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Purpose: Mantle cell lymphoma (MCL) is a B-cell lymphoma characterized by cyclin D1 expression. Autologous hematopoietic cell transplantation (AHCT) consolidation after induction chemotherapy is often used for eligible patients; however, the benefit remains uncertain in the rituximab era. Herein we retrospectively assessed the impact of AHCT consolidation on survival in a large cohort of transplantation-eligible patients age 65 years or younger., Patients and Methods: We retrospectively studied transplantation-eligible adults age 65 years or younger with newly diagnosed MCL treated between 2000 and 2015. The primary objective was to assess for improved progression-free survival (PFS) with AHCT consolidation and secondarily to assess for improved overall survival (OS). Cox multivariable regression analysis and propensity score-weighted (PSW) analysis were performed., Results: Data were collected from 25 medical centers for 1,254 patients; 1,029 met inclusion criteria. Median follow-up for the cohort was 76 months. Median PFS and OS were 62 and 139 months, respectively. On unadjusted analysis, AHCT was associated with improved PFS (75 v 44 months with v without AHCT, respectively; P < .01) and OS (147 v 115 months with v without AHCT, respectively; P < .05). On multivariable regression analysis, AHCT was associated with improved PFS (hazard ratio [HR], 0.54; 95% CI, 0.44 to 0.66; P < .01) and a trend toward improved OS (HR, 0.77; 95% CI, 0.59 to 1.01; P = .06). After PSW analysis, AHCT remained associated with improved PFS (HR, 0.70; 95% CI, 0.59 to 0.84; P < .05) but not improved OS (HR, 0.87; 95% CI, 0.69 to 1.1; P = .2)., Conclusion: In this large cohort of younger, transplantation-eligible patients with MCL, AHCT consolidation after induction was associated with significantly improved PFS but not OS after PSW analysis. Within the limitations of a retrospective analysis, our findings suggest that in younger, fit patients, AHCT consolidation may improve PFS.

Purpose Patients with double-hit lymphoma (DHL) rarely achieve long-term survival following disease relapse. Some patients with DHL undergo consolidative autologous stem-cell transplantation (autoSCT) to reduce the risk of relapse, although the benefit of this treatment strategy is unclear. Methods Patients with DHL who achieved first complete remission following completion of front-line therapy with either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or intensive front-line therapy, and deemed fit for autoSCT, were included. A landmark analysis was performed, with time zero defined as 3 months after completion of front-line therapy. Patients who experienced relapse before or who were not followed until that time were excluded. Results Relapse-free survival (RFS) and overall survival (OS) rates at 3 years were 80% and 87%, respectively, for all patients (n = 159). Three-year RFS and OS rates did not differ significantly for autoSCT (n = 62) versus non-autoSCT patients (n = 97), but 3-year RFS was inferior in patients who received R-CHOP compared with intensive therapy (56% v 88%; P = .002). Three-year RFS and OS did not differ significantly for patients in the R-CHOP or intensive therapy cohorts when analyzed by receipt of autoSCT. The median OS following relapse was 8.6 months. Conclusion In the largest reported series, to our knowledge, of patients with DHL to achieve first complete remission, consolidative autoSCT was not associated with improved 3-year RFS or OS. In addition, patients treated with R-CHOP experienced inferior 3-year RFS compared with those who received intensive front-line therapy. When considered in conjunction with reports of patients with newly diagnosed DHL, which demonstrate lower rates of disease response to R-CHOP compared with intensive front-line therapy, our findings further support the use of intensive front-line therapy for this patient population.

Rearrangement of MYC is associated with a poor prognosis in patients with diffuse large B cell lymphoma (DLBCL) and B cell lymphoma unclassifiable (BCLU), particularly in the setting of double hit lymphoma (DHL). However, little is known about outcomes of patients who demonstrate MYC rearrangement without evidence of BCL2 or BCL6 rearrangement (single hit) or amplification (>4 copies) of MYC. We identified 87 patients with single hit lymphoma (SHL), 22 patients with MYC-amplified lymphoma (MYC amp) as well as 127 DLBCL patients without MYC rearrangement or amplification (MYC normal) and 45 patients with DHL, all treated with either R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or intensive induction therapy. For SHL and MYC amp patients, the 2-year progression-free survival rate (PFS) was 49% and 48% and 2-year overall survival rate (OS) was 59% and 71%, respectively. SHL patients receiving intensive induction experienced higher 2-year PFS (59% vs. 23%, P = 0·006) but similar 2-year OS as compared with SHL patients receiving R-CHOP. SHL DLBCL patients treated with R-CHOP, but not intensive induction, experienced significantly lower 2-year PFS and OS (P < 0·001 for both) when compared with MYC normal patients. SHL patients appear to have a poor prognosis, which may be improved with receipt of intensive induction., Competing Interests: The authors have declared no conflicts of interest., (© 2016 John Wiley & Sons Ltd.)

Background: The objective of this study was to compare the outcomes of patients with classical Hodgkin lymphoma (cHL) who achieved complete remission with frontline therapy and then underwent either clinical surveillance or routine surveillance imaging., Methods: In total, 241 patients who were newly diagnosed with cHL between January 2000 and December 2010 at 3 participating tertiary care centers and achieved complete remission after first-line therapy were retrospectively analyzed. Of these, there were 174 patients in the routine surveillance imaging group and 67 patients in the clinical surveillance group, based on the intended mode of surveillance. In the routine surveillance imaging group, the intended plan of surveillance included computed tomography and/or positron emission tomography scans; whereas, in the clinical surveillance group, the intended plan of surveillance was clinical examination and laboratory studies, and scans were obtained only to evaluate concerning signs or symptoms. Baseline patient characteristics, prognostic features, treatment records, and outcomes were collected. The primary objective was to compare overall survival for patients in both groups. For secondary objectives, we compared the success of second-line therapy and estimated the costs of imaging for each group., Results: After 5 years of follow-up, the overall survival rate was 97% (95% confidence interval, 92%-99%) in the routine surveillance imaging group and 96% (95% confidence interval, 87%-99%) in the clinical surveillance group (P = .41). There were few relapses in each group, and all patients who relapsed in both groups achieved complete remission with second-line therapy. The charges associated with routine surveillance imaging were significantly higher than those for the clinical surveillance strategy, with no apparent clinical benefit., Conclusions: Clinical surveillance was not inferior to routine surveillance imaging in patients with cHL who achieved complete remission with frontline therapy. Routine surveillance imaging was associated with significantly increased estimated imaging charges., (© 2014 American Cancer Society.)

Background: Despite advances in treatments for Hodgkin's lymphoma, about 20% of patients still die from progressive disease. Current prognostic models predict the outcome of treatment with imperfect accuracy, and clinically relevant biomarkers have not been established to improve on the International Prognostic Score., Methods: Using gene-expression profiling, we analyzed 130 frozen samples obtained from patients with classic Hodgkin's lymphoma during diagnostic lymph-node biopsy to determine which cellular signatures were correlated with treatment outcome. We confirmed our findings in an independent cohort of 166 patients, using immunohistochemical analysis., Results: Gene-expression profiling identified a gene signature of tumor-associated macrophages that was significantly associated with primary treatment failure (P=0.02). In an independent cohort of patients, we found that an increased number of CD68+ macrophages was correlated with a shortened progression-free survival (P=0.03) and with an increased likelihood of relapse after autologous hematopoietic stem-cell transplantation (P=0.008), resulting in shortened disease-specific survival (P=0.003). In multivariate analysis, this adverse prognostic factor outperformed the International Prognostic Score for disease-specific survival (P=0.003 vs. P=0.03). The absence of an elevated number of CD68+ cells in patients with limited-stage disease defined a subgroup of patients with a long-term disease-specific survival of 100% with the use of current treatment strategies., Conclusions: An increased number of tumor-associated macrophages was strongly associated with shortened survival in patients with classic Hodgkin's lymphoma and provides a new biomarker for risk stratification., (2010 Massachusetts Medical Society)

Purpose: Health disparities exist according to an individual's place of residence. We evaluated the association between primary area of residence (urban v rural) according to treatment provider (university based v community based) and overall survival in patients with lymphoma and determined whether there are patient groups that could benefit from better coordination of care., Patients and Methods: Population-based, retrospective cohort study of 2,330 patients with centrally confirmed lymphoma from Nebraska and surrounding states and treated by university-based or community-based oncologists from 1982 to 2006., Results: Among urban residents, 321 (14%) were treated by university-based providers (UUB) and 816 (35%) were treated by community-based providers (UCB). Among rural residents, 332 (14%) were treated by university-based providers (RUB), and 861 (37%) were treated by community-based providers (RCB). The relative risk (RR) of death among UUB, UCB, and RUB were not statistically different. However, RCB had a higher risk of death (RR, 1.37; 95% CI, 1.14 to 1.65; P = .01; and RR, 1.26; 95% CI, 1.06 to 1.49; P = .01) when compared with UUB and RUB, respectively. This association was true in both low- and intermediate-risk patients. Among high-risk patients, UCB, RUB, and RCB were all at higher risk of death when compared with UUB., Conclusion: Survival outcomes of patients with lymphoma may be associated with place of residence and treatment provider. High-risk patients from rural areas may benefit from better coordination of care.

Purpose: Although preliminary studies suggest that non-Hodgkin's lymphoma (NHL) complicating rheumatoid arthritis (RA) may be a clinically distinct entity compared with that occurring in the general population, studies examining the impact of antecedent RA on survival are limited. In this prospective study, we examined the association of RA with survival in patients with NHL., Patients and Methods: Using two large lymphoma registries, we identified patients with evidence of RA preceding NHL. Survival in RA patients was compared with that of controls using proportional hazards regression, adjusting for the effects of age, sex, lymphoma diagnosis-to-treatment lag time, calendar year, International Prognostic Index score, and NHL grade., Results: The frequency of NHL subtypes was similar in RA patients (n = 65) and controls (n = 1,530). Compared with controls, RA patients with NHL had similar overall survival (hazard ratio [HR] = 0.95; 95% CI, 0.70 to 1.30) but were at lower risk of lymphoma progression or relapse (HR = 0.41; 95% CI, 0.25 to 0.68) or death related to lymphoma or its treatment (HR = 0.60; 95% CI, 0.37 to 0.98), but were more than twice as likely to die from causes unrelated to lymphoma (HR = 2.16; 95% CI, 1.33 to 3.50)., Conclusion: RA is associated with improved NHL-related outcomes, including a 40% reduced risk of death occurring as a result of lymphoma or its treatment and approximately a 60% lower risk of lymphoma relapse or progression compared with non-RA controls. However, the survival advantage gained in RA from the acquisition of lymphomas with favorable prognoses is negated through an increased mortality from other comorbid conditions.

The term "B-cell small lymphocytic lymphoma" (B-SLL) is generally reserved for patients with lymph node masses that show the histology and immunophenotype of B-cell chronic lymphocytic leukemia (B-CLL) but who are not leukemic. The aim of our study was to define clinical factors that predict for survival in B-SLL. Thirty-nine patients with B-SLL and with less than 5,000 mature-appearing lymphocytes/microL in the peripheral blood were studied. The median follow-up of survivors was 6.6 years (range, 1.6-12.3 years). The estimated 5-year overall survival (OS) and failure-free survival (FFS) were 66% and 23%, respectively. In the univariate analysis, significant adverse predictors for OS were age > or =60 years, B symptoms, elevated serum LDH, low hemoglobin (<11 g/dL), and high International Prognostic Index (IPI) score (3-5). In multivariate analysis, the IPI score was the only significant predictor of OS. Anemia and B symptoms were additionally predictive of poor OS in patients with low IPI scores., (Copyright 2004 Wiley-Liss, Inc.)

Purpose: To investigate whether primary mediastinal large B-cell lymphoma (PMLBL) is a distinct clinicopathologic entity with a more aggressive course than other diffuse large B-cell lymphomas (DLBL)., Materials and Methods: All patients with CD20-positive DLBL who presented with a mediastinal mass measuring at least 5.0 cm and were treated with curative intent were identified. A control group of 352 patients with nonmediastinal DLBL was selected for comparison., Results: The 43 patients with PMLBL had a male to female ratio of 20:23 and a median age of 42 years. Stage I/II disease was present in 58% of the patients, with only 9% having bone marrow involvement. A complete remission was achieved in 63% of the patients, and the 5-year overall and failure-free survivals were 46% and 38%, respectively. Among the clinical variables, an elevated serum lactate dehydrogenase level, a low performance score, more than one extranodal site, and an intermediate or high International Prognostic Index score were predictive of poor survival. When compared with the DLBL group, a younger median age was the only clinical feature that was significantly different in the PMLBL group., Conclusion: The clinical features of PMLBL do not appear to be significantly different from those of nonmediastinal DLBL. Although the younger age of onset, slight female predominance, mediastinal location, and size of the mass may justify the recognition of PMLBL as a clinical syndrome, additional evidence is needed to define it as a distinct disease entity.

Lymphomatous polyposis (LP) is generally thought to be an expression of non-Hodgkin's lymphoma (NHL) of follicular mantle cell (MC) origin. We report nine patients with LP from more than 3,500 cases of NHL studied by the Nebraska Lymphoma Study Group. Our patients differed from those reported previously in that LP represented a follicular center cell (FCC) NHL in two of the nine cases, with the remainder consisting of MC NHL. Three patients developed LP during a relapse of previously diagnosed and treated extraintestinal MC NHL (parotid gland, tonsil, and inguinal lymph node, respectively), whereas the other six patients presented with primary LP. In seven of the nine LP cases, a large mass predominated among a myriad of small polyps. The FCC cases were confined to the small intestine, whereas the MC cases were either pan-intestinal or colonic on their localization. Two MC cases studied by Southern blotting exhibited rearrangement of the bcl-1 locus. Bcl-2 rearrangement was not detected in any of the nine cases when studied by either a polymerase chain reaction-based assay (seven cases) or by Southern blotting (two cases). To date, four patients (three MC, one FCC) have experienced recurrent NHL in gastrointestinal sites. With follow-up ranging from 13 to 147 months, the entire group had a median survival of 41 months (primary MC LP:13, 13, 41, and 77 months; primary FCC LP:45 and 147 months; secondary MC LP:17, 41 and 76 months), and only one patient has died. We conclude that LP is a rare manifestation of NHL of either follicular MC or germinal center cell origin.

Purpose: We studied the effect of morphology and extent of bone marrow (BM) infiltrate on the survival of patients with diffuse aggressive B-cell non-Hodgkin's lymphoma (NHL), along with clinical features., Patients and Methods: Sixty adult patients with diffuse aggressive B-cell NHL and BM involvement at the time of presentation were studied. All patients were uniformly staged and treated with a curative high-dose chemotherapy regimen. BM involvement was assessed according to the cytology, pattern of infiltration, and extent of involvement, and was correlated with overall survival (OS) and failure-free survival (FFS)., Results: Patients with BM involvement that consisted of > or = 50% large cells or BM involvement of > or = 70% had a poorer OS (P = .065 and P = .055, respectively). Those who presented with an infiltrate of less than 50% large cells and an international prognostic index (IPI) of < or = 3 had a significantly longer postrelapse survival time (P = .003). A diffuse or interstitial pattern of BM involvement was predictive of both poor OS and FFS (P = .008 and .009, respectively). Multivariate analysis indicated that only IPI (P = .0005) and pattern of BM infiltration (P = .009) were independent predictors of OS, and only the former was predictive of FFS (P = .03)., Conclusion: The IPI is predictive of OS and FFS, while BM involvement with a diffuse or interstitial pattern is associated with significantly poorer OS. Patients with BM infiltration that involved > or = 70% of the marrow or contained > or = 50% large cells had poor OS, but more patients need to be studied to determine the significance. Two parameters, IPI < or = 3 and BM large cells less than 50%, identify a group of patients with long-term survival after relapse.

Background: Although mantle cell lymphoma (MCL) is a distinct disease entity with well described clinical and pathological features, little information exists regarding its therapy. This paper will evaluate patients with MCL receiving either induction therapy with an anthracycline or high-dose chemotherapy and autologous hematopoietic stem cell transplantation for relapsed disease., Patients and Methods: The cases of 14 previously untreated patients with MCL who received an anthracycline-containing combination chemotherapy regimen on Nebraska Lymphoma Study Group protocols from 3/83 to 2/92 were reviewed. During the same time period, a different set of nine patients with recurrent MCL were referred for high-dose chemoradiotherapy and autologous stem cell rescue as salvage therapy., Results: The five year overall (OS) and failure-free (FFS) survivals from the initiation of chemotherapy for the patients receiving an induction therapy with an anthracycline containing regimen were 23% and 8%, respectively. At the time of this analysis, three of the nine transplant patients remain progression-free 7, 12, and 25 months post-transplant. Two year overall and FFS for all nine patients was 34%., Conclusions: Longer follow-up of greater patient numbers is required to determine whether high-dose therapy can overcome the chemoresistance and increase the cure rate of MCL. Since most patients with this disease have minimal chance of cure with standard chemotherapy, the optimal timing for high dose therapy may be as part of front-line treatment. Further clinical trials are required to investigate the potential benefits of high-dose therapy for patients with MCL.

We have considered the cytogenetic abnormalities present in 27 unpublished cases of B-immunoblastic lymphoma. Among these 27 patients, the chromosome changes were heterogeneous and complex. The chromosomes most commonly gained were 3 (44% of cases), 18 (44%), 6 (30%) and 11 (30%). The most common structural abnormalities involved band 14q32 (26%), band 18q21 (15%) and bands 6q16-21 (19%). Study of these 27 immunoblastic lymphomas did not allow us to tentatively identify a common primary cytogenetic abnormality unique to B-immunoblastic lymphoma, however, a translocation at 14q32 may be the primary cytogenetic lesion in some of the cases. Rather, we have added to the number of abnormalities reported in immunoblastic lymphoma and in non-Hodgkin's lymphoma in general.

Background and Methods: The diffuse large cell non-Hodgkin lymphomas are a heterogeneous group of neoplasms that are potentially curable. To identify important predictors of clinical outcome, the authors evaluated the clinical and pathologic features of 114 patients with newly diagnosed diffuse large B-cell lymphoma who were uniformly staged and treated with curative intent. The authors were particularly interested in determining whether any pathologic features added to the ability of the clinical features to predict patient survival., Results: Several clinical and pathologic features were found to be associated with survival by univariate analysis. However, multivariate analysis disclosed that only the stage of disease and the symptom status were significantly associated with survival. Low stage and lack of B symptoms were favorable indicators of overall survival and failure-free survival., Conclusions: The authors suggest that the evaluation of pathologic features in diffuse large B-cell lymphoma has little prognostic utility and recommend that the pathology evaluation be limited to features that are useful for diagnostic purposes.

Forty-two patients with advanced-stage nodular sclerosing Hodgkin's disease (NSHD) were treated uniformly with combination chemotherapy and radiation therapy at the University of Nebraska Medical Center between 1982 and 1987. The cases were subclassified into low-grade (13 cases) and high-grade (29 cases) categories using the British National Lymphoma Investigation (BNLI) histologic criteria. After a median follow-up interval of 48 months, no significant differences with regard to the complete remission rate (100% versus 90%), remission durability (85% versus 96%), or predicted 4-year actuarial survival (92% versus 86%) were observed between the two groups, respectively. It was concluded that the BNLI grading scheme for NSHD does not predict the clinical outcome of patients with advanced-stage NSHD who receive optimal therapy.

The morphologic, phenotypic, molecular genetic, and clinical features of 34 cases of clear-cell immunoblastic lymphoma (IBLC) are described. Sixteen cases were of B-cell type (IBLC-B) and 18 cases were of T-cell type (IBLC-T). There were no significant differences in the morphologic characteristics of the neoplastic cells in the two types, although IBLC-B was less likely to be polymorphic than IBLC-T. Interfollicular proliferation, a higher mitotic rate, infiltration by eosinophils, and an increase in capillary-sized blood vessels were also features of IBLC-T, whereas necrosis and fibrosis were more extensive in IBLC-B. Patients with IBLC-B were predominantly female, whereas those with IBLC-T were predominantly male. The mean age was 62 years for those with IBLC-B and 46 years for those with IBLC-T. Patients with IBLC-B usually had lower-stage disease, but there was no significant difference in survival rate between those with IBLC-B and those with IBLC-T. Although most cases of IBLC have been considered to be of peripheral T-cell origin, the authors conclude that IBLC-B is more common than previously considered and that clear-cell morphologic characteristics are not a reliable indicator of T-cell type.

Controversy has recently arisen as to whether diffuse intermediate lymphocytic lymphoma (ILL) should be considered a low-grade or an intermediate-grade non-Hodgkin's lymphoma for clinical purposes. Therefore, the authors performed a clinicopathologic study to determine the biologic course of diffuse ILL (40 cases) and compared it with small lymphocytic lymphoma (SLL; 51 cases) and diffuse small cleaved cell lymphoma (DSCCL; 14 cases). They found that patients with diffuse ILL having pseudofollicular proliferation centers (PC) had a significantly longer median survival (84 months) than those without PC (46.5 months; P = 0.03). The median survival of patients with SLL was 72 months, whereas those with DSCCL had a median survival of only 18 months. Based on these findings, the authors conclude that diffuse ILL with PC should be included in the low-grade category of SLL for clinical purposes, whereas diffuse ILL without PC (true diffuse ILL) should be considered an intermediate-grade non-Hodgkin's lymphoma. True diffuse ILL is similar to centrocytic lymphoma in the Kiel classification and should be accorded a similar status in a modified Working Formulation.

A clinicopathologic analysis of 22 cases of mantle zone lymphoma (MZL) was performed. In lymph node sections, MZL was characterized by the proliferation of neoplastic small lymphoid cells in wide mantles around benign germinal centers. Eighteen cases were of the intermediate lymphocytic type and four cases were of the small lymphocytic type. Immunohistologic analysis of paraffin sections revealed the following characteristic immunophenotype of MZL: L26, LN2, NUB1 and T2/48 positive, and LN5, LN1, AF6 and UCHL1 negative. The immunophenotype of MZL was identical to that of normal primary lymphoid follicles and the mantle zones of secondary follicles, except for the absence of staining with LN5 in MZL. The median age of the patients was 63 years, and the male-to-female ratio was 1.2:1. B symptoms were present in 55% of the patients, and 81% had splenomegaly. An absolute lymphocytosis was present at the time of initial diagnosis in 13% of the patients, and 67% had bone marrow involvement by lymphoma. Thirteen percent of the patients had Stage II disease, 23% had Stage III disease, and 64% had Stage IV disease. All 22 patients received some form of therapy, with 73% receiving multiagent chemotherapy. Eleven patients achieved a complete remission at some time during their course. The overall median survival of the entire group was 88 months. Clinical features which appeared to influence survival adversely included an absolute lymphocyte count above 4000/microliters, a platelet count less than 100,000/microliters, and male sex. Achievement of a complete remission at any time favorably influenced survival. Pathologic features which appeared to influence survival adversely were a mitotic rate of 10 or more per 10 high-power fields (HPF) and the presence of 40 or more large lymphoid cells per 10 HPF. These findings lead the authors to conclude that MZL is a distinctive form of low-grade non-Hodgkin's lymphoma.