Multifactorial White Matter Damage in the Acute Phase and Pre-Existing Conditions May Drive Cognitive Dysfunction after SARS-CoV-2 Infection: Neuropathology-Based Evidence.

BACKGROUND: There is an urgent need to better understand the mechanisms underlying acute and long-term neurological symptoms after COVID-19. Neuropathological studies can contribute to a better understanding of some of these mechanisms. METHODS: We conducted a detailed postmortem neuropathological analysis of 32 patients who died due to COVID-19 during 2020 and 2021 in Austria. RESULTS: All cases showed diffuse white matter damage with a diffuse microglial activation of a variable severity, including one case of hemorrhagic leukoencephalopathy. Some cases revealed mild inflammatory changes, including olfactory neuritis (25%), nodular brainstem encephalitis (31%), and cranial nerve neuritis (6%), which were similar to those observed in non-COVID-19 severely ill patients. One previously immunosuppressed patient developed acute herpes simplex encephalitis. Acute vascular pathologies (acute infarcts 22%, vascular thrombosis 12%, diffuse hypoxic-ischemic brain damage 40%) and pre-existing small vessel diseases (34%) were frequent findings. Moreover, silent neurodegenerative pathologies in elderly persons were common (AD neuropathologic changes 32%, age-related neuronal and glial tau pathologies 22%, Lewy bodies 9%, argyrophilic grain disease 12.5%, TDP43 pathology 6%). CONCLUSIONS: Our results support some previous neuropathological findings of apparently multifactorial and most likely indirect brain damage in the context of SARS-CoV-2 infection rather than virus-specific damage, and they are in line with the recent experimental data on SARS-CoV-2-related diffuse white matter damage, microglial activation, and cytokine release.

[Rare differential diagnosis in bilateral gonalgia]. / Seltene Differenzialdiagnose bei bilateraler Gonalgie.

We report on a 47-year-old patient suffering from bilateral gonalgia, weight loss and night sweats without fever of several months' duration. Diagnostic work-up for infectious and autoimmune diseases showed no abnormal results. A CT scan showed extensive foci of sclerosis throughout the axial skeleton. In the trephine biopsy, foamy cell infiltrates were found with expression of histiocytic markers without expression of Langerhans cell markers. Molecular analysis revealed a low allelic BRAF V600E and BCOR mutation. The diagnosis of Erdheim-Chester disease (ECD) was made. The histologic findings and molecular findings, the clinical and radiologic presentation before and 6 months after therapy as well as possible differential diagnoses of this very rare disease are discussed.

Thyroid MALT lymphoma: self-harm to gain potential T-cell help.

The development of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) is driven by chronic inflammatory responses and acquired genetic changes. To investigate its genetic bases, we performed targeted sequencing of 93 genes in 131 MALT lymphomas including 76 from the thyroid. We found frequent deleterious mutations of TET2 (86%), CD274 (53%), TNFRSF14 (53%), and TNFAIP3 (30%) in thyroid MALT lymphoma. CD274 was also frequently deleted, together with mutation seen in 68% of cases. There was a significant association between CD274 mutation/deletion and TNFRSF14 mutation (p = 0.001). CD274 (PD-L1) and TNFRSF14 are ligands for the co-inhibitory receptor PD1 and BTLA on T-helper cells, respectively, their inactivation may free T-cell activities, promoting their help to malignant B-cells. In support of this, both the proportion of activated T-cells (CD4+CD69+/CD4+) within the proximity of malignant B-cells, and the level of transformed blasts were significantly higher in cases with CD274/TNFRSF14 genetic abnormalities than those without these changes. Both CD274 and TNFRSF14 genetic changes were significantly associated with Hashimoto's thyroiditis (p = 0.01, p = 0.04, respectively), and CD274 mutation/deletion additionally associated with increased erythrocyte sedimentation rate (p = 0.0001). In conclusion, CD274/TNFRSF14 inactivation in thyroid MALT lymphoma B-cells may deregulate their interaction with T-cells, promoting co-stimulations and impairing peripheral tolerance.

Death of unknown cause? Post-mortem diagnosis of fulminant course of an EBV-associated secondary hemophagocytic lymphohistiocytosis.

HLH is a life-threatening disease, which is characterized by a dysregulated immune response with uncontrolled T cell and macrophage activation. The often fulminant course of the disease needs a fast diagnostic work-up to initiate as soon as possible the appropriate therapy. We present herein the case of a 71-year-old patient with rapidly progressive hyperinflammatory syndrome, which post mortem resulted in the diagnosis of EBV-associated HLH. With this case report, we intend to highlight the relevance of the HScore in the diagnosis of HLH, to create a greater awareness for EBV as a trigger of HLH, and to demonstrate the importance of treating EBV-associated HLH as early as possible.

Follicular lymphoma t(14;18)-negative is genetically a heterogeneous disease.

Fifty-five cases of t(14;18)- follicular lymphoma (FL) were genetically characterized by targeted sequencing and copy number (CN) arrays. t(14;18)- FL predominated in women (M/F 1:2); patients often presented during early clinical stages (71%), and had excellent prognoses. Overall, t(14;18)- FL displayed CN alterations (CNAs) and gene mutations carried by conventional t(14;18)+ FL (cFL), but with different frequencies. The most frequently mutated gene was STAT6 (57%) followed by CREBBP (49%), TNFRSF14 (39%), and KMT2D (27%). t(14;18)- FL showed significantly more STAT6 mutations and lacked MYD88, NOTCH2, MEF2B, and MAP2K1 mutations compared with cFL, nodal marginal zone lymphoma (NMZL), and pediatric-type FL (PTFL). We identified 2 molecular clusters. Cluster A was characterized by TNFRSF14 mutations/1p36 alterations (96%) and frequent mutations in epigenetic regulators, with recurrent loss of 6q21-24 sharing many features with cFL. Cluster B showed few genetic alterations; however, a subgroup with STAT6 mutations concurrent with CREBBP mutations/16p alterations without TNFRSF14 and EZH2 mutations was noted (65%). These 2 molecular clusters did not distinguish cases by inguinal localization, growth pattern, or presence of STAT6 mutations. BCL6 rearrangements were demonstrated in 10 of 45 (22%) cases and did not cluster together. Cases with predominantly inguinal presentation (20 of 50; 40%) had a higher frequency of diffuse growth pattern, STAT6 mutations, CD23 expression, and a lower number of CNAs, in comparison with noninguinal cases (5.1 vs 9.1 alterations per case; P < .05). STAT6 mutations showed a positive correlation with CD23 expression (P < .001). In summary, t(14;18)- FL is genetically a heterogeneous disorder with features that differ from cFL, NMZL, and PTFL.

High activation of STAT5A drives peripheral T-cell lymphoma and leukemia.

Recurrent gain-of-function mutations in the transcription factors STAT5A and much more in STAT5B were found in hematopoietic malignancies with the highest proportion in mature T- and natural killer-cell neoplasms (peripheral T-cell lymphoma, PTCL). No targeted therapy exists for these heterogeneous and often aggressive diseases. Given the shortage of models for PTCL, we mimicked graded STAT5A or STAT5B activity by expressing hyperactive Stat5a or STAT5B variants at low or high levels in the hematopoietic system of transgenic mice. Only mice with high activity levels developed a lethal disease resembling human PTCL. Neoplasia displayed massive expansion of CD8+ T cells and destructive organ infiltration. T cells were cytokine-hypersensitive with activated memory CD8+ T-lymphocyte characteristics. Histopathology and mRNA expression profiles revealed close correlation with distinct subtypes of PTCL. Pronounced STAT5 expression and activity in samples from patients with different subsets underline the relevance of JAK/STAT as a therapeutic target. JAK inhibitors or a selective STAT5 SH2 domain inhibitor induced cell death and ruxolitinib blocked T-cell neoplasia in vivo We conclude that enhanced STAT5A or STAT5B action both drive PTCL development, defining both STAT5 molecules as targets for therapeutic intervention.

Multiple cerebral lesions in a patient with refractory celiac disease: A case report.

BACKGROUND: Enteropathy-associated T cell lymphoma (EATL) is an aggressive intestinal T cell lymphoma derived from intraepithelial lymphocytes, which occurs in individuals with celiac disease (CD). Cerebral involvement is an extremely rare condition and as described so far, lymphoma lesions may present as parenchymal predo-minantly supratentorial or leptomeningeal involvement. We describe a case of EATL with multifocal supra- and infratentorial brain involvement in a patient with refractory celiac disease (RCD). CASE SUMMARY: A 58-years old man with known CD developed ulcerative jejunitis and was diagnosed with RCD type II. Six months later he presented with subacute cerebellar symptoms (gait ataxia, double vision, dizziness). Cranial magnetic resonance imaging (MRI) revealed multifocal T2 hyperintense supra- and infratentorial lesions. Laboratory studies of blood and cerebrospinal fluid were inconspicuous for infectious, inflammatory or autoimmune diseases. 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (18FDG-PET/CT) scan showed a suspect hypermetabolic lesion in the left upper abdomen and consequent surgical jejunal resection revealed the diagnosis of EATL. During the diagnostic work-up, neurological symptoms aggravated and evolved refractory to high-dosage cortisone. Recurrent MRI scans showed progressive cerebral lesions, highly suspicious for lymphoma and methotrexate chemotherapy was initiated. Unfortunately, clinically the patient responded only transiently. Finally, cerebral biopsy confirmed the diagnosis of cerebral involvement of EATL. Considering the poor prognosis and deterioration of the performance status, best supportive care was started. The patient passed away three weeks after diagnosis. CONCLUSION: EATL with cerebral involvement must be considered as a possible differential diagnosis in patients with known RCD presenting with neurological symptoms.

SYK expression in monomorphic epitheliotropic intestinal T-cell lymphoma.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), formerly known as type II enteropathy associated T-cell lymphoma (type II EATL), is a rare, aggressive primary intestinal T-cell lymphoma with a poor prognosis and an incompletely understood pathogenesis. We collected 40 cases of MEITL and 27 cases of EATL, formerly known as type I EATL, and comparatively investigated the T-cell receptor (TCR) itself and associated signaling molecules using immunohistochemistry, amplicon deep sequencing and bisulfite pyrosequencing. The TCR showed both an αß-T-cell origin (30%) and a γδ-T-cell derivation (55%) resulting in a predominant positive TCR phenotype in MEITL compared with the mainly silent TCR phenotype in EATL (65%). The immunohistochemical expression of the spleen tyrosine kinase (SYK) turned out to be a distinctive feature of MEITL (95%) compared with EATL (0%). Aberrant SYK overexpression in MEITL is likely caused by hypomethylation of the SYK promoter, while no common mutations in the SYK gene or in its promoter could be detected. Using amplicon deep sequencing, mutations in DNMT3A, IDH2, and TET2 were infrequent events in MEITL and EATL. Immunohistochemical expression of linker for activation of T-cells (LAT) subdivided MEITL into a LAT expressing subset (33%) and a LAT silent subset (67%) with a potentially earlier disease onset in LAT-positive MEITL.

AL Amyloidoma of the Skin/Subcutis: Cutaneous Amyloidosis, Plasma Cell Dyscrasia or a Manifestation of Primary Cutaneous Marginal Zone Lymphoma?

It is unclear whether AL amyloidoma of the skin/subcutis represents a distinct entity, an indolent precursor of systemic amyloidosis, or a manifestation of cutaneous marginal zone lymphoma (cMZL). We collected 10 cases of cutaneous AL amyloidoma in order to better characterize the clinicopathologic features of this elusive entity (M:F=4:6; median age: 62.5 y, range: 31 to 82 y). Nine patients had a solitary nodule or plaque on the lower extremity (n=7), upper extremity (n=1), or chin (n=1). One patient had an AL amyloidoma on the right thigh and a second lesion on the right arm showing histopathologic features of cMZL without amyloid deposits. Clinical investigations excluded relevant systemic disease in all cases. Microscopically, dermal/subcutaneous deposits of amyloid were associated with sparse to moderate perivascular infiltrates of lymphocytes and monotypic plasma cells (7 with kappa and 3 with lambda light chain restriction). The plasma cells expressed CD56 in one of 9 studied cases. One case was characterized by a t(14;18)(q32;q21)/IGH-MALT1 translocation. Follow-up was available in 8 cases. All remain systemically well after a median time of 86.5 months (range: 40 to 144 mo). Local recurrence of disease was observed in 3 patients. A fourth patient presented with a cMZL without amyloid deposits 8 years after excision of the cutaneous AL amyloidoma. Although our series is small, careful categorization and follow-up of the cases, together with updated information in the literature, show clinical and biological links between AL amyloidomas of the skin/subcutis and cMZL, suggesting that at least a subset of cutaneous AL amyloidoma may represent an unusual manifestation of cMZL (cutaneous mucosa-associated lymphoid tissue lymphomas).

Case report: impressive response to pembrolizumab in a patient with mismatch-repair deficient metastasized colorectal cancer and bulky disease.

Here, we report the history of a 42-year-old female patient with sporadic mismatch-repair-deficient metastatic colorectal cancer and abdominal bulky disease, who received pembrolizumab (200 mg every 3 weeks) after the failure of third-line treatment. Restaging 3 months after initiation of treatment revealed a striking response with shrinkage of the bulky peritoneal tumour mass (baseline size 11×11×14 cm) to nearly 25% of the original tumour volume (6.2×7.1×10.4 cm). Restaging 8 months after initiation showed further downsizing of the tumour mass (5.5×7.0×8.0 cm). Tumour markers CEA and CA 19-9 decreased to normal levels, haemoglobin level increased from 8 to 13 mg/dL and her overall clinical performance status increased from ECOG 3 to 1 within 3 months. Therapy with pembrolizumab was continued and is still ongoing. We emphasise the importance of testing for mismatch-repair status in metastatic disease.

Impact of Single or Combined Genomic Alterations of TP53, MYC, and BCL2 on Survival of Patients With Diffuse Large B-Cell Lymphomas: A Retrospective Cohort Study.

MYC and BCL2 translocations as well as TP53 deletion/mutation are known risk factors in diffuse large B-cell lymphoma (DLBCL) but their interplay is not well understood.In this retrospective cohort study, we evaluated the combined prognostic impact of TP53 deletion and mutation status, MYC and BCL2 genomic breaks in tumor samples of 101 DLBCL patients. The cohort included 53 cases with MYC rearrangements (MYC+).TP53 deletions/mutations (TP53+) were found in 32 of 101 lymphomas and were equally distributed between MYC+ and MYC- cases (35.8% vs. 27.1%). TP53+ lymphomas had lower responses to treatment than TP53- (complete remission 34.4% vs. 60.9%; P = 0.01). TP53 alteration was the dominant independent prognostic factor in multivariate analysis (P = 0.01). Overall survival (OS) varied considerably between subgroups with different genomic alterations: Patients with sole MYC translocation, and interestingly, with triple MYC+/BCL2+/TP53+ aberration had favorable outcomes (median OS not reached) similar to patients without genomic alterations (median OS 65 months). In contrast, patients with MYC+/BCL2+/TP53- double-hit lymphomas (DHL) (28 months), MYC+/BCL2-/TP53+ lymphomas (10 months) or sole TP53 mutation/deletion (12 months) had a poor median OS. Our findings demonstrate differences in OS of DLBCL patients depending on absence or presence of single or combined genetic alterations of MYC, BCL2, and TP53. Cooccurrence of TP53 and BCL2 aberrations ameliorated the poor prognostic impact of single TP53+ or BCL2+ in MYC positive patients.This pilot study generates evidence for the complex interplay between the alterations of genetic pathways in DLBCL, which goes beyond the concept of DHL. The variable survival of DLBCL patients dependent on single or combined alterations in the TP53, MYC, and BCL2 genes indicates the need for comprehensive genomic diagnosis.

Rituximab maintenance for patients with aggressive B-cell lymphoma in first remission: results of the randomized NHL13 trial.

We investigated rituximab maintenance therapy in patients with diffuse large B-cell lymphoma (n=662) or follicular lymphoma grade 3b (n=21) in first complete remission. Patients were randomized to rituximab maintenance (n=338) or observation (n=345). At a median follow-up of 45 months, the event-free survival rate (the primary endpoint) at 3 years was 80.1% for rituximab maintenance versus 76.5% for observation. This difference was not statistically significant for the intent-to-treat population (likelihood ratio P=0.0670). The hazard ratio by treatment arm was 0.79 (95% confidence interval 0.57-1.08; P=0.1433). The secondary endpoint, progression-free survival was also not met for the whole statistical model (likelihood ratio P=0.3646). Of note, rituximab maintenance was superior to observation when treatment arms only were compared (hazard ratio: 0.62; 95% confidence interval 0.43-0.90; P=0.0120). Overall survival remained unchanged (92.0 versus 90.3%). In subgroup analysis male patients benefited from rituximab maintenance with regards to both event-free survival (84.1% versus 74.4%) (hazard ratio: 0.58; 95% confidence interval 0.36-0.94; P=0.0267) and progression-free survival (89.0% versus 77.6%) (hazard ratio: 0.45; 95% confidence interval 0.25-0.79; P=0.0058). Women had more grade 3/4 adverse events (P=0.0297) and infections (P=0.0341). Men with a low International Prognostic Index treated with rituximab had the best outcome. In summary, rituximab maintenance in first remission after R-CHOP-like treatment did not prolong event-free, progression-free or overall survival of patients with aggressive B-non-Hodgkin lymphoma. The significantly better outcome of men warrants further studies prior to the routine use of rituximab maintenance in men with low International Prognostic Index. This trial is registered under EUDRACT #2005-005187-90 and www.clinicaltrials.gov as #NCT00400478.

Early recognition of possible pitfalls in histological diagnosis of celiac disease.

OBJECTIVE: A state-of-the-art assessment of duodenal biopsies by the pathologist in the diagnosis of celiac disease (CelD) is of highest importance. However, inaccurate characterization of specific features can lead to misdiagnosis. Our hypothesis is that a detailed histological report guarantees a good quality and helps in the primary diagnostic process by preventing false-positive diagnosis of CelD. MATERIAL AND METHODS: A total of 52 patients primarily diagnosed with CelD and suspicion of misdiagnosis were selected for this retrospective study. External histological reports of duodenal biopsies were obtained and later reassessed by an experienced in-house pathologist. For an objective evaluation a histology quality score (HQS) was created. Both pathological reports were compared and causes for a possible misdiagnosis were analyzed. Diagnostic systems by Catassi and Korponay-Szabo were compared with each other. RESULTS: The original diagnosis had been confirmed in 27% by our pathologist. The HQS was significantly lower (worse) in cases where the original diagnosis were dismissed than in confirmed CelD (p = 0.018). The new diagnostic approach by Catassi and Korponay-Szabo showed a sensitivity of 89% and 83%, respectively, a specificity of 97%, a positive predictive value of 94% and a negative predictive value of 94% and 92%, respectively. CONCLUSIONS: A low quality of the histological evaluation can lead to a high probability of misdiagnosing CelD. By applying the HQS the physician can estimate whether the report is fraught with uncertainty. Ideally the score minimizes false-positive results and prevents a delay of the correct diagnosis.

Antibiotic treatment as sole management of Helicobacter pylori-negative gastric MALT lymphoma: a single center experience with prolonged follow-up.

Relatively little is known about the long-term outcome of patients with Helicobacter pylori (HP)-negative gastric lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) with antibiotic therapy as sole management. We have analyzed all patients with HP-negative gastric MALT lymphoma undergoing antibiotic therapy as sole management of their disease. HP negativity was defined as negative histology, breath test and serology, and response to treatment, survival and long-term outcome was assessed together with clinico-pathological characteristics including t(11; 18) (q21; q21) translocation. Out of 97 patients with gastric MALT lymphoma, 24 were HP-negative, and 13 (5 females and 8 males) underwent only antibiotic management for initial therapy. Eight had stage I and five were found to have stage II disease, with three patients suffering from an underlying autoimmune disease. Antibiotic therapy consisted of standard HP eradication regimens consisting of clarithromycin in all patients, along with metronidazole in seven and amoxicillin in six plus a proton-pump inhibitor. After a median follow-up of 95 months (42-, 181+), 12/13 patients are alive. Six patients with stage I disease achieved an objective response (five complete (CR) and one partial remission, 46 %), four had stable disease (lasting 11-27 months), and three progressed. All patients with stable disease received chemotherapy, but only one patient due to clear cut progression. One patient relapsed 23 months after initial CR, and achieved a second CR with antibiotics now lasting 87 months. These results indicate that a relevant percentage of patients with HP-negative gastric MALT lymphoma may benefit from antibiotic therapy and do not require additional oncological therapies. Our data suggest that the remissions seen in these patients might be durable as evidenced by prolonged follow-up in our series.

Decreasing Clostridium difficile infections by an antimicrobial stewardship program that reduces moxifloxacin use.

Clostridium difficile infections (CDI) in hospitalized patients are known to be closely related to antibiotic exposure. Although several substances can cause CDI, the risk differs between individual agents. In Vienna and other eastern parts of Austria, CDI ribotype 027 is currently highly prevalent. This ribotype has the characteristic of intrinsic moxifloxacin resistance. Therefore, we hypothesized that moxifloxacin restriction can decrease the number of CDI cases in hospitalized patients. Our antibiotic stewardship (ABS) group applied an information campaign on CDI and formal restriction of moxifloxacin in Wilhelminenspital (Vienna, Austria), a 1,000- bed tertiary care hospital. The preintervention period (period 1) was January through May 2013, and the intervention period (period 2) was June through December 2013. We recorded the defined daily doses (DDD) of moxifloxacin and the number of CDI patients/month. Moxifloxacin use was reduced from a mean (±standard error of the mean [SEM]) of 1,038±109 DDD per month (period 1) to 42±10 DDD per month (period 2) (P=0.0045). Total antibiotic use was not affected. The mean (±SEM) numbers of CDI cases in period 1 were 59±3 per month and in period 2 were 32±3 per month (46% reduction; P=0.0044). Reducing moxifloxacin use in combination with providing structured information on CDI was associated with an immediate decrease in CDI rates in this large community teaching hospital.

Follow-up of pediatric celiac disease: value of antibodies in predicting mucosal healing, a prospective cohort study.

BACKGROUND: In diagnosing celiac disease (CD), serological tests are highly valuable. However, their role in following up children with CD after prescription of a gluten-free diet is unclear. This study aimed to compare the performance of antibody tests in predicting small-intestinal mucosal status in diagnosis vs. follow-up of pediatric CD. METHODS: We conducted a prospective cohort study at a tertiary-care center. 148 children underwent esophohagogastroduodenoscopy with biopsies either for symptoms ± positive CD antibodies (group A; n = 95) or following up CD diagnosed ≥ 1 year before study enrollment (group B; n = 53). Using biopsy (Marsh ≥ 2) as the criterion standard, areas under ROC curves (AUCs) and likelihood-ratios were calculated to estimate the performance of antibody tests against tissue transglutaminase (TG2), deamidated gliadin peptide (DGP) and endomysium (EMA). RESULTS: AUCs were higher when tests were used for CD diagnosis vs. follow-up: 1 vs. 0.86 (P = 0.100) for TG2-IgA, 0.85 vs. 0.74 (P = 0.421) for TG2-IgG, 0.97 vs. 0.61 (P = 0.004) for DPG-IgA, and 0.99 vs. 0.88 (P = 0.053) for DPG-IgG, respectively. Empirical power was 85% for the DPG-IgA comparison, and on average 33% (range 13-43) for the non-significant comparisons. Among group B children, 88.7% showed mucosal healing (median 2.2 years after primary diagnosis). Only the negative likelihood-ratio of EMA was low enough (0.097) to effectively rule out persistent mucosal injury. However, out of 12 EMA-positive children with mucosal healing, 9 subsequently turned EMA-negative. CONCLUSIONS: Among the CD antibodies examined, negative EMA most reliably predict mucosal healing. In general, however, antibody tests, especially DPG-IgA, are of limited value in predicting the mucosal status in the early years post-diagnosis but may be sufficient after a longer period of time.

Screening for adenoviruses in haematological neoplasia: High prevalence in mantle cell lymphoma.

Human adenoviruses possess oncogenic capacity which is well documented in mammalian animal models, but their possible implication in human malignancy has remained enigmatic. Following primary infection, adenoviruses can persist in a latent state in lymphocytes where the virus is apparently able to evade immune surveillance. In the present study, we have employed a broad-spectrum adenovirus polymerase chain reaction (PCR) assay to systematically screen more than 200 diagnostic specimens of different lymphoid malignancies including acute lymphocytic leukaemia (n=50), chronic lymphocytic leukaemia (n=50), various types of malignant lymphoma (n=100) and multiple myeloma (n=11) for the presence of adenoviral sequences. While most entities analysed revealed negative findings in virtually all specimens tested, adenoviral DNA was detected in 15/36 (42%) mantle cell lymphomas investigated. The most prevalent adenoviral species detected was C, and less commonly B. Adenovirus-positive findings in patients with mantle cell lymphoma were made at different sites including bone marrow (n=7), intestine (n=5), lymph nodes (n=2) and tonsillar tissue (n=1). The presence of adenoviral sequences identified by PCR was confirmed in individual cells by fluorescence in-situ hybridisation (FISH). The frequent observation of adenoviruses in mantle cell lymphoma is intriguings, and raises questions about their possible involvement in the pathogenesis of this lymphoid malignancy.

Early lesions of follicular lymphoma: a genetic perspective.

The pathogenesis of follicular lymphoma is a multi-hit process progressing over many years through the accumulation of numerous genetic alterations. Besides the hallmark t(14;18), it is still unclear which other oncogenic hits contribute to the early steps of transformation and in which precursor stages these occur. To address this issue, we performed high-resolution comparative genomic hybridization microarrays on laser-capture micro-dissected cases of follicular lymphoma in situ (n=4), partial involvement by follicular lymphoma (n=4), and duodenal follicular lymphoma (n=4), assumed to represent, potentially, the earliest stages in the evolution of follicular lymphoma. Cases of reactive follicular hyperplasia (n=2), uninvolved areas from follicular lymphoma in situ lymph nodes, follicular lymphoma grade 1-2 (n=5) and follicular lymphoma grade 3A (n=5) were used as controls. Surprisingly, alterations involving several relevant (onco)genes were found in all entities, but at significantly lower proportions than in overt follicular lymphoma. While the number of alterations clearly assigns all these entities as precursors, the pattern of partial involvement by follicular lymphoma alterations was quantitatively and qualitatively closer to that of follicular lymphoma, indicating significant selective pressure in line with its faster rate of progression. Among the most notable alterations, we observed and validated deletions of 1p36 and gains of the 7p and 12q chromosomes and related oncogenes, which include some of the most recurrent oncogenic alterations in overt follicular lymphoma (TNFRSF14, EZH2, MLL2). By further delineating distinctive and hierarchical molecular and genetic features of early follicular lymphoma entities, our analysis underlines the importance of applying appropriate criteria for the differential diagnosis. It also provides a first set of candidates likely to be involved in the cascade of hits that pave the path of the various progression phases to follicular lymphoma development.

Case report: lymphogranuloma venereum proctitis-from rapid screening to molecular confirmation of a masked sexually transmitted disease.

Proctitis caused by Chlamydia trachomatis L2b can manifest with very mild, nonspecific symptoms, and appropriate diagnostic evaluation is crucial. The case report demonstrates that rapid screening test, detection of specific antibodies in serum, and direct pathogen identification by PCR performed on tissue sample or rectal swab allow successful diagnosis of the still emerging sexually transmitted disease among homosexual patients.

Incidence of preclinical manifestations of mantle cell lymphoma and mantle cell lymphoma in situ in reactive lymphoid tissues.

Recently, the occurrence of cyclin D1-positive B cells with mantle cell lymphoma phenotype in the inner mantle zones of morphologically inconspicuous lymph nodes has been described and termed mantle cell lymphoma 'in situ'. Prevalence and clinical significance of this lesion and related minimal mantle cell lymphoma infiltrates in reactive lymphoid tissues of healthy individuals, and of mantle cell lymphoma patients are unknown. All 1292 reactive lymph nodes from unselected consecutive surgical specimens of 131 patients without a history of lymphoma obtained over a 3-month period were stained for cyclin D1. In addition, all morphologically reactive lymph nodes and benign-appearing extranodal lymphoid infiltrates of patients diagnosed with mantle cell lymphoma in the years 2000-2011 were studied. Samples predating the lymphoma diagnosis for at least 2 months were available from 37/423 (9%) patients. A mantle cell lymphoma 'in situ' was not identified in any of the two groups. However, in four patients with subsequent mantle cell lymphoma diagnosis, an early manifestation of mantle cell lymphoma was detected retrospectively, antedating the lymphoma diagnosis for 2-86 months. In six mantle cell lymphoma patients, only small groups of cyclin D1-positive cells in morphologically reactive extranodal infiltrates were detected >2 months before the diagnosis of mantle cell lymphoma (range 3-59 months). Mantle cell lymphoma 'in situ' is an extremely rare phenomenon in morphologically reactive lymph nodes, in line with the low prevalence of t(11;14)-positive cells described in the peripheral blood of a healthy population. In mantle cell lymphoma patients, however, immunohistochemically detectable infiltrates of mantle cell lymphoma cells antedating the lymphoma diagnosis were found in a significant proportion of cases (10/37=27%). These consisted either of early mantle cell lymphoma with mantle zone growth pattern, or small extranodal accumulations of cyclin D1+ cells, whereas typical mantle cell lymphoma 'in situ' was not detected.