cause-specific survival was 93%. There was no difference in relapse rate following initial histological CR or pMRD. CONCLUSIONS Patients with early stage gastric MALT lymphoma have a favorable long-term outcome following conservative treatment. Outcome after H. pylori eradication followed by delayed radiotherapy on indication was excellent. In our series pMRD was not associated with increased risk of recurrence.

Risk of multiple primary malignancies following treatment of Hodgkin lymphoma

We assessed risk, localization, and timing of third malignancies in Hodgkin lymphoma (HL) survivors. In a cohort of 3122 5-year HL survivors diagnosed before the age of 51 years and treated between 1965 and 1995, we examined whether risk factors for second and third malignancies differ and whether the occurrence of a second malignancy affects the risk of subsequent malignancies, using recurrent event analyses. After a median follow-up of 22.6 years, 832 patients developed a second malignancy and 126 patients a third one. The risk of a second malignancy was 4.7-fold increased (95% confidence interval [CI], 4.4-5.1) compared with risk in the general population; the risk for a third malignancy after a second malignancy was 5.4-fold (95% CI, 4.4-6.5) increased. The 10-year cumulative incidence of any third malignancy was 13.3%. Compared with patients still free of a second malignancy, patients with a second malignancy had a higher risk of developing subsequent malignancies. This risk depended on age, with hazard ratios of 2.2, 1.6, and 1.1 for patients aged <25, 25 to 34, and 35 to 50 years at HL treatment, respectively. In HL survivors who had a second malignancy, treating physicians should be aware of the increased risk of subsequent malignancies.