Soo Hee Kim

Overexpression of ERG and Wild-Type PTEN Are Associated with Favorable Clinical Prognosis and Low Biochemical Recurrence in Prostate Cancer

Objectives The aim of this study was to investigate the expression of two commonly altered genes ERG and PTEN in prostate cancer (PC) and evaluate their prognostic significance. Despite conflicting published results, TMPRSS2-ERG gene fusion and PTEN loss are generally considered unfavorable markers for PC progression. Materials and Methods Of the 762 prostatic adenocarcinoma specimens obtained from radical prostatectomy, 613 without neoadjuvant hormone therapy were included in tissue microarrays for quantitatively assessment of ERG and PTEN expression via immunohistochemistry. Statistical analysis of the association between such expression and clinicopathological parameters, including clinical prognosis, was performed with a p-value of <0.05 considered significant. Results During a median follow-up period of 44.0 months, 132 (21.5%) patients developed biochemical recurrence (BCR). ERG overexpression and PTEN loss were observed in 145 (23.7%) and 253 (41.3%) cases, respectively. BCR-free survival was significantly better in patients with ERG overexpression (p=0.005), but unfavorable among those with PTEN loss (p=0.142). Sub-group analysis revealed that patients with PTEN loss and negative ERG expression had the worst BCR-free survival outcome (p=0.021). Furthermore, multivariate analysis identified prostate-specific antigen level (≥10 ng/mL), Gleason score (>6), pathologic T stage (≥T3), positive surgical margin, and extraprostatic capsule extension as significant risk factors for BCR (p<0.05). Conclusions Our results indicated that ERG overexpression was associated with favorable BCR-free survival after radical prostatectomy for PC, whereas PTEN loss was with unfavorable outcomes.

What Is the Ideal Tumor Regression Grading System in Rectal Cancer Patients after Preoperative Chemoradiotherapy

Purpose Tumor regression grade (TRG) is predictive of therapeutic response in rectal cancer patients after chemoradiotherapy (CRT) followed by curative resection. However, various TRG systems have been suggested, with subjective categorization, resulting in interobserver variability. This study compared the prognostic validity of four different TRG systems in order to identify the most ideal TRG system. Materials and Methods This study included 933 patients who underwent preoperative CRT and curative resection. Primary tumors alone were graded according to the American Joint Committee on Cancer (AJCC), Dworak, and Ryan TRG systems, and both primary tumors and regional lymph nodes were graded according to a modified Dworak TRG system. The ability of each TRG system to predict recurrence-free survival (RFS) and overall survival (OS) was analyzed using chi-square and C statistics. Results All four TRG systems were significantly predictive of both RFS and OS (p < 0.001 each), however none was a better predictor of prognosis than ypStage. Among the four TRGs, the mDworak TRG system was a better predictor of RFS and OS than the AJCC, Dworak, and Ryan TRG systems, and both the chi-square and C statistics were higher for the former, although the differences were not statistically significant. The combination of ypStage and the modified Dworak TRG better predicted RFS and OS than ypStage alone. Conclusion The modified Dworak TRG system for evaluation of entire tumors including regional lymph nodes is a better predictor of survival than current TRG systems for evaluation of the primary tumor alone.

CD56-Negative Extranodal NK/T-Cell Lymphoma, Nasal Type, with Extranasal Cutaneous Involvement

Dear Editor: Extranodal NK/T-cell lymphoma (ENTCL), nasal type, is a well-defined aggressive cytotoxic lymphoma1. Although immunophenotyping with CD56 is known to be positive in practically all cases, CD56-negative cases have also been reported, particularly in the upper respiratory tract. However, there are very few reports of skin involvement2. Here, we report a unique case of a CD56-negative, Epstein-Barr virus (EBV)-positive ENTCL, nasal type, with cutaneous involvement. A 35-year-old Korean female patient presented with a tender violaceous crusted indurated plaque on the right thigh and a light brown ill-defined induration on the right upper arm (Fig. 1). Histopathologic examination showed an atypical lymphocytic infiltration composed of small- to medium-sized cells with irregular folded nuclei, and inconspicuous nucleoli. The infiltrate demonstrated angiocentric growth with frequent mitoses. Focal epidermal and dermal necrosis were also noted (Fig. 2A, B). The infiltrated cells stained positively for antibodies against surface CD3, CD8, and granzyme B, whereas they were negative against CD4, CD56, and CD20 (Fig. 2C~E). EBV-encoded RNA (EBER) in situ hybridization was positive in many infiltrated cells (Fig. 2F). Three months before, the patient had been diagnosed with ENTCL, nasal type, for her recurrent nasopharyngeal ulcer. The microscopic evaluation of the uvula showed similar findings to that of the skin. Bone marrow biopsy, computed tomography and whole body 18-fluoro-2-deoxyglucose positron emission tomography scan revealed no systemic invasion of the lymphoma. Despite cisplatin-based concurrent chemoradiation therapy, there was only a partial reduction of the tumor. Fig. 1 Clinical manifestation of the skin lesions. (A) A tender dark erythematous scaly indurated plaque with oozing on the right thigh. (B) A tender light brown, ill-defined induration with cigarette-paper-like fine scales on the right upper lateral arm. Fig. 2 Microphotograph of the lesion on the right thigh. (A) Dense cellular infiltrates involving the deep dermis. Angiocentricity is conspicuous and epidermal necrosis is visible (H&E, ×12). (B) Atypical lymphocytes composed of small- to medium-sized ... ENTCL, nasal type, is a rare aggressive lymphoma that occurs more commonly in East Asia. Patients are typically middle-aged adults and have a male predominance3. The prognosis is poor regardless of therapeutic strategies, with a median survival no more than 12 months. The skin is known to be the second most common site of involvement and the disease usually manifests as multiple ulcerated plaques or tumors on the trunk or extremities. Histopathologically, ENTCL is characterized by dense infiltrates involving the dermis and often the subcutis. The cells have irregular or oval nuclei, moderately dense chromatin, and a pale cytoplasm. Prominent angiocentricity and angiodestruction often accompany extensive necrosis1. Immunophenotypically, the neoplastic cells typically stain for antibodies against CD2, CD56, cytoplasmic CD3, and cytotoxic proteins (TIA-1, granzyme B, and perforin), but lack surface CD34. However, rare cases are CD56 negative, and they stain positively for surface CD3, CD5 and CD8. Detection of EBV and expression of cytotoxic proteins are required for the diagnosis of these CD56-negative cases4. Most of the reported CD56-negative cases occurred in the upper respiratory tract5. Concerning skin involvement, to our knowledge, there have only been three cases recorded in the literature2. CD56-negative cases seem to be as aggressive as CD56-positive cases, and are usually unresponsive to conventional chemotherapy, with poor prognosis and a short median survival2. This case emphasizes that CD56 might not be invariably positive in ENTCL even in cases with extranasal cutaneous involvement. The immunohistochemistry and EBER in situ hybridization would be important ancillary studies for the accurate diagnosis of this rare aggressive cytotoxic lymphoma.

Long Non-coding RNA HOTAIR Expression in Diffuse Large B-Cell Lymphoma: In Relation to Polycomb Repressive Complex Pathway Proteins and H3K27 Trimethylation.

Background A long non-coding RNA hox transcript antisense intergenic RNA (HOTAIR) is involved in epigenetic regulation through chromatin remodeling by recruiting polycomb repressive complex 2 (PRC2) proteins (EZH2, SUZ12, and EED) that induce histone H3 trimethylation at lysine 27 (H3K27me3). Deregulation of c-MYC and interaction between c-MYC and EZH2 are well known in lymphomagenesis; however, little is known about the expression status of HOTAIR in diffuse large B-cell lymphomas (DLBCLs). Methods The expression status of PRC2 (EZH2, SUZ12, and EED), H3K27me3, c-MYC, and BCL2 was analyzed using immunohistochemistry (n = 231), and HOTAIR was investigated by a quantification real-time polymerase chain reaction method (n = 164) in DLBCLs. Results The present study confirmed the positive correlation among PRC2 proteins, H3K27me3, and c-MYC in DLBCLs. Expression level of HOTAIR was also positively correlated to EZH2 (p < .05, respectively). Between c-MYC and HOTAIR, and between c- MYC/BCL2 co-expression and HOTAIR, however, negative correlation was observed in DLBCLs (p < .05, respectively). High level of H3K27me3 was determined as an independent prognostic marker in poor overall survival (hazard ratio, 2.0; p = .023) of DLBCL patients. High expression of HOTAIR, however, was associated with favorable overall survival (p = .004) in the univariate analysis, but the impact was not significant in the multivariate analysis. The favorable outcome of DLBCL with HOTAIR high expression levels may be related to the negative correlation with c- MYC expression or c-MYC/BCL2 co-expression. Conclusions HOTAIR expression could be one of possible mechanisms for inducing H3K27me3 via EZH2-related PRC2 activation, and induced H3K27me3 may be strongly related to aggressive DLBCLs which show poor patient outcome.

Association of the long non-coding RNA MALAT1 with the polycomb repressive complex pathway in T and NK cell lymphoma

Recently, various long non-coding RNAs (lncRNAs) have been reported to have significant therapeutic or prognostic value. However, the expression of lncRNAs has not been investigated in T and NK cell lymphoma. Thus, we evaluated the biological and prognostic role of lncRNAs related to the polycomb repressive complex (PRC) and PRC markers in tissue samples and cell lines of T and NK cell lymphoma. Among the tested lncRNAs, MALAT1 was most highly expressed in clinical samples and cell lines. High expression of MALAT1 as well as BMI1 was related to poor prognosis in patients with mature T cell lymphoma. In the tissue samples, BMI1 expression showed a positive correlation with EZH2, SUZ12, H3K27me3, and MALAT1. Multiple linear regression analysis showed that BMI1 expression was independently associated with H3K27me3. Direct binding of MALAT1 to the PRC2 components (EZH2 and SUZ12) was observed in a T cell lymphoma cell line; however, no direct binding of MALAT1 with H3K27me3 and BMI1 (a PRC1 component) was observed. In T and NK cell lymphomas, MALAT1 was related to poor prognosis. MALAT1 directly binds to EZH2 and SUZ12, and BMI1 activation may be induced possibly through H3K27me3.

A novel TP53-KPNA3 translocation defines a de novo treatment-resistant clone in osteosarcoma

Osteosarcoma is the most common primary bone cancer. It can be cured by aggressive surgery and chemotherapy, but outcomes for metastatic or chemoresistant disease remain dismal. Cancer sequencing studies have shown that the p53 pathway is dysregulated in nearly every case, often by translocation; however, no studies of osteosarcoma evolution or intratumor heterogeneity have been done to date. We studied a patient with chemoresistant, metastatic disease over the course of 3 years. We performed exome sequencing on germline DNA and DNA collected from tumor at three separate time points. We compared variant calls and variant allele frequencies between different samples. We identified subclonal mutations in several different genes in the primary tumor sample and found that one particular subclone dominated subsequent tumor samples at relapse. This clone was marked by a novel TP53-KPNA3 translocation and loss of the opposite-strand wild-type TP53 allele. Future research must focus on the functional significance of such clones and strategies to eliminate them.

Chronic granulomatous dermatosis as a presenting sign of a lymphoepithelioid T-cell lymphoma (Lennert lymphoma)

Lennert lymphoma (LL), under the WHO classification, is defined as a “lymphoepithelioid cell variant of the peripheral T-cell lymphomas, unspecified”, due to its lack of specific clinical features. Lennert lymphoma is primarily a nodal disease which presents with lymphadenopathy, with characteristic pathologic features of epithelioid histiocytes and atypical small lymphoid cells [1]. While skin involvement of LL is known to be infrequent, we report a case of LL that initially presented as atypical [...]

Upregulated Neuro-oncological Ventral Antigen 1 (NOVA1) Expression Is Specific to Mature and Immature T- and NK-Cell Lymphomas.

Background: Recent studies have revealed that the splicing factor neuro-oncological ventral antigen 1 (NOVA1) is enriched in fibroblasts and accumulated T cells of tertiary lymphoid structures. In the present study, we investigated NOVA1 expression in various subtypes of mature and immature T- and natural killer (NK)-cell lymphomas as well as in various B-cell lymphoma subtypes. Methods: NOVA1 immunoexpression was evaluated in hyperplastic palatine tonsils (n = 20), T- and NK-cell lymphomas (n = 177), diffuse large B-cell lymphomas (n = 151), and other types of B cell lymphomas (n = 31). Nuclear staining intensity and percentage of positive tumor cells were graded. NOVA1 mRNA expression was analyzed in various lymphoma cell lines. Results: Tumor cells of T- and NK-cell lymphomas showed higher expression levels of NOVA1 than did normal paracortical T cells, and 56.5% of T- and NK-cell lymphoma cases showed diffuse and strong expression. The NOVA1 expression level varied according to the subtype; it was higher in angioimmunoblastic T-cell lymphoma, anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL), and T lymphoblastic leukemia/lymphoma (T-LBL), but it was lower in ALK-positive ALCL. In almost all B-cell lymphomas, NOVA1 expression was very low or negative. NOVA1 mRNA was also expressed in Jurkat, a T-LBL cell line. Conclusions: The present findings suggest that NOVA1 upregulation may be involved in certain subtypes of T- and NK-cell lymphomas, but not in B-cell lymphomas. Upregulated NOVA1 expression seems to be a specific biological feature of activated T cells such as T- and NK-cell lymphomas.

Frequent expression of follicular dendritic cell markers in Hodgkin lymphoma and anaplastic large cell lymphoma.

Aims Although the tumour cells of Hodgkin lymphoma (HL) are derived from mature B-cells, the lineage infidelity of Hodgkin/Reed–Sternberg cells (HRSs) often causes diagnostic problems. Recently introduced HRS markers are also positive for follicular dendritic cells (FDCs). We investigated the expression of several FDC markers in HL and anaplastic large cell lymphoma (ALCL) and evaluated their diagnostic efficacy. Methods Eighty-five cases of HL and 52 cases of ALCL were included in this study. Immunohistochemistry was performed for glioma-associated homologue (GLI) 3, class III β-tubulin (TUBB3), fascin, clusterin, γ-synuclein, podoplanin, syntenin, CD21, CD35 and EGFR. Results HRSs were diffusely positive for GLI3, fascin and TUBB3; the mean positivity rates per case were 94% for GLI3, 82% for fascin, 69% for TUBB3, 17% for clusterin, 17% for γ-synuclein and 14% for syntenin. Podoplanin, CD21, CD35 and EGFR were almost negative. However, the frequency of marker expression was not associated with the histologic subtype or the presence of Epstein–Barr virus (EBV). ALCL showed a similar pattern to HL, but the overall frequency of positivity was lower than that observed in HL. The mean positivity rates were 56% for GLI3, 62% for fascin, 58% for TUBB3 and 21% for clusterin. The other markers were nearly negative. Anaplastic large cell lymphoma kinase positivity did not affect the expression rates. Conclusions This study confirmed the frequent expression of FDC markers in HL and ALCL. Especially, GLI3, fascin and TUBB3 are the most sensitive markers. Further studies are required to evaluate the association between FDCs, HRSs and ALCL cells.

Incidence and Survival of Pediatric Soft Tissue Sarcomas: Comparison between Adults and Children

Purpose Pediatric-type sarcomas such as rhabdomyosarcoma (RMS), Ewing sarcoma (EWS), primitive neuroectodermal tumor (PNET), and desmoplastic small round-cell tumor (DSRCT) are rare in adults, with limited studies on their prognosis and optimal treatment strategies. We aimed to examine the outcome of children and adult patients with RMS, EWS, PNET, and DSRCT and relevant prognostic factors. Materials and Methods We retrospectively reviewed 220 pediatric-type sarcoma patients at a single institution between 1985 and 2011. Comparisons were made in order to examine differences in demographics, disease characteristics, and survival. Survival analyses were performed using the Kaplan-Meier method with log-rank tests and Cox proportional hazards models. Results A total of 220 consecutive patients were identified at our institute. Median age was 15.6 years (range, 0 to 81 years) and there were 108 children (49%) and 112 adult patients (51%). According to histological classification, 106 patients (48.2%) had RMS, 60 (27.3%) had EWS, 50 (22.7%) had PNET, and 4 (1.8%) had DSRCT. With a median follow-up period of 6.6 years, the estimated median overall survival (OS) of all patients was 75 months (95% confidence interval [CI], 27.2 to 122.8 months) and median event-free survival (EFS) for all patients was 11 months (95% CI, 8.8 to 13.2 months). No significant difference in OS and EFS was observed between adults and children. In multivariate analysis, distant metastasis (hazard ratio [HR], 1.617; 95% CI, 1.022 to 2.557; p=0.040) and no debulking surgery (HR, 1.443; 95% CI, 1.104 to 1.812; p=0.012) showed independent association with worse OS. Conclusion Metastatic disease and no surgical treatment are poor prognostic factors for OS among pediatric-type sarcomas for both adults and children.