[Show abstract][Hide abstract] ABSTRACT: Bartonella henselae lymphadenitis, or cat-scratch lymphadenitis (CSL), is classically associated with stellate microabscesses, occasional giant cells, and extension of the inflammatory infiltrate into perinodal soft tissue. Availability of B. henselae molecular testing on tissue specimens has broadened our understanding of the morphologic variation in this disease. Here we sought to describe the histopathologic features of the largest series to date of molecularly proven CSL. B. henselae polymerase chain reaction-positive tissue specimens from 2010 to 2012 were identified, and hematoxylin and eosin slides were reviewed. A single-step 16S-23S rRNA-based polymerase chain reaction testing was used to identify B. henselae on formalin-fixed, paraffin-embedded tissues. A total of 100 B. henselae-positive cases were identified. The median age of the patients was 26.5 years (range, 1 to 69 y). Ninety-two percent of cases presented in lymph nodes, with 66% of these occurring above the diaphragm, most commonly in the cervical chain. Of 100 cases, 57 had classical CSL features of necrotizing granulomas with microabscesses, with or without surrounding palisading histiocytes. In contrast, 43/100 cases lacked the prototypical microabscesses of CSL including: 23 cases (53.5%) with features of fungal/mycobacterial lymphadenitis, 6 (14%) cases with features of Kikuchi lymphadenitis, and 4 cases (9.3%) with the classic histologic triad of toxoplasma lymphadenitis. In summary, B. henselae lymphadenitis may lack the typical microabscesses in almost half of cases and may closely mimic other reactive, especially infectious, lymphadenopathies. Given the lack of specificity of many of these features, a low threshold for B. henselae molecular testing on tissue is warranted in the appropriate clinical context.
The American journal of surgical pathology 11/2015; DOI:10.1097/PAS.0000000000000552 · 5.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We recently defined event-free survival at 24 months (EFS24) as a clinically relevant outcome for patients with DLBCL. Patients who fail EFS24 have very poor overall survival, while those who achieve EFS24 have a subsequent overall survival equivalent to that of the age- and sex-matched general population. Here, we develop and validate a clinical risk calculator (IPI24) for EFS24. Model building was performed on a discovery dataset of 1348 patients with DLBCL and treated with anthracycline-based immunochemotherapy. A multivariable model containing age, Ann Arbor stage, normalized serum LDH, ALC, ECOG performance status, bulky disease and sex was identified. The model was then applied to an independent validation dataset of 1177 DLBCL patients. The IPI24 score estimates the probability of failing to achieve the EFS24 endpoint for an individual patient. The IPI24 model showed superior discriminatory ability (c-statistic=0.671) in the validation dataset compared to the IPI (c-statistic=0.649) or the NCCN-IPI (c-statistic=0.657). After recalibration of the model on the combined dataset, the median predicted probability of failing to achieve EFS24 was 36% (range, 12% to 88%), and the IPI24 showed an EFS24 gradient in all IPI groups. The IPI24 also identified a significant percentage of patients with high risk disease, with over 20% of patients having a 50% or higher risk of failing to achieve EFS24. The IPI24 provides an individual patient level probability of achieving the clinically relevant EFS24 endpoint. It can be utilized via electronic apps. This article is protected by copyright. All rights reserved.
American Journal of Hematology 10/2015; DOI:10.1002/ajh.24223 · 3.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Systemic anaplastic large cell lymphomas (ALCLs) are classified into ALK-positive and ALK-negative types. We recently reported that ALK-negative ALCLs are genetically heterogenous. The largest subset, representing 30% of cases, had rearrangements of the DUSP22 locus. These cases had favorable outcomes similar to ALK-positive ALCL, and superior to other ALK-negative ALCLs. Here, we examined the morphologic features of these cases in more detail. First, we conducted blinded review of hematoxylin and eosin slides of 108 ALCLs from our previous study, scoring cases for the presence of 3 histologic patterns and 5 cell types. Cases then were unblinded and re-reviewed to understand these features further. DUSP22-rearranged ALCLs were more likely than other ALK-negative ALCLs to have so-called doughnut cells (23% vs. 5%; P=0.039), less likely to have pleomorphic cells (23% vs. 49%; P=0.042), and nearly always (95%) had areas with sheet-like growth (common pattern). To examine the reproducibility of these findings, we conducted blinded review of hematoxylin and eosin slides of 46 additional ALK-negative ALCLs using a 0 to 3 scoring system to predict likelihood of DUSP22 rearrangement, the results of which correlated strongly with subsequent findings by fluorescence in situ hybridization (P<0.0001). Although all ALCLs share certain morphologic features, ALCLs with DUSP22 rearrangements show significant differences from other ALK-negative ALCLs, typically showing sheets of hallmark cells with doughnut cells and few large pleomorphic cells. These morphologic findings and our previous outcome data suggest that ALK-positive ALCLs and DUSP22-rearranged ALCLs represent prototypical ALCLs, whereas ALCLs lacking rearrangements of both DUSP22 and ALK require further study.
The American journal of surgical pathology 09/2015; DOI:10.1097/PAS.0000000000000500 · 5.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although transformation to Hodgkin lymphoma (HL) is a recognized complication in patients with chronic lymphocytic leukemia (CLL), its incidence, clinical characteristics and outcomes are not well defined.We used the Mayo Clinic CLL and Lymphoma Databases to identify CLL patients who developed biopsy-proven HL (CLL/HL) on follow-up, as well as cases of de novo HL (i.e., without prior CLL). Among 3887 CLL patients seen at Mayo Clinic from January 1995 through August 2011, 26 (0.7%) developed HL. In a nested cohort of 2465 newly diagnosed CLL patients followed prospectively, the incidence of HL was 0.05%/year (10 year risk=0.5%). The median overall survival (OS) from date of HL diagnosis in patients with CLL/HL was 3.9 years compared to not reached for de novo HL patients (n=709) seen during the same time interval (p<0.001). The shorter OS of CLL/HL patients persisted after adjusting for differences in age and Ann Arbor stage of disease. The International Prognostic score (IPS) developed for de novo HL stratified prognosis among CLL/HL patients with median survival of not reached, 6.2 years, 2.4 years and 0.3 years (p=0.006) for those with IPS scores of ≤2, 3, 4 and ≥5, respectively. In summary, approximately 1 of every 200 CLL patients will develop HL within 10 years. Survival after HL diagnosis in patients with CLL is shorter than de novo HL patients. The IPS for de novo HL may be useful for stratifying survival in CLL/HL patients. This article is protected by copyright. All rights reserved.
American Journal of Hematology 01/2015; 90(4). DOI:10.1002/ajh.23939 · 3.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Mantle cell lymphoma (MCL) is a unique type of lymphoma with a prognosis intermediate between indolent and aggressive types. The purpose of this study was to study blood cytokine levels in newly diagnosed and relapsed MCL patients with respect to patterns of abnormalities and relationship to the MCL International Prognostic Index (MIPI) score.Patients and Methods: We analyzed blood levels of 30 cytokines using a multiplex ELISA in 88 patients with newly diagnosed MCL (pre-treatment levels) and 20 with relapsed MCL and compared them with controls without known lymphoma. Elevated cytokine levels were compared with clinical outcome and the MIPI score.Results: In the 88 newly diagnosed MCL patients we found significantly elevated levels compared to controls of IL-12, IP-10, sIL-2Rα, MIG, IL-1RA, IL-8, MIP-1α and MIP-1β (all p<0.05). Of these elevated cytokines, sIL-2Rα, IL-8, MIG, MIP-1α and MIP-1β were predictive of inferior event-free survival, and sIL-2Rα (HR=1.94; p=0.038), IL-8 (HR=2.17; p=0.015), and MIP-1β (HR=2.10; p=0.016) were independent of MIPI score; only sIL-2Rα (HR=2.35; p=0.041) was associated with overall survival after adjustment for MIPI. In the relapsed MCL patient group, the only significantly elevated plasma cytokines that predicted EFS were sILȐ2Rα (HR=2.90; p=0.04) and IL-8 (HR=3.75; p=0.02).Conclusion: Elevated blood levels of sIL-2Rα and the pro-inflammatory cytokines IL-8 and MIP-1β are poor prognostic factors in MCL patients and independent of MIPI score. These factors, if validated, will provide important additions to the MIPI and guide the development of new therapies for patients with elevated levels of these cytokines.
American Journal of Hematology 12/2014; 89(12). DOI:10.1002/ajh.23838 · 3.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
We examined the utility of post-therapy surveillance imaging in a large, prospectively enrolled cohort of patients with diffuse large B-cell lymphoma (DLBCL) from the United States and confirmed our results in an independent cohort of patients from France.
Patients with newly diagnosed DLBCL and treated with anthracycline-based immunochemotherapy were identified from the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence and the Léon Bérard Cancer Center, Lyon, France. In those with relapse, details at relapse and outcomes were abstracted from records.
680 individuals with DLBCL were identified from the MER, 552 (81%) of whom achieved remission after induction. 112 of the 552 patients (20%) suffered a relapse. The majority (64%) of relapses were identified before a scheduled follow-up visit. Surveillance imaging detected DLBCL relapse before clinical manifestations in nine out of 552 patients (1.6%) observed after therapy. In the Lyon cohort, imaging identified asymptomatic DLBCL relapse in four out of 222 patients (1.8%). There was no difference in survival after DLBCL relapse in patients detected at scheduled follow-up versus before scheduled follow-up in both the MER (P = .56) and Lyon cohorts (P = .25).
The majority of DLBCL relapses are detected outside of planned follow-up, with no difference in outcome in patients with DLBCL detected at a scheduled visit compared with patients with relapse detected outside of planned follow-up. These data do not support the use of routine surveillance imaging for follow-up of DLBCL.
[Show abstract][Hide abstract] ABSTRACT: ABSTRACT The natural history of limited-stage peripheral T-cell lymphomas PTCL remains poorly defined. Therefore, we examined outcomes in patients with the most common PTCL subtypes (PTCL, NOS, AITL, ALCL) and limited-stage disease. In this retrospective, multicenter study, 75 patients with limited-stage disease were identified. The median event-free (EFS) and overall survival (OS) observed were 2.1 and 6.5 years, respectively. In a landmark analysis excluding patients with primary refractory disease, no significant benefit was observed for patients undergoing consolidative radiation therapy. With the exception of patients undergoing salvage hematopoietic stem cell transplantation, survival following disease relapse or progression was poor, thus highlighting the need for improved therapeutic strategies.
Leukemia and Lymphoma 09/2014; 56(6):1-17. DOI:10.3109/10428194.2014.963078 · 2.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: aPatients with diffuse large B-cell lymphoma (DLBCL) and pre-treatment bone marrow (BM) involvement require a restaging BM biopsy to document complete remission (CR). We investigated whether BM assessment by restaging PET-CT could obviate the need for a repeat BM biopsy. Patients with DLBCL and a positive BM biopsy at diagnosis were identified from the Mayo Clinic Lymphoma Data Base. The concordance of BM status on restaging histopathology and PET-CT reports and the positive (PPV) and negative predictive value (NPV) of PET-CT were determined. 1080 patients with DLBCL were evaluated and 69 patients (6%) had DLBCL involving the BM at diagnosis. Of 46 patients who completed frontline chemoimmunotherapy, 34 had a restaging PET-CT and BM biopsy and were included in the analysis. Thirty-three patients had a negative BM by both PET-CT and BM biopsy; one patient had persistent BM involvement by biopsy and PET-CT. Thus, restaging PET-CT had 100% PPV and 100% NPV for assessing residual BM disease. The findings were validated in a prospective cohort of 68 DLBCL patients treated on a phase II clinical trial where four patients (6%) had DLBCL involving the BM at diagnosis. All had a negative BM by both restaging BMB and PET-CT. Compared with the gold standard of BM biopsy, PET-CT had a 100% NPV to exclude residual BM disease after frontline therapy. If further validated, DLBCL practice guidelines and response criteria could be modified so that BM biopsy is no longer required to document CR if the restaging PET-CT is negative.
American Journal of Hematology 09/2014; 89(9). DOI:10.1002/ajh.23760 · 3.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Lenalidomide has significant single-agent activity in relapsed diffuse large B-cell lymphoma (DLBCL). We demonstrated that lenalidomide can be safely combined with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone); this new combination is known as R2CHOP. The goal of this phase II study was to evaluate the efficacy of this combination in newly diagnosed DLBCL.
Patients and methods:
Eligible patients were adults with newly diagnosed untreated stages II to IV CD20(+) DLBCL. Patients received lenalidomide 25 mg orally per day on days 1 through 10 with standard-dose R-CHOP every 21 days for six cycles. All patients received pegfilgrastim on day 2 of each cycle and aspirin prophylaxis throughout. DLBCL molecular subtype was determined by tumor immunohistochemistry and classified as germinal center B-cell (GCB) versus non-GCB in the R2CHOP patients and 87 control patients with DLBCL from the Lymphoma Database who were treated with conventional R-CHOP.
In all, 64 patients with DLBCL were enrolled, and 60 were evaluable for response. The overall response rate was 98% (59 of 60) with 80% (48 of 60) achieving complete response. Event-free survival and overall survival (OS) rates at 24 months were 59% (95% CI, 48% to 74%) and 78% (95% CI, 68% to 90%), respectively. In R-CHOP patients, 24-month progression-free survival (PFS) and OS were 28% versus 64% (P < .001) and 46% versus 78% (P < .001) in non-GCB DLBCL versus GCB DLBCL, respectively. In contrast, there was no difference in 24-month PFS or OS for R2CHOP patients on the basis of non-GCB and GCB subtype (60% v 59% [P = .83] and 83% v 75% [P = .61] at 2 years, respectively).
R2CHOP shows promising efficacy in DLBCL. The addition of lenalidomide appears to mitigate a negative impact of non-GCB phenotype on patient outcome.
[Show abstract][Hide abstract] ABSTRACT: ALK-negative anaplastic large cell lymphoma (ALCL) is a CD30-positive T-cell non-Hodgkin lymphoma that morphologically resembles ALK-positive ALCL but lacks chromosomal rearrangements of the ALK gene. The genetic and clinical heterogeneity of ALK-negative ALCL has not been delineated. We performed immunohistochemistry and fluorescence in situ hybridization on 73 ALK-negative ALCLs and 32 ALK-positive ALCLs and evaluated the associations among pathology, genetics, and clinical outcome. Chromosomal rearrangements of DUSP22 and TP63 were identified in 30% and 8% of ALK-negative ALCLs, respectively. These rearrangements were mutually exclusive and were absent in ALK-positive ALCLs. Five-year overall survival rates were 85% for ALK-positive ALCLs, 90% for DUSP22-rearranged ALCLs, 17% for TP63-rearranged ALCLs, and 42% for cases lacking all three genetic markers (p<0.0001). Hazard ratios for death in these 4 groups after adjusting for International Prognostic Index and age were 1.0 (reference group), 0.58, 8.63, and 4.16, respectively (p=7.10 x 10(-5)). These results were similar when restricted to patients receiving anthracycline-based chemotherapy as well as to patients not receiving stem-cell transplantation. Thus, ALK-negative ALCL is a genetically heterogeneous disease with widely disparate outcomes following standard therapy. DUSP22 and TP63 rearrangements may serve as predictive biomarkers to help guide patient management.
[Show abstract][Hide abstract] ABSTRACT: Peripheral T-cell lymphomas (PTCLs) are a heterogenous group of aggressive non-Hodgkin's lymphomas that are incurable in the majority of patients with current therapies. Outcomes associated with anthracycline-based therapies are suboptimal, but remain the standard of care for most patients, even though the benefits of this approach remain uncertain. This study retrospectively examined outcomes in a cohort of North American PTCL patients treated with both anthracycline- and nonanthracycline-containing regimens. The incorporation of anthracycline-containing regimens was associated with improved progression-free survival (PFS) and overall survival (OS). Patients treated with nonanthracycline-containing regimens were more likely to have high-risk features and were less likely to undergo high-dose therapy and stem cell transplantation. However, anthracycline use remained an independent predictor of improved PFS and OS when adjusting for these confounding variables. Anthracycline-based regimens and consolidation with high-dose therapy and autologous stem cell transplantation in appropriately selected patients remains a viable option for patients unable to participate in a clinical trial. Long-term disease-free survival is not optimal, highlighting the need for an improved understanding of disease pathogenesis, and the development of novel therapeutic strategies.
Blood Cancer Journal 05/2014; 4(5):e214. DOI:10.1038/bcj.2014.34 · 3.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abstract There are few studies examining complementary and alternative medicine (CAM) use and beliefs among non-Hodgkin lymphoma (NHL) survivors. 719 NHL patients from the University of Iowa/Mayo Clinic Molecular Epidemiology Resource who completed the 3-year post-diagnosis questionnaire were included in this study. 636 (89%) reported ever using CAM, with 78% utilizing vitamins, 54% alternative therapies and 45% herbals. Female gender was associated with increased overall CAM use (P<.0001) as well as use of vitamins (P<.0001), herbals (P=.006) and alternative therapy (P=.0002) for cancer. Older age (>60) was associated with increased vitamin use (P=.005) and decreased herbal use (P=.008). Among users, 143 (20%) believe CAM assists healing, 123 (17%) believe CAM relieves symptoms, 122 (17%) believe CAM gives a feeling of control, 110 (15%) believe CAM assists other treatments, 108 (15%) believe CAM boosts immunity, 26 (4%) believe CAM cures cancer, and 36 (5%) believe CAM prevents the spread of cancer.