Background: Liver biopsy is the essential method to diagnose non-alcoholic steatohepatitis (NASH), but histological features of NASH are too subjective to achieve reproducible diagnoses in early stages of disease. We aimed to identify the key histological features of NASH and devise a scoring model for diagnosis. Methods: Thirteen pathologists blindly assessed 12 histological factors and final histological diagnoses (`not-NASH,' `borderline,' and `NASH') of 31 liver biopsies that were diagnosed as non-alcoholic fatty liver disease (NAFLD) or NASH before and after consensus. The main histological parameters to diagnose NASH were selected based on histological diagnoses and the diagnostic accuracy and agreement of 12 scoring models were compared for final diagnosis and the NAFLD Activity Score (NAS) system. Results: Inter-observer agreement of final diagnosis was fair (kappa = 0.25) before consensus and slightly improved after consensus (kappa =0.33). Steatosis at more than 5% was the essential parameter for diagnosis. Major diagnostic factors for diagnosis were fibrosis except 1C grade and presence of ballooned cells. Minor diagnostic factors were lobular inflammation (>= 2 foci/x 200 field), microgranuloma, and glycogenated nuclei. All 12 models showed higher inter-observer agreement rates than NAS and post-consensus diagnosis (kappa = 0.52-0.69 vs. 0.33). Considering the reproducibility of factors and practicability of the model, summation of the scores of major (x 2) and minor factors may be used for the practical diagnosis of NASH. Conclusions: A scoring system for the diagnosis of NAFLD would be helpful as guidelines for pathologists and clinicians by improving the reproducibility of histological diagnosis of NAFLD.

Background: The Korean Society of Pathologists (KSP) and the Korean Society for Cytopathology (KSC) have held the Korean-Mongolian International Joint Workshop on Pathology and Cytopathology every year since 2007. We introduce the activities of KSP/KSC in Mongolia for eight years.Methods: The Joint Workshops have several characteristics. First, Korean pathologists have shown that pathologists can perform medical services to overseas public society by education. Second, it is the first international cooperative education project which KSP/KSC has carried out. Third, it is not a temporary event but a long-lasting continuous educational program held in the capital as well as in the cities of provinces, Mongolia. Fourth, KSP/KSC has helped setting up the laboratories as well as has supplied reagents and instruments for Papanicolaou staining. KSP/KSC has also educated Mongolian pathologists and cytotechnologists for diagnosis and PAP screening. Fifth, the members of KSP/KSC have performed volunteer services paying all the travel expenses by themselves.Results: In Ulan Baator, the Joint Workshops have been held seven times since 2007. The education program has covered all the fields of pathology starting from cervicovaginal smear. Since 2008, the Joint Workshops have been held in the cities of Mongolian provinces including Dornod/Choibalsan, Arhangay, Orkon/Erdenet Umnugovi and Ulaangom/Uvs. The number of Mongolian attendees was increased from 60 (2007) to 206 (2014). The members of KSP/KSC who participated in the Joint Workshops increased from nine to 18. In addition, the members of KSP/KSC have invited Mongolian pathologists and technologists to Korea for training in their departments.Conclusions: The KSP and KSC are proud of continuing the Korean-Mongolian International Joint Workshops on Pathology and Cytopathology for eight years. We believe that the Joint Workshops have strengthened the Korean-Mongolian relationship and have expanded Mongolian pathologist’s knowledge and experience in pathologic diagnosis, new technologies and quality assurance. Background: The Korean Society of Pathologists (KSP) and the Korean Society for Cytopathology (KSC) have held the Korean-Mongolian International Joint Workshop on Pathology and Cytopathology every year since 2007. We introduce the activities of KSP/KSC in Mongolia for eight years. Methods: The Joint Workshops have several characteristics. First, Korean pathologists have shown that pathologists can perform medical services to overseas public society by education. Second, it is the first international cooperative education project which KSP/KSC has carried out. Third, it is not a temporary event but a long-lasting continuous educational program held in the capital as well as in the cities of provinces, Mongolia. Fourth, KSP/KSC has helped setting up the laboratories as well as has supplied reagents and instruments for Papanicolaou staining. KSP/KSC has also educated Mongolian pathologists and cytotechnologists for diagnosis and PAP screening. Fifth, the members of KSP/KSC have performed volunteer services paying all the travel expenses by themselves. Results: In Ulan Baator, the Joint Workshops have been held seven times since 2007. The education program has covered all the fields of pathology starting from cervicovaginal smear. Since 2008, the Joint Workshops have been held in the cities of Mongolian provinces including Dornod/Choibalsan, Arhangay, Orkon/Erdenet Umnugovi and Ulaangom/Uvs. The number of Mongolian attendees was increased from 60 (2007) to 206 (2014). The members of KSP/KSC who participated in the Joint Workshops increased from nine to 18. In addition, the members of KSP/KSC have invited Mongolian pathologists and technologists to Korea for training in their departments. Conclusions: The KSP and KSC are proud of continuing the Korean-Mongolian International Joint Workshops on Pathology and Cytopathology for eight years. We believe that the Joint Workshops have strengthened the Korean-Mongolian relationship and have expanded Mongolian pathologist’s knowledge and experience in pathologic diagnosis, new technologies and quality assurance.

Primary hepatic paraganglioma is an extremely rare type of tumor originating from extra-adrenal chromaffin cells. We report a case of primary intrahepatic paraganglioma in a 52-year-old man, with pathologic confirmation through right hepatectomy. An imaging study indicated a predominately hemorrhagic septated cystic mass and peripheral marked enhancement of the solid portions, which showed persistent enhancement.

Background: The histomorphologic criteria for the pathological features of liver tissue from patients with non-alcoholic fatty liver disease (NAFLD) remain subjective, causing confusion among pathologists and clinicians. In this report, we studied interobserver agreement of NAFLD pathologic features and analyzed causes of disagreement. Methods: Thirty-one cases of clinicopathologically diagnosed NAFLD from 10 hospitals were selected. One hematoxylin and eosin and one Masson's trichrome-stained virtual slide from each case were blindly reviewed with regard to 12 histological parameters by 13 pathologists in a gastrointestinal study group of the Korean Society of Pathologists. After the first review, we analyzed the causes of disagreement and defined detailed morphological criteria. The glass slides from each case were reviewed a second time after a consensus meeting. The degree of interobserver agreement was determined by multi-rater kappa statistics. Results: Kappa values of the first review ranged from 0.0091-0.7618. Acidophilic bodies (k = 0.7618) and portal inflammation (k = 0.5914) showed high levels of agreement, whereas microgranuloma (k = 0.0984) and microvesicular fatty change (k = 0.0091) showed low levels of agreement. After the second review, the kappa values of the four major pathological features increased from 0.3830 to 0.5638 for steatosis grade, from 0.1398 to 0.2815 for lobular inflammation, from 0.1923 to 0.3362 for ballooning degeneration, and from 0.3303 to 0.4664 for fibrosis. Conclusions: More detailed histomorphological criteria must be defined for correct diagnosis and high interobserver agreement of NAFLD.

Zosteriform metastasis from malignant melanoma is a rare type of skin metastasis that shows cutaneous lesions including patches, plaques, and nodules along with dermatomes, and thus needs to be distinguished from herpes zoster skin infection. Although some authors have explained the mechanism of zosteriform metastasis, its pathogenesis remains unknown. Herein, we describe an 85-year-old woman with zosteriform metastasis of malignant melanoma arising in a medium-sized congenital melanocytic nevus. (Korean J Dermatol 2015;53(9):708∼712)

The tumor microenvironment is known to play a critical role in tumor progression, invasion and metastasis. The epithelial-to-mesenchymal transition (EMT) is understood as a process of tumor invasion and metastasis. Therefore, we investigated the relation between the EMT and the microenvironment of colorectal carcinoma (CRC). The histological features and expression of EMT markers in tumor cells and surrounded stromal cells were obtained from the surgically resected tissues of 39 patients using microscopic review and immunohistochemistry. The loss of expression of E-cadherin was more prominent in the invasive front of tumor than the surface, where α-smooth muscle actin-positive carcinoma-associated fibroblasts (CAFs) are accumulated. The signaling molecules of the Wnt and TGF-β1-Smad pathway were expressed more frequently in the tumor cells and/or CAFs of the invasive margin than those of the tumor surface. The expressions of related transcription factors, such as SNAIL and ZEB1, were increased in the tumor cells and CAFs. The process of EMT may be activated in the tumor margin of CRC under the control of CAFs. Related signaling molecules and transcription factors might be induced by paracrine effects of the surrounding CAFs.

Reports of constitutional ring chromosome 22, r(22) are rare. Individuals with r(22) present similar features as those with the 22q13 deletion syndrome. The instability in the ring chromosome contributes to the development of variable phenotypes. Central nervous system (CNS) atypical teratoid rhabdoid tumors (ATRTs) are rare, highly malignant tumors, primarily occurring in young children below 3 years of age. The majority of ATRT cases display genetic alterations of SMARCB1 (INI1/hSNF5), a tumor suppressor gene located on 22q11.2. The coexistence of a CNS ATRT in a child with a r(22) is rare. We present a case of a 4-month-old boy with 46,XY,r(22)(p13q13.3), generalized hypotonia and delayed development. High-resolution microarray analysis revealed a 3.5-Mb deletion at 22q13.31q13.33. At 11 months, the patient had an ATRT (5.6 cm×5.0 cm×7.6 cm) in the cerebellar vermis, which was detected in the brain via magnetic resonance imaging.

INTRODUCTION Desmoplastic fibroblastomas (DFs) are rare fibrous soft tissue tumors that usually arise in subcutaneous tissue or skeletal muscle in a variety of anatomical sites. This was first described by Evans in 1995 and was classified as a distinctive form of benign fibrous soft tumor. In 1996 the lesion was renamed as a “ collagenous fibroma” by Nielsen and colleagues. The arm or the shoulders are the most frequent sites of involvement. They have also been described in the neck, tongue, lacrimal gland and palate. To the best of our knowledge, we report the first case of DF (collagenous fibroma) occurring in genital area.

The tumor microenvironment has many roles involving tumor progression, invasion and metastasis. The tumor cells at the tumor border loose epithelial properties and acquire mesenchymal features. This, epithelial-to-mesenchymal transition (EMT) has been suggested to be an important process for tissue and lymphovascular invasion. Pulmonary tissue samples from 15 patients with primary adenocarcinoma were evaluated with using immunofluorescence multi-staining the EMT-associated markers including E-cadherin and alpha-smooth muscle actin (α-SMA), and transcription factors including E-SNAIL and SLUG, and ZEB1. The data were analyzed in specific area, such as tumor center and tumor border. In this study we show that the invasive adenocarcinoma differentially expressed SNAIL and SLUG, and Zeb1 and it was associated with the loss of epithelial marker (E-cadherin) and gaining of mesenchymal marker (α-SMA) at the invasive border of lung carcinoma. The positive rates of SNAIL and ZEB1 were 26.7% and 0% in the tumor center and 40% and 20% in tumor margin, respectively. In addition, the expression of both SNAIL and ZEB1 at the border of tumor was observed in two cases (2/10). These two cases were associated with lymph node metastasis and advanced stage. The process of EMT has been suggested to be of prime importance for tissue and lymphovascular invasion. The process of EMT may be activated in the tumor border of lung adenocarcinoma. Related transcription factors, such as SNAIL and SLUG, and ZEB1, might be induced by paracrine effects of surrounded inflammatory cells and fibroblasts.

Fascin expression has been associated with clinicopathological parameters and clinical outcome in many carcinomas. The aim of this study was to evaluate the prognostic impact of fascin expression in small intestinal carcinomas (SICs). We constructed tissue microarrays for evaluation of immunohistochemical expression of fascin in a total of 194 SICs. Fascin was expressed in 47 (24.2%) of the 194 SICs, and fascin expression showed an association with poorly and undifferentiated histology (p < 0.001) and lymphatic invasion (p = 0.019). No fascin expression was observed in tumour cells of metastatic lymph nodes in cases of SIC without fascin expression (p < 0.001). Patients with fascin expression showed significantly shorter overall survival compared to patients without expression (p = 0.001). In multivariate analysis, fascin expression was an independent prognostic factor in SIC patients (p = 0.043). Fascin expression showed significant correlation with lack of differentiation and lymphatic invasion, and may be a useful predictive marker for lymph node metastasis. Fascin expression in SICs showed an association with poor overall survival and was an independent poor prognostic factor.

Epithelial-to-mesenchymal transition (EMT) is a process for fully differentiated epithelial cells to undergo a phenotypic change to fibroblasts via diverse intracellular signaling pathways. While the pivotal role of fibroblasts in renal fibrosis is widely accepted, their origin remains undefined. In addition, although a large number of studies have provided evidence of EMT in human kidney diseases, specific signaling pathways leading to EMT have not yet been discovered in humans. To evaluate the origin of interstitial fibroblasts and signaling pathways involved in the EMT process, we analyzed the differential expression of EMT-related molecules in paraffin-fixed sections from 19 human fibrotic kidneys and 4 control kidneys. In human fibrotic kidneys, tubular epithelial cells (TECs) with intact tubular basement membrane (TBM) showed loss or down-regulation of an epithelial marker (E-cadherin), de novo expression of mesenchymal markers (vimentin and fibronectin), and significant up-regulation of inducers and mediators controlling the EMT process (transforming growth factor-β1 (TGF-β1), p-Smad2/3, β1-integrin, p38 mitogen-activated protein kinase (MAPK), WNT5B and β-catenin) in the areas of interstitial inflammation and fibrosis, compared with their expression in control kidneys. In conclusion, the type II EMT process in humans is thought to be an adaptive response of TECs to chronic injury and is regulated by interconnections of TGF-β/Smad, integrin/integrin-linked kinase (ILK) and wnt/β-catenin signaling pathways.

Intratumoral electroporation (IT-EP) with IL-12 cDNA (IT-EP/IL12) can lead to the eradication of established B16 melanoma tumors in mice. Here, we explore the immunological mechanism of the antitumor effects generated by this therapy. The results show that IT-EP/IL12 applied only once resulted in eradication in 70% animals with large established B16 tumors. Tumor eradication required the participation of CD8+ T cells, but not CD4+ T cells and NK cells. IT-EP/IL12 induced antigen-specific CD8+ T cell responses against the immunodominant Trp2 180–188 epitope and generated a systemic response, resulting in significant therapeutic effects against distal, untreated tumors. The therapeutic effect of IT-EP/IL12 was absent in perforin-deficient mice, indicating that tumor elimination occurred through conventional perforin/granzyme lysis by CTLs. Moreover, this therapy induced some degree of immunological memory that protected approximately one-third of the cured mice against a subsequent tumor challenge. Moreover, antitumor efficacy and long-term protection against B16 were significantly improved by concurrent Trp2 peptide immunization through more induction of Ag-specific CTL responses and more attraction of IFN-γ-expressing CD8+ T cells into tumor sites. The antitumor effect of IT-EP/IL12 required the participation of IFN-γ, which was shown to induce MHC class I expression on B16 cells and increase the lytic activity of the CD8+ CTL generated by IT-EP/IL12. The results from these animal studies may help in the development of IT-EP/IL12 for cancer patients.

BACKGROUND/AIMS:Although primary small intestinal carcinoma (SIC) is morphologically similar to colorectal carcinoma and shares many of the genetic changes of carcinogenesis, little is known about the role of defective mismatch repair (MMR) genes involved in the SIC. The aim of this study is to investigate the role of defective MMR genes and correlation between clinicopathological factors and loss of MMR protein in SIC.METHODOLOGY:A total of 195 SIC cases were collected from 20 institutions in Korea and tissue microarrays (TMA) were made. The loss of expression of hMLH1, hMSH2 and hMSH6 was examined by immunohistochemistry (IHC).RESULTS:The loss of expression of hMLH1, hMSH2 and hMSH6 was identified in 25/193 (13.0%), 25/193 (13%) and 29/195 (15%), respectively. The loss of hMSH2 expression was associated with retroperitoneal seeding. Patients with loss of hMSH6 expression had a tendency to invade deeply and a higher frequency of pancreas invasion. The loss of hMSH6 expression was associated less frequently with peritumoral adenoma. There was no survival difference by MMR protein expression status.CONCLUSIONS:The loss of MMR protein was associated with some distinct clinicopathological features. MMR pathway seems to be major pathway in carcinogenesis of SICs. MMR defect seems to be related with sporadic-microsatellite instability (MSI).

DNA vaccines are known to be lacking in immunogenicity in humans. Presently, electroporation (EP) is thought to overcome this limitation. Here, we investigate whether human papillomavirus 16 E7 DNA vaccines delivered by EP might elicit potent antitumor activity in animal cervical cancer models, with a focus on the underlying mechanism(s). Intramuscular (IM)-EP delivery of E7 DNA vaccines induced more potent antitumor therapeutic and antimetastatic activity compared with IM delivery. Moreover, the tumor-controlled animals by IM-EP possessed long-term memory responses to parental tumor cells. This improved antitumor effect was concomitant with augmented Ag-specific CTL activities. IM-EP also induced IgG and Th-cell responses higher than IM delivery. Finally, IM-EP resulted in more antigen production in and more attraction of immune cells into the site of DNA injection, suggesting that these biological and immunological changes made by IM-EP might be responsible for enhanced CTL activities and antitumor resistance. Thus, this study shows that IM-EP can induce more potent antitumor activity by augmenting CTL responses possibly through more antigen production in and more attraction of immune cells into the muscle sites. This study also suggests that IM-EP of E7 DNA vaccines might be a potential approach toward treating patients with cervical cancer.

To the Editor: Pigmented mammary Paget disease is an uncommon clinicopathologic variant of mammary Paget disease. Since the clinical appearances and histologic findings of the disease are similar to those of malignant melanoma, immunohistochemical stains including effective markers, such as cytokeratin and antibodies against S-100, Melan-A and HMB-45, have been used to distinguish between the diagnoses in the differential diagnosis.1Requena L. Sangueza M. Sangueza O.P. Kutzner H. Pigmented mammary Paget disease and pigmented epidermotropic metastases from breast carcinoma.Am J Dermatopathol. 2002; 24: 189-198Crossref PubMed Scopus (87) Google Scholar A 39-year-old woman presented with a nonpruritic, pigmented macule on her left nipple which she had had for 2 weeks. On physical examination, the lesion was a 0.5 × 0.5 cm, dark brown macule with an underlying palpable breast mass (Fig. 1). Histopathological examination of the dark lesion showed atypical clustered large cells within the epidermis having pale cytoplasm and hyperchromatic nuclei with prominent nucleoli. In addition, scattered melanin pigmented granules were seen in the cytoplasm of tumor cells. Tumor cells which increased invasiveness were found in lactiferous ducts of the deep dermis. Immunohistochemically, the tumor cells were positive to cytokeratin 7 (CK7) and EMA. In addition, tumor cells were negative to Melan A, but positive to HMB-45 and S-100 (Fig 2). The patient was diagnosed with pigmented mammary Paget disease because the lesion showed positive staining to Paget cell markers and had an underlying invasive ductal carcinoma. Modified radical mastectomy was performed. The patient is currently undergoing adjuvant chemotherapy with 5-fluorouracil, doxorubicin, and cyclophosphamide and hormone therapy with tamoxifen because the tumor was positive for estrogen receptor, progesteron receptor, and human epidermal growth factor receptor 2. There has been no evidence of recurrence during the last 19 months. HMB-45 and Melan A are used as diagnostic tools for malignant melanoma; however, the mechanism of each stain differs. HMB-45 is a monoclonal antibody which reacts to melanosome specific GP-100.2Elenitsas R. Nousari C.H. Ayli E. Seykora J.T. Laboraty methods.in: Elder D.E. Elenitsas R. Johnson Jr., B.L. Murphy G.F. Xu X. Lever histopathology of the skin. 10th ed. Lippincott-Raven, Philadelphia2009: 77-78Google Scholar, 3Sheffield M.V. Yee H. Dorvault C.C. Weilbaecher K.N. et al.Comparison of five antibodies as markers in the diagnosis of melanoma in cytologic preparations.Am J Clin Pathol. 2002; 118: 930-936Crossref PubMed Scopus (88) Google Scholar In contrast, Melan A is a recently discovered melanocytic differentiation marker and its antibody stains the cytoplasm of melanocytes.4Fetsch P.A. Cormier J. Hijazi Y.M. Immunocytochemical detection of MART-1 in fresh and paraffin embedded melanomas.J Immunother. 1997; 20: 60-64Crossref PubMed Scopus (52) Google Scholar Considering the different mechanisms of the two markers, melanosomes produced by stimulated melanocytes are carried (or picked up) into the cytoplasm of Paget cells and reactive melanin granules in the cytoplasm of Paget cells are thought to explain the positive reaction to HMB-45 that was seen in our case. S-100 protein should be used with other diagnostic markers because it has high sensitivity but low specificity.2Elenitsas R. Nousari C.H. Ayli E. Seykora J.T. Laboraty methods.in: Elder D.E. Elenitsas R. Johnson Jr., B.L. Murphy G.F. Xu X. Lever histopathology of the skin. 10th ed. Lippincott-Raven, Philadelphia2009: 77-78Google Scholar S-100 has been used as a differential diagnostic tool with melanoma; however, recently many cases have reported a positive response of Paget cells with one case reporting a positive response in 12 out of 20 cases.5Ramachandra S. Gillett C.E. Millis R.R. A comparative immunohistochemical study of mammary and extramammary Paget's disease and superficial spreading melanoma, with particular emphasis on melanocytic markers.Virchows Arch. 1996; 429: 371-376Crossref PubMed Scopus (34) Google Scholar In conclusion, S-100 and HMB-45, which have been used as differential diagnostic markers to differentiate pigmented mammary Paget disease from malignant melanoma, are sometimes not reliable, as in our case. More studies are needed on pigmented mammary Paget disease and the role of various melanocytic markers.

Nevus with cyst is defined as a single lesion in which there is the coexistence of an epidermoid cyst and a melanocytic nevus. Similar clinical and histopathologic changes can be observed when a hair follicle ruptures and subsequent folliculitis with supprative granulomatous reaction occurs beneath a melanocytic nevus. This cystic change due to inflammation is a different pathologic phenomenon from the formation of an epidermal cyst. Hence, it is necessary to differentiate between these two conditions. We report here on a case of congenital melanocytic nevus combined with cystic change due to inflammation in a 39-year-old man. (Korean J Dermatol 2010;48(12): 1078∼1080)Key Words: Congenital melanocytic nevus, Cystic change, Folliculitis서 론

Despite remarkable progress in understanding and treating gastrointestinal stromal tumors (GISTs) during the past two decades, the pathological characteristics of GISTs have not been made clear yet.Furthermore, concrete diagnostic criteria of malignant GISTs are still uncertain.We collected pathology reports of 1,227 GISTs from 38 hospitals in Korea between 2003 and 2004 and evaluated the efficacy of the NIH and AFIP classification schemes as well as the prognostic factors among pathologic findings.The incidence of GISTs in Korea is about 1.6 to 2.2 patients per 100,000.Extra-gastrointestinal GISTs (10.1%) are more common in Korea than in Western countries.In univariate analysis, gender, age, tumor location, size, mitosis, tumor necrosis, vascular and mucosal invasions, histologic type, CD34 and s-100 protein expression, and classifications by the NIH and AFIP criteria were found to be significantly correlated with patient's survival.However, the primary tumor location, stage and classification of the AFIP criteria were prognostically significant in predicting patient's survival in multivariate analysis.The GIST classification based on original tumor location, size, and mitosis is more efficient than the NIH criteria in predicting patient's survival, but the mechanism still needs to be clarified through future studies.