Primary Cutaneous B‐Cell Lymphoma: Management and Patterns of Recurrence at the Multimodality Cutaneous Lymphoma Clinic of The Ohio State University

Background.

The increasing incidence of primary cutaneous B-cell lymphomas (PCBCLs) presents new challenges for clinicians. Despite advances in the clinical and pathologic characterization of PCBCL, the significance of the current staging approach as a risk profiling tool and the effect of various treatments on outcome remain unclear.

Materials and Methods.

We retrospectively reviewed patients who presented with a diagnosis of PCBCL seen at The Ohio State University between 1998 and 2012. We reviewed the initial presentation and treatment modality. We then assessed whether the treatment modality (conservative skin-directed vs. definitive radiation with or without systemic therapy), stage (T1 or ≥T2), or histologic subtype (primary cutaneous follicle center lymphoma [PCFCL] vs. primary cutaneous marginal zone B-cell lymphoma [PCMZL]) affected the risk of recurrence.

Results.

We identified 67 patients referred with an initial diagnosis of PCBCL. After imaging, 12 did not meet the criteria for PCBCL and were classified as having systemic B-cell lymphoma with cutaneous involvement. The remaining 55 patients included 25 with PCMZL, 24 with PCFCL, 2 with primary cutaneous large B-cell lymphoma leg type, and 4 with unclassifiable disease. According to the International Society of Cutaneous Lymphoma-European Organization for Research and Treatment of Cancer staging, 30 cases were T1 (55%), 14 T2 (25%), and 11 T3 (20%). Comparing the time to first recurrence (TFR) by indolent PCBCL subtypes, we found no difference in the recurrence risk for either stage (T1, p = .51 vs. T2/T3, p = .30). Comparing TFR by treatment modality, we found no difference in TFR within T1 patients (p = .34) or T2/T3 patients (p = .44).

Conclusion.

Our limited analysis highlights the importance of complete staging at diagnosis and suggests that the treatment modality does not affect the risk of recurrence in T1 indolent PCBCL.

Implications for Practice:

Primary cutaneous B-cell lymphoma (PCBCL) is a rare malignancy with an increasing incidence. Clinicians must recognize the importance of a complete workup to accurately diagnose PCBCL, given the effect on prognosis and treatment. It was observed that nearly 20% of the patients who presented initially with cutaneous B-cell lymphoma were classified as having systemic B-cell lymphoma after whole body imaging. The findings from the present retrospective analysis of a single-institution cohort suggest that for early-stage indolent PCBCL, no front-line treatment strategy that decreases the risk of recurrence is obvious. No difference in the risk of recurrence between conservative skin-directed and other therapies was observed. These data support a continued need to compare front-line treatment therapies.     

Antibodies against lytic and latent Kaposi's sarcoma-associated herpes virus antigens and lymphoma in the European EpiLymph case-control study

Background:

Kaposi''s sarcoma-associated herpes virus is associated with primary effusion lymphoma and multicentric Castleman''s disease.

Methods:

Seropositivity to lytic and latent Kaposi''s sarcoma herpes virus (KSHV) antigens were examined in 2083 lymphomas and 2013 controls from six European countries.

Results:

Antibodies against KSHV latent and lytic antigens were detectable in 4.5% and 3.4% of controls, respectively, and 3.6% of cases (P>0.05). The KSHV seropositivity was associated with splenic marginal zone lymphoma (SMZL) (odds ratio (OR)=4.11, 95% confidence interval (CI)=1.57–10.83) and multiple myeloma (OR=0.31, 95% CI=0.11–0.85).

Conclusion:

The KSHV is unlikely to contribute importantly to lymphomagenesis among immunocompetent subjects. However, the observed association with SMZL may underline a chronic antigen mechanism in its aetiology.     

Phase II study of gemcitabine and bexarotene (GEMBEX) in the treatment of cutaneous T-cell lymphoma

Background:

Both gemcitabine and bexarotene are established single agents for the treatment of cutaneous T-cell lymphoma (CTCL). We investigated the feasibility and efficacy of combining these drugs in a single-arm phase II study.

Methods:

Cutaneous T-cell lymphoma patients who had failed standard skin-directed therapy and at least one prior systemic therapy were given four cycles of gemcitabine and concurrent bexarotene for 12 weeks. Responders were continued on bexarotene maintenance until disease progression or unacceptable toxicity.

Results:

The median age was 65 years, stage IB (n=5), stage IIA (n=2), stage IIB (n=8), stage III (n=8) and stage IVA (n=12), 17 patients were erythrodermic, 17 patients were B1, and 10 patients were both erythrodermic and B1. Thirty (86%) patients completed four cycles of gemcitabine. In all, 80.0% of patients demonstrated a reduction in modified Severity-Weighted Assessment Tool (mSWAT) score although the objective disease response rate at 12 weeks was 31% (partial response (PR) 31%) and at 24 weeks 14% (PR 14%, stable disease (SD) 23%, progressive disease (PD) 54%, not evaluable 9%). Median progression-free survival was 5.3 months and median overall survival was 21.2 months.

Conclusion:

The overall response rate of the combination did not reach the specified target to proceed further and is lower than that previously reported for gemcitabine as a single agent.     

Risk of lymphoma subtypes after solid organ transplantation in the United States

Background:

Solid organ transplant recipients have high risk of lymphomas, including non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). A gap in our understanding of post-transplant lymphomas involves the spectrum and associated risks of their many histologic subtypes.

Methods:

We linked nationwide data on solid organ transplants from the US Scientific Registry of Transplant Recipients (1987–2008) to 14 state and regional cancer registries, yielding 791 281 person-years of follow-up for 19 distinct NHL subtypes and HL. We calculated standardised incidence ratios (SIRs) and used Poisson regression to compare SIRs by recipient age, transplanted organ, and time since transplantation.

Results:

The risk varied widely across subtypes, with strong elevations (SIRs 10–100) for hepatosplenic T-cell lymphoma, Burkitt''s lymphoma, NK/T-cell lymphoma, diffuse large B-cell lymphoma, and anaplastic large-cell lymphoma (both systemic and primary cutaneous forms). Moderate elevations (SIRs 2–4) were observed for HL and lymphoplasmacytic, peripheral T-cell, and marginal zone lymphomas, but SIRs for indolent lymphoma subtypes were not elevated. Generally, SIRs were highest for younger recipients (<20 years) and those receiving organs other than kidneys.

Conclusion:

Transplant recipients experience markedly elevated risk of a distinct spectrum of lymphoma subtypes. These findings support the aetiologic relevance of immunosuppression for certain subtypes and underscore the importance of detailed haematopathologic workup for transplant recipients with suspected lymphoma.     

Oral contraceptive and reproductive risk factors for ovarian cancer within sisters in the breast cancer family registry

Background:

Oral contraceptive use has been consistently associated with a reduced risk of ovarian cancer in unrelated, average risk women; however little data exist on whether this benefit extends to higher risk women from cancer families. To examine this, we conducted family-based analyses using the Breast Cancer Family Registry.

Methods:

We used generalised estimating equations to obtain the population average effect across all families (n=389 cases, n=5643 controls) and conditional logistic regression to examine within-family differences in a subset with at least two sisters discordant on ovarian cancer status (n=109 cases, n=149 unaffected sister controls).

Results:

In the multivariable generalised estimating equation model there was a reduced risk of ovarian cancer for ever use of oral contraceptives compared with never use (OR=0.58, 95% CI: 0.37, 0.91), and in the conditional logistic model there was a similar inverse association; however, it was not statistically significant (OR=0.52, 95% CI: 0.23, 1.17). We examined this association by BRCA1/2 status and observed a statistically significant reduced risk in the non-carriers only.

Conclusion:

We observed a decreased risk of ovarian cancer with oral contraceptive use supporting that this association observed in unrelated women extends to related women at higher risk.     

Occupational exposure to endocrine disruptors and lymphoma risk in a multi-centric European study

Background:

Incidence rates of lymphoma are usually higher in men than in women, and oestrogens may protect against lymphoma.

Methods:

We evaluated occupational exposure to endocrine disrupting chemicals (EDCs) among 2457 controls and 2178 incident lymphoma cases and subtypes from the European Epilymph study.

Results:

Over 30 years of exposure to EDCs compared to no exposure was associated with a 24% increased risk of mature B-cell neoplasms (P-trend=0.02). Associations were observed among men, but not women.

Conclusions:

Prolonged occupational exposure to endocrine disruptors seems to be moderately associated with some lymphoma subtypes.     

Delayed Efficacy After Treatment With Lenalidomide or Thalidomide in Patients With Mucosa‐Associated Lymphoid Tissue Lymphoma

Background.

The immunomodulatory drugs (IMiDs) thalidomide and lenalidomide have both been tested for treatment of mucosa-associated lymphoid tissue (MALT) lymphoma, with lenalidomide, in particular, showing promising activity. However, long-term results are missing. Because of the late-onset remissions registered in individual patients, we have systemically analyzed the patients treated with IMiDs at our institution for long-term results.

Methods.

Within the present retrospective analysis, we identified 25 patients who had been treated with lenalidomide (n = 18) or thalidomide (n = 7) and were available for long-term assessments of outcome. All patients were followed up according to a standardized follow-up protocol.

Results.

Of the 25 patients, 7 (28%) experienced delayed-onset responses without further treatment (thalidomide, n = 2; lenalidomide, n = 5). In 4 patients (16%), the initial outcome switched to a better result (partial remission [PR] to complete remission [CR], n = 1; stable disease [SD] to PR, n = 1; SD to CR, n = 1; and PD to CR, n = 1) after a median time of 19.5 months (range, 10.9–32.0). Furthermore, 2 patients showed ongoing shrinkage of the target lesion for 47.4+ and 43.5+ months, respectively, and 1 patient had durable disease stabilization for 16.2+ months. The median time to the best response for all responding patients (13 of 25; 53%) was 7.3 months (interquartile range [IQR], 5.6–22.5). After a median follow-up of 46 months (IQR, 32.0–58.5), 23 of 25 patients (92%) were alive.

Conclusion.

Our findings suggest that late-onset remissions might be a common phenomenon in the use of IMiDs for the treatment of MALT lymphoma. Thus, sufficient follow-up time after treatment before the initiation of further therapy appears crucial to assess the full effect of therapy and avoid unnecessary overtreatment.

Implications for Practice:

The immunomodulatory drugs (IMiDs) thalidomide and lenalidomide have been tested for the treatment of mucosa-associated lymphoid tissue (MALT) lymphoma, with lenalidomide showing promising activity. However, long-term results are missing. The present findings suggest that late-onset remissions and delayed responses could be a common phenomenon with IMiD use for MALT lymphoma. Using a standardized restaging protocol to ensure concise follow-up data, these findings suggest it is of major importance to ensure a sufficient follow-up time after treatment with these compounds and before initiation of further treatment lines, because nearly one third of treated patients showed further improvement during prolonged follow-up.     

Lymphoma B-cell responsiveness to CpG-DNA depends on the tumor microenvironment

Background

Toll-like receptor (TLR) agonists have important properties that can be exploited for immunotherapy against tumors. Locally injected immunostimulatory oligodeoxynucleotides containing CpG motifs (CpG-ODNs), which are TLR9 agonists, have shown promise in cancer models. Several studies have demonstrated that these motifs have immunologic effects similar to those of bacterial DNA and can stimulate monocytes, macrophages, dendritic, and B cells, which then produce several proinflammatory cytokines. However, these CpG-ODNs appear to produce opposite effects on tumor B cells.

Methods

In this study, we investigated the direct effects of a murine class B CpG (1826) ODNs on lymphoma B cells in vitro and in vivo, using mouse models of non-Hodgkin B lymphomas developing in immunoprivileged sites, specifically the brain and the eye, and in subcutaneous sites.

Results

In vitro, CpG-ODNs produced antiproliferative and proapoptotic effects on lymphoma B cells. In vivo, it had an antitumor effect when injected into tumors in murine models of subcutaneous lymphoma (SCL) and primary cerebral lymphoma (PCL). However, its intravitreal administration into a primary intraocular lymphoma (PIOL) mouse model did not produce an antitumor effect. In vitro experiments using supernatant from mouse PIOL samples demonstrated that the PIOL molecular microenvironment inhibits the antiproliferative effect of CpG-ODNs on lymphoma B-cells.

Conclusions

Responsiveness to CpG stimulation differs in subcutaneous, cerebral, and ocular tumors, according to the tumoral and molecular microenvironment, and this should be considered for further therapeutic approaches.     

Exposure to animals and increased risk of marginal zone B-cell lymphomas of the ocular adnexae

Background:

Ocular adnexal marginal zone B-cell lymphoma (OAMZL) has been associated with Chlamydophila psittaci, an infection that may be transmitted by carrier animals. However, it is still unclear whether exposure to animals affects the risk of OAMZL in comparison with other lymphoma histotypes. We therefore investigated the role of professional and/or domestic exposures to animals in the occurrence of OAMZL, as compared with other types of lymphoma.

Methods:

A hospital-based case–control study was carried out on 43 consecutive OAMZL patients (cases) and 87 consecutive patients with nodal non-Hodgkin''s lymphomas (NHLs; controls). Multiple logistic regression (MLR) odds ratios (ORs), and 95% confidence intervals (CIs) were used to estimate the association between exposures to animals and OAMZL risk.

Results:

A higher proportion of cases reported a lifetime exposure to household animals (79.1% vs 64.4% among controls), with a non-statistical significant MLR-OR of 2.18 (95% CI: 0.85–5.62). The OAMZL cases more frequently reported a history of occupation in breeding and/or slaughtering than controls (34.9% vs 6.9%), with an overall increased risk of 7.69 (95%CI: 2.65–22.34).

Conclusion:

These results indicate that, compared with nodal NHLs, the risk of OAMZL is markedly increased by contact with animals, particularly by occupational exposures.     

Impact of relative dose intensity (RDI) in CHOP combined with rituximab (R-CHOP) on survival in diffuse large B-cell lymphoma

Background

Recently, maintaining higher relative dose intensity (RDI) of chemotherapeutic drugs has become a widespread practice in an attempt to achieve better outcomes in the treatment of aggressive lymphoma. The addition of rituximab to chemotherapy regimens has significantly improved outcome in diffuse large B-cell lymphoma (DLBL). However, it is unknown if higher RDI in chemotherapy when combined with rituximab leads to a better outcome in aggressive B-cell lymphoma.

Methods

We retrospectively evaluated the impact of the RDI of initial chemotherapy (consisting of cyclophosphamide, doxorubicin, vincristine and prednisolone with rituximab (R-CHOP) on outcome in 100 newly diagnosed DLBL patients.

Results

A multivariate Cox regression model showed that RDI trended towards a significant association with mortality [hazard ratio per 0.1 of RDI = 0.8; 95% confidence interval 0.6–1.0; P = 0.08]. Additionally, on multivariate logistic analysis, advanced age was a significant factor for reduced RDI.

Conclusion

Our data suggest that in DLBL patients, mortality was affected by RDI of R-CHOP as the initial treatment, and the retention of a high RDI could therefore be crucial.     

Alcohol intake and risk of thyroid cancer in the NIH-AARP Diet and Health Study

Background:

Certain studies suggest that alcohol may reduce the risk of thyroid cancer in women, but the effect in men remains unclear.

Methods:

We analysed the association between alcohol and thyroid cancer in a large (n=490 159) prospective NIH-AARP Diet and Health Study with self-reported beer, wine, and liquor intakes.

Results:

Over 7.5 years of follow-up (median), 170 men and 200 women developed thyroid cancer. Overall, the thyroid cancer risk decreased with greater alcohol consumption (⩾2 drinks per day vs none, relative risk=0.57, 95% CI 0.36–0.89, P-trend=0.01).

Conclusions:

These results suggest a potential protective role for alcohol consumption in thyroid cancer.     

TERT promoter mutations in ocular melanoma distinguish between conjunctival and uveal tumours

Background:

Recently, activating mutations in the TERT promoter were identified in cutaneous melanoma. We tested a cohort of ocular melanoma samples for similar mutations.

Methods:

The TERT promoter region was analysed by Sanger sequencing in 47 uveal (ciliary body or choroidal) melanomas and 38 conjunctival melanomas.

Results:

Mutations of the TERT promoter were not identified in uveal melanomas, but were detected in 12 (32%) conjunctival melanomas. Mutations had a UV signature and were identical to those found in cutaneous melanoma.

Conclusion:

Mutations of TERT promoter with UV signatures are frequent in conjunctival melanomas and favour a pathogenetic kinship with cutaneous melanomas. Absence of these mutations in uveal melanomas emphasises their genetic distinction from cutaneous and conjunctival melanomas.     

Breast Cancer Mimic: Cutaneous B-Cell Lymphoma Presenting as an Isolated Breast Mass

Background

Primary cutaneous B-cell lymphoma typically localizes to the skin, and dissemination to internal organs is rare. Lymphomatous involvement of the breasts is also rare. We describe the clinical and radiological findings of an unusual case of primary cutaneous B-cell lymphoma presenting as an isolated breast mass without associated skin changes.

Case Presentation

The patient was a 55-year-old Caucasian female who initially presented with cutaneous B-cell lymphoma around her eyes and forehead with recurrence involving the skin between her breasts. Three years after terminating treatment due to a lack of symptoms, she presented for an annual screening mammogram that found a new mass in her upper inner right breast without imaging signs of cutaneous extension. On physical examination, there were no corresponding skin findings. Due to the suspicious imaging features of the mass that caused concern for primary breast malignancy, she underwent a core biopsy which revealed cutaneous B-cell lymphoma.

Conclusion

When evaluating patients with a systemic disease who present with findings atypical for that process, it is important to still consider the systemic disease as a potential etiology, particularly with lymphoma given its reputation as a great mimicker.Key words: Primary cutaneous B-cell lymphoma, Breast mass, Lymphoma     

Fluorine‐18‐Fluorodeoxyglucose Positron Emission Tomography in Response Assessment Before High‐Dose Chemotherapy for Lymphoma: A Systematic Review and Meta‐Analysis

Background.

We conducted a systematic review and meta-analysis to better define the prognostic ability of fluorine-18-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET) following salvage chemotherapy for relapsed or refractory Hodgkin''s lymphoma (HL) and aggressive non-Hodgkin''s lymphoma.

Methods.

We searched PubMed (from inception to January 31, 2010), bibliographies, and review articles without language restriction. Two assessors independently assessed study characteristics, quality, and results. We performed a meta-analysis to determine prognostic accuracy.

Results.

Twelve studies including 630 patients were eligible. The most commonly evaluated histologies were diffuse large B-cell lymphoma (n = 313) and HL (n = 187), which were typically treated with various salvage and high-dose chemotherapy regimens. Studies typically employed nonstandardized protocols and diagnostic criteria. The prognostic accuracy was heterogeneous across the included studies. ¹⁸F-FDG PET had a summary sensitivity of 0.69 (95% confidence interval [CI], 0.56–0.81) and specificity of 0.81 (95% CI, 0.73–0.87). The summary estimates were stable in sensitivity analyses. In four studies that performed direct comparisons between PET and conventional restaging modalities, PET had a superior accuracy for predicting treatment outcomes. Subgroup and metaregression analyses did not identify any particular factor to explain the observed heterogeneity.

Conclusion.

¹⁸F-FDG PET performed after salvage therapy appears to be an appropriate test to predict treatment failure in patients with refractory or relapsed lymphoma who receive high-dose chemotherapy. Some evidence suggests PET is superior to conventional restaging for this purpose. Given the methodological limitations in the primary studies, prospective studies with standardized methodologies are needed to confirm and refine these promising results.     

Src,a potential target for overcoming trastuzumab resistance in HER2-positive breast carcinoma

Background:

Src is a non-receptor tyrosine kinase involved in signalling and crosstalk between growth-promoting pathways. We aim to investigate the relationship of active Src in response to trastuzumab of HER2-positive breast carcinomas.

Methods:

We selected 278 HER2-positive breast cancer patients with (n=154) and without (n=124) trastuzumab treatment. We performed immunohistochemistry on paraffin-embedded tissue microarrays of active Src and several proteins involved in the PI3K/Akt/mTOR pathway, PIK3CA mutational analysis and in vitro studies (SKBR3 and BT474 cancer cells). The results were correlated with clinicopathological factors and patients'' outcome.

Results:

Increased pSrc-Y416 was demonstrated in trastuzumab-resistant cells and in 37.8% of tumours that correlated positively with tumour size, necrosis, mitosis, metastasis to the central nervous system, p53 overexpression and MAPK activation but inversely with EGFR and p27. Univariate analyses showed an association of increased active Src with shorter survival in patients at early stage with HER2/hormone receptor-negative tumours treated with trastuzumab.

Conclusions:

Src activation participates in trastuzumab mechanisms of resistance and indicates poor prognosis, mainly in HER2/hormone receptor-negative breast cancer. Therefore, blocking this axis may be beneficial in those patients.     

The collagen prolyl hydroxylases are novel transcriptionally silenced genes in lymphoma

Background:

Prolyl hydroxylation is a post-translational modification that affects the structure, stability and function of proteins including collagen by catalysing hydroxylation of proline to hydroxyproline through action of collagen prolyl hydroxylases3 (C-P3H) and 4 (C-P4H). Three C-P3Hs (nomenclature was amended according to approval by the HGNC symbols and names at (http://www.genenames.org) and Entrez database at (http://www.ncbi.nlm.nih.gov/gene) leucineproline-enriched proteoglycan (leprecan) 1 (Lepre1), leprecan-like 1 (Leprel1), leprecan-like 2 (Leprel2) and two paralogs Cartilage-Related Protein (CRTAP) and leprecan-like 4 (Leprel4) are found in humans. The C-P4Hs are tetrameric proteins comprising a variable α subunit, encoded by the P4HA1, P4HA2 and P4HA3 genes and a constant β subunit encoded by P4HB.

Methods:

We used RT–PCR, qPCR, pyrosequencing, methylation-specific PCR, western blotting and immunohistochemistry to investigate expression and regulation of the C-P3H and C-P4H genes in B lymphomas and normal bone marrow.

Results:

C-P3H and C-P4H are downregulated in lymphoma. Down-regulation is associated with methylation in the CpG islands and is detected in almost all common types of B-cell lymphoma, but the CpG islands are unmethylated or methylated at lower levels in DNA isolated from normal bone marrow and lymphoblastoid cell lines. Methylation of multiple C-P3H and C-P4H genes is present in some lymphomas, particularly Burkitt''s lymphoma.

Conclusions:

Methylation of C-P3H and C-P4H is common in B lymphomas and may have utility in differentiating disease subtypes.     

The influence of folate pathway polymorphisms on high-dose methotrexate-related toxicity and survival in children with non-Hodgkin malignant lymphoma

Background

We evaluated the influence of folate pathway polymorphisms on high-dose methotrexate (HD-MTX) related toxicity in paediatric patients with T-cell non-Hodgkin lymphoma (NHL).

Patients and methods

In total, 30 NHL patients were genotyped for selected folate pathway polymorphisms.

Results

Carriers of at least one MTHFR 677T allele had significantly higher MTX area under the time-concentration curve levels at third MTX cycle (P = 0.003). These patients were also at higher odds of leucopoenia (P = 0.006) or thrombocytopenia (P = 0.041) and had higher number of different HD-MTX-related toxicity (P = 0.035) compared to patients with wild-type genotype.

Conclusions

Our results suggest an important role of MTHFR 677C>T polymorphism in the development of HD-MTX-related toxicity in children with NHL.     

The use of herbal medicines by people with cancer: a cross-sectional survey

Background:

A large proportion of cancer patients are estimated to use herbal medicines, but data to substantiate this are lacking. This study aimed to investigate the prevalence of herbal medicine use among cancer patients in the West Midlands, and determine the characteristics predicting herbal medicine use.

Methods:

A cross-sectional survey of oncology patients (n=1498) being followed up at a hospital in Coventry was undertaken. Recipients were asked about herbal medicine use since their cancer diagnosis, and the association between sociodemographic and cancer-related characteristics and herbal medicine use was evaluated.

Results:

A total of 1134 responses were received (75.7%). The prevalence of herbal medicine use was 19.7% (95% CI: 17.4–22.1; n=223). Users were more likely to be affluent, female, and aged under 50 years. Usage increased with time since cancer diagnosis (X² for trend=4.63; P=0.031). A validation data set, derived from a survey of oncology patients in Birmingham (n=541) with differing socioeconomic characteristics showed no significant difference in estimated prevalence (16.6% 95% CI: 11.9–22.2).

Conclusion:

A substantial number of people with cancer are likely to be taking herbal medicines. Understanding the self-medication behaviours of these individuals is essential if health-care professionals are to support treatment adherence and avoid unwanted pharmacological interactions.