Gastric Mucosal Atrophy Impedes Housekeeping Gene Methylation in Gastric Cancer Patients / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Helicobacter pylori infection induces phenotype-stabilizing methylation and promotes gastric mucosal atrophy that can inhibit CpG-island methylation. Relationship between the progression of gastric mucosal atrophy and the initiation of CpG-island methylation was analyzed to delineate epigenetic period for neoplastic transformation. MATERIALS AND METHODS: Normal-appearing gastric mucosa was biopsied from 110 H. pylori–positive controls, 95 H. pylori–negative controls, 99 gastric cancer patients, and 118 gastric dysplasia patients. Gastric atrophy was assessed using endoscopic-atrophic-border score. Methylation-variable sites of eight CpG-island genes adjacent to Alu (CDH1, ARRDC4, PPARG, and TRAPPC2L) or LTR (MMP2, CDKN2A, RUNX2, and RUNX3) retroelements and stomach-specific TFF3 gene were analyzed using radioisotope-labeled methylation-specific polymerase chain reaction. RESULTS: Mean ages of H. pylori–positive controls with mild, moderate, and severe atrophy were 51, 54, and 65 years and those of H. pylori–associated TFF3 overmethylation at the three atrophic levels (51, 58, and 63 years) tended to be periodic. Alu-adjacent overmethylation (50 years) was earlier than TFF3 overmethylation (58 years) in H. pylori–positive controls with moderate atrophy. Cancer patients with moderate atrophy showed late Alu-adjacent (58 years) overmethylation and frequent LTR-adjacent overmethylation. LTR-adjacent overmethylation was frequent in cancer (66 years) and dysplasia (68 years) patients with severe atrophy. CONCLUSION: Atrophic progression is associated with gastric cancer at moderate level by impeding the initiation of Alu-adjacent methylation. LTR-adjacent methylation is increased in cancer patients and subsequently in dysplasia patients.

Prognostic role of beclin-1 in locally advanced non-small cell lung cancer in patients receiving docetaxel-platinum induction chemotherapy

BACKGROUND/AIMS@#The outcome of local treatment for advanced non-small cell lung cancer (NSCLC) remains poor, with therapies such as induction chemotherapy (IC) yielding conflicting results. This study aimed to assess the clinicopathologic and prognostic significance of the excision repair cross-complementation group 1 (ERCC1), beclin-1, and glucose-regulated protein of molecular mass 78 (GRP78) in patients with locally advanced NSCLC receiving docetaxel-platinum IC, along with efficacy and safety.@*METHODS@#This is a retrospective observational cohort study. We reviewed medical records of 31 NSCLC patients receiving docetaxel-platinum IC, and conducted immunohistochemical staining of ERCC1, beclin-1, and GRP78.@*RESULTS@#Response rate was 67.8% with 10.7 months of median relapse-free survival (RFS) and 23.1 months of median overall survival (OS), and no treatment-related death was reported. High expression of ERCC1, beclin-1, and GRP78 was identified in 67.7%, 87.1%, and 67.7%, respectively. Expression of ERCC1 and GRP78 did not reveal statistical significance in survival, whereas high beclin-1 expression revealed longer OS (7.6 months vs. 23.2 months; log-rank p = 0.024). In multivariate analysis, histologic differentiation (hazard ratio [HR], 3.48; p < 0.001), stage (HR, 8.5; p = 0.024), and adjuvant treatment (HR, 16.1; p = 0.001) were related to RFS, and in OS, stage (HR, 5.4; p = 0.037), adjuvant treatment (HR, 8.6; p = 0.004), and beclin-1 expression (HR, 8.2; p = 0.011) were identified as significant prognostic factors.@*CONCLUSIONS@#Our findings suggest that high beclin-1 expression predicts longer survival in locally advanced NSCLC and docetaxel-platinum IC is a treatment option that deserves consideration.

Coronary Arterial Lesions of Kawasaki Disease Observed in a Mouse Model of Sepsis: A Pilot Study and a Review of the Literature

PURPOSE: Coronary arterial lesions (CALs) were reported to have developed in children with systemic inflammatory diseases, as well as those with Kawasaki disease (KD). The purpose of this study was to confirm that the CAL development in children with KD occurs in a mouse model of sepsis presenting typical systemic inflammatory response syndrome (SIRS). METHODS: To induce the sepsis mouse model with SIRS, 6-week-old C57BL/6 mice were intraperitoneally injected with endotoxin. We compared histological findings of the major organs between the control and the sepsis groups and examined CAL in the heart of the septic mice. RESULTS: Infiltrating inflammatory cells were relatively increased in the heart, liver, and kidneys of the sepsis group, compared with those of the control group. We confirmed lymphocytic infiltration in the myocardium (myocarditis) and the pericardial soft tissue of the heart. Furthermore, coronary artery of the septic mouse was identified, but CAL was not observed. CONCLUSIONS: In this study, we failed to confirm the existence of CAL in a mouse model of sepsis. However, it is well-known that CALs are seen in many kinds of diseases that cause SIRS. Our findings suggest further investigation into the clinical significance of CAL in various systemic inflammatory diseases, including KD.

CK20 Negative and CK7 Positive Merkel Cell Carcinoma of the Conjunctiva: Brief Case Report

Merkel cell carcinoma (MCC) is an uncommon but potentially aggressive neuroendocrine carcinoma of the skin. It typically develops on sun-exposed areas of the head and neck, particularly the eyelid, periorbital region, and extremities. We report a case of unusually located MCC, presenting as a conjunctival mass, which has only been reported once in the English literature. An 83-year-old male presented with a 0.8 x 0.7 cm sized mass protruding from the lower fornix of the right conjunctiva. The mass was excised. The tumor was located in the submucosa without connection to the overlying mucosa. Light microscopic findings showed a carcinoma with undifferentiated small round cells and the presence of cytokeratin (CK AE1/3, CK7) and neuroendocrine markers. We established a diagnosis of MCC. As reported in the literature, the majority of MCCs are positive for CK20 but negative for CK7. But, this case showed an uncommon cytokeratin immunohistochemical profile of positive for CK7 and negative for CK20, suggesting a new immunophenotypic MCC variant.

Evaluation of the HPV ISH Assay in Cervical Cancer

BACKGROUND: Human papillomavirus (HPV) infection can be detected by in situ hybridization (ISH), in which a punctate signal pattern indicates integrated HPV DNA and a diffuse pattern denotes the presence of episomal viral DNA. This study was conducted to evaluate the usefulness of an HPV ISH assay for invasive cervical cancer. METHODS: The HPV ISH assay for high-risk HPV and immunohistochemical staining for p16(INK4a), p53, bcl-2, and Ki-67 were performed in a tissue microarray of 279 cervical cancers. RESULTS: High-risk HPV ISH was positive in 194 (69.5%) of the samples. Punctate, diffuse, and mixed signal patterns were observed in 157 (56.3%), one (0.4%), and 36 cases (12.9%), respectively. Positive results in high-risk HPV ISH were associated with p16 and bcl-2 expression (p = 0.01 and p < 0.01, respectively). According to a Cox regression analysis, HPV infection and its surrogate immunohistochemical markers such as p16, bcl-2, and Ki-67 were not independent prognostic factors, but stage and grade were independent prognostic factors. CONCLUSIONS: Our results confirm that an HPV ISH assay is reasonably sensitive for HPV infection and that it might be useful to identify integrated HPV DNA in formalin-fixed and paraffin-embedded specimens. Further study encompassing HPV type, E2/E6 ratio, and therapeutic modality is necessary to understand the clinical meaning of HPV status in cervical cancer.

Evaluation of the HPV ISH Assay in Cervical Cancer

BACKGROUND: Human papillomavirus (HPV) infection can be detected by in situ hybridization (ISH), in which a punctate signal pattern indicates integrated HPV DNA and a diffuse pattern denotes the presence of episomal viral DNA. This study was conducted to evaluate the usefulness of an HPV ISH assay for invasive cervical cancer. METHODS: The HPV ISH assay for high-risk HPV and immunohistochemical staining for p16(INK4a), p53, bcl-2, and Ki-67 were performed in a tissue microarray of 279 cervical cancers. RESULTS: High-risk HPV ISH was positive in 194 (69.5%) of the samples. Punctate, diffuse, and mixed signal patterns were observed in 157 (56.3%), one (0.4%), and 36 cases (12.9%), respectively. Positive results in high-risk HPV ISH were associated with p16 and bcl-2 expression (p = 0.01 and p < 0.01, respectively). According to a Cox regression analysis, HPV infection and its surrogate immunohistochemical markers such as p16, bcl-2, and Ki-67 were not independent prognostic factors, but stage and grade were independent prognostic factors. CONCLUSIONS: Our results confirm that an HPV ISH assay is reasonably sensitive for HPV infection and that it might be useful to identify integrated HPV DNA in formalin-fixed and paraffin-embedded specimens. Further study encompassing HPV type, E2/E6 ratio, and therapeutic modality is necessary to understand the clinical meaning of HPV status in cervical cancer.

C1q Nephropathy: A Distinct Pathologic Entity

BACKGROUND: C1q nephropathy (C1qN) is a controversial diagnostic entity defined by Jennette and Hipp in 1985. The prevalence is very low and a few large scale studies have been reported. Application of the criteria for clinical diagnostics of C1qN may cause confusion with other glomerulonephropathies, such as minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS). In order to clarify the confusion with glomerulonephropathies, we did this study to identify the clinicopathological characteristics and the exact disease entity of C1qN. METHODS: A total of 5,258 kidney biopsies at Kangnam St Mary's Hospital were reviewed. Twenty three cases (0.44%) met the criteria of C1qN. Twenty eight cases showing dominant C1q deposits without electron dense depostis (EDD) grouped as C1q+EDD-, and previously diagnosed typical cases of MCD and FSGS were selected for this study. Four groups were compared to each other with regard to the clinical and pathological aspects of the disease. RESULTS: C1qN patients had an average age of 30.4 years. Eighteen were males and 5 were females. Eighty seven percent had proteinuria and 18% had hematuria. By electron microscopy analysis, 100% had mesangial EDD and 47.8% showed foot process effacement. C1qN had some significant differences compared with C1q+EDD-, MCD and FSGS. CONCLUSIONS: C1qN is clinically and morphologically different from MCD and FSGS. However, additional long term studies are needed to fully define C1qN from other glomerulonephritis with C1q deposits.

HPV in situ hybridization and immunohistochemical expression of L1 capsid protein in cervical intraepithelial neoplasia / 대한산부인과학회지

OBJECTIVE: HPV in situ hybridization (ISH) is able to detect HPV DNA and identify integrated HPV DNA by punctuate staining and episomal HPV by diffuse staining in the nuclei. Because the expression of L1 capsid protein disappears after integration of HPV DNA, immunohistochemistry (IHC) of L1 capsid protein can be used as a indirect evidence of integration. Therefore, we tried to evaluate the usefulness of HPV ISH and IHC of L1 capsid protein in Cervical intraepithelial neoplasia (CIN). METHODS: Twenty six cervical lesions from patients with CIN and 19 normal cervical epithelium from patients with leiomyoma were evaluated with HPV ISH and IHC of L1 capsid protein. RESULTS: HPV ISH was positive in 80.8% (21/26) in CIN. Among 21 positive cases, diffuse staining was observed in 42.9% and punctuated and diffuse staining in 57.1%. L1 capsid protein was positive in 65.4% (17/26) of cervical tissue sections and 15.4% (4/26) of cervical smears. The punctuated staining of HPV ISH was correlated with high grade CIN (P=0.007) but expression of L1 capsid protein was not associated with grade of CIN (P>0.05). CONCLUSION: HPV ISH is a useful tool to identify integrated HPV DNA in paraffin-embedded, formalin-fixed cervical tissue. HPV integration confirmed by HPV ISH was associated with high-grade CIN. IHC of L1 capsid protein showed better result using cytology smears than tissue sections.

The Diagnostic Accuracy of Fine Needle Aspiration Cytology and the Diagnostic Usefulness of Galectin-3 Immunostaining for the Follicular Variant of Papillary Thyroid Carcinoma / 대한세포병리학회지

The cytologic diagnosis of the follicular variant of papillary thyroid carcinoma (FVPTC) has become one of the common causes of false negative diagnoses when performing fine needle aspiration cytology (FNAC) of the thyroid gland. We retrospectively reviewed all the aspirates for which a diagnosis of FVPTC had been made based on the surgically excised specimens, regardless of the cytologic diagnosis. 145 FNACs was performed in 135 patients. The cytologic diagnoses were categorized as 2 unsatisfactory specimens (1.4%), 16 benign (11.0%), 49 atypical (33.8%) and 78 malignant lesions (53.8%). The tumor cells consistently showed significant nuclear overlapping, irregular nuclei and fine chromatin in all cases; however, nuclear grooves and inclusions were scarce. Galectin-3 immunostaining was performed on the cell blocks of 65 cases and this was positive for 45 cases (69.2%). The results of our study demonstrate that the determination of minimal cytologic criteria is needed to raise the sensitivity of detecting FVPTC by FNAC, and galectin-3 immunostaining is useful to make decisions on the surgical treatment of cytologically atypical thyroid nodules.

A Case of Bronchioloalveolar Carcinoma Presenting Adult-onset Still's Disease-like Manifestations due to Paraneoplastic Syndrome / 대한류마티스학회지

Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder with the characteristics of high spiking fever, evanescent salmon-colored skin rash, arthralgia or arthritis, lymphadenopathy, hepato-splenomegaly, sore throat, leukocytosis, negative autoantibody and hyperferritinemia. There are reports that rheumatic diseases such as dermatomyositis, polymyositis, hypertrophic osteoarthropathy, and polymyalgia rheumatica are associated with neoplasms. And small cell lung cancer, thymoma, lymphoma, leukemia, and breast cancer are known to be more associated with paraneoplastic syndromes mimicking rheumatic diseases. We experienced a case with bronchioloalveolar carcinoma who developed clinical manifestations of AOSD. Although there are several reports that AOSD is associated with paraneoplastic syndrome, to our knowledge, this is the first case of bronchioloalveolar carcinoma mimicking AOSD reported in the world.

Fine Needle Aspiration Cytology of Invasive Micropapillary Carcinoma of the Breast / 대한세포병리학회지

Invasive micropapillary carcinoma (IMPC) of the breast is recently described rare variant of invasive ductal carcinoma. This variant has a distinctive histological features and aggressive biological behavior. We reviewed the cytologic features of eight cases of IMPC. The cytologic smears showed moderate to high cellularity and the tumor tissue was composed of atypical, angulated, cohesive clusters of neoplastic cells with a papillary to tubuloalveolar architecture, and a morular growth pattern without fibrovascular cores was seen on the histopathology. IMPC of the breast has distinctive cytologic features and it is important to make an early diagnosis via fine needle aspiration cytology due to this tumor's aggressive behavior.

Pigmented Trichogerminoma: A Case Report

Trichogerminoma is a rare cutaneous adnexal tumor that dysplays differentiation toward the hair germ epithelium. This tumor was first described by Sau et al. in 1992 and it is characterized by densely packed round nests or cell balls resembling hair bulbs. Herein, we report on a deeply pigmented and sharply circumscribed nodular tumor that was excised on the abdomen of a 48-year-old woman. Histologically the tumor involved both dermis and subcutis without any epidermal connection. The main nodule was subdivided into the smaller lobules by fibrous stroma. The lobules were composed of masses of basaloid cells that displayed peripheral palisading. Within the lobules, the basaloid cells formed numerous cell balls. The tumor presented the characteristic features of trichogerminoma. Interestingly, our case was the pigmented type, which was remarkable by virtue of the heavy melanin deposits found within and around the tumor nests. To the best of our knowledge, this is the first case of pigmented trichogerminoma that has been reported worldwide.

Expression of Cell Cycle-Regulatory Proteins in Rectal Cancer: Significance of the Tumor Response to Preoperative Radiochemotherapy and for the Prognosis

BACKGROUND: Preoperative radiochemotherapy (PRCT) improves the outcomes for patients suffering with locally advanced rectal carcinoma, compared with surgery alone. However, there are no reliable factors predicting the survival and therapeutic benefits. METHODS: The cell-cycle regulatory proteins were investigated in the pretreatment biopsies from 68 patients who were suffering with rectal cancer by performing immunohistochemical studies of p53, p21, cyclin D1, Rb and p16 protein. The tumor response was graded on a three-scale grading system: no response (NR), partial remission (PR) and complete remission (CR). RESULTS: The tumors were positive for p53, p21 and cyclin D1 in 46 (67.6%), 32 (47.1%) and 14 (20.6%) cases, respectively. Abnormalities in Rb immunostaining were observed in 9 (13.2%) cases, while an abnormal p16 expression was noted in 59 (86.8%) tumors. Forty-two patients (61.8%) responded to PRCT: 18 (26.5%) cases achieved a CR and 24 (35.3%) cases achieved a PR. None of the above molecular markers were significantly associated with tumor response. However, the altered expression of p16 showed a significant correlation with overall survival (p=0.001). The high expression of p21 demonstrated a trend for longer survival (p=0.061). CONCLUSIONS: Of the cell-cycle regulatory proteins, p16 may be a valuable marker for to predict rectal cancer patients' survival; however, the role of each cell-cycle regulatory protein for the therapeutic benefits of PRCT needs to be further studied.

Ectopic Sebaceous Glands in the Esophagus: A Case Report

There are few reports of the endoscopic and histological features of ectopic sebaceous glands in the esophagus. Recently we observed a 2 mm whitish flat elevated nodule in the lower esophagus. A biopsy was taken under the clinical impression of a papilloma or ulcer scar. Histology revealed normal esophageal mucosa with mature ectopic sebaceous glands located in the lamina propria with no visible hair follicles. We report this case with a brief review of the literature related to the histological findings and histogenesis of esophageal ectopic sebaceous glands.