B-cell receptor reactivity against Rothia mucilaginosa in nodular lymphocyte-predominant Hodgkin lymphoma.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a Hodgkin lymphoma expressing functional B-cell receptors (BCR). Recently, we described a dual stimulation model of IgD+ lymphocyte-predominant cells by Moraxella catarrhalis antigen RpoC and its superantigen MID/hag, associated with extralong CDR3 and HLA-DRB1*04 or HLADRB1* 07 haplotype. The aim of the present study was to extend the antigen screening to further bacteria and viruses. The fragment antibody-binding (Fab) regions of seven new and 15 previously reported cases were analyzed. The reactivity of non-Moraxella spp.-reactive Fab regions against lysates of Rothia mucilaginosa was observed in 5/22 (22.7%) cases. Galactofuranosyl transferase (Gltf) and 2,3-butanediol dehydrogenase (Bdh) of R. mucilaginosa were identified by comparative silver- and immuno-staining in two-dimensional gels, with subsequent mass spectrometry and validation by western blots and enzyme-linked immunosorbent assay. Both R. mucilaginosa Gltf and Bdh induced BCR pathway activation and proliferation in vitro. Apoptosis was induced by recombinant Gltf/ETA'-immunotoxin conjugates in DEV cells expressing recombinant R. mucilaginosa-reactive BCR. Reactivity against M. catarrhalis RpoC was confirmed in 3/7 newly expressed BCR (total 10/22 reactive to Moraxella spp.), resulting in 15/22 (68.2%) cases with BCR reactivity against defined bacterial antigens. These findings strengthen the hypothesis of bacterial trigger contributing to subsets of NLPHL.

Long-term (10-year) outcomes and prognostic factors in resected intraductal papillary mucinous neoplasm tumors in Finland: A nationwide retrospective study.

BACKGROUND: The degree of dysplasia is the most important prognostic factor for patients with resected intraductal papillary mucinous neoplasms. Intraductal papillary mucinous neoplasms are predominantly premalignant conditions; in most cases, surveillance is an adequate treatment. If worrisome features are present, surgery should be considered. However, there is limited data on the long-term prognosis of resected intraductal papillary mucinous neoplasms. We aimed to ascertain the nationwide survival of patients with resected intraductal papillary mucinous neoplasms and identify factors associated with survival. METHODS: This is a retrospective nationwide cohort study. All intraductal papillary mucinous neoplasms operated on in Finland between 2000 and 2008 were identified. Patient records were evaluated, and original radiologic data and histologic samples were re-evaluated. Survival data were collected after a 10-year follow-up period. RESULTS: Out of 2,024 pancreatic resections, 88 were performed for intraductal papillary mucinous neoplasm. The median age of the patients was 65 years. Histologic diagnoses were main duct intraductal papillary mucinous neoplasm 47/88 (53,4%), mixed-type intraductal papillary mucinous neoplasm 27/88 (30.7%), and branchduct intraductal papillary mucinous neoplasm 14/88 (15.9%). Of the tumors, 40/88 (45.5%) were low-grade dysplasia, 9/88 (10.2%) high-grade, and 39/88 (44.3%) were invasive cancer. The median survival was 121 (range 0-252) months. Ten-year survival was 72.5%, 66.7%, and 23.1% in the low-grade dysplasia, high-grade dysplasia, invasive cancer groups, respectively. Ten-year mortality for pancreatic cancer was 5%, 9.1%, and 71.8% in the low-grade dysplasia, high-grade dysplasia, invasive cancer groups, respectively. CONCLUSION: Overall, 44.3% of the patients had a malignant tumor, and three-quarters (74.5%) of the main duct intraductal papillary mucinous neoplasms were malignant or high-grade dysplasia at the time of surgery. Ten-year survival was significantly better in patients operated on at the stage of a premalignant tumor (low-grade dysplasia + high-grade dysplasia) than in patients operated on at the stage of a malignant tumor.

Differential diagnosis and long-term outcomes of non-atrophic duodenal changes in children.

Objectives and study: Gastrointestinal endoscopy is often performed when investigating abdominal complaints in children. While atrophic changes of the duodenal mucosa are usually caused by celiac disease, the prevalence and clinical significance of non-atrophic duodenal changes are less clear. We studied these issues in a large pediatric endoscopic cohort. Methods: Comprehensive data on clinical features, diagnostic findings and long-term outcomes of children who had undergone upper gastrointestinal endoscopy with systematic duodenal sampling were collected. Study variables were compared between children with non-atrophic changes and normal histology, and between those with non-atrophic changes who did and did not receive a diagnosis. Results: The study comprised 1,170 consecutive children, of whom 51 (4.4%) had non-atrophic and 315 (26.9%) atrophic duodenal changes and 804 (68.7%) normal histology. The most common non-atrophic findings were non-specific inflammation (n = 19) and intraepithelial lymphocytosis (n = 14). Patients with non-atrophic changes presented more often with blood in stools (23.5 vs. 11.3%; p = 0.009), anemia (43.2 vs. 36.5%; p = 0.028) and positive celiac serology (34.3 vs. 12.9%; p < 0.001) than those with a normal duodenum. Twenty-four (44%) of those with non-atrophic changes received an initial diagnosis, the most common of which were inflammatory bowel disease (IBD) (n = 8), Helicobacter pylori infection (n = 3) and food allergy (n = 3). The prevalence of the diagnoses did not differ from those with a normal duodenum. Those who received a diagnosis had more often blood in stools (37.5 vs. 11.1%; p = 0.027), anemia (70.6 vs. 20.0%; p = 0.002) and negative celiac serology (50.0 vs. 7.7%; p = 0.013) than those without diagnosis. During a follow-up of 6.1-13.3 years, five of the 12 initially undiagnosed seropositive patients developed celiac disease, and one patient also developed ulcerative colitis. Conclusion: Non-atrophic duodenal changes are relatively common and associated with anemia, blood in stools, and positive celiac disease serology. Excluding potential celiac disease, those without an initial diagnosis have a favorable long-term prognosis.

Incidence and clinicopathological features of Follicular T-cell lymphoma in Finland: a population-based immunohistochemical study.

Follicular T-cell lymphoma (FTCL) is a rare subtype of mature T-cell lymphoma. It was recently recognized as a separate lymphoma entity in the 2017 revised fourth edition of the World Health Organization classification. The main goals of the present study were to gain better knowledge of the incidence and histopathological and clinical features of FTCL in Finland. In this study, we reviewed all angioimmunoblastic T-cell (AITL) and peripheral T-cell lymphomas, not otherwise specified, from the patient records in three hospital districts in Finland over a 10-year period, to identify FTCL cases and estimate its incidence. Five patients rediagnosed with FTCL and 34 with AITL were analyzed. Hodgkin/Reed-Sternberg (HRS)-like cells were observed in 24 of the 34 AITL cases and four of the five FTCL cases. We found that the main features that differentiated FTCL from AITL were rosetting of T-cells around HRS-like cells, the absence of clear cells, follicular dendritic cell meshwork and T-cell monoclonality. Our estimated incidence of FTCL is 0.20 per 100,000 people in Finland.

Evolutionary clonal trajectories in nodular lymphocyte-predominant Hodgkin lymphoma with high risk of transformation.

The B-cell architecture of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is complex since it is composed of malignant lymphocyte-predominant cells along with a rich B-cell bystander environment. To gain insight into molecular determinants of disease transformation, we studied B-cell evolutionary trajectories in lymphoma tissue from diagnosis to relapse or transformation to non- Hodgkin lymphoma by next-generation sequencing of immunoglobulin heavy chains. Patients with NLPHL that later transformed were older and showed IgD negativity, absence of the characteristic IGHV3/IGHD3/IGHJ6 lymphocyte-predominant rearrangement and high repertoire clonality. We constructed phylogenetic trees within the compartment of the malignant clone to investigate clonal evolution. In all relapsing cases, the lymphocyte-predominant rearrangement was identical at diagnosis and relapse. NLPHL cases with transformation showed more complex trajectories with strong intraclonal diversification. The dominant founder clone in transformations showed clonal evolution if derived from the same cell of origin, or arose from a different cell of origin. Together, our data point to a significant role of antigenic drive in the transformation of NLHPL and identify high B-cell repertoire clonality with dominant intraclonal lymphocyte-predominant cell diversification as a hallmark of transformation. Sequencing of initial paraffin-embedded tissue may therefore be applied diagnostically to identify NLPHL cases with high risk of transformation.

Lymphocyte predominant cells detect Moraxella catarrhalis-derived antigens in nodular lymphocyte-predominant Hodgkin lymphoma.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma of B-cell origin with frequent expression of functional B-cell receptors (BCRs). Here we report that expression cloning followed by antigen screening identifies DNA-directed RNA polymerase beta' (RpoC) from Moraxella catarrhalis as frequent antigen of BCRs of IgD+ LP cells. Patients show predominance of HLA-DRB1*04/07 and the IgVH genes encode extraordinarily long CDR3s. High-titer, light-chain-restricted anti-RpoC IgG1/κ-type serum-antibodies are additionally found in these patients. RpoC and MID/hag, a superantigen co-expressed by Moraxella catarrhalis that is known to activate IgD+ B cells by binding to the Fc domain of IgD, have additive activation effects on the BCR, the NF-κB pathway and the proliferation of IgD+ DEV cells expressing RpoC-specific BCRs. This suggests an additive antigenic and superantigenic stimulation of B cells with RpoC-specific IgD+ BCRs under conditions of a permissive MHC-II haplotype as a model of NLPHL lymphomagenesis, implying future treatment strategies.

Prevalence and diagnostic outcomes of children with duodenal lesions and negative celiac serology.

BACKGROUND: Celiac disease diagnostics begin by measuring autoantibodies, which may fail to identify seronegative patients. Duodenal lesion in the absence of antibodies is scarcely studied, especially in children. AIMS: To investigate the prevalence and diagnostic outcomes of children with seronegative duodenal lesion in two countries with different disease profiles. METHODS: Medical data, including the results of histology and transglutaminase (tTGab) and endomysium (EmA) antibody measurements were collected from 1172 Finnish and 264 Romanian children with systematic duodenal sampling. Database of 509 Finnish children with celiac disease was examined to identify earlier seronegative patients. RESULTS: Celiac disease was diagnosed in 307 Finnish and 83 Romanian children in the endoscopy cohorts. No seronegative patients were found among 899 celiac disease patients, although some were only tTGab or EmA positive. Non-celiac duodenal lesion was detected in eight Finnish and 32 Romanian children, their most common diagnoses being inflammatory bowel disease and infections, respectively. Six children with morphological lesion received no diagnosis. None of them developed celiac disease during a follow-up of 3-11 years. CONCLUSION: Pediatric seronegative celiac disease is exceptional in the era of modern autoantibodies. Other reasons for duodenal lesion should therefore be sought, bearing in mind possible differences across countries.

Characteristics and long-term survival of resected pancreatic cystic neoplasms in Finland. The first nationwide retrospective cohort analysis.

BACKGROUND: Pancreatic cystic neoplasms (PCN) are being found increasingly in imaging studies. Even though the characteristics of PCN lesions have been studied extensively in single and multicentre settings, nationwide data is lacking. The aim of this study was to determine the nationwide epidemiologic characteristics and long-term survival of all resected PCNs. METHODS: For this retrospective cohort analysis, all PCNs operated on in Finland during the period 2000-2008 were identified. Data was collected from all patients: on demographics, comorbidities, symptoms, radiological findings, surgical procedures, complications, histopathological diagnoses and survival. Incomplete pathology reports and any uncertain diagnoses were re-assessed. Survival data was collected after a five-year follow-up period. RESULTS: The final database included 225 patients with operated PCN. After reviewing the incomplete pathology reports, in 44 cases the original diagnosis was changed, mostly from MCN to IPMN. The most common histopathological diagnoses were IPMN (94/225; 50/225 MD-IPMN, 30/225 MX-IPMN and 14/225 BD-IPMN), SCN (41/225) and MCN (40/225). Overall, 53/225 (23.6%) of the tumours were malignant. Malignancy was detected in MD-IPMN 29/50 (58%), MX-IPMN 10/30 (33.3%), MCN 12/40 (30%), BD-IPMN 2/14 (14.3%) patients. Median 5-year survival for all patients was 77%: 87% in patients without malignancy, 77% with HGD and 27% in patients with a malignant resected PCN. CONCLUSION: One fourth of the PCNs operated on nationwide were malignant, with a five-year survival of 27%, compared to overall survival of 87% in patients with non-malignant disease and 77% in those with HGD. Detecting - and operating on - a PCN before the malignant transfer remains a great challenge.

JUNB, DUSP2, SGK1, SOCS1 and CREBBP are frequently mutated in T-cell/histiocyte-rich large B-cell lymphoma.

T-cell/histiocyte-rich large B-cell lymphoma is a rare aggressive lymphoma showing histopathological overlap with nodular lymphocyte-predominant Hodgkin lymphoma. Despite differences in tumor microenvironment and clinical behavior, the tumor cells of both entities show remarkable similarities, suggesting that both lymphomas might represent a spectrum of the same disease. To address this issue, we investigated whether these entities share mutations. Ultra-deep targeted resequencing of six typical and 11 histopathological variants of nodular lymphocyte-predominant Hodgkin lymphoma, and nine cases of T-cell/histiocyte-rich large B-cell lymphoma revealed that genes recurrently mutated in nodular lymphocyte-predominant Hodgkin lymphoma are affected by mutations at similar frequencies in T-cell/histiocyte-rich large B-cell lymphoma. The most recurrently mutated genes were JUNB, DUSP2, SGK1, SOCS1 and CREBBP, which harbored mutations more frequently in T-cell/histiocyte-rich large B-cell lymphoma and the histopathological variants of nodular lymphocyte-predominant Hodgkin lymphoma than in its typical form. Mutations in JUNB, DUSP2, SGK1 and SOCS1 were highly enriched for somatic hypermutation hotspot sites, suggesting an important role of aberrant somatic hypermutation in the generation of these somatic mutations and thus in the pathogenesis of both lymphoma entities. Mutations in JUNB are generally rarely observed in malignant lymphomas and thus are relatively specific for nodular lymphocyte-predominant Hodgkin lymphoma and T-cell/histiocyte-rich large B-cell lymphoma at such high frequencies (5/17 and 5/9 cases with JUNB mutations, respectively). Taken together, the findings of the present study further support a close relationship between T-cell/histiocyte-rich large B-cell lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma by showing that they share highly recurrent genetic lesions.

Characteristics and Outcomes of 79 Patients with an Insulinoma: A Nationwide Retrospective Study in Finland.

OBJECTIVE: Insulinomas are rare pancreatic tumours. Population-based data on their incidence, clinical picture, diagnosis, and treatment are almost nonexistent. The aim of this study was to clarify these aspects in a nationwide cohort of insulinoma patients diagnosed during three decades. DESIGN AND METHODS: Retrospective analysis on all adult patients diagnosed with insulinoma in Finland during 1980-2010. RESULTS: Seventy-nine patients were diagnosed with insulinoma over the research period. The median follow-up from diagnosis to last control visit was one (min 0, max 31) year. The incidence increased from 0.5/million/year in the 1980s to 0.9/million/year in the 2000s (p = 0.002). The median diagnostic delay was 13 months and did not change over the study period. The mean age at diagnosis was 52 (SD 16) years. The overall imaging sensitivity improved from 39% in the 1980s to 98% in the 2000s (p < 0.001). Seventy-one (90%) of the patients underwent surgery with a curative aim, two (3%) had palliative surgery, and 6 (8%) were inoperable. There were no significant differences in the types of surgical procedures between the 1980s, 1990s, and 2000s; tumour enucleations comprised 43% of the operations, distal pancreatic resections 45%, and pancreaticoduodenectomies 12%, over the whole study period. Of the patients who underwent surgery with a curative aim, 89% had a full recovery. Postoperative complications occurred in half of the patients, but postoperative mortality was rare. CONCLUSIONS: The incidence of insulinomas has increased during the past three decades. Despite the improved diagnostic options, diagnostic delay has remained unchanged. To shorten the delay, clinicians should be informed and alert to consider the possibility of hypoglycemia and insulinoma, when symptomatic attacks are investigated in different sectors of the healthcare system. Developing the surgical treatment is another major target, in order to lower the overall complication rate, without compromising the high cure rate of insulinomas.

Patients with resected, histologically re-confirmed pancreatic ductal adenocarcinoma (PDAC) can achieve long-term survival despite T3 tumour or nodal involvement. The Finnish Register Study 2000-2013.

BACKGROUND: Long-term survival of patients with operated pancreatic ductal adenocarcinoma (PDAC) has been associated with resection status, disease stage and centralisation. However, no previous reports are available about long-term survivors of PDAC with confirmed histology covering an entire nation. Our aim was to analyze retrospectively confirmed long-term survivors of PDAC operated on in Finland 2000-2008. METHOD: PDAC patients operated between 2000 and 2008 were selected from Finnish patient registers and archives. Histological slides of patients with over four-year survival were re-evaluated by an expert pancreatic pathologist. From the confirmed PDAC patients, demographic, oncologic and operative parameters were recorded. The cut-point of survival was 31.12.2013. RESULTS: Out of the 598 patients operated on and originally diagnosed with PDAC, 52 of the long-term survivors (LTS) were confirmed as having had true PDAC. The four-year survival rate in high volume centres (HVC) was 13.0% and 6.7% elsewhere (p = 0.017). Five-year survival rate was 7.2%. After multivariate analysis only the size of the tumour persisted as prognostic factor for over four-year survival. Among LTSs, 50% of patients had stage IIB tumour and 40% had a R1 resection without difference with patients with shorter survival. The use of adjuvant therapy did not differ between the groups. CONCLUSION: This is the largest single-nationwide cohort of long-term survivors with confirmed PDAC. Comprehensive pathological evaluation is mandatory for an adequate PDAC diagnosis and true survival analysis. Long-term survival can be achieved even in T3 patients with nodal involvement and may be explained by favorable tumour biology.

A strong host response and lack of MYC expression are characteristic for diffuse large B cell lymphoma transformed from nodular lymphocyte predominant Hodgkin lymphoma.

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is an indolent lymphoma, but can transform into diffuse large B cell lymphoma (DLBCL), showing a more aggressive clinical behavior. Little is known about these cases on the molecular level. Therefore, the aim of the present study was to characterize DLBCL transformed from NLPHL (LP-DLBCL) by gene expression profiling (GEP). GEP revealed an inflammatory signature pinpointing to a specific host response. In a coculture model resembling this host response, DEV tumor cells showed an impaired growth behavior. Mechanisms involved in the reduced tumor cell proliferation included a downregulation of MYC and its target genes. Lack of MYC expression was also confirmed in 12/16 LP-DLBCL by immunohistochemistry. Furthermore, CD274/PD-L1 was upregulated in DEV tumor cells after coculture with T cells or monocytes and its expression was validated in 12/19 cases of LP-DLBCL. Thereby, our data provide new insights into the pathogenesis of LP-DLBCL and an explanation for the relatively low tumor cell content. Moreover, the findings suggest that treatment of these patients with immune checkpoint inhibitors may enhance an already ongoing host response in these patients.

A Prospective Study on the Usefulness of Duodenal Bulb Biopsies in Celiac Disease Diagnosis in Children: Urging Caution.

OBJECTIVES: Several recent celiac disease guidelines recommend the acquisition of duodenal bulb biopsies for diagnostics. This is in conflict with previously reported evidence and routine practice from the 1960s onward. We reopened the issue in a prospective multicenter study and used morphometric variables in evaluating the usefulness of bulb biopsies in children. We further sought to establish whether deposits of IgA targeting bulb transglutaminase 2 (TG2) could be of diagnostic help. METHODS: Diagnoses of celiac disease were based on clinic and distal duodenal histopathology statements. Centralized reading of villous height (VH) to crypt depth (CrD) ratios and IgA deposits was performed on anatomical duodenal bulb specimens. All children participating also underwent routine investigations for other diseases. RESULTS: Twenty-two children had celiac disease, and another 22 served as non-celiac disease controls. The quality of the anatomical bulb specimens was unsatisfactory for reliable morphometric measurements in 20 out of 44 (45%) patients even after recuttings. All celiac disease patients had VH:CrD<2.0 (mean 0.2) but also 10 out of 13 (77%) non-celiac control patients had an injured bulb mucosal lining (mean 1.3) even up to false-positive "flat lesion". Bulb IgA deposits were able to separate celiac disease from disease controls. CONCLUSIONS: Morphological injury is common in the anatomical bulb even without celiac disease, increasing the risk of false-positive diagnoses. Premature conclusions might have been drawn on current care guidelines as to celiac disease diagnosis based solely on anatomical bulb specimens. Bulb mucosal IgA targeting TG2 in poor quality biopsy specimens is a powerful clinical tool in finding celiac disease patients.

Dermatitis Herpetiformis Refractory to Gluten-free Dietary Treatment.

Dermatitis herpetiformis (DH) is a blistering skin disease, which is regarded as an extra-intestinal manifestation of coeliac disease. Refractory cases of coeliac disease, that do not respond to a gluten-free diet and which carry an increased risk of lymphoma, are well-known in coeliac disease. To determine whether refractory cases of DH with active rash and persistent small bowel atrophy occur we analysed our series of 403 patients with DH. Seven (1.7%) patients, who had been on a gluten-free diet for a mean of 16 years, but who still required dapsone to treat the symptoms of DH, were identified. Of these, one patient died from mucinous adenocarcinoma before re-examination. At re-examination skin immunoglobulin A (IgA) deposits were found in 5/6 refractory and 3/16 control DH patients with good dietary response. Small bowel mucosa was studied at re-examination from 5 refractory and 8 control DH patients and was normal in all 5 refractory and 7/8 control DH patients. One refractory DH patient died from adenocarcinoma, but no lymphoma developed in any of the patients. This study documents for the first time refractory DH, in which the rash is non-responsive to a gluten-free diet, but the small bowel mucosa heals. This differs from refractory coeliac disease, in which the small bowel mucosa does not heal on a gluten-free diet.

[Insulinomas in Tampere University Hospital Special Responsibility Area in 1980-2010]. / Insulinoomat Tampereen yliopistollisen sairaalan erityisvastuualueella 1980-2010.

BACKGROUND: Insulin-producing neuroendocrine tumours (iNETs) are rare, but their incidence is increasing. We studied the incidence, clinical picture, diagnostics, and treatment of insulinomas diagnosed in 1980 to 2010. METHODS: Retrospective analysis of insulinomas diagnosed in Tampere University Hospital. RESULTS: We found 23 iNET cases corresponding to an incidence of 0.7/million/year. All had neuroglycopenic symptoms and 83% had autonomic ones. The median diagnostic delay (from first symptoms up to diagnosis) was 25 months. Preoperative imaging found the tumor in 87%. Twenty-one out of 22 patients who underwent surgery recovered completely. CONCLUSIONS: Despite improved imaging the diagnostic delay of iNETs remained unchanged. Hypoglycemia and insulinoma should be considered as a cause of unspecific, symptomatic attacks.

Constant pattern of relapse in primary central nervous lymphoma patients treated with high-dose methotrexate combinations. A Finnish retrospective study.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare brain tumour with a dismal prognosis. Several phase II studies with high-dose methotrexate-based regimens have shown promising early results, but in all hospital-based data published so far, the disease outcome is poor. MATERIAL AND METHODS: We performed a hospital-based retrospective analysis to evaluate the long-term results of the Nordic type of Bonn chemotherapy regimen in PCNSL patients. The study included 54 patients with newly diagnosed PCNSL who received chemotherapy with curative intent as their first-line treatment. RESULTS: We found promising response rates, 76% of the patients achieving CR and 22% patients achieving PR, with corresponding two-year EFS 53% and OS 76%. However, with longer follow-up a constant pattern of relapses was observed with only one patient remaining in primary remission after 60 months. DISCUSSION: The finding suggests that basic biological differences exist between PCNSL and systemic diffuse large B-cell lymphoma and there is a need for consolidation or maintenance therapy after achieving a remission in patients with PCNSL.

Diffuse large B cell lymphoma derived from nodular lymphocyte predominant Hodgkin lymphoma presents with variable histopathology.

BACKGROUND: Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) usually presents in middle aged men and shows an indolent clinical behavior. However, up to 30% of the patients present a secondary transformation into aggressive diffuse large B cell lymphoma (DLBCL). The aim of the present study was to characterize morphology and immunophenotype of this kind of DLBCL in detail and compare it with conventional DLBCL. METHODS: Morphology and immunophenotype of 33 cases of NLPHL with simultaneous or sequential transformation into DLBCL were investigated. These cases were compared with 41 de novo DLBCL in Finnish men. RESULTS: The majority of cases exhibited different immunophenotypes in the NLPHL and the DLBCL components. The immunophenotype of the DLBCL secondary to NLPHL was heterogeneous. However, BCL6, EMA, CD75 and J-chain were usually expressed in both components (≥73% positive). Overall, the NLPHL component was more frequently positive for EMA, CD75 and J-chain than the DLBCL component. In contrast, B cell markers, CD10 and BCL2, were more frequently expressed and were expressed at higher levels in the DLBCL component than in the NLPHL component. In the independent series of de novo DLBCL 4 cases could be identified with a growth pattern and immunophenotype that suggested that they had arisen secondarily from NLPHL. CONCLUSIONS: The morphology and immunophenotype of DLBCL arisen from NLPHL is heterogeneous. Further characterization of the particular molecular features of this subgroup is warranted to be able to better identify these cases among conventional DLBCL.

Early interim PET/CT predicts post-treatment response in diffuse large B-cell lymphoma.

BACKGROUND: (18)F-FDG-PET/CT has been widely used in the staging of malignant lymphomas, and accepted as a tool for response assessment. Among PET parameters, the most frequently studied is maximal standardized uptake value (SUVmax). Metabolic tumor burden (MTB) is a parameter in which both metabolic tumor volume (MTV) and tumor activity are integrated. Here, we analyzed the prognostic value of SUVmax, SUVsum (sum of the SUVmax), whole-body MTV (MTVwb) and MTBwb from baseline and interim PET/CT in patients with diffuse large B-cell lymphoma (DLBCL). MATERIAL AND METHODS: Twenty-nine patients with histologically proven DLBCL were imaged by PET/CT before treatment (Exam I), and one week after the first dose of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) therapy (Exam II). Biopsy specimens were examined by an expert hematopathologist, the Ki-67 proliferation index (PI) was estimated for each biopsy site from the MIB-1 stained sections. The response evaluation was performed after chemotherapy completion (6-8 cycles). RESULTS: All patients had one or more visualized lymphomatous lesions on (18)F-FDG-PET/CT. The SUVmax of the whole-body (BmSUVmax) was higher than the SUVmax at biopsy site (BxSUVmax) (mean: 20.1 vs. 17.3, p < 0.01). The PI correlated with the BxSUVmax (p < 0.05). One week after chemotherapy, SUVmax, SUVsum, MTVwb, and MTBwb decreased significantly (p < 0.01, respectively), SUVsum, MTVwb and MTBwb at Exam II correlated with chemotherapy response at treatment completion (p < 0.05, respectively). CONCLUSION: SUVmax is more accurate to detect tumor aggressiveness than biopsy in DLBCL, since BmSUVmax represents the most aggressive tumor of the patient. Interim PET/CT as early as one week after R-CHOP therapy predicts response. Thus, it could be used as a tool for guidance of risk stratification in DLBCL.

Cat scratch disease caused by Bartonella grahamii in an immunocompromised patient.

Bartonella grahamii colonizes rodents worldwide and has been detected in questing Ixodes ricinus ticks. Here, the first human B. grahamii infection confirmed by multilocus sequence typing is reported. The route of transmission and clinical picture of the patient are similar to those seen in patients with cat scratch disease, which is typically diagnosed as a Bartonella henselae infection.