A population-based study of transformed marginal zone lymphoma:identifying outcome-related characteristics

Histological transformation of marginal zone lymphoma (tMZL) into diffuse large B-cell lymphoma is associated with poor outcomes. Clinical characteristics associated with transformation risk and outcome after transformation are largely unknown due to scarcity of data. In this population-based study, competing risk analyses were performed to elucidate clinical characteristics associated with developing transformation among 1793 MZL patients using the Netherlands Cancer Registry. Cox regression analyses were performed to elucidate clinical characteristics associated with risk of relapse and mortality after transformation. Transformation occurred in 75 (4%) out of 1793 MZL patients. Elevated LDH and nodal MZL subtype at MZL diagnosis were associated with an increased risk, and radiotherapy with a reduced risk of developing tMZL. Most tMZL patients received R-(mini)CHOP (n = 53, 71%). Age &gt;60 years and (immuno)chemotherapy before transformation were associated with an increased risk of relapse and mortality after transformation. Two-year progression-free survival (PFS) and overall survival (OS) were 66% (95% CI 52-77%) and 75% (95% CI 62-85%) for R-(mini)CHOP-treated tMZL patients, as compared to a PFS and OS both of 41% (95% CI 19-63%) for patients treated otherwise. Our study offers comprehensive insights into characteristics associated with transformation and survival after transformation, thereby optimizing guidelines and patient counseling.</p

Low Mutational Burden of Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue in Patients with Primary Sjogren's Syndrome

SIMPLE SUMMARY: Patients with primary Sjogren’s syndrome (pSS) are at risk of developing extranodal marginal zone lymphoma (ENMZL) of the mucosa-associated lymphoid tissue (MALT) in the parotid glands. The genetic mechanism underlying development of MALT lymphoma in the context of pSS is unknown. The aim of our study was to define the genomic landscape of pSS-associated MALT lymphoma. For 17 localized pSS-associated MALT lymphomas, we analyzed the presence of nonsynonymous mutations, copy number alterations (CNAs) and MALT1 translocations. pSS-associated MALT lymphomas were characterized by a low mutational load (median number of nonsynonymous somatic variants per case was 7, range 2–78) and a limited number of CNAs. Unlike the recurrent genomic aberrations observed in MALT lymphoma, which were not associated with pSS, pSS-associated MALT lacked a clear lymphoma-related profile. The data suggest that localized pSS-associated MALT lymphomas are a distinct type of ENMZL, which are genomically stable and most likely depend on a stimulatory micro-environment. ABSTRACT: Patients with primary Sjogren’s syndrome (pSS) are at risk of developing extranodal marginal zone lymphoma (ENMZL) of the mucosa-associated lymphoid tissue (MALT) in the parotid glands. Unlike recurrent genomic aberrations observed in MALT lymphoma, which were not associated with pSS (non-pSS), it is unknown which somatic aberrations underlie the development of pSS-associated MALT lymphomas. Whole-exome sequencing was performed on 17 pSS-associated MALT lymphomas. In total, 222 nonsynonymous somatic variants affecting 182 genes were identified across the 17 cases. The median number of variants was seven (range 2–78), including three cases with a relatively high mutational load (≥24/case). Out of 16 recurrently mutated genes, ID3, TBL1XR1, PAX5, IGLL5 and APC are known to be associated with lymphomagenesis. A total of 18 copy number alterations were detected in eight cases. MALT1 translocations were not detected. With respect to outcome, only two cases relapsed outside of the salivary glands. Both had a high mutational load, suggesting a more advanced stage of lymphoma. The low mutational load and lack of a clear lymphoma-related mutation profile suggests that localized pSS-associated MALT lymphomas are genomically more stable than non-pSS MALT lymphomas and most likely depend on a stimulatory micro-environment

Quantitative Evaluation of Scintillation Camera Imaging Characteristics of Isotopes Used in Liver Radioembolization

Scintillation camera imaging is used for treatment planning and post-treatment dosimetry in liver radioembolization (RE). In yttrium-90 (90Y) RE, scintigraphic images of technetium-99m (99mTc) are used for treatment planning, while 90Y Bremsstrahlung images are used for post-treatment dosimetry. In holmium-166 (166Ho) RE, scintigraphic images of 166Ho can be used for both treatment planning and post-treatment dosimetry. The aim of this study is to quantitatively evaluate and compare the imaging characteristics of these three isotopes, in order that imaging protocols can be optimized and RE studies with varying isotopes can be compared.Phantom experiments were performed in line with NEMA guidelines to assess the spatial resolution, sensitivity, count rate linearity, and contrast recovery of 99mTc, 90Y and 166Ho. In addition, Monte Carlo simulations were performed to obtain detailed information about the history of detected photons. The results showed that the use of a broad energy window and the high-energy collimator gave optimal combination of sensitivity, spatial resolution, and primary photon fraction for 90Y Bremsstrahlung imaging, although differences with the medium-energy collimator were small. For 166Ho, the high-energy collimator also slightly outperformed the medium-energy collimator. In comparison with 99mTc, the image quality of both 90Y and 166Ho is degraded by a lower spatial resolution, a lower sensitivity, and larger scatter and collimator penetration fractions.The quantitative evaluation of the scintillation camera characteristics presented in this study helps to optimize acquisition parameters and supports future analysis of clinical comparisons between RE studies

Measuring the depth of invasion in vulvar squamous cell carcinoma: interobserver agreement and pitfalls

Aims: The depth of invasion is an important prognostic factor for patients with vulvar squamous cell carcinoma (SCC). The threshold of 1 mm distinguishes between FIGO stages IA and ≥IB disease and guides the need for groin surgery. Therefore, high interobserver agreement is crucial. The conventional and the alternative method are described to measure the depth of invasion. The aims of this study were to assess interobserver agreement for classifying the depth of invasion using both methods and to identify pitfalls. Methods and results: Fifty slides of vulvar SCC with a depth of invasion approximately 1 mm were selected, digitally scanned and independently assessed by 10 pathologists working in a referral or oncology centre and four pathologists in training. The depth of invasion was measured using both the conventional and alternative method in each slide and categorised into ≤1 and >1 mm. The percentage of agreement and Light’s kappa for multi-rater agreement were calculated, and 95% confidence intervals were calculated by bootstrapping (1000 runs). The agreement using the conventional method was moderate (κ = 0.57, 95% confidence interval = 0.45–0.68). The percentage of agreement among the participating pathologists using the conventional method was 85.0% versus 89.4% using the alternative method. Six pitfalls were identified: disagreement concerning which invasive nest is deepest, recognition of invasive growth and where it starts, curved surface, carcinoma situated on the edge of the tis

Low Mutational Burden of Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue in Patients with Primary Sjogren&rsquo;s Syndrome

Patients with primary Sjogren&rsquo;s syndrome (pSS) are at risk of developing extranodal marginal zone lymphoma (ENMZL) of the mucosa-associated lymphoid tissue (MALT) in the parotid glands. Unlike recurrent genomic aberrations observed in MALT lymphoma, which were not associated with pSS (non-pSS), it is unknown which somatic aberrations underlie the development of pSS-associated MALT lymphomas. Whole-exome sequencing was performed on 17 pSS-associated MALT lymphomas. In total, 222 nonsynonymous somatic variants affecting 182 genes were identified across the 17 cases. The median number of variants was seven (range 2&ndash;78), including three cases with a relatively high mutational load (&ge;24/case). Out of 16 recurrently mutated genes, ID3, TBL1XR1, PAX5, IGLL5 and APC are known to be associated with lymphomagenesis. A total of 18 copy number alterations were detected in eight cases. MALT1 translocations were not detected. With respect to outcome, only two cases relapsed outside of the salivary glands. Both had a high mutational load, suggesting a more advanced stage of lymphoma. The low mutational load and lack of a clear lymphoma-related mutation profile suggests that localized pSS-associated MALT lymphomas are genomically more stable than non-pSS MALT lymphomas and most likely depend on a stimulatory micro-environment

Measuring the depth of invasion in vulvar squamous cell carcinoma : interobserver agreement and pitfalls

Aims The depth of invasion is an important prognostic factor for patients with vulvar squamous cell carcinoma (SCC). The threshold of 1 mm distinguishes between FIGO stages IA and >= IB disease and guides the need for groin surgery. Therefore, high interobserver agreement is crucial. The conventional and the alternative method are described to measure the depth of invasion. The aims of this study were to assess interobserver agreement for classifying the depth of invasion using both methods and to identify pitfalls. Methods and results Fifty slides of vulvar SCC with a depth of invasion approximately 1 mm were selected, digitally scanned and independently assessed by 10 pathologists working in a referral or oncology centre and four pathologists in training. The depth of invasion was measured using both the conventional and alternative method in each slide and categorised into 1 mm. The percentage of agreement and Light's kappa for multi-rater agreement were calculated, and 95% confidence intervals were calculated by bootstrapping (1000 runs). The agreement using the conventional method was moderate (kappa = 0.57, 95% confidence interval = 0.45-0.68). The percentage of agreement among the participating pathologists using the conventional method was 85.0% versus 89.4% using the alternative method. Six pitfalls were identified: disagreement concerning which invasive nest is deepest, recognition of invasive growth and where it starts, curved surface, carcinoma situated on the edge of the tissue block, ulceration and different measurement methods. Conclusions Pathologists reached only moderate agreement in determining the depth of invasion in vulvar SCC, without a notable difference between the two measurement methods

Interobserver variability and the effect of education in the histopathological diagnosis of differentiated vulvar intraepithelial neoplasia

<p>No published data concerning intraobserver and interobserver variability in the histopathological diagnosis of differentiated vulvar intraepithelial neoplasia (DVIN) are available, although it is widely accepted to be a subtle and difficult histopathological diagnosis. In this study, the reproducibility of the histopathological diagnosis of DVIN is evaluated. Furthermore, we investigated the possible improvement of the reproducibility after providing guidelines with histological characteristics and tried to identify histological characteristics that are most important in the recognition of DVIN. A total number of 34 hematoxylin and eosin-stained slides were included in this study and were analyzed by six pathologists each with a different level of education. Slides were reviewed before and after studying a guideline with histological characteristics of DVIN. Kappa statistics were used to compare the interobserver variability. Pathologists with a substantial agreement were asked to rank items by usefulness in the recognition of DVIN. The interobserver agreement during the first session varied between 0.08 and 0.54, which slightly increased during the second session toward an agreement between - 0.01 and 0.75. Pathologists specialized in gynecopathology reached a substantial agreement (kappa 0.75). The top five of criteria indicated to be the most useful in the diagnosis of DVIN included: atypical mitosis in the basal layer, basal cellular atypia, dyskeratosis, prominent nucleoli and elongation and anastomosis of rete ridges. In conclusion, the histopathological diagnosis of DVIN is difficult, which is expressed by low interobserver agreement. Only in experienced pathologists with training in gynecopathology, kappa values reached a substantial agreement after providing strict guidelines. Therefore, it should be considered that specimens with an unclear diagnosis and/or clinical suspicion for DVIN should be revised by a pathologist specialized in gynecopathology. When adhering to suggested criteria the diagnosis of DVIN can be made easier.</p>

Prognostic impact of isolated tumor cells in breast cancer axillary nodes: single tumor cell(s) versus tumor cell cluster(s) and microanatomic location.

Item does not contain fulltextIn breast cancer, it has been shown that pN0(i+) and pN1mi have a comparable negative impact on disease-free survival, compared with pN0. However, pN0(i+) is considered to be a heterogeneous group. We determined the effect of metastatic size and microanatomic location within the pN0(i+) group on breast cancer recurrence. We included all Dutch breast cancer patients diagnosed in 1998-2005 with favorable primary tumor characteristics and a final nodal status of pN0(i+). For this analysis, only patients without adjuvant systemic therapy were eligible (n = 513). Presence of single tumor cells versus cell clusters, metastatic size and microanatomic location were recorded. Primary endpoint was disease-free survival. Analyses were adjusted for age at diagnosis, tumor size, tumor grade, axillary treatment and hormone receptor status. The 5-year disease-free survival of patients with single tumor cell(s) (n = 93) was 78.6% and with tumor cell cluster(s) (n = 404) 77.1%. The hazard ratio for disease events was 1.05 (95% CI 0.63-1.76) for cell cluster(s) compared with single cell(s). In a Cox regression model, doubling of metastatic tumor size corresponded to a hazard ratio of 1.21 (95% CI 1.02-1.43). The adjusted hazard ratio was 0.90 (95% CI 0.54-1.50) for parenchymal (n = 112) versus sinusoidal location (n = 395). Single tumor cells bear similar prognostic information as small tumor cell clusters, even though results do suggest that within the pN0(i+) group, increasing size of nodal involvement is associated with reduced survival. Microanatomic location does not seem to have prognostic relevance.1 januari 201