Disseminated herpes simplex virus type 1 infection manifested as extensive oral ulcers, pneumonitis, and ileo-colitis in a neutropenic patient post-chemotherapy for osteosarcoma.

Herpes simplex virus (HSV) is a common cause of recurrent oropharyngeal ulcers or stomatitis resulting from the reactivation of latent infection since childhood. Extensive ulceration and dissemination to vital organs such as pneumonitis or colitis is mostly encountered among hematologic malignancy or hematologic stem cell transplants. We hereby reported a case with osteosarcoma who developed disseminated HSV infection during neutropenia after chemotherapy.

Primary anaplastic large cell lymphoma arising from central nervous system.

A 22-year-old man presented at the emergency department with progressive headache, vomiting and horizontal diplopia over 2-month period. He also developed blurred vision in his left eye. He complained of loss of appetite for the past 2 months, resulting in a 5-kg weight loss. Examination upon arrival revealed papilledema and bilateral abducens nerve palsy. Motor and sensory functions were intact. Magnetic resonance imaging (MRI) of the brain revealed multiple extra-axial nodular enhancing lesions with size of 5-10 mm mainly along with both sides of falx cerebri and vasogenic brain oedema (Fig. 1). Stereotactic brain biopsy was performed to obtain tissue diagnosis. Histologic examination revealed brain infiltration by few atypical cells hidden amongst abundant and mixed population of inflammatory cells including lymphocytes and histiocytes. The atypical cells are large cells with horseshoe nuclei (red arrow; Fig. 2A ×100 and Fig. 2B ×400). Immunohistochemistry showed strong, uniform CD30 expression (Fig. 2C ×400) and cytoplasmic ALK staining (Fig. 2D ×400), as well as for CD3 (Fig. 2E ×400) and CD68 (Fig. 2F ×400). B-cell markers (CD20) were negative (Fig. 2G ×400).

Germline HAVCR2 mutations and their relation to the clinical spectrum of subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis: results from a multicenter study and meta-analysis.

Germline HAVCR2 mutations are frequently detected in subcutaneous panniculitis-like T-cell lymphoma (SPTCL) patients with/without hemophagocytic lymphohistiocytosis (HLH) but factors associated with variable manifestations remain undetermined. To evaluate clinical variations and associated factors in SPTCL and/or HLH with/without HAVCR2 mutations, we performed direct sequencing of HAVCR2 exon 2 using DNA from patients with SPTCL or idiopathic HLH/HLH-like systemic illnesses, defined by HLH alone without secondary causes. The systematic review and individual patient data (IPD) level meta-analysis which included the present and previously published studies reporting HAVCR2 mutations in SPTCL with/without HLH populations was subsequently conducted using random-effects meta-analysis and multivariate logistic regression. Among 34 patients enrolled, ten of 28 SPTCL patients developed HLH/HLH-like systemic illnesses. Six cases with HAVCR2Y82C mutation manifested with HLH without panniculitis. Male sex (P=0.03) and age <18 years (P=0.04) were associated with HLH, corresponding to the inverse correlation between age and HLH-2004 score (r=-0.40; P=0.02). Homozygous HAVCR2Y82C mutation was more common in the presence of HLH compared with the absence (75.0% vs. 44.4%; P=0.02). Using IPD from the present and the other three eligible cohorts (N=127), male sex, heterozygous and homozygous/compound heterozygous HAVCR2 mutations were associated with HLH by the adjusted odds ratio of 2.93 (95% confidence interval [CI]: 1.22-7.06), 4.77 (95% CI: 1.05-21.63) and 8.48 (95% CI: 2.98-24.10), respectively. Patients with male sex and/or germline HAVCR2 mutations showed an increased risk of developing HLH. Younger patients tended to manifest with HLH, while older patients typically presented with SPTCL with less frequent HLH/HLH-like systemic illnesses.

Expression of Programmed Cell Death-1 and Programmed Cell Death Ligands in Nodal Peripheral T-Cell Lymphoma: Expression Pattern and Potential Prognostic Relevance.

Programmed cell death (PD)/PD-ligands (PD-Ls) pathway plays an important role in the regulation of physiologic immune response. Several cancers, including lymphoma exhibit abnormal PD-1/PD-Ls expression, which may contribute to treatment failure, progression, and inferior outcomes. PD-1/PD-Ls expression has predominantly been described in B-cell lymphoma; such data in peripheral T-cell lymphoma (PTCL) is limited. We described PD-1/PD-Ls expression patterns and associations with clinical characteristics and outcomes, in patients with systemic PTCLs. Correlation between PD-1/PD-Ls expression and outcomes was analyzed in patients who received lymphoma-specific therapy. PD-1/PD-Ls expression was observed across all common PTCL histologies at different proportions (PD-1 0%-76.9%, PD-L1 38.5%-62.5%, and PD-L2 62.5%-100%) with PD-1 being highly expressed in angioimmunoblastic T-cell lymphoma. Baseline characteristics were comparable between PD-1/PD-Ls expression status. Of 47 patients who received lymphoma-specific therapy, outcomes were similar across all PD-L1/PD-L2 subgroups. In the Cox proportional hazard analysis, treatment response was the only factor associated with survival outcomes. However, PD-1/PD-Ls expression, either in lymphoma or stroma, was not a predictor for survival outcomes. In conclusion, differential PD-1/PD-Ls expressions were observed among various histological PTCL subtypes. In this study, we were unable to demonstrate an association between PD-1/PD-Ls expression, clinical characteristics, treatment response, and outcomes of PTCL patients.

The influence of programmed cell death ligand 2 (PD-L2) expression on survival outcome and tumor microenvironment in diffuse large B cell lymphoma.

The frequency and significance of programmed cell death ligand (PD-L) 2 expression in diffuse large B cell lymphoma (DLBCL) remain undefined. We described the expression pattern of PD-L/PD-1 in 88 DLBCL patients using immunohistochemistry. The association between PD-L expression and clinical characteristics/outcomes were analyzed. PD-L1 and PD-L2 were expressed in 14.8% and 68.2% of DLBCL patients with median positivity on tumor cells of 100% and 90%, respectively. PD-1 on tumor-infiltrating lymphocytes (TILs) was expressed in 12.5% of patients. Interestingly, 45.5% of patients had PD-L2 expressing TILs which were significantly associated with bulky disease (p = .046) and elevated lactate dehydrogenase (p = .048). PD-L1 and/or PD-L2 expression on lymphoma cells was associated with inferior progression-free survival (Hazard ratio [HR] 2.20; 95% Confidence Interval [CI] 1.004-4.84, p = .049) and overall survival (HR 2.27; 95%CI 1.03-4.98, p = .042), using multivariate analysis. In summary, PD-L2 expression on DLBCL is common and, together with PD-L1, were related to poor outcomes.

Immunopathology of Kikuchi-Fujimoto disease: A reappraisal using novel immunohistochemistry markers.

AIMS: Kikuchi-Fujimoto disease (KFD) is a self-limited disease characterised by destruction of the lymph node parenchyma. Few studies have assessed the immunohistological features of KFD, and most employed limited antibody panels that lacked many of the novel immunohistochemistry markers currently available. METHODS AND RESULTS: We used immunohistochemistry to reappraise the microanatomical distribution of plasmacytoid dendritic cells (pDCs), follicular helper T cells and cytotoxic T cells, B cells, follicular dendritic cell (FDC) meshworks, and histiocytes in lymph nodes involved by KFD. The study group consisted of 138 KFD patients (89 women; 64.5%) with a median age of 27 years (range, 3-50 years). Cervical lymph nodes were most commonly involved, in 108 (78.3%) patients. The numbers of pDCs were increased, predominantly around and within apoptotic areas and the paracortex, and tapering off within xanthomatous areas. pDCs formed sizeable tight clusters, most notably around apoptotic/necrotic areas. T cells consisted mostly of CD8-positive cells with predominant expression of T-cell receptor-ß. There were notable increases in the numbers of CD8-positive T cells within lymphoid follicles, and their numbers correlated with alterations in FDC meshworks (P < 0.001). The number of follicular helper T cells was decreased within distorted FDC meshworks. CD21 highlighted frequent distortion of FDC meshworks, even in lymph node tissue that was distant from apoptotic/necrotic areas. Distorted FDC meshworks spanned all morphological patterns, and FDC meshwork characteristics (intact; distorted; remnant/nearly absent) correlated with morphological patterns (P < 0.01). CONCLUSIONS: The immunohistological landscape of KFD is complex and characterised by increased numbers of pDCs that frequently cluster around apoptotic/necrotic foci, increased numbers of cytotoxic T cells, and substantial distortion of FDC meshworks.

Diffuse large B-cell lymphoma variants: an update.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma, representing approximately one-third of all cases worldwide. In the World Health Organization (WHO) classification of lymphomas, most cases of DLBCL are designated as not otherwise specified (NOS). About 20% of cases, however, are designated as specific variants of DLBCL. These variants, 13 in total, are specified on the basis of distinctive morphological or immunophenotypic findings or distinctive biological or clinical issues associated with their diagnoses. In this review we discuss the following variants: T-cell/histiocyte-rich large B-cell lymphoma; ALK-positive large B-cell lymphoma; plasmablastic lymphoma; intravascular large B-cell lymphoma; large B-cell lymphoma with IRF4 rearrangement; primary mediastinal large B-cell lymphoma; primary cutaneous diffuse large B-cell lymphoma, leg type; primary diffuse large B-cell lymphoma of the central nervous system; diffuse large B-cell lymphoma associated with chronic inflammation; lymphomatoid granulomatosis; primary effusion lymphoma; and HHV8-positive diffuse large B-cell lymphoma, NOS. Two additional variants recognised in the WHO classification, EBV-positive diffuse large B-cell lymphoma and EBV-positive mucocutaneous ulcer are discussed elsewhere in another review within this issue of Pathology. Although not recognised as a specific variant in the current WHO classification, primary testicular diffuse large B-cell lymphoma also has unique biological features and requires some modification of the standard treatment approach for patients with DLBCL. Therefore, we suggest that primary testicular diffuse large B-cell lymphoma also should be recognised as a specific variant of DLBCL in a future version of the WHO classification.

Gaucher disease type 1 first recognized in an elderly patient with thrombocytopenia and lung adenocarcinoma.

Recognizing Gaucher disease in elderly patients can be challenging. We present a Gaucher disease type 1 case diagnosed in an elderly patient with thrombocytopenia and lung adenocarcinoma. The diagnosis of Gaucher disease was delayed due to lack of familiarity about Gaucher Disease type 1 which can manifest in adulthood.

Immunohistochemistry Innovations for Diagnosis and Tissue-Based Biomarker Detection.

PURPOSE OF REVIEW: Immunohistochemistry is an integral technique for tissue-based diagnostics and biomarker detection with broad worldwide adoption. Advances in core chemistries, antibody design, and automation have ushered unprecedented sensitivity, specificity, and reproducibility in immunohistochemistry assays. As a result, clinical immunohistochemistry assays that utilize dual-color approaches and mutation-specific antibodies provide novel tools in clinical diagnostics that until recently were in the realm of investigational research. This review provides an overview of innovations in clinical immunohistochemistry assays with emphasis on those used for patients with hematopoietic neoplasms. RECENT FINDINGS: Advances in clinical-grade immunohistochemistry techniques have allowed labs to develop and validate multiplex assays that improve diagnostic utility-such as CD5/PAX5 and TCF4/CD123 dual-color stains-and have the potential to enhance the specificity of biomarker detection. In addition, the increased availability of immunohistochemistry assays that detect mutant proteins (e.g., BRAF V600E and IDH1 R132H) provides a helpful replacement and/or adjunct for molecular testing. These techniques are highly reproducible, entail reasonable technical and interpretation complexity, and are relatively cost-effective, making them valuable novel tools in modern cancer care. Multiplex and mutation-specific immunohistochemistry assays represent important innovations that provide improved utility in the context of personalized medicine and targeted therapy.

Dual Expression of TCF4 and CD123 Is Highly Sensitive and Specific For Blastic Plasmacytoid Dendritic Cell Neoplasm.

The diagnosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN) has been based on the expression status of multiple markers, including CD123. TCF4 was discovered recently to be an obligatory master regulator of plasmacytoid dendritic cells. We postulated that a tissue-based assay designed to detect dual CD123 and TCF4 expression would provide a highly reliable and practical marker for BPDCN in biopsy material. We designed, optimized, and validated a dual-color TCF4/CD123 immunohistochemistry stain for use in formalin-fixed paraffin-embedded tissue sections. The performance characteristics of the TCF4/CD123 stain were evaluated in 48 confirmed BPDCN cases. TCF4/CD123 coexpression was detected reproducibly in plasmacytoid dendritic cells. In BPDCN, the TCF4/CD123 stain showed coexpression in all (48/48; 100%) cases analyzed. Cases with concurrent samples from different anatomic sites showed comparable staining characteristics. In contrast, of 464 non-BPDCN cases comprising a wide range of hematolymphoid neoplasms and cutaneous lesions that might enter in the differential diagnosis of BPDCN, we identified dual expression of TCF4 and CD123 in only 1 case of B-lymphoblastic leukemia/lymphoma. On the basis of these findings, the TCF4/CD123 dual-color immunohistochemical stain had an analytic sensitivity of 100% and a specificity of 99.8%. Receiver operator characteristic analysis demonstrated an area under the curve of 1.000 (95% confidence interval: 0.999-1.000). In summary, the dual-color TCF4/CD123 immunohistochemistry stain provides a robust standalone and cost-effective assay for the diagnosis of BPDCN.

PD1/PD-L1 Expression in Blastic Plasmacytoid Dendritic Cell Neoplasm.

Patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN) have poor outcomes despite intensive chemotherapy, underscoring the need for novel therapeutic approaches. The expression status of PD1/PD-L1 in BPDCN remains unknown. We evaluated PD1/PD-L1 by immunohistochemistry and RNAseq expression profiling in a cohort of BPDCN patients. The study group included 28 patients with a median age of 66.8 years (range, 22.8-86.7), 22 men and 6 women. PD-L1 expression was detected by immunohistochemistry in 10/21 (47.6%) cases. PD-L1 expression had a median H-score of 157. The H-score was ≥60 in 7 patients. PD-L1 protein levels (H-score) were proportional to normalized PD-L1 mRNA transcript levels (CD274 mRNA). In addition, high-level PD-L1 expression correlated with higher numbers of PD1-positive cells within BPDCN tumors. There was no correlation between clinicopathologic characteristics and PD-L1 expression status. Similarly, there was no significant difference in overall survival between patients with PD-L1-positive and PD-L1-negative BPDCN (median 12 vs. 23 month, respectively; p = 0.743). In conclusion, PD-L1 expression by tumor cells is detectable in a sizeable subset of patients with BPDCN, suggesting that exploration of the effectiveness of therapeutic inhibition of the PD1/PD-L1 axis in patients with refractory or progressive BPDCN is warranted.

Unusual case of human herpesvirus 8-positive large B-cell lymphoma associated with Castleman disease.

An overlap between human herpesvirus 8 (HHV8) -positive diffuse large B-cell lymphoma and HHV8-positive germinotropic lymphoproliferative disorder has been proposed. We present a unique Epstein-Barr virus-associated case in which features of both conditions were present.

Histopathology of ethmoid mucosa versus polyp tissue in diagnosing eosinophilic mucin rhinosinusitis.

BACKGROUND: This study aims to compare histopathology of nasal polyp and ethmoid mucosa for diagnosing eosinophilic mucin rhinosinusitis (EMRS). METHODOLOGY: Patients with chronic rhinosinusitis with polyps (CRSwNP) were enrolled. Using eosinophilic mucin as a reference, histopathology of polyp apex, polyp pedicle and ethmoid mucosa was compared for density of tissue eosinophil and sensitivity for diagnosing EMRS. Associations with asthma were assessed for each site. RESULTS: Thirty patients with CRSwNP were enrolled. When polyp apex, polyp pedicle and ethmoid mucosa were assessed for tissue eosinophilia, consistent results were reported in 16 patients (53%). Median tissue eosinophil was greater in polyp apex (58, IQR: 7-100) than ethmoid mucosa (10, IQR: 2-21), but not different from polyp pedicle (22, IQR: 1-96). Sensitivity for diagnosing EMRS were 100% (95%CI: 47.8 - 100) for polyp apex, 60% (95%CI: 14.7 - 94.7) for polyp pedicle, 80% (95%CI: 28.4 â€" 99.5) for ethmoid mucosa. Associations with asthma were significant for polyp pedicle, and ethmoid mucosa but not polyp apex. CONCLUSION: Density of tissue eosinophil was greater in nasal polyp than in ethmoid mucosa. Histopathology of polyp apex had good sensitivity for diagnosing EMRS. Polyp pedicle and ethmoid mucosal eosinophilia associated with asthma.