Distinct Clinicopathologic Subtype Research Articles

Outcomes of Patients with Acute Myeloid Leukemia with Myelodysplasia Related Changes (AML-MRC) Receiving Intensive Vs. Non-Intensive First Line Treatment

Background: Acute myeloid leukemia with myelodysplasia related changes (AML-MRC) a distinct clinico-pathologic subtype of AML recognized in the WHO and ICC 2022 classifications of hematolymphoid neoplasms (AML-MRC and AML-MR respectively). Compared to other subtypes, patients with AML-MRC/AML-MR have a worse prognosis and are less likely to respond to treatment. Traditionally, patients who are eligible for allogenic stem cell transplant (SCT) with AML-MRC/AML-MR are given high intensity chemotherapy (IC), such as daunorubicin and cytarabine (“7+3”), liposomal 7+3 or fludarabine+cytarabine+idarubicin (FLAG-IDA) whereas patients who are not transplant-eligible were treated with hypomethylating agents (i.e. azacitidine). Recently, azacitidine + venetoclax (aza/ven) has emerged as an important option for all AML patients over 75 years of age or with significant comorbidities who are not eligible for IC. However, the efficacy of aza/ven compared to IC for AML-MRC who are candidates for either has not been clearly established. Methodology: We conducted a single centre retrospective review of patients diagnosed with AML-MRC/AML-MR at Sunnybrook Health Science Centre (SHSC). A list of patients with AML-MRC/AML-MR was compiled from records from the Sunnybrook Hematology Biobank, which collects specimens and clinical data from 95% of acute leukemia patients presenting to SHSC. 65 patient charts were reviewed, and 60 patients were included in the study. 3 patients were not treated at SHSC and 2 were more appropriately classified as AML with recurrent genetic abnormalities. Treatment with a “7+3” backbone or FLAG-IDA were considered ‘intensive’ regimens; treatment with azacitidine with or without venetoclax, and low dose cytarabine (LDAC), with or without venetoclax were considered ‘non-intensive.‘ ELN 2022 criteria were used to evaluate responses to therapy. Results: 60 patients with AML-MRC/AML-MR were treated at SHSC from January 2021 to April 2023. The median age was 74 (37-99) y.o. 34 patients were male. The upper age of eligibility for allogeneic stem cell transplant was considered 72 years for this study. 28 patients were SCT eligible (31-72y.o.) and 32 patients were SCT ineligible (73-99y.o.). For SCT eligible patients, 14/28 were treated intensively and 10/28 were treated non intensively. 4 patients did not receive treatment. Of the SCT eligible group, 6/14 intensively treated patients achieved a CR/CRi compared to 5/10 non-intensively treated patients. For SCT ineligible patients, 8/32 did not receive treatment and the remaining 24 were treated non intensively. 12/24 SCT ineligible patients receiving treatment were given azacitidine+ venetoclax (aza/ven) and 9/12 achieved a CR/CRi. 7/24 patients received LDAC + venetoclax and 3/7 achieved a CR. In total, 14/60 patients were treated intensively, 21/60 patients were treated with aza/ven, 7/60 received LDAC+venetoclax, 5/60 azacitidine alone and 1/60 LDAC alone. 12/60 patients did not receive leukemia-directed therapy, either due to concomitant illness precluding treatment or a decision to decline treatment. Notably, 14/21 patients receiving aza/ven achieved a CR/CRi compared to 6/14 intensively treated patients, though more intensively treated patients ultimately proceeded to transplant (Figure 1). 48 patients who underwent therapy had next generation sequencing data for mutations of interest in AML. The most common mutations found in this cohort were ASXL1 (32), SRSF2 (20), RUNX1 (18), TET2 (17), IDH2 (16) and TP53 (12). No differences were found between patients that responded to first line therapy compared to those that did not, or those that responded to intensive chemotherapy compared to those responding to non-intensive treatment (Figure 2). Conclusion: Aza/Ven is an effective treatment regimen for AML-MRC/AML-MR, with 14/21 patients achieving CR/CRi after firstline treatment compared to 6/14 patients after IC. 4/4 patients achieved CR/CRi with salvage aza/ven after failing to respond to IC. Our study suggests that aza/ven should be considered as a firstline treatment option even in patients who are fit for intensive therapy as a means to achieve adequate responses to bridge to allogenic stem cell transplant without attendant toxicities associated with IC. Further studies are required to determine if specific mutations can predict response to either aza/ven or intensive treatment.

Case report of a patient with unclassified tauopathy with molecular and neuropathological features of both progressive supranuclear palsy and corticobasal degeneration

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are distinct clinicopathological subtypes of frontotemporal lobar degeneration. They both have atypical parkinsonism, and they usually have distinct clinical features. The most common clinical presentation of PSP is Richardson syndrome, and the most common presentation of CBD is corticobasal syndrome. In this report, we describe a patient with a five-year history of Richardson syndrome and a family history of PSP in her mother and sister. A tau PET scan (18F-APN-1607) revealed low-to-moderate uptake in the substantia nigra, globus pallidus, thalamus and posterior cortical areas, including temporal, parietal and occipital cortices. Neuropathological evaluation revealed widespread neuronal and glial tau pathology in cortical and subcortical structures, including tufted astrocytes in the motor cortex, striatum and midbrain tegmentum. The subthalamic nucleus had mild-to-moderate neuronal loss with globose neurofibrillary tangles, consistent with PSP. On the other hand, there were also astrocytic plaques, a pathological hallmark of CBD, in the neocortex and striatum. To further characterize the mixed pathology, we applied two machine learning-based diagnostic pipelines. These models suggested diagnoses of PSP and CBD depending on the brain region – PSP in the motor cortex and superior frontal gyrus and CBD in caudate nucleus. Western blots of insoluble tau from motor cortex showed a banding pattern consistent with mixed features of PSP and CBD, whereas tau from the superior frontal gyrus showed a pattern consistent with CBD. Real-time quaking-induced conversion (RT-QuIC) using brain homogenates from the motor cortex and superior frontal gyrus showed ThT maxima consistent with PSP, while reaction kinetics were consistent with CBD. There were no pathogenic variants in MAPT with whole genome sequencing. We conclude that this patient had an unclassified tauopathy and features of both PSP and CBD. The different pathologies in specific brain regions suggests caution in diagnosis of tauopathies with limited sampling.

Diffuse large B-cell lymphoma and new insights into its pathobiology and implication in treatment.

The most common non-Hodgkin lymphoma (NHL) subtype is diffuse large B-cell lymphoma (DLBCL). It accounts for roughly 30% of all cases of NHL affecting both nodal and extra nodal sites. There are molecular subtypes of DLBCL, germinal centre subtype (GCB), and activated B-cell (ABC), based on gene expression profiling (GEP), in accumulation to distinct morphological and clinicopathological subtypes. To prognosticate patients, the International Prognostication Index (IPI) and its variants are used. In ABC type DLBCL, limited stage disease is treated with a combination of abbreviated systemic chemotherapy (three cycles) and field radiation therapy. Although advanced stage disease is treated with a full course of chemotherapy as well as novel agents (Bortezomib, Ibrutinib, Lenalidomide). In this review study, we looked at the role of multiple aspects of genetic and microenvironment changes which have effects in DLBCL tumours.

A novel HNRNPH1::ERG rearrangement in aggressive acute myeloid leukemia.

FUS::ERG rearrangement is a recurrent abnormality seen in a subgroup of acute myeloid leukemia (AML) with a poor prognosis. We described here a novel HNRNPH1::ERG rearrangement in a de novo AML. The patient was unresponsive to routine chemotherapy and succumbed to the disease just 3 months after diagnosis. Two additional cases of AML with HNRNPH1::ERG rearrangement were discovered by searching a publicly available sequencing database. The three patients share several clinical phenotypes with the FUS::ERG rearranged AML, including high blast count at diagnosis, pediatric or young adult-onset, and poor overall survival. In addition, hnRNPH1 and FUS are both hnRNP family members, a group of RNA-binding proteins functioning in RNA metabolism and transport. Therefore, we suggest that patients with HNRNPH1::ERG or FUS::ERG rearrangement belong to the same distinct clinicopathologic subtype of AML, that is, AML with ERG rearrangement. Based on a previous study showing that FUS::ERG binds to the retinoic acid-responsive elements and that all-trans retinoic acid-induced cell differentiation of AML cells, we support the clinical evaluation of an APL-like therapeutic regimen for AML with ERG rearrangement.

Castleman disease and mimickers: Clinicopathological findings of atypical lymphoproliferative disorders associated with autoimmune disease.

Atypical lymphoproliferative disorders (LPDs) related with autoimmune disease (AID) show marked clinicopathological diversity, which are defined as three distinct clinicopathological subtypes such as those resembling Castleman disease (CD), atypical paracortical hyperplasia with lymphoid follicles (APHLF), and atypical lymphoplasmacytic and immunoblastic proliferation (ALPIB). We studied excisional biopsy specimens from 31 patients with atypical LPDs associated with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjögren syndrome (SjS). The lesions in these 31 cases were classified into 6 (19.4%) cases resembling CD, 14 (45.2%) cases of APHLF, and 11 (35.5%) cases of ALPIB. Five cases (83.3%) resembling CD were in the active stage with systemic symptoms and multicentric lymphadenopathy. Thirteen cases (92.9%) of APHLF showed systemic symptoms, multicentric lymphadenopathy and abnormal laboratory findings. Histologic findings for cases resembling CD were rare in patients with RA and SjS. In AID patients, histologic findings for cases resembling CD or APHLF findings correlated with disease activity and multicentric lymphadenopathy. Six cases (54.5%) of ALPIB were in the active phase with systemic symptoms and multicentric lymphadenopathy. ALPIB tended to be unrelated to AID activity, especially in the majority of patients with no abnormal laboratory findings. Atypical LPDs associated with AID is a group of diseases that may be overdiagnosed and overtreated. The diagnosis of atypical LPDs associated with AID requires an understanding of the histological findings as well as a comprehensive assessment of the presence of systemic symptoms, the distribution of lymphadenopathy, and abnormal laboratory findings.

Advances in the Treatment of RET Fusion-positive Advanced Non-small Cell Lung Cancer

转染重排（rearranged during transfection, RET）融合阳性发生于0.7%-2%的非小细胞肺癌（non-small cell lung cancer, NSCLC）。RET基因与其他结构域之间的融合代表了NSCLC独特的生物学和临床病理学亚型。近些年以来，RET融合阳性晚期NSCLC治疗领域取得了重要进展。传统化疗能够带来一定的临床获益。在靶向药物临床应用之前或不适用的情况下，以铂类为基础的系统性化疗方案是患者初始治疗选择。免疫治疗在RET融合阳性人群中的报告数据较少且通常结果较差，不推荐免疫单药或免疫联合化疗方案作为这类患者的系统性治疗。多靶点激酶抑制剂在这类人群中的重新应用能够取得一定的治疗反应，目前仅卡博替尼和凡德他尼推荐在有限条件下作为初始或后续治疗。然而，依然存在不能满足的临床需求。普拉替尼（Pralsetinib）和塞尔帕替尼（Selpercatinib）作为RET选择性酪氨酸激酶抑制剂（tyrosine kinase inhibitor, TKI），显著改善了RET融合阳性NSCLC患者生存及预后。普拉替尼和塞尔帕替尼已确立成为这类患者一线或后续治疗的首选方案。与其他TKI治疗时观察到的类似，RET靶向抑制治疗也会导致耐药问题，而获得性耐药的出现将影响治疗的远期有效性，并限制后续的药物选择。因此，本文将围绕RET融合阳性晚期NSCLC治疗进展进行综述。

A Review of Genetic Abnormalities in Unicentric and Multicentric Castleman Disease.

Simple SummaryCastleman disease is a rare hematopoietic disorder with a broad spectrum of clinical presentations. Different subtypes have been described based on how many lymph nodes are involved, histologic appearance, and associated viral infections. Recently, significant molecular and genetic abnormalities associated with Castleman disease have been described. However, we continue to lack a framework of the biological mechanisms driving this disease process. Thus, our aim was to review all published cases of Castleman disease to date that described molecular abnormalities and correlate cytogenetic, molecular, and genetic alterations with disease subtypes. Our comprehensive review identifies subtype-specific and novel pathways which may allow for more targeted treatment options and unique biologic therapies for Castleman disease.Castleman disease (CD) is a rare lymphoproliferative disorder known to represent at least four distinct clinicopathologic subtypes. Large advancements in our clinical and histopathologic description of these diverse diseases have been made, resulting in subtyping based on number of enlarged lymph nodes (unicentric versus multicentric), according to viral infection by human herpes virus 8 (HHV-8) and human immunodeficiency virus (HIV), and with relation to clonal plasma cells (POEMS). In recent years, significant molecular and genetic abnormalities associated with CD have been described. However, we continue to lack a foundational understanding of the biological mechanisms driving this disease process. Here, we review all cases of CD with molecular abnormalities described in the literature to date, and correlate cytogenetic, molecular, and genetic abnormalities with disease subtypes and phenotypes. Our review notes complex karyotypes in subsets of cases, specific mutations in PDGFRB N666S in 10% of unicentric CD (UCD) and NCOA4 L261F in 23% of idiopathic multicentric CD (iMCD) cases. Genes affecting chromatin organization and abnormalities in methylation are seen more commonly in iMCD while abnormalities within the mitogen-activated protein kinase (MAPK) and interleukin signaling pathways are more frequent in UCD. Interestingly, there is a paucity of genetic studies evaluating HHV-8 positive multicentric CD (HHV-8+ MCD) and POEMS-associated CD. Our comprehensive review of genetic and molecular abnormalities in CD identifies subtype-specific and novel pathways which may allow for more targeted treatment options and unique biologic therapies.

The Genetic Evolution of Treatment-Resistant Cutaneous, Acral, and Uveal Melanomas.

Melanoma is a biologically heterogeneous disease composed of distinct clinicopathologic subtypes that frequently resist treatment. To explore the evolution of treatment resistance and metastasis, we used a combination of temporal and multilesional tumor sampling in conjunction with whole-exome sequencing of 110 tumors collected from 7 patients with cutaneous (n = 3), uveal (n = 2), and acral (n = 2) melanoma subtypes. Primary tumors, metastases collected longitudinally, and autopsy tissues were interrogated. All but 1 patient died because of melanoma progression. For each patient, we generated phylogenies and quantified the extent of genetic diversity among tumors, specifically among putative somatic alterations affecting therapeutic resistance. In 4 patients who received immunotherapy, we found 1-3 putative acquired and intrinsic resistance mechanisms coexisting in the same patient, including mechanisms that were shared by all tumors within each patient, suggesting that future therapies directed at overcoming intrinsic resistance mechanisms may be broadly effective.

Diagnostic and therapeutic considerations in biopsy-proven type 2 autoimmune pancreatitis: comparative analysis with biopsy-proven type 1 autoimmune pancreatitis.

Autoimmune processes are now an increasingly recognized cause of acute and chronic pancreatitis. Autoimmune pancreatitis is a rare, benign pathology with two distinct clinicopathologic subtypes. The aim of this study was to compare the presentation, diagnostic considerations and outcomes of patients with biopsy-proven type 1 and 2 autoimmune pancreatitis (AIP). A retrospective review of the Queensland Health pathology database of histologically proven AIP was conducted. Parameters compared included demographics, diagnostic criterion and post-treatment outcomes. Twenty-three patients had a confirmed histological diagnosis of AIP (type 1=13, type 2=10). Patients with type 2 AIP were younger (median age 49 versus 59 years, P< 0.05). There was no significant difference in gender distribution of disease at presentation. Type 2 AIP presented with significant increased focal pancreatic changes on cross-sectional imaging (80% versus 54%, P< 0.05). Serum IgG4 levels were raised (>1.40 g/L) in 69% of patients with type 1 AIP and not detected in type 2 (P< 0.01). Concurrent underlying inflammatory bowel disease was present in a higher proportion of type 2 AIP (40% versus 15%, P< 0.05). A significantly increased proportion of patients with type 2 AIP underwent surgical resection (70% versus 30%, P< 0.05). Conservative management was utilized in more patients with type 1 disease (54% versus 30%). On follow-up, two patients have experienced symptomatic relapse at 6-18 months. Diagnostic challenges do exist and clinicians must suspect 2 type AIP in young, serum IgG4-negative inflammatory bowel disease patients with recurrent pancreatitis.

CSF biomarkers of neuroinflammation in distinct forms and subtypes of neurodegenerative dementia

BackgroundIn neurodegenerative dementias (NDs) such as prion disease, Alzheimer’s disease (AD), and frontotemporal lobar degeneration (FTLD), protein misfolding leads to the tissue deposition of protein aggregates which, in turn, trigger neuroinflammation and neurodegeneration. Cerebrospinal fluid (CSF) biomarkers have the potential to reflect different aspects of these phenomena across distinct clinicopathological subtypes and disease stages.MethodsWe investigated CSF glial markers, namely chitotriosidase 1 (CHIT1), chitinase-3-like protein 1 (YKL-40) and glial fibrillary acidic protein (GFAP) in prion disease subtypes (n = 101), AD (n = 40), clinicopathological subgroups of FTLD (n = 72), and controls (n = 40) using validated, commercially available ELISA assays. We explored glial biomarker levels’ associations with disease variables and neurodegenerative CSF biomarkers and evaluated their diagnostic accuracy. The genotype of the CHIT1 rs3831317 polymorphic site was also analyzed.ResultsEach ND group showed increased levels of CHIT1, YKL-40, and GFAP compared to controls with a difference between prion disease and AD or FTLD limited to YKL-40, which showed higher values in the former group. CHIT1 levels were reduced in both heterozygotes and homozygotes for the CHIT1 24-bp duplication (rs3831317) in FTLD and controls, but this effect was less significant in AD and prion disease. After stratification according to molecular subgroups, we demonstrated (i) an upregulation of all glial markers in Creutzfeldt-Jakob disease VV2 compared to other disease subtypes, (ii) a difference in CHIT1 levels between FTLD with TAU and TDP43 pathology, and (iii) a marked increase of YKL-40 in FTLD with amyotrophic lateral sclerosis (ALS) in comparison with FTLD without ALS. In prion disease, glial markers correlated with disease stage and were already elevated in one pre-symptomatic case of Gerstmann-Sträussler-Scheinker disease. Regarding the diagnostic value, YKL-40 was the only glial marker that showed a moderate accuracy in the distinction between controls and NDs.ConclusionsNDs share a CSF profile characterized by increased levels of CSF CHIT1, YKL-40, and GFAP, which likely reflects a common neuroinflammatory response to protein misfolding and aggregation. CSF glial markers of neuroinflammation demonstrate limited diagnostic value but have some potential for monitoring the clinical and, possibly, preclinical phases of NDs.

Clinico-neuropathological features of isocitrate dehydrogenase 2 gene mutations in lower-grade gliomas.

Background:Mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes are important for both the integrated diagnosis and the prognosis of diffuse gliomas. The p.R132H mutation of IDH1 is the most frequently observed IDH mutation, while IDH2 mutations were relatively rarely studied. The aim of the study was to determine the pathological and genetic characteristics of lower-grade gliomas that carry IDH2 mutations.Methods:Data from 238 adult patients with lower-grade gliomas were retrospectively analyzed. The status of IDH1/2 gene mutations, telomerase reverse transcriptase (TERT) promoter mutations, O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation, 1p/19q co-deletion and the expressions of IDH1 R132H, alpha-thalassemia X-linked mental retardation, and p53 were evaluated. Progression-free survival (PFS) and overall survival (OS) were calculated via Kaplan-Meier estimation using the log-rank test.Results:Totally, 71% (169/238) of patients were positive for IDH mutations, including 12 patients harboring mutations in IDH2. Among the 12 patients with IDH2 mutations, ten patients harbored the R172K mutation, one patient harbored the R172S mutation and one harbored the R172W mutation. Of these, 11 tumors occurred in the frontal lobe and showed morphology typical of oligodendroglioma. The proportion of grade II tumors was higher than that of grade III tumors in IDH2 mutant-gliomas. IDH2 mutations were frequently associated with TERT promoter mutations, 1p/19q co-deletion and MGMT promoter methylation. IDH2 mutations were associated with better outcomes compared with IDH wild-type gliomas (P < 0.05). However, the PFS and OS did not differ from that of IDH1 mutant patients (P = 0.95 and P = 0.60, respectively).Conclusions:IDH2 mutations are more frequent in oligodendrogliomas and associated with a better prognosis. IDH2 mutations may segregate in distinct clinico-pathological and genetic subtypes of gliomas, and therefore may merit routine investigation.

A Meta-Analysis of Genetic Abnormalities and Next Generation Sequencing of Primary Cases of Castleman Disease

Castleman disease is a rare lymphoproliferative disorder known to represent at least four distinct clinico-pathologic sub-types. Large advancements in our clinical and histopathologic description of these diverse diseases have been made, resulting in subtyping based on degree of nodal involvement (unicentric versus multicentric) and according to viral infection (human herpes virus 8 - HHV8 and Human Immunodeficiency Virus - HIV). However, we continue to lack a foundational understanding of the biologic mechanisms driving at least a subset of patients with these diseases. In recent years, significant molecular and genetic abnormalities that may be associated with this disease have been described; yet we are still unclear as to a unified vision of what loci and genes are involved in at least a subset of cases of Castleman disease. In our study we performed a meta-analysis of all cases (unicentric and multicentric) of Castleman disease described in literature to date, and correlate cytogenetic, molecular and genetic abnormalities with disease subtypes, phenotypes and clinical outcomes. We further performed targeted DNA deep sequencing and RNA-sequencing on a cohort of Castleman Disease cases. Our results demonstrate that genetic abnormalities in the MAPK-pathways, PI3K-pathway and Interleukin signaling are frequent in unicentric Castleman disease, whereas abnormalities in DNA methylation are seen more commonly in idiopathic multicentric Castleman disease, along with abnormalities in MAPK-pathways. We conclude that UCD and iMCD may share similar pathways of MAPK pathogenesis but can also be distinguished by cytokine and other DNA modification pathways that differ. Disclosures Ohgami: Agilent technologies: Other: received support/funding.

Brain metastases in ALK-positive NSCLC - time to adjust current treatment algorithms.

The progress in molecular biology has revolutionized systemic treatment of advanced non-small-cell lung cancer (NSCLC) from conventional chemotherapy to a treatment stratified by histology and genetic aberrations. Tumors harboring a translocation of the anaplastic-lymphoma-kinase (ALK) gene constitute a distinct genetic and clinico-pathologic NSCLC subtype with patients with ALK-positive disease being at a higher risk for developing brain metastases. Due to the introduction of effective targeted therapy with ALK-inhibitors, today, patients with advanced ALK-positive NSCLC achieve high overall response rates and remain progression-free for long time intervals. Moreover, ALK-inhibitors seem to exhibit efficacy in the treatment of brain metastases. In the light of this, it needs to be discussed how treatment algorithms for managing patients with brain metastases should be modified. By integrating systemic ALK-inhibitor therapy, radiotherapy, in particular whole brain radiotherapy might be postponed deferring potential long-term impairment by neurocognitive deficits to a later time point in the course of the disease. An early treatment of asymptomatic brain metastases might offer patients a longer time without impairment of cerebral symptoms or radiotherapeutic interventions. Based on an updated extensive review of the literature this article provides an overview on the epidemiology and the treatment of patients’ brain metastases. It describes the specifics of ALK-positive disease and proposes an algorithm for the treatment of patients with advanced ALK-positive NSCLC and brain metastases.

Corticobasal degeneration with TDP-43 pathology presenting with progressive supranuclear palsy syndrome: a distinct clinicopathologic subtype.

Corticobasal degeneration (CBD) is a clinically heterogeneous tauopathy, which has overlapping clinicopathologic and genetic characteristics with progressive supranuclear palsy (PSP). This study aimed to elucidate whether transactive response DNA-binding protein of 43kDa (TDP-43) pathology contributes to clinicopathologic heterogeneity of CBD. Paraffin-embedded sections of the midbrain, pons, subthalamic nucleus, and basal forebrain from 187 autopsy-confirmed CBD cases were screened with immunohistochemistry for phospho-TDP-43. In cases with TDP-43 pathology, additional brain regions (i.e., precentral, cingulate, and superior frontal gyri, hippocampus, medulla, and cerebellum) were immunostained. Hierarchical clustering analysis was performed based on the topographical distribution and severity of TDP-43 pathology, and clinicopathologic and genetic features were compared between the clusters. TDP-43 pathology was observed in 45% of CBD cases, most frequently in midbrain tegmentum (80% of TDP-43-positive cases), followed by subthalamic nucleus (69%). TDP-43-positive CBD was divided into TDP-limited (52%) and TDP-severe (48%) by hierarchical clustering analysis. TDP-severe patients were more likely to have been diagnosed clinically as PSP compared to TDP-limited and TDP-negative patients (80 vs 32 vs 30%, P < 0.001). The presence of downward gaze palsy was the strongest factor for the antemortem diagnosis of PSP, and severe TDP-43 pathology in the midbrain tectum was strongly associated with downward gaze palsy. In addition, tau burden in the olivopontocerebellar system was significantly greater in TDP-positive than TDP-negative CBD. Genetic analyses revealed that MAPT H1/H1 genotype frequency was significantly lower in TDP-severe than in TDP-negative and TDP-limited CBD (65 vs 89 vs 91%, P < 0.001). The homozygous minor allele frequencies in GRN rs5848 and TMEM106B rs3173615 were not significantly different between the three groups. In conclusion, the present study indicates that CBD with severe TDP-43 pathology is a distinct clinicopathologic subtype of CBD, characterized by PSP-like clinical presentations, severe tau pathology in the olivopontocerebellar system, and low frequency of MAPT H1 haplotype.

Diffuse large B-Cell lymphoma-review

Diffuse large B cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma (NHL) accounting for approximately 30 percent of all NHL cases, involving both nodal and extra-nodal sites. Apart from distinct morphological and clinicopathological subtypes, DLBCL can be dived into molecular subtypes, Germimal Centre Subtype (GCB) and Activated B-Cell (ABC) based on gene expression profiling. IPI (International Prognostication Index) and its variants are used to prognosticate the patients. Limited stage DLBCL is primarily treated with combined modality therapy consisting of abbreviated systemic chemotherapy (three cycles), and involved field radiation therapy, whereas advanced stage disease is treated with full course of chemotherapy with recommendation of addition of novel agents ( Bortezomib, Ibrutinib, Lenalidomide) in ABC type DLBCL.

Epstein-Barr virus (EBV)-positive sporadic burkitt lymphoma: an age-related lymphoproliferative disorder?

Epstein-Barr virus (EBV) is detected in 20% to 30% of sporadic Burkitt lymphoma (sBL). However, only a few studies of EBV-positive (EBV) sBL have been reported, and its characteristics still remain controversial. To highlight the features of EBV sBL, we compared the clinicopathologic characteristics of 33 cases of EBV and 117 cases of EBV-negative (EBV) sBL in Japan. EBV sBL showed significantly higher age distribution (median, 42 vs. 13 y; P<0.0001) and higher frequency of patients older than 50 years (48% vs. 16%, P<0.0001). We also revealed the difference of the involved sites. The EBV group showed significantly higher incidence of involvement of tonsil (P=0.027), adrenal gland (P=0.011), and cervical lymph node (P=0.040). In addition, the EBV group tended to have higher incidence of nodal involvement (P=0.078) and involvement of para-aorta lymph node (P=0.084) and heart (P=0.050). In contrast, the gastrointestinal tract was less frequently affected in EBV sBL (P=0.024). In addition, the less positivity for MUM1 (P=0.020) of EBV sBL was highlighted. These results indicate that biological behavior and pathogenesis of EBV sBL might be different from those of EBV sBL. Our results demonstrate that EBV sBL has an aspect of age-related disease and is a distinct clinicopathologic subtype, which should be distinguished from EBV sBL.

Cytopathologic diagnosis of Kaposi sarcoma in unusual clinical settings

Kaposi sarcoma (KS) is a rare disease that presents as 1 of 4 distinct clinicopathologic subtypes; however, it may present in populations outside those normally encountered. In such cases, it will be important to consider KS in the differential diagnosis, as it may mimic other neoplastic and non-neoplastic entities. We describe 2 cases of KS, 1 in a patient not clinically fitting any of the 4 subtypes and the other in a patient with atypical presentation in human immunodeficiency virus (HIV)-associated disease. The first is an 81-year-old African American (AA) woman with a history of KS of the leg, who presented with groin lymphadenopathy and the second is a 42-year-old AA man with a known history of HIV infection, no skin lesions, and new axillary lymphadenopathy. Fine-needle aspiration of the groin and axillary lymph node, respectively, showed atypical spindle cells in a lymphoplasmacytic background. The spindle cells were positive for human herpesvirus-8 on the cell block and subsequent lymph node excision. In patients with HIV infection, in addition to reactive and lymphoproliferative processes, KS should be considered. In the former case, the demographic of an elderly AA woman without immunosuppression would not cause concern for systemic KS, but for a metastatic tumor or lymphoma. Cytology is a helpful tool in narrowing the differential diagnosis for spindle cell lesions. With a diagnosis of KS, clinicians would be able to query the clinical history for a possible etiology, such as HIV, and exclude the possibility of metastatic disease.

Neuropathology of Dementia Disorders

Dementia, being not a specific disease but a syndrome characterized by deficits in several cognitive domains, is a major public health and socio-economic problem of our century. It is caused by dysfunction/loss of synapses and neurons inducing default neuronal networks. Despite updated concensus criteria for the clinical diagnosis of the major neurodegenerative disorders and new biomarkers, the diagnostic accuracy ranges from 65 to 96% (for Alzheimer’s disease /AD), with a sensitivity versus other dementias of around 85.4% and a specificity of up to 77.7%. Pathologic assessment, using genetic and molecular biological methods, based on homogenous definitions, harmonized interlaboratory and assessment standards, can achieve a classification in up to 95%, without, however, clarifying the etiology of most of these disorders. The new National Institute on Aging-Alzheimer Association guidelines (“ABC” score) for the neuropathologic diagnosis of AD combine β-amyloid plaque phases and Braak neurofibrillary scores, also considering other concomitant pathologies, but do not consider distinct clinico-pathologic subtypes of AD. Revised research criteria are available for dementia with Lewy bodies, Parkinson disease-dementia, frontotemporal lobe degeneration, vascular cognitive impairment, prion diseases, and other degenerative dementias. However, due to overlap between proteinopathies, frequent confounding lesions and co-occurence of multiple pathologies in aged brains, human postmortem studies entail biases that affect both their general applicability and validity. Although most degenerative dementias are incurable at present, prospective studies using validated protocols and data fusion may overcome the limitations of the current diagnostic framework as a basis for future personalized therapy options.

The Role Of PET Imaging For Predicting Treatment Failure In Primary Mediastinal B-Cell Lymphoma

IntroductionPrimary mediastinal B-cell lymphoma (PMBL) is a distinct clinicopathologic subtype of diffuse large B-cell lymphoma (DLBCL). The optimal management of PMBL remains controversial. While R-CHOP with or without radiation therapy (RT) is established as a potentially curative regimen in this setting, there have been concerns about a subgroup of PMBL patients (pts) who are refractory to R-CHOP (Soumerai et al, Leuk Lymphoma, 2013). Efforts to improve outcomes led to the use of aggressive chemotherapy regimens such as dose-adjusted R-EPOCH despite the lack of a randomized trial demonstrating benefit (Dunleavy et al, N Engl J Med., 2013). Identifying early predictors of R-CHOP treatment failure may inform risk-adapted treatment strategies in PMBL. 18F-fluorodeoxyglucose-positron-emission tomography fused with CT (PET-CT) has been used as a predictor of treatment failure in Hodgkin lymphoma and DLBCL, but the role in PMBL has not been well described. MethodsWe conducted a retrospective analysis using our institutional database of PMBL pts treated with R-CHOP with or without RT. Overall survival (OS) and progression-free survival (PFS) for the entire cohort and for those with positive versus negative interim and post-treatment PET-CT were calculated by Kaplan Meier method (STATA version 12). PET-CT scans were graded as positive or negative based on the consensus criteria from the International Harmonization Project (IHP) (Juweid et al, J Clin Oncol, 2007). We also determined positive predictive value (PPV) and negative predictive value (NPV) for interim and post-treatment PET-CTs. ResultsWe identified 26 pts with PMBL treated with R-CHOP at our institution between 11/2001 and 5/2013. The median age at diagnosis was 36 years (range 18-57 years). Eight pts had stage I, 15 had stage II, 0 had stage III and 3 had stage IV PMBL. At diagnosis, IPI was low-risk in 21, low-intermediate in 2 and high-intermediate in 3 pts. LDH level was elevated in 18 pts (69%). Thirteen pts (50%) had bulky disease (> 10 cm). After R-CHOP, 19 pts (73%) underwent consolidative RT. At a median follow-up of 35.7 months, median OS was 94.7% (95%CI: 68.1-99.2%) and PFS was 75.3% (95%CI: 52.9-88.1%) for the entire cohort. The PFS and OS at 1 year was 75.3% and 100%, respectively. Six pts (23%) had progressive disease (PD): 5 progressed during or immediately following treatment with R-CHOP (prior to RT). Four pts with PD underwent high dose chemotherapy and autologous stem cell transplantation (ASCT) and all achieved complete response (CR). Only 1 of 26 pts died of progressive PMBL. Two patients required steroids for radiation pneumonitis which resolved.Twenty-two pts (85%) underwent an interim PET-CT following 2 cycles of R-CHOP (N=12), 4 cycles of R-CHOP (N=20) or at both time points (N=10). The PFS at 1 year for pts who had a positive interim PET-CT after either cycle 2 or cycle 4 (N=17) versus pts who had negative interim PET-CT (N=5) was 68.9% vs. 100%, respectively. The NPV of interim PET-CT was 100%, but the PPV was low at 43%. Fifteen pts (58%) underwent a PET-CT at the completion of therapy. Nine (60%) had a negative scan and did not relapse. Six (40%) had a positive scan at the completion of therapy: 3 pts with PD were treated with salvage therapy, one underwent a biopsy that was negative and has not relapsed, and 2 underwent sequential PET-CT scans until resolution of the abnormality. The PFS at 1 year for pts who had a positive post-treatment PET-CT (N=6) versus pts who had a negative post-treatment PET-CT (N=9) was 50% vs. 100% respectively. The NPV for a post-treatment PET-CT was 100% and the PPV was 50%. ConclusionIn our cohort, pts with PMBL had excellent outcomes using R-CHOP with or without RT. Those who failed primary therapy were salvaged with ASCT. There were no relapses after 6 months of completing primary therapy. Negative interim or negative post-treatment PET-CT identified patients who achieve long term remission. However, positive PET-CT in this setting is of limited clinical value in predicting treatment failure. Distinctive characteristics of this DLBCL subtype, including bulky presentation, localization to mediastinum, and necrosis, probably contribute to the high false positive rate, limiting the utility of IHP criteria. We are actively studying other factors (pathological, clinical, and radiographic) which would allow early prediction of therapeutic outcome and the ability to tailor first line therapy for PMBL. Disclosures:No relevant conflicts of interest to declare.

Challenges in the Neuropathological Diagnosis of Dementias

Dementia, defined as deterioration in several cognitive domains, is a major public health problem that threatens to become the scourge of the 21th century. It is caused by dysfunction/loss of synapses and neurons inducing default neuronal networks. Consensus criteria for the diagnosis of different dementia disorders have recently been updated. Clinical diagnostic accuracy using revised research criteria and new chemical, imaging and genetic biomarkers ranges from 65 to 96% (for Alzheimer disease), with a sensitivity versus other dementias of 71 to 87% and specificity of 44 to 71%. Morphological assessment, using immunohistochemistry, molecular biological and genetic methods and based on homogenous definitions, harmonized inter-laboratory methods and assessment standards, can achieve a diagnosis/classificaion in almost 99%, without, however, clarifying the etiology of most of these disorders. The new National Institute on Aging-Alzheimer Association (ABC) guidelines for pathological diagnosis of Alzheimer disease combine βamyloid plaque phases, Braak neurofibrillary and neuritic plaque scores, also considering other pathologies. Major difficulties arise from recent separation of distinct clinico-pathological subtypes (tangleand plaque intensive, tangle predominant, limbic-predominant and -sparing) from classical Alzheimer disease. Revised research criteria are available for dementia with Lewy bodies, Parkinson disease-dementia, frontotemporal lobe degeneration, vascular cognitive impairment/dementia, prion diseases, and other neurodegenerative dementias. However, due to considerable overlap between various neurodegenerative proteinopathies and cases with mixed pathologies, human postmortem studies entail numerous biases that affect both their general applicability and the validity of correlations. Although most neurodegenerative dementias are incurable at present, concerted prospective clinico-pathological studies using validated protocols and data fusion are required to overcome the limitations of the current diagnostic framework as a basis for efficient new therapy options.