Sanghui Park

Epstein–Barr virus-associated T/natural killer-cell lymphoproliferative disorders

Primary infection with Epstein–Barr virus (EBV) is usually asymptomatic and, in a normal host, EBV remains latent in B cells after primary infection for the remainder of life. Uncommonly, EBV can infect T or natural killer (NK) cells in a person with a defect in innate immunity, and EBV infection can cause unique systemic lymphoproliferative diseases (LPD) of childhood. Primary infection in young children can be complicated by hemophagocytic lymphohistiocytosis or fulminant systemic T‐cell LPD of childhood. Uncommonly, patients can develop chronic active EBV (CAEBV) disease‐type T/NK LPD, which includes CAEBV infection of the systemic form, hydroa vacciniforme‐like T‐cell LPD, and mosquito‐bite hypersensitivity. The clinical course of CAEBV disease‐type T/NK LPD can be smoldering, persistent or progressive, depending on the balance between viral factors and host immunity. Aggressive NK‐cell leukemia, hydroa vacciniforme‐like T‐cell lymphoma, or uncommonly extranodal NK/T‐cell lymphoma can develop in children and young adults with CAEBV disease‐type T/NK‐cell LPD. Extranodal T/NK‐cell lymphoma is a disease of adults, and its incidence begins to increase in the third decade and comprises the major subtype of T/NK LPD throughout life. Aggressive NK‐cell leukemia and nodal T/NK‐cell lymphoma of the elderly are fulminant diseases, and immune senescence may be an important pathogenetic factor. This review describes the current progress in identifying different types of EBV‐associated T/NK‐cell LPD and includes a brief presentation of data from Korea.

Integrated copy number and gene expression profiling analysis of epstein–barr virus‐positive diffuse large b‐cell lymphoma

Viral oncogenes and host immunosenescence have been suggested as causes of Epstein‐Barr virus‐positive diffuse large B‐cell lymphoma (EBVu2009+u2009DLBCL) of the elderly. To investigate the molecular genetic basis of immune evasion and tumor outgrowth, we analyzed copy number alterations (CNAs) and gene expression profiles in EBVu2009+u2009DLBCL samples compared with EBVu2009−u2009DLBCL. There were relatively few genomic alterations in EBVu2009+u2009DLBCL compared with those detected in EBV‐negative DLBCL. The most frequent CNAs (>30%) in EBVu2009+u2009DLBCLs were gains at 1q23.2–23.3, 1q23.3, 1q32.1, 5p15.3, 8q22.3, 8q24.1–24.2, and 9p24.1; losses at 6q27, 7q11.2, and 7q36.2–36.3 were also recurrent. A gene expression profile analysis identified the host immune response as a key molecular signature in EBVu2009+u2009DLBCL. Antiviral response genes, proinflammatory cytokines, and chemokines associated with the innate immune response were overexpressed, indicating the presence of a virusinduced inflammatory microenvironment. Genes associated with the B‐cell receptor signaling pathway were downregulated. An integrated analysis indicated that SLAMF1 and PDL2 were key targets of the gains detected at 1q23.2–23.3 and 9p24.1. The chromosomal gain at 9p24.1 was associated with poor overall survival. Taken together, our results led to the identification of recurrent copy number alterations and distinct gene expression associated with the host immune response in EBVu2009+u2009DLBCL. We suggest that the upregulation of PDL2 on 9p24.1 promotes immune evasion and is associated with poor prognosis in EBVu2009+u2009DLBCL.

Peripheral T cell lymphoma in Asia

AbstractnPeripheral T-cell lymphomas (PTCLs) comprise a heterogeneous group of mature T- and NK-cell neoplasms, the incidence of which is higher in Asian countries than in Western countries. Although its etiology is mainly unknown, several risk factors (such as genetic factors, abnormal immunity, environmental factors, and infectious causes) have been proposed. PTCL are classified based on a combination of several parameters, including morphology, site of presentation, viral status, immunophenotype, and specific genetic alterations. Their classification is ongoing, with the emergence of new entities and refinement of existing entities because of the development of diagnostic markers and new genetic alterations. This review presents epidemiologic data for PTCL in Asia, together with recent progress in the pathology of PTCL compared with the WHO 2008 classification.

Primary Central Nervous System ALK Positive Anaplastic Large Cell Lymphoma with Predominantly Leptomeningeal Involvement in an Adult

A 31-year-old Korean male presented with altered consciousness and severe headache. Brain MRI delineated focal leptomeningeal enhancement without any intracerebral lesions. Diagnosis was made based on a brain biopsy showing anaplastic large cell lymphoma (ALCL), immunohistochemical stains revealing positivity for anaplastic lymphoma kinase (ALK) and an absence of involvement in any other organs; specifically, the primary central nervous system ALK+ALCL. Complete remission was achieved following 5 cycles of systemic chemotherapy with a high dose of Methotrexate and a simultaneous 7 cycles of intrathecal triple chemotherapy. Diagnosis of primary leptomeningeal ALK+ALCL is challenging given its rarity and non-specific symptoms along with non-pathognomonic radiologic findings. We present the first case of primary leptomeningeal ALK-positive ALCL where the clinical course, pathologic characteristics and treatment modality are described as well as a review of literature.

Strong Correlation of Indoleamine 2,3-Dioxygenase 1 Expression with Basal-Like Phenotype and Increased Lymphocytic Infiltration in Triple-Negative Breast Cancer.

Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive enzyme involved in tumor immune escape. Blockade of the IDO1 pathway is an emerging modality of cancer immunotherapy. Triple-negative breast cancer (TNBC) lacks established therapeutic targets and may be a good candidate for this novel immunotherapeutic agent. The purpose of this study was to evaluate the clinicopathologic characteristics of the IDO1-expressing TNBC subset. A tissue microarray was constructed from 200 patients with TNBC. Immunohistochemistry (IHC) for IDO1 and TNBC molecular subtype-surrogate markers (AR, GCDFP-15, claudin-3, E-cadherin, CK5/6, and EGFR) was performed using this tissue microarray. Real-time polymerase chain reaction was performed to confirm the IDO1 mRNA expression level in 16 fresh-frozen TNBC samples. Two hundred TNBCs were classified into four subtypes based on surrogate IHC results: 22 luminal androgen receptor type (11.0%), 23 claudin-low type (11.4%), 103 basal-like type (51.5%), and 52 mixed type (26.0%). IDO1 positivity (defined as expression of >10% tumor cells) was observed in 37% of all TNBCs. IDO1 IHC expression was well correlated with mRNA expression. IDO1 positivity was significantly associated with smaller tumor size, dense stromal lymphocytic infiltration, and basal-like phenotype; however, it did not affect the patients prognosis. IDO1 expression in basal-like TNBCs is considered an immune inhibitory signal that counterbalances active immunity and may reflect the high mutational load of these tumors. Our results suggest which patients with TNBC would be more efficaciously treated with IDO1 blockade.

Expression patterns of GATA3 and the androgen receptor are strongly correlated in patients with triple-negative breast cancer.

GATA-binding protein 3 (GATA3) is a diagnostically useful immunohistochemical marker of breast cancer. Because of its strong association with estrogen receptor expression, GATA3 has markedly reduced sensitivity in triple-negative breast cancer (TNBC). We constructed a tissue microarray using a large series of TNBCs and evaluated GATA3 expression by TNBC subtype as defined by surrogate immunohistochemical markers. A total of 205 TNBCs were classified into cancers of the molecular apocrine type (n=23, 11.2%), claudin-low type (n=21, 10.2%), basal-like type (n=91, 44.4%), mixed type (n=62, 30.2%), and null type (n=8, 3.9%). The GATA3 scores (staining intensity × proportion) were categorized as negative (0), focally positive (1-10), or positive (11-300). GATA3 staining was negative in 153 cancers (74.6%), focally positive in 11 (5.4%), and positive in 41 (20.0%). The rate of focal positivity or positivity for GATA3 was significantly higher in the molecular apocrine type (73.9%, 17/23) than in other types of TNBCs (P=.001). The mean GATA3 score of molecular apocrine-type TNBC was significantly higher than that of the other types (P=.001) and differed significantly between androgen receptor (AR)-positive and AR-negative TNBCs (P<.001). In conclusion, GATA3 expression was correlated strongly with AR-positive, molecular apocrine-type TNBCs. Co-expression of AR and GATA3 is a specific feature of molecular apocrine-type TNBC, which may serve as a diagnostic aid for cancer of unknown primary.

Increased plasmacytic differentiation in gastric mucosa–associated lymphoid tissue lymphomas: Helicobacter pylori eradication response and IgG4+ plasma cell association

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is a rare extranodal marginal zone B-cell lymphoma that is often associated with plasmacytic differentiation. However, the clinicopathological characteristics of gastric MALT lymphoma with increased plasmacytic differentiation have not yet been studied. To assess the clinicopathological implications of gastric MALT lymphoma with increased plasmacytic differentiation, 36 cases with increased plasmacytic differentiation and a control group of 16 cases with minimal plasmacytic differentiation were retrospectively collected from 65 primary gastric MALT lymphomas (2010-2012). The hematoxylin and eosin slides were reviewed, and IgG, IgG4, and κ and λ immunohistochemical staining was performed. Clinicopathological differences between the 2 groups were compared using the χ2 test and odds ratios. Logistic regression analyses were used to evaluate resistance to Helicobacter pylori eradication therapy. Increased plasmacytic differentiation is significantly correlated with the H pylori eradication response (94.4% versus 66.7%, P=.018), lower frequency of relapse (5.6% versus 35.7%, P=.014), the presence of more than one IgG4+ cell per high-power field (27.8% versus 0%, P=.022), and light-chain restriction (33.3% versus 6.2%, P=.044). Univariable logistic regression indicated that negative H pylori status (P=.016) and minimal plasmacytic differentiation (P=.019) were statistically significant predictive factors for resistance to H pylori eradication. Multivariable logistic regression analyses identified no statistically significant predictive factors. However, H pylori negativity and minimal plasmacytic differentiation showed a statistical trend toward significance (P=.078 and P=.09). Gastric MALT lymphomas with increased plasmacytic differentiation have different clinicopathological characteristics, and plasmacytic differentiation is associated with H pylori eradication response.

Cytomegalovirus-associated intussusception with florid vascular proliferation in an infant.

Intussusception is usually idiopathic, with no pathologic lead point except for the presence of reactive lymphoid hyperplasia, which is probably associated with gastrointestinal infection or a reaction to newly introduced food proteins. Viral infections, such as those caused by non-enteric adenovirus, human herpes virus (HHV)-6, HHV-7, and Epstein-Barr virus, are known etiologic factors of intussusception. Cytomegalovirus (CMV)-associated intussusception has been reported rarely; there have been three case reports in immunocompetent and human immunodeficiency virus–infected infants [1-3]. None of these three case reports described a detailed histologic pattern, except ischemic necrosis of the small intestine due to a prolonged clinical history and delayed surgery. Here, we report a case of a CMV-associated inflammatory polyp with unique gross and microscopic findings as a leading cause of ileoileal intussusception in an 8-week-old healthy female.

Identification of distinctive clinical significance in hospitalized patients with endoscopic duodenal mucosal lesions

Background/Aims Duodenitis is not infrequent finding in patient undergoing endoscopy. However, hospitalized patients have a higher incidence of secondary duodenal mucosal lesions that might be related with inflammatory bowel disease (IBD), cytomegalovirus (CMV) infection, tuberculosis, immunologic disorders, or other rare infections. We aimed to identify clinicopathologic features of duodenal mucosal lesions in hospitalized patients. Methods All hospitalized patients having duodenal mucosal lesions were identified by endoscopic registration data and pathologic data query from 2011 to 2014. The diagnostic index was designed to be sensitive; however, a detailed review of medical record and endoscopic findings was undertaken to improve specificity. Secondary duodenal lesion was defined as having specific reason to explain the duodenal lesion. Results Among 6,334 hospitalized patients have undergone upper endoscopy, endoscopic duodenal mucosal lesions was detected in 475 patients. Secondary duodenal lesions was 21 patients (4.4%) and the most frequent secondary cause was IBD (n = 7). The mean age of secondary group was significantly lower than that in primary group (42.3 ± 18.9 years vs. 58.5 ± 16.8 years, p = 0.00), and nonsteroidal anti-inflammatory drugs were less frequently used in secondary group, but there was no differences of gender or presence of Helicobacter pylori. The involvement of distal part of duodenum including postbulbitis or panduodenitis was more frequently detected in secondary group than in primary group. By multivariate regression analysis, younger age of 29 years and the disease extent were significant predictors for the secondary mucosal lesions. Conclusions Secondary duodenal mucosal lesions with different pathophysiology, such as IBD or CMV infection, are rare. Disease extent and age seems the most distinctive feature of secondary duodenal mucosal lesions.

Clinicopathologic Characteristics and Mutational Status of Succinate Dehydrogenase Genes in Paraganglioma of the Urinary Bladder: A Multi-Institutional Korean Study

CONTEXTn- Because of the limited number of available primary bladder paraganglioma (PBPG) cases, the rates of succinate dehydrogenase (SDH) mutations and the clinicopathologic characteristics of SDH-deficient tumors have not been fully studied.nnnOBJECTIVEn- To define the clinicopathologic and molecular characteristics of PBPGs.nnnDESIGNn- A total of 52 PBPGs were collected retrospectively. SDHA and SDHB immunohistochemical stains were performed. In cases of SDHB expression loss, mutation analyses of SDHB, SDHC, and SDHD were performed.nnnRESULTSn- The clinicopathologic features were analyzed for 52 cases (M:F = 27:25), with a mean age of 56 years (range, 22-79 years). Tumor sizes were 0.5 to 8 cm (mean, 2.4 cm). Tumor necrosis was present in 5 of 52 cases (10%), involvement of muscularis propria in 41 (79%), and lymphovascular tumor invasion in 6 (12%). During a mean follow-up period of 41 months (range, 1-161 months), 3 of 52 patients (6%) developed metastases, but no one died from the disease. Immunohistochemistry for SDHA and SDHB showed that all cases were SDHA intact. Among them, 43 cases had intact SDHB, whereas 9 cases were SDHB deficient. Compared with the SDHB-intact cases, the SDHB-deficient cases were characterized by large tumor sizes (4.5 versus 1.9 cm; P < .001), a higher number of mitoses per 10 high-powered fields (2.6 versus 0.1; P = .002), and frequent lymphovascular tumor invasion (33% versus 7%; P = .02) and metastases (22% versus 2%; P = .02). Mutational analyses for SDHB, SDHC, and SDHD were performed in 9 SDHB-deficient cases. Among them, 6 cases were successfully sequenced and revealed SDHB mutations only.nnnCONCLUSIONSn- Large tumor size, a higher number of mitoses, and the presence of lymphovascular tumor invasion and SDHB mutations suggest malignant paraganglioma.