Jo-Heon Kim

Assessment of DNA methylation for the detection of cervical neoplasia in liquid-based cytology specimens.

OBJECTIVE DNA methylation is an early event in carcinogenesis. Testing for DNA methylation has potential in cancer screening. The aim of this study was to investigate the feasibility of methylated DNA detection as a screening tool for squamous cell carcinomas (SCC) and squamous intraepithelial lesions (SIL) in cervical scrapings. METHODS A multiplex, nested, methylation-specific polymerase chain reaction approach was used to examine promoter methylation of 12 genes (CDH1, DAPK, GSTP1, HIC-1, HIN-1, hMLH1, MGMT, p16, RAR-beta, RASSF1A, SHP-1, and Twist) in biopsy-proven SCC (n=69), high-grade SIL (HSIL, n=67), low-grade SIL (LSIL, n=32), and negative (n=41) liquid-based cytology samples. RESULTS The methylation frequency in normal, LSIL, HSIL, and SCC was significantly different (p<0.01) for eight genes (DAPK, HIC-1, HIN-1, MGMT, RAR-beta, RASSF1A, SHP-1, and Twist). There was a trend toward increasing methylation of HIN-1, MGMT, RAR-beta, RASSF1A, and SHP-1 with increasing severity of cervical squamous lesions. The number of methylated genes increased with the severity of cervical squamous lesions (p<0.001). In receiver-operating characteristic analysis, the three-gene combination (RAR-beta/Twist/MGMT) showed the best performance to distinguish HSIL/SCC from LCIS/negative samples. The estimated specificity of this three-gene panel for detecting HSIL/SCC was 82.2%, and its sensitivity was 78.7%. CONCLUSION Although aberrant DNA methylation has the potential to function as a molecular biomarker of HSIL and SCC in liquid-based cytology tests, additional genes that are selectively methylated in HSIL and SCC are needed to improve clinical performance.

Immunocytochemical panel for distinguishing between adenocarcinomas and reactive mesothelial cells in effusion cell blocks.

The aim of our study was to determine the value of a panel that consisted of one epithelial marker (MOC‐31) and two mesothelial markers (D2‐40 and calretinin) for distinguishing between reactive mesothelial cells (RMCs) and adenocarcinomas (ACs) in effusion fluids. A total of 118 cell block specimens from pleural and peritoneal effusions, including 88 ACs and 30 benign effusions with RMCs were stained with antibodies against MOC‐31, D2‐40, and calretinin. MOC‐31 membranous activity was observed in all samples from ACs, regardless of the primary tumor site. All benign effusion samples with RMCs were negative for MOC‐31. All benign effusion samples with RMCs exhibited membranous staining for D2‐40, and one AC case had focal reactivity for D2‐40. Almost all benign effusions reacted positively with calretinin. Staining was noted in both the cytoplasm and the nucleus in the majority of cases. Scattered tumor cells had weak calretinin positivity in two AC cases. Background RMCs in AC effusions were consistently positive for D2‐40 and calretinin. In general, D2‐40 identified more RMCs than calretinin. The staining combination of positive for MOC‐31 and negative for D2‐40 or calretinin were 100% specific and 99% sensitive for ACs. Our data suggest that immunohistochemical studies performed on cell blocks with MOC‐31, D2‐40, and calretinin were useful in the differentiation between ACs and RMCs. D2‐40 was a more sensitive marker for RMCs than calretinin. Diagn. Cytopathol. 2009.

Stromal matrix metalloproteinase-14 expression correlates with the grade and biological behavior of mammary phyllodes tumors.

Phyllodes tumors (PTs) of the breast are rare biphasic tumors with the potential for invasion and metastatic spread. Matrix metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs) are involved in several key aspects of tumoral growth, invasion, and metastasis, but little is known of their expression in PTs. The objective of this study was to assess the expression of MMPs and TIMPs in PTs and to determine their association with grade and clinical behavior of PTs. Eighty-two PTs (50 benign, 22 borderline, and 10 malignant) were studied. Automated immunohistochemical staining for MMP-1, -2, -7, -9, -11, -13, and -14 and TIMP-1, -2, and -3 was performed using tissue microarray blocks and the expression of MMPs and TIMPs was assessed in the stromal component. There were no significant differences in the expression of stromal MMPs and TIMPs in the 3 groups of PTs, except for MMP-14. There was a significant increase in stromal MMP-14 expression with increasing PT grade (P<0.01). The stromal MMP-14 expression in the borderline and malignant PTs was higher than that in benign PTs (P<0.05 and P<0.05, respectively). Furthermore, the expression of stromal MMP-14 was associated with a higher rate of recurrence (P<0.05). Our results show for the first time that stromal MMP-14 expression is associated with the grade and clinical behavior of PTs of the breast.

Borderline and malignant phyllodes tumors display similar promoter methylation profiles.

Mammary phyllodes tumors (PTs) are uncommon fibroepithelial neoplasms. On the basis of histologic criteria, PTs can be divided into benign, borderline, and malignant groups; however, the histologic distinction of PTs is often difficult and arbitrary. In breast cancer, promoter hypermethylation is a common phenomenon, but there are no data available concerning methylation status in PTs. The aim of this study was to assess whether the methylation profiles support the classification of PTs into three subgroups. A multiplex, nested, methylation-specific polymerase chain reaction approach was used to examine promoter methylation of five genes (GSTP1, HIN-1, RAR-β, RASSF1A, and Twist) in 87 PTs (54 benign, 23 borderline, and 10 malignant). Immunohistochemical staining for GSTP1 was performed using tissue microarray blocks to determine whether GSTP1 promoter hypermethylation correlated with loss of GSTP1 expression. There was a trend of increasing methylation frequency with increasing grade of PTs. The methylation frequency of all genes and the mean number of methylated genes in borderline and malignant PTs were higher than those in benign PTs; however, there were no statistically significant differences between borderline and malignant PTs. GSTP1 promoter hypermethylation was associated with loss of GSTP1 expression (p < 0.001). These results suggest that PTs segregate into only two groups on the basis of their methylation profiles: the benign group and the combined borderline/malignant group.

Epstein-Barr virus–positive nodal T/NK-cell lymphoma: an analysis of 15 cases with distinct clinicopathological features

Nodal peripheral T-cell lymphoma, not otherwise specified, is a heterogeneous entity with variable biologic behavior. We analyze the clinicopathological features of 15 patients with Epstein-Barr virus-positive (EBV+) nodal T/NK-cell lymphoma, including 9 males and 6 females, with a median age of 64 years. All patients presented with multiple lymphadenopathy with common B symptoms (80%, 12/15) at an advanced Ann Arbor stage (III, IV) (87%, 13/15). The International Prognostic Index was high or high/intermediate in 87% (13/15) of patients, and the prognostic index for peripheral T-cell lymphoma was group 3 or 4 in 73% (11/15). Spleen and liver involvement was observed in 73% (11/15) and 60% (9/15) of patients, respectively. In contrast, extranodal involvement was infrequent, with no more than 1 site in 71% (10/15) of patients. Moreover, none had nasal lesions, and only 1 had mucocutaneous involvement. The cell lineage of EBV+ tumor cells was determined to be T cell in all except 1 patient, who was NK-cell lineage. Cytotoxic molecules were expressed in all cases, and 64% (9/14) of patients expressed the αβT-cell receptor. Moreover, most patients (67%, 10/15) showed CD8 positivity, with 2 of them being CD4CD8 double positive; the others were CD4 positive (n = 2) or CD4CD8 double negative (n = 3). The clinical course was very aggressive, with a median survival time of 3.5 months, and 10 patients died within 6 months of diagnosis. Taken together, our data demonstrate that EBV+ nodal T/NK-cell lymphoma is a distinct clinicopathological entity characterized by cytotoxic molecule expression, a frequent CD8-positive αβT-cell lineage, and a very aggressive clinical behavior.

The Prognostic Significance of FGFR4 Gly388 Polymorphism in Esophageal Squamous Cell Carcinoma after Concurrent Chemoradiotherapy

Purpose The purpose of this study is to investigate the role of fibroblast growth factor receptor 4 (FGFR4) polymorphism in esophageal cancer after chemoradiotherapy (CRT). Materials and Methods Peripheral blood samples from 244 patients treated with CRT for esophageal squamous cell carcinoma were assessed for the role of FGFR4 genotype on treatment response and survival. Results A total of 94 patients were homozygous for the Gly388 allele, and 110 were heterozygous and 40 homozygous for the Arg388 allele. No significant association was found between the FGFR4 genotype and clinicopathological parameters. However, patients carrying the Gly388 allele showed a better overall response rate than Arg388 carriers (p=0.038). In addition, Gly388 allele patients at an earlier stage showed better overall survival (OS) and progression-free survival than Arg388 carriers. Among these, the Gly388 allele showed significantly improved OS compared to Arg388 carriers in the lymph node (LN) metastasis group (p=0.042) compared to the no LN metastasis group (p=0.125). However, similar survival outcomes were observed for advanced-stage disease regardless of genotype. Conclusion This result suggests that the role of FGFR4 Gly388 in treatment outcomes differs according to esophageal cancer stage. It showed a predictive role in the response of esophageal cancer patients to CRT with a better trend for OS in Gly388 than Arg388 carriers in the early stages. In particular, LN-positive early-stage patients carrying the Gly388 allele showed improved OS compared to those carrying Arg388.

Utility of Thyroid Transcription Factor-1 and CDX-2 in Determining the Primary Site of Metastatic Adenocarcinomas in Serous Effusions

OBJECTIVE To evaluate the usefulness of thyroid transcription factor-1 (TTF-1) and CDX-2 in determining the primary tumor site of metastatic adenocarcinomas (ACs) in serous effusions. STUDY DESIGN Cell blocks were constructed from cells in metastatic AC effusion fluids (n = 97) that had been previously stained with a panel of antibodies against MOC-31, D2-40 and calretinin. Primary tumor sites included the lungs (n = 52), ovaries (n = 6), pancreas (n = 4), breasts (n = 3), bile duct (n = 2) and gastrointestinal (GI) tract (30), including stomach (n = 28) and colon (n = 2). Primary sites were determined by tissue confirmation of the original tumor or review of the clinical charts. Immunocytochemical staining was performed with antibodies against TTF-1 and CDX-2. RESULTS The lung ACs showed TTF-1 positivity in 58% (30/52) of cases. All nonpulmonary ACs lacked TTF-1 staining. Among the 30 GI ACs, 9 (30%) (7 from the stomach and 2 from the colon) showed CDX-2 positivity. All non-GI ACs lacked CDX-2 staining. Specificities and positive predictive values for TTF-1 and CDX-2 equaled 100% for metastatic pulmonary and GI ACs, respectively. CONCLUSION Our results suggested that TTF-1 and CDX-2 are specific markers to separate metastatic pulmonary and GI ACs, respectively, from other metastatic ACs in serous effusions. However, sensitivity values of these markers were low.

Aggressive angiomyxoma of the lung

Aggressive angiomyxoma (AAM) is a rare mesenchymal neoplasm that usually occurs in the pelvic–perineal region. Only two cases of AAM occurring outside this region have been reported. The case of AAM reported here originated from lung. A 70-year-old woman was admitted for evaluation of an incidentally detected pulmonary mass on chest radiography. Tumour resection under the thoracoscopy was performed. Pathological examination revealed microscopical features that were characteristic of AAM. The features were oval- to spindle-shaped tumour cells in a myxoid stroma, hyalinised thick vessels, and characteristic immunophenotype. The differential diagnosis of AAM and other mesenchymal neoplasms of lung is also discussed.

Giant cell tumor with secondary aneurysmal bone cyst: A unique presentation with an ossified extraosseous soft tissue mass

The authors describe a case of giant cell tumor (GCT) with secondary aneurysmal bone cyst (ABC) in a 44-year-old man with chronic, intermittent knee pain. A unique feature is the presentation of GCT with an ossified extraosseous soft tissue mass. Radiograph demonstrates a multiloculated lytic lesion in the distal meta-epiphyseal region of the femur with an adjacent extraosseous soft tissue mass. The soft tissue mass was partially ossified along its margin and internal septa. MRI demonstrates a multiloculated lesion in the distal femur with multiple fluid–fluid levels and cortical penetration of the lesion. Both the intraosseous lesion and extraosseous soft tissue mass have similar MR signal characteristics. At surgery, the intraosseous component was found to be contiguous with the extraosseous soft tissue mass through a cortical perforation. To the best of our knowledge, this is the first case report of GCT with aneurysmal bone cyst initially presenting with an extraosseous soft tissue mass.

Intravascular Papillary Endothelial Hyperplasia of the Chest Wall Misdiagnosed as a Malignancy on Fine Needle Aspiration

Intravascular papillary endothelial hyperplasia (IPEH) is an exuberant proliferation of endothelial cells that may occur within the lumen of a pre-existing vessel or vascular malformation.1 Although IPEH is regarded as a non-neoplastic reactive process, misdiagnoses as a malignancy have been reported, particularly based on fine needle aspiration (FNA) findings.2-4 We report a case of IPEH on the chest wall that was initially misdiagnosed as an adenocarcinoma on FNA.