Mixed Carcinoma as an Independent Prognostic Factor in Submucosal Invasive Gastric Carcinoma

Mixed carcinoma shows a mixture of glandular and signet ring/poorly cohesive cellular histological components and the prognostic significance of each component is not fully understood. This study aimed to investigate the significance of the poorly cohesive cellular histological component as a risk factor for lymph node metastasis and to examine the diagnostic reliability of endoscopic biopsy. Clinicopathologic characteristics of 202 patients who underwent submucosal invasive gastric carcinoma resection with lymph node dissection in 2005-2012 were reviewed. Mixed carcinoma accounted for 27.2% (56/202) of cases. The overall prevalence of lymph node metastasis was 17.3% (35/202). Lymphatic invasion (P < 0.001), family history of carcinoma (P = 0.025), tumor size (P = 0.004), Lauren classification (P = 0.042), and presence of any poorly cohesive cellular histological component (P = 0.021) positively correlated with the lymph node metastasis rate on univariate analysis. Multivariate analyses revealed lymphatic invasion, family history of any carcinoma, and the presence of any poorly cohesive cellular histological component to be significant and independent factors related to lymph node metastasis. Review of preoperative biopsy slides showed that preoperative biopsy demonstrated a sensitivity of 63.6% and a specificity of 100% in detecting the presence of the poorly cohesive cellular histological component, compared with gastrectomy specimens. The presence of any poorly cohesive cellular histological component was an independent risk factor associated with lymph node metastasis in submucosal invasive gastric carcinoma. Endoscopic biopsy had limited value in predicting the presence and proportion of the poorly cohesive cellular histologic component due to the heterogeneity of mixed carcinoma.

Expression of Peroxisome Proliferato Activated Receptor gamma in Prostatic Adenocarcinoma

Peroxisome proliferator-activated receptor gamma (PPAR-gamma), a ligand-activated transcription factor has been investigated as the target for cancer treatment as well as metabolic disorders. Recent studies have demonstrated that PPAR-gamma ligands are anti-tumorigenic in prostate cancer due to anti-proliferative and pro-differentiation effects. The aim of this study was to validate PPAR-gamma expression in malignant and benign prostate tissues by immunohistochemistry and quantitative real-time polymerase chain reaction (PCR). A total of 730 prostatic adenocarcinomas (PCAs) including 63 whole sections from radical prostatectomy specimens and tissue microarrays containing 667 PCAs were subject to immunostaining for two PPAR-gamma antibodies. Twenty-five benign prostate tissues and PCAs were selected for investigating mRNA expression by quantitative real-time PCR. 10.7% of PCAs (78/730) showed cytoplasmic immunoreactivity of PPAR-gamma and no nuclear immunoreactivity was noted in PCAs. Most benign prostatic glands showed negative immunoreactivity of PPAR-gamma except for variable weak cytoplasmic staining in some glands. Nuclear immunoreactivity of PPAR-gamma was noted some central zone and verumontanum mucosal epithelium. The constitutive PPAR-gamma mRNA showed significantly lower level in PCAs compared to that in the benign tissues. There was no difference of PPAR-gamma mRNA expression between low (7) Gleason score groups. There was no association of PPAR-gamma mRNA level or cytoplasmic immunostaining with Gleason grade or pathologic stage. Our study supported the evidence of extra-nuclear localization and nongenomic actions of PPAR-gamma. Further studies are needed to assess the functional role of PPAR-gamma and to validate its therapeutic implication in prostate cancer.

Molecular Diagnosis for Cytologically Indeterminate Thyroid Nodules

An accurate diagnosis of cancer or benign disease is important for the effective clinical management of the patients. Thyroid fine needle aspiration cytology (FNAC) is a safe and cost effective technic for evaluating thyroid nodules. However, 20-30% of thyroid FNAC specimens are indeterminate and fall into one of the following categories; AUS/FLUS (atypical ceils of undetermined significance/follicular cells of undetermined significance), FN/SFN (follicular neoplasm/suspicious for follicular neoplasm), and SMC (suspicious for malignant cells). The AUS/FLUS, FN/SFN, and SMC diagnostic category is associated with a 5-15%, 15-30%, and 60-75% risk of malignancy, respectively. Of the indeterminate thyroid nodules that are surgically resected, 10-40% were confirmed to be malignant. A significant progress has been made in the development of molecular tests for cancer diagnosis in thyroid nodules. Most common molecular alteration in thyroid cancer is the activation of mitogen-activated protein kinase (MAPK) pathway. Activation of this pathway in thyroid cells results from point mutation of BRAF and RAS genes and rearrangement of RET/PTC and NTRK genes and these genetic alterations are mutually exclusive. Preoperative molecular diagnostic techniques could be applied in FNAC specimen when optimum dissection techniques are provided to collect sufficient numbers of target cells without contamination of blood cells, inflammatory cells including histiocytes, and stromal cells. The optimum number of cells for PCR is about 100 although as few 50 cells has been successful. To obtain a good DNA yield from a very limited number of target cells, avoid DNA loss as much as possible.

Radiologic and Pathologic Findings of a Follicular Variant of Papillary Thyroid Cancer with Extensive Stromal Fat: A Case Report

Thyroid cancer may have small adipose structures detected by microscopy. However, there are no reports of thyroid cancer with gross fat evaluated by radiological methods. We reported a case of a 58-year-old woman with a fat containing thyroid mass. The mass was hyperechoic and ovoid in shape with a smooth margin on ultrasonography. On computed tomography, the mass had markedly low attenuation suggestive of fat, and fine reticular and thick septa-like structures. The patient underwent a right lobectomy. The mass was finally diagnosed as a follicular variant of papillary thyroid cancer with massive stromal fat.

Neuroendocrine Dysplasia Combined in a Tubular Adenoma of Rectum: A Case Report

No abstract available.

Erratum: Correction of Acknowledgments. ERG Immunohistochemistry as an Endothelial Marker for Assessing Lymphovascular Invasion

The Acknowledgments were marked incorrectly.

A Case of Multifocal Papillary Thyroid Carcinoma Consisting of One Encapsulated Follicular Variant with BRAF K601E Mutation and Three Conventional Types with BRAF V600E Mutation

Multifocal papillary thyroid carcinoma (mPTC) comprises about 20-30% of PTC. In mPTC, individual tumor foci can be identical or frequently composed of different histological types including follicular, solid, tall-cell or conventional patterns. We report a case of mPTC consisting of one encapsulated follicular variant of papillary thyroid carcinoma (FVPTC) and three conventional PTCs in a 44-year-old woman. This case genetically demonstrates unique features including the simultaneous presence of the BRAF V600E (T1799A) mutation and the BRAF K601E (A1801G) mutation in conventional PTC and FVPTC, respectively.

ERG Immunohistochemistry as an Endothelial Marker for Assessing Lymphovascular Invasion

BACKGROUND: ERG, a member of the ETS family of transcription factors, is a highly specific endothelial marker. We investigated whether the use of ERG immunostaining can help pathologists detect lymphovascular invasion (LVI) and decrease interobserver variability in LVI diagnosis. METHODS: Fifteen cases of surgically resected colorectal cancers with hepatic metastasis were selected and the most representative sections for LVI detection were immunostained with ERG, CD31, and D2-40. Eight pathologists independently evaluated LVI status on hematoxylin and eosin (H&E) and the corresponding immunostained sections and then convened for a consensus meeting. The results were analyzed by kappa (kappa) statistics. RESULTS: The average rate of LVI positivity was observed in 43% with H&E only, 10% with CD31, 29% with D2-40, and 16% with ERG. Agreement among pathologists was fair for H&E only (kappa=0.27), D2-40 (kappa=0.21), ERG (kappa=0.23), and was moderate for CD31 (kappa=0.55). Consensus revealed that ERG nuclear immunoreactivity showed better visual contrast of LVI detection than the other staining, with improved agreement and LVI detection rate (kappa=0.65, LVI positivity rate 80%). CONCLUSIONS: The present study demonstrated a superiority with ERG immunostaining and indicated that ERG is a promising panendothelial marker that might help pathologists increase LVI detection and decrease interobserver variability in LVI diagnosis.

Rhabdoid Colorectal Carcinomas: Reports of Two Cases

Rhabdoid colorectal carcinomas are very rare and only 10 cases have been previously reported. We report two cases of rhabdoid colorectal carcinoma, one arising in the sigmoid colon of a 62-year-old man and another in the rectum of an 83-year-old woman. In both cases, the patients had advanced tumors with lymph node metastases. The tumors mostly showed a diffuse arrangement with rhabdoid features and small glandular regions were combined. Transitional areas from the adenocarcinomas to the rhabdoid tumors were also noted. Adenocarcinoma cells were positive for mixed cytokeratin (CK), CK20 and epithelial membranous antigen (EMA), but focal positive for vimentin. The rhabdoid tumor cells were positive for mixed CK, but focal positive or negative for CK20 and EMA. In addition, they were diffusely positive for vimentin, but negative for desmin. The histological and immunohistologial findings of these two cases suggest that the rhabodid tumor cells originated from dedifferentiated adenocarcinomas.

Familial Amyloidotic Polyneuropathy With Transthyretin Gene Mutation

Familial amyloidotic polyneuropathy (FAP) is a rare hereditary amyloidosis that is characterized by slowly progressive peripheral polyneuropathy with other systemic involvement. More than 100 amyloidogenic transthyretin gene mutations have been reported, mainly in endemic areas of Portugal, Japan, and Sweden. We describe two brothers who exhibited progressive painful sensorimotor polyneuropathy with autonomic dysfunction. Gene analysis revealed a heterozygous Asp38Ala substitution in the transthyretin gene; this represents the first reported case of FAP in Korea.

Prognostic Implication of Programmed Death-1-Positive Tumor-infiltrating Lymphocytes in Diffuse Large B-Cell Lymphoma

BACKGROUND: Programmed death-1 (PD-1) is physiologically expressed by germinal center-associated helper T-cells and has an inhibitory effect on T-cell activity. METHODS: We examined 63 cases of diffuse large B-cell lymphoma (DLBCL) and determined the number of PD-1-positive helper T-cells in a representative tumor area after immunohistochemical staining using a monoclonal antibody against PD-1. The PD-1-positive cells were counted in 3 high-power fields (HPFs; 400x). RESULTS: Patients were divided into 2 groups: one with a high number of PD-1-positive cells (>20/HPF, n=33) and one with a low number of PD-1-positive cells (< or =20/HPF, n=30). The former group showed decreased overall survival, but at a statistically non-significant level (p=0.073). A high number of PD-1-positive cells was more common in patients at an advanced clinical stage and with high international prognostic index score (p=0.025 and p=0.026, respectively). The number of extranodal sites also somewhat correlated with the PD-1 staining status (p=0.071). However, the number of PD-1-positive cells was not associated with patient age, serum lactate dehydrogenase level, and Eastern Cooperative Oncology Group performance score. CONCLUSIONS: The high number of PD-1-positive cells might be associated with an unfavorable outcome in DLBCL patients.

A Consideration of MGMT Gene Promotor Methylation Analysis for Glioblastoma Using Methylation-Specific Polymerase Chain Reaction and Pyrosequencing

BACKGROUND: O6-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation is currently the most promising predictive marker for the outcome and benefit from temozolomide treatment in patients with glioblastoma, but there is no consensus on the analysis method for assessing the methylation status in the molecular diagnostic field. The objective of this study was to evaluate methylation-specific polymerase chain reaction (MSP) and pyrosequencing methods for assessing MGMT gene promotor methylation of glioblastoma as well as assessing the MGMT protein expression by immunohistochemistry. METHODS: Twenty-seven cases of glioblastoma from the archives at the Department of Pathology Konkuk University Hospital were selected. MGMT promoter methylation was evaluated by MSP and the pyrosequencing methods. The MGMT expression was also measured at the protein level by immunohistochemistry. RESULTS: Overall, MGMT hypermethylation was observed in 44.4% (12/27 cases) of the case of glioblastoma using either MSP or pyrosequencing. The concordant rate was 70.3% (19/27 cases) between MSP and pyrosequencing for MGMT methylation. There was no correlation between MGMT methylation and the protein expression. No significant differences in progression free survival and overall survival were seen between the methylated group and the unmethylated group by using either MSP or pyrosequencing. The status of the MGMT protein expression was correlated with progression free survival (p=0.026). CONCLUSIONS: In this study the concordance rate between MSP and the pyrosequencing methods for assessing MGMT gene promotor methylation was relatively low for the cases of glioblastoma. This suggests that more reliable techniques for routine MGMT methylation study of glioblastoma remain to be developed because of quality control and assurance issues.

Clinical Usefulness of SurePath(TM) Liquid-based Cytology in Thyroid Fine Needle Aspiration: Comparison with the Conventional Smear in Diagnostic Efficacy and Applicability of BRAF Mutation Test

BACKGROUND: Recently, liquid-based cytology (LBC) has been introduced as an alternative to the conventional smear (CS) technique in thyroid fine needle aspiration, due to its diagnostic convenience. METHODS: We assessed 77 cases of thyroid fine needle aspiration using the SurePath(TM) method (SP) as LBC and CS via split-sample techniques. BRAF mutation tests were carried out via polymerase chain reaction and pyrosequencing immediately after diagnosis or a delay of more than one year. RESULTS: In a comparison between SP and CS, the rate of concordance between SP and CS was as high as 84.4% (kappa value, 0.754). In comparison with histologic diagnosis, the overall sensitivity was 100% for both. The specificity was 62.5% for SP and 56.3% for CS. Relative to CS, papillary carcinomas on SP slides revealed more accentuated nuclear irregularities, nucleoli, and reduced nuclear size. In contrast to CS, the delayed BRAFV600E mutation test using SP slides after 1-2 years failed. The use of new primers amplifying shorter product size could help the delayed test achieve success. CONCLUSIONS: Differences in the diagnostic efficacy of SP and CS were negligible. The failure of the delayed BRAF mutation test on the SP slides might be associated with DNA degradation.

Desmoplastic Small Round Cell Tumor with Ovarian Involvement: A Case Report

Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive neoplasm that preferentially involves the abdominal and pelvic cavities in relatively young males. We present a rare case of DSRCT arising in the ovary of a 16-year-old girl. During surgery, a 15 cm-sized huge mass was noted in the right ovary and wide spreading of the tumor was identified in the left ovary, uterine wall, and omentum and bowel wall. Histological investigation showed nests of small round cells with round nuclei and scanty eosinophilic cytoplasm accompanied with dense desmoplastic stroma. The immunohistochemistry showed that the tumor coexpressed epithelial, mesenchymal, and neuronal markers. The tumor cells ultrastructurally showed poorly developed cell junctions and occasionally showed intracytoplasmic aggregates of intermediate filaments. Molecular analysis of the tumor revealed chromosomal translocation t(11:22)(p13;q12) associated with the EWS-WT1 fusion protein. DSRCT should be included in the differential diagnosis of ovarian neoplasms in young patients.

Molecular Biologic Techniques in Cytopathologic Diagnosis

Molecular diagnosis is an application of the knowledge on molecular mechanisms of disease to diagnosis, therapeutic decision-making, and prognostication. Basically any molecular diagnostic technique could be used in molecular diagnostic cytopathology. Currently applicable molecular techniques in the cytopathology field include PCR based molecular techniques (SSCP, DHPLC, RFLP, LOH, MSI, RT-PCR, QRT-PCR, allele-specific PCR, sequencing, and methylation analysis), FISH, cDNA microarray, aCGH, and reverse-phase protein microarray, etc. Exfoliative cytology as well as fine needle aspiration cytology specimen can be used for analysis. In order to obtain a successful result, collection of target cells without contamination of the blood cells, inflammatory cells including histiocytes, and stromal cells, and a good DNA yield are most important. Molecular diagosis finds its full meaning when interpreted by those who can combine the clinical background of the disease with morphological, immunocytochemical, and molecular diagnostic results. Therefore, these assays would fulfill their full potential when interpreted by the cytopathologists.

Hyperplastic Polyposis Associated with Two Synchronous Colon Cancers

Hyperplastic polyps are common large-bowel tumors, are frequently detected in middle- to old- aged people, and usually are minuscule lesions in the distal colon and rectum. Most hyperplastic polyps have no malignant potential, but recent studies suggest that some hyperplastic polyps can progress to colorectal cancers, possibly by the so-called serrated pathway. Hyperplastic polyposis is a rare syndrome characterized by multiple hyperplastic polyps, primarily in the proximal colon. Different from sporadic hyperplastic polyps, hyperplastic polyposis is alleged to have high potential for malignancy because patients with this syndrome may frequently have conventional adenomas, serrated adenomas, and adenocarcinomas. We report the case of a patient with hyperplastic polyposis, who had two synchronous colon cancers, as well as sessile serrated adenomas and tubular adenomas.

Sonic Hedgehog Expression in Colorectal Neoplasms

BACKGROUND/AIMS: Dysregulation of the hedgehog pathway has been implicated in regeneration and carcinogenesis, leading to the expression of the sonic hedgehog (Shh) protein in gastrointestinal neoplasms. The expression of Shh in colon neoplasms and paired normal colonic mucosa was therefore investigated. METHODS: Forty-four colon cancers and 73 colon adenomas that were removed by surgical colectomy or colon polypectomy between August 2005 and August 2006 were included. Colorectal neoplasms and the adjacent normal colon tissue were examined by immunohistochemistry using rabbit polyclonal Shh antibody. RESULTS: Expression of Shh was up-regulated in adenomas and adenocarcinomas of the colon compared to normal colon tissues (p<0.001). The degree of Shh expression was not associated with the size, shape, or, location of the tumor, or as the age and gender of the patient. In normal colonic epithelium, Shh was expressed at the apex of the crypts and in a few basally-located cells. CONCLUSIONS: Higher levels of Shh expression in colonic adenoma and adenocarcinoma suggest that Shh is required during epithelial proliferation in the colon. Hedgehog signaling is likely to be associated with early tumorigenesis in colonic neoplasms.

Presence of Iron in Colorectal Adenomas and Adenocarcinomas

BACKGROUND/AIMS: Iron overload reportedly increases the risk of colorectal neoplasms, but the distribution of tissue iron in a colorectal neoplasm remains controversial. In this study, we attempted to determine the significance of tissue iron in colorectal adenomas and adenocarcinomas. METHODS: This study investigated 138 colorectal neoplasms (54 adenocarcinomas, 25 adenomas with high-grade dysplasia, and 59 adenomas with low-grade dysplasia) that were removed by surgical or endoscopic resection in Konkuk University Hospital between August 2005 and August 2006. Adjacent normal colon tissues and colorectal neoplasms were stained with Perls' Prussian blue to reveal ferric compounds. RESULTS: Positive Perls' staining was evident in 35.2% (19/54) of the adenocarcinomas and 22.6% (19/84) of the adenomas, and in only 2.2% (3/138) of the samples of adjacent normal colon tissue (p<0.001). Iron appears to reside exclusively in the stroma and outside the gland, rather than in the epithelial cells. Iron expression was strong in larger (p=0.004) and pedunculated (p<0.001) adenomas, and in all types of adenocarcinomas regardless of their size, shape, and location. CONCLUSIONS: The frequent presence of iron in the stroma of large adenomas, pedunculated adenomas, and adenocarcinomas indicates that iron deposition is a secondary phenomenon to intralesional hemorrhage rather than a consequence of epithelial-cell carcinogenesis.

Clinical Efficacy of Human Papillomavirus DNA Detection in Urine from Patients with Various Cervical Lesions

A considerable number of adult Korean women avoid a Pap smear due to fear and discomfort of the pelvic examination. A reliable but noninvasive and comfortable screening method would considerably increase the participation rate. To evaluate the clinical efficacy of urine-based human papillomavirus (HPV) detection by oligonucleotide microarray, the results of HPV test from matched cervical swab specimens were compared. HPV DNA was detected in 70 of 100 cervical samples. HPV 16 was the most prevalent type (38/70), followed by types 18, 58, 52, 33, 35, 31, and 51. HPV DNA was identified in 47 of 90 urine samples. HPV 16 was the most prevalent type (30/45), followed by types 18, 52, 35, 51, 58, 33, and 56. The HPV detection rates of the cervical swabs increased in accordance with the severity of the cytologic and histologic diagnosis. The type specific agreement of HPV DNA tests between cervical swabs and urine was good in HPV 16 (kappa index=0.64 [95% CI: 0.50-0.79]), 18, 52, and 58 and fair in HPV 33 and 35. We propose that a urine HPV test is a valuable adjunctive method for a conventional Pap smear and can be used in population screening for cervical cancer in countries where it is difficult to obtain colposcopic specimens for cultural or religious reasons.

Polymorphisms in ERCC1 and ERCC2/XPD and Survival in Non-Small-Cell Lung Cancer Patients Treated with Cisplatin Based Chemotherapy

PURPOSE: The expressions of low levels of ERCC1 (excision repair crosscomplementation group 1) and ERCC2/XPD (excision repair cross- complementation group 2) have been studied in order to find a potential marker for predicting the prognosis or treatment response in cancer patients. However, polymorphisms in these genes have been rarely evaluated in terms of predicting the survival of cancer patients. MATERIALS AND METHODS: We investigated whether these polymorphisms had an effect on the response to chemotherapy and on the survival in 109 patients, with non-small-cell lung cancer, treated with cisplatin plus gemcitabine, paclitaxel or docetaxel. The polymorphisms of ERCC1 Asn118Asn (C->T), ERCC2 Lys751Gln and Asp312Asn were evaluated using a SNaPshot kit. RESULTS: The treatment responses showed no statistically significant differences according to the polymorphisms of ERCC1 Asn118Asn, ERCC2 Lys751Gln or Asp312Asn. The median survival time was 376 days (95% CI, 291~488). The overall survival rate showed no significant difference according to age, sex, chemotherapy regimen, clinical stage or sequential radiation therapy. The polymorphisms of ERCC2 Lys751Gln and Asp312Asn did not affect the survival of the patients (p=0.4711 and 0.4542, respectively). The polymorphism of ERCC1 Asn118Asn, chemotherapy response, performance status and body weight loss had effect on the overall survival of the patients (p=0.0001, 0.0001, 0.0176 and 0.0082 respectively). As for survival rate, according to the polymorphism in ERCC1 Asn118Asn, the median survival time in those patients showing the wild genotype (C/C) was 480 days (95% CI, 333~544), which was statistically significant compared with the 281 days for the patients with the variant genotype (T/T, C/T) (hazard ratio 3.497) (95% CI, 214~376). CONCLUSION: It is suggested that the presence of the wild genotype in ERCC1 Asn118Asn, in non-small-cell lung cancer patients treated with cisplatin based chemotherapy, was a surrogate marker for predicting a better survival.