[Show abstract][Hide abstract] ABSTRACT: Purpose:
Advanced-stage mycosis fungoides (MF; stage IIB to IV) and Sézary syndrome (SS) are aggressive lymphomas with a median survival of 1 to 5 years. Clinical management is stage based; however, there is wide range of outcome within stages. Published prognostic studies in MF/SS have been single-center trials. Because of the rarity of MF/SS, only a large collaboration would power a study to identify independent prognostic markers.
Patients and methods:
Literature review identified the following 10 candidate markers: stage, age, sex, cutaneous histologic features of folliculotropism, CD30 positivity, proliferation index, large-cell transformation, WBC/lymphocyte count, serum lactate dehydrogenase, and identical T-cell clone in blood and skin. Data were collected at specialist centers on patients diagnosed with advanced-stage MF/SS from 2007. Each parameter recorded at diagnosis was tested against overall survival (OS).
Staging data on 1,275 patients with advanced MF/SS from 29 international sites were included for survival analysis. The median OS was 63 months, with 2- and 5-year survival rates of 77% and 52%, respectively. The median OS for patients with stage IIB disease was 68 months, but patients diagnosed with stage III disease had slightly improved survival compared with patients with stage IIB, although patients diagnosed with stage IV disease had significantly worse survival (48 months for stage IVA and 33 months for stage IVB). Of the 10 variables tested, four (stage IV, age > 60 years, large-cell transformation, and increased lactate dehydrogenase) were independent prognostic markers for a worse survival. Combining these four factors in a prognostic index model identified the following three risk groups across stages with significantly different 5-year survival rates: low risk (68%), intermediate risk (44%), and high risk (28%).
To our knowledge, this study includes the largest cohort of patients with advanced-stage MF/SS and identifies markers with independent prognostic value, which, used together in a prognostic index, may be useful to stratify advanced-stage patients.
Journal of Clinical Oncology 10/2015; DOI:10.1200/JCO.2015.61.7142 · 18.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Primary cutaneous anaplastic large cell lymphoma (pcALCL) is an indolent T-cell lymphoproliferative disorder managed with low-dose radiation therapy, surgery, and/or mild chemotherapy; patients with extensive limb disease (ELD) have a more aggressive clinical course. We have previously demonstrated that histologically apparent vascular involvement in pcALCL is lymphatic. We hypothesized that histologically occult lymphatic involvement may be associated with particular patterns of disease spread that could involve lymphangitic spread including locoregional spread of disease in the form of ELD and extracutaneous spread of disease. We have therefore set out to quantitate the incidence of occult lymphovascular involvement in pcALCL and to assess for an association between lymphovascular involvement and these patterns of disease. We performed immunohistochemistry for the lymphovascular marker D2-40 on skin biopsies from 29 patients with pcALCL followed in the Stanford Cutaneous Lymphoma Clinic. Immunohistochemically evident dermal lymphovascular involvement was found in nearly half of cases examined (48%; 95% confidence interval, 29%-67%). There was a nonsignificant trend toward a higher prevalence of ELD among patients with pcALCL involving dermal lymphatics (7% vs. 29%; p = 0.12). In this small cohort, there was no indication of a significantly more aggressive disease course in patients with lymphatic involvement either in the form of disease-related mortality (one each in the lymphatic and nonlymphatic groups) or in time to extracutaneous involvement.
The American Journal of dermatopathology 09/2015; 37(10):767-70. DOI:10.1097/DAD.0000000000000377 · 1.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Here we survey variation and dynamics of active regulatory elements genome-wide using longitudinal samples from human individuals. We applied Assay of Transposase Accessible Chromatin with sequencing (ATAC-seq) to map chromatin accessibility in primary CD4+ T cells isolated from standard blood draws of 12 healthy volunteers over time, from cancer patients, and during T cell activation. Over 4,000 predicted regulatory elements (7.2%) showed reproducible variation in accessibility between individuals. Gender was the most significant attributable source of variation. ATAC-seq revealed previously undescribed elements that escape X chromosome inactivation and predicted gender-specific gene regulatory networks across autosomes, which coordinately affect genes with immune function. Noisy regulatory elements with personal variation in accessibility are significantly enriched for autoimmune disease loci. Over one third of regulome variation lacked genetic variation in cis, suggesting contributions from environmental or epigenetic factors. These results refine concepts of human individuality and provide a foundational reference for comparing disease-associated regulomes.
[Show abstract][Hide abstract] ABSTRACT: Cutaneous T-cell lymphoma (CTCL) is a rare heterogeneous group of non-Hodgkin lymphomas that arises in the skin but can progress to systemic disease (lymph nodes, blood, viscera). Historically, in CTCL clinical trials there has been little consistency in how responses were defined in each disease "compartment"-some studies only assessed responses in the skin. The histone deacetylase inhibitor romidepsin is approved by the US FDA for the treatment of CTCL in patients who have received at least 1 prior systemic therapy. Phase II studies that led to approval used rigorous composite end points that incorporated disease assessments in all compartments. The objective of this analysis was to thoroughly examine the activity of romidepsin within each disease compartment in patients with CTCL. Romidepsin was shown to have clinical activity across disease compartments and is suitable for use in patients with CTCL having skin involvement only, erythroderma, lymphadenopathy, and/or blood involvement.
[Show abstract][Hide abstract] ABSTRACT: : Primary cutaneous gamma-delta T-cell lymphoma (PCGD-TCL) is a rare disorder, constituting less than 1% of primary cutaneous lymphomas. Most cases occur in adults and may present as plaques or nodules with ulceration. Here we describe an unusual case of PCGD-TCL in a 3-year-old boy who presented with asymptomatic subcutaneous nodules. To our knowledge, this report represents one of the youngest reported patients with gamma-delta lymphoma/lymphoproliferative disorder. In addition, our patient has an indolent clinical presentation with greater than 1 year clinical follow-up. Because gamma-delta T-cell lymphomas are exceedingly rare in children, we acknowledge that the clinical course/outcome in young patients is still unclear. We hope to add to the recognition that PCGD-TCLs demonstrate a wide clinical spectrum of disease with relatively indolent presentations in some cases.
American Journal of Dermatopathology 07/2014; 37(7). DOI:10.1097/DAD.0000000000000185 · 1.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Intravascular large B-cell lymphomas and EBV NK/T-cell lymphomas commonly follow an aggressive clinical course. We recently reported an entirely intravascular anaplastic large cell lymphoma (ALCL) in the skin with a surprisingly indolent clinical course; interestingly, this lymphoma involved the lymphatic rather than the blood vasculature. We hypothesized that intravascular skin-limited ALCL is distinct from aggressive systemic intravascular lymphomas in its intralymphatic localization and clinical course. We now describe 18 cases of cutaneous intravascular large cell lymphoproliferations from 4 institutions. All 12 intravascular large T-cell lesions were intralymphatic; the majority (9) were CD30 T-cell lymphoproliferative disorders (TLPDs), 5 further classified as intravascular ALK ALCL. One ALK ALCL and 2 benign microscopic intravascular T-cell proliferations were also intralymphatic. A single case of otherwise typical cutaneous follicle center lymphoma contained intralymphatic centroblasts. The clinical and pathologic characteristics of the CD30 TLPDs were similar to those of their extravascular counterparts, including extralymphatic dermal involvement in a subset, DUSP22-IRF4 translocations in half of tested ALK ALCLs, and associated mycosis fungoides in 1; most were skin-limited at baseline and remained so at relapse. All 5 cases of intravascular large B-cell lymphoma involved the blood vasculature and behaved in a clinically aggressive manner; the ALK ALCL, although intralymphatic, was systemic and clinically aggressive. We propose that cutaneous ALK ALCL and related CD30 ALK TLPDs involving the lymphatics are part of an expanding spectrum of CD30 TLPDs. The identification of intralymphatic as distinct from blood vascular localization may provide critical prognostic and therapeutic information.
The American journal of surgical pathology 05/2014; 38(9). DOI:10.1097/PAS.0000000000000217 · 5.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: IMPORTANCE Mycosis fungoides and Sézary syndrome (MF/SS) are rare in children and young adults, and thus the incidence and outcomes in this patient population are not well studied. OBJECTIVE To assess the incidence and outcomes of MF/SS in patients diagnosed before 30 years of age. DESIGN, SETTING, AND PARTICIPANTS Retrospective study of 2 population-based cancer registries-the California Cancer Registry (n = 204) and 9 US cancer registries of the Surveillance, Epidemiology, and End Results program (SEER 9; n = 195)-for patients diagnosed with MF/SS before 30 years of age. MAIN OUTCOMES AND MEASURES Overall survival was calculated by the Kaplan-Meier method. The risk of a second cancer was assessed by calculating the standard incidence ratio (SIR) comparing observed cancer incidence in patients with MF/SS with the expected incidence in the age-, sex-, and race-standardized general population. RESULTS The incidence of MF/SS is rare before 30 years of age, with an incidence rate of 0.05 per 100 000 persons per year before age 20 years and 0.12 per 100 000 persons per year between ages 20 and 29 years in the California Cancer Registry. At 10 years, patients with MF/SS had an overall survival of 94.3% (95% CI, 89.6%-97.2%) in the California Cancer Registry and 88.9% (95% CI, 82.4%-93.2%) in SEER 9. In SEER 9, there was a significant excess risk of all types of second cancers combined (SIR, 3.40; 95% CI, 1.55-6.45), particularly lymphoma (SIR, 12.86; 95% CI, 2.65-37.59) and melanoma (SIR, 9.31; 95% CI, 8.75-33.62). In the California Cancer Registry, the SIR for risk of all types of second cancers was similar to that in SEER 9 (SIR, 3.45; 95% CI, 0.94-8.83), although not statistically significant. CONCLUSIONS AND RELEVANCE Young patients with MF/SS have a favorable outcome, despite a strong suggestion of an increased risk of second primary cancers. Prolonged follow-up is warranted to definitively assess their risk of developing second cancers in a lifetime.
[Show abstract][Hide abstract] ABSTRACT: A phase II multicenter trial was performed to evaluate single-agent lenalidomide in advanced, refractory mycosis fungoides/Sézary syndrome. Thirty-two patients were enrolled with a median of six prior treatment regimens, including a median of four systemic therapies. Patients achieved an overall response rate of 28% (9 patients); all partial responses. Median overall survival was 43 months, median progression-free survival was 8 months, and median duration of response was 10 months. No grade 4 toxicities occurred. Grade 3 adverse events included fatigue (22%), infection (9%), and leukopenia (3%). Patients were frequently unable to tolerate the 25mg starting dose of lenalidomide used in other hematologic malignancies due to fatigue, pain and transient flare reaction (TFR) as a contributory factor. TFR appeared to correlate with clinical response, but the small sample size limited definitive conclusions, and the underlying mechanisms of this reaction are not known. Data from correlative studies on peripheral blood samples suggest that the effects of lenalidomide could be associated with decreased circulating CD25+ T-cells and CD4+ T-cell numbers. Skin lesions showed a trend for increased CD8, CD25 and FoxP3 expression with decreased CD4:CD8 ratio. In conclusion, lenalidomide monotherapy demonstrated activity in refractory CTCL, along with acceptable toxicity. This study is registered at ClinicalTrials.gov, identifier NCT00466921.
[Show abstract][Hide abstract] ABSTRACT: Mycosis fungoides (MF) and the leukemic presentation Sézary syndrome (SS) are clonal T cell lymphomas arising from the skin and are considered noncurable with standard therapies. To develop a specific and sensitive monitoring tool, we tested the ability of high-throughput sequencing (HTS) of T cell receptors (TCRB) to monitor minimal residual disease (MRD) after allogeneic hematopoietic cell transplantation. Genomic DNA was extracted from peripheral blood mononuclear cells (PBMCs) or skin samples. The rearranged TCRβ loci were amplified using Vβ- and Jβ-specific primers, followed by HTS, to generate up to 1,000,000 reads spanning the CDR3 region of individual cells. Malignant clones were identified in diagnostic samples in all cases by a dominant CDR3 sequence. Before transplant, four patients had circulating Sézary cells by the routine flow cytometry, which was confirmed by TCRB HTS. Although the flow cytometry found no detectable Sézary cells, malignant clones were detected by TCRB HTS in all other six cases. Five patients achieved "molecular remission" in blood between +30 and +540 days after transplant. Four of these patients also achieved molecular clearance in skin after transplant. Experiments using blood samples spiked with purified Sézary cells demonstrated that TCRB HTS can detect Sézary cells at the level of 1 in 50,000 PBMCs, which is more sensitive than standard diagnostics. We have thus demonstrated the utility of TCRB HTS to assess MRD with increased sensitivity and specificity compared to other current methodologies, and to monitor response to therapy in this MF/SS patient population.
Science translational medicine 12/2013; 5(214):214ra171. DOI:10.1126/scitranslmed.3007420 · 15.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Intravascular large T-cell or NK-cell lymphomas rarely present with cutaneous involvement. Intravascular cytotoxic T or NK lymphomas presenting in the skin (cIT/NKL) are often EBV, and reported cases follow a highly aggressive clinical course. Intravascular anaplastic large cell lymphoma (ALCL) by contrast is extraordinarily rare and, when it presents in the skin, raises the question of aggressive clinical behavior in the manner of cIT/NKL versus indolent clinical behavior in the manner of primary cutaneous ALCL. Here we describe a case of localized cutaneous intravascular anaplastic lymphoma kinase-negative ALCL (cIALCL) with a very indolent clinical course. The patient experienced a single cutaneous relapse and remains alive without disease 4 years after diagnosis. Review of the literature reveals multiple clinicopathologic differences between cIALCL and cIT/NKL: distribution (cIALCL, single skin region, P=0.021, Fisher exact test); histology (cIALCL, cohesive with necrosis, P=0.005); immunophenotype (cIALCL, strongly CD30, P=0.021; cIT/NKL, CD56 and/or EBV, P=0.003); and indolent clinical behavior with a trend toward better overall survival (P=0.067, Kaplan-Meier survival analysis). Our index case of cIALCL and 1 other tested case were immunohistochemically confirmed to be intralymphatic (contained within D2-40+vessels) as compared with the blood vessel localization of cIT/NKL. Recognition of cIALCLs as a distinct clinicopathologic entity, and in particular their distinction from aggressive, usually EBV cIT/NKLs, may be possible on the basis of a combination of clinicopathologic criteria, allowing for localized therapy in a subset of patients.
The American journal of surgical pathology 04/2013; 37(4):617-623. DOI:10.1097/PAS.0b013e318280aa9c · 5.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: These NCCN Guidelines Insights summarize several key updates to the 2012 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Hodgkin's Lymphomas (NHL) and describe the clinical evidence supporting the updates. The featured updates include changes to the recommendations for treatment options in patients with chronic lymphocytic leukemia (including in elderly or frail patients and patients with poor-risk cytogenetics), guidance surrounding surveillance imaging for follow-up of patients with NHL, and the addition of first-line consolidation options for patients with mantle cell lymphoma.
Journal of the National Comprehensive Cancer Network: JNCCN 12/2012; 10(12):1487-1498. · 4.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We reviewed our multicenter experience with gamma-delta (γδ) T-cell lymphomas first presenting in the skin. Fifty-three subjects with a median age of 61 years (range, 25 to 91 y) were diagnosed with this disorder. The median duration of the skin lesions at presentation was 1.25 years (range, 1 mo to 20 y). The most common presentation was deep plaques (38 cases) often resembling a panniculitis, followed by patches resembling psoriasis or mycosis fungoides (10 cases). These lesions tended to ulcerate overtime (27 cases). Single lesions or localized areas of involvement resembling cellulitis or pyoderma were reported in 8 cases. The most common anatomic site of involvement was the legs (40 cases), followed by the torso (30 cases) and arms (28 cases). Constitutional symptoms were reported in 54% (25/46) of the patients, including some with limited skin involvement. Significant comorbidities included autoimmunity (12 cases), other lymphoproliferative disorders (5 cases), internal carcinomas (4 cases), and viral hepatitis (2 cases). Lymphadenopathy (3/42 cases) and bone marrow involvement (5/28 cases) were uncommon, but serum lactose dehydrogenase (LDH) was elevated in 55% (22/39) of the patients. Abnormal positron emission tomography and/or computed tomography scans in 20/37 subjects mostly highlighted soft tissue or lymph nodes. Disease progression was associated with extensive ulcerated lesions resulting in 27 deaths including complications of hemophagocytic syndrome (4) and cerebral nervous system involvement (3). Median survival time from diagnosis was 31 months. Skin biopsies varied from a pagetoid pattern to purely dermal or panniculitic infiltrates composed of intermediate-sized lymphocytes with tissue evidence of cytotoxicity. The most common immunophenotype was CD3/CD4/CD5/CD8/BF1/γ-M1/TIA-1/granzyme-B/CD45RA/CD7, and 4 cases were Epstein-Barr virus positive. This is the largest study to date of cutaneous γδ T-cell lymphomas and demonstrates a variety of clinical and pathologic presentations with a predictable poor outcome.
The American journal of surgical pathology 11/2012; 36(11):1656-1665. DOI:10.1097/PAS.0b013e31826a5038 · 5.15 Impact Factor