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Gastric-type endocervical adenocarcinoma (ECAC) represents a unique variant of endocervical adenocarcinoma that is distinguished by lack of HPV association and an aggressive clinical course with unfavorable prognosis.

Transitional cell metaplasia (TCM) of the uterine cervix and vagina is typically seen in patients with adrenogenital syndrome with high serum androgen levels and in those under androgen treatment as well as in some peri/postmenopausal women. Considering that TCM occurs in patients with increased serum androgen levels, a microenvironment with altered sex hormones might be involved in the urothelial-like differentiation observed in TCM. To investigate a histogenetic role of androgen in TCM development, we compared the distribution patterns and intensity of androgen receptor (AR), estrogen receptor (ER), GATA3 (a transcription factor involved in androgen regulation), Ki-67, and AKR1C3 (an enzyme involved in androgen biosynthesis) expression in normal exocervical mucosa in young women (n = 25), senile atrophy (n = 23), and TCM (n = 29). In TCM, AR, ER, AKR1C3, and GATA3, expression was stronger and significantly increased upward into the intermediate and superficial layers compared with the senile atrophic mucosa and normal mucosa in young women. The epithelial layer in TCM is thicker than that in senile atrophic mucosa, although both conditions may occur in the same age group. Proliferation in TCM was significantly lower than that in young women but slightly higher than that in senile atrophy. Considering the conversion activity of AKR1C3, thicker epithelial layers in TCM compared with those in senile atrophy might be due to increased conversion of androstenedione to testosterone via increased AKR1C3 activity, increased conversion of testosterone to 17β-estradiol by aromatization, and AR activation.

Objective To investigate the expression of different histone deacetylases and their association with disease characteristics and survival outcomes in uterine leiomyosarcoma patients. Methods The immunohistochemical expression of different histone deacetylases and p53 by tissue microarray and histological subtypes were assessed in tumor tissue samples of 42 eligible patients. Results Histone deacetylases 1–4, 6 and 8 showed prevalent and strong (3+) expression (88.1, 90.5, 95.2, 92.9, 83.3 and 100%, respectively). Histone deacetylases 5, 7 and 9 showed infrequent strong expression (33.3, 50 and 38.1%, respectively). There were trends of higher disease-free survival rates according to the combination of weaker expression of histone deacetylase 5, 7 or 9 with positive p53 expression or with non-epithelial subtype. The patients with triple-positive favorable prognostic factors (any of weaker histone deacetylase 5, 7 and 9 expression, p53 positive, and non-epithelioid subtype) had the better survival outcomes while the patients with other combinations had the worse survival outcomes. In multivariate analysis, histone deacetylase 5 in combination with epithelioid subtype was an independent predictor for disease-free survival. Conclusions Expression of histone deacetylase 5, 7 and 9 is a potential prognostic marker in uterine leiomyosarcoma when combined with pathologically relevant prognostic factors (p53 and histological subtype). This prevalent and strong histone deacetylase expression warrants further study in well-designed investigations of histone deacetylases as therapeutic targets in uterine leiomyosarcoma.

Background Breast cancer treatment with selective estrogen receptor modulators (SERMs) increases the incidence of uterine malignant mixed Müllerian tumors (uMMMTs). We examine clinicopathologic characteristics and prognosis of SERM-associated uMMMTs (S-uMMMTs) and discuss possible pathogenetic mechanisms. Methods Among 28,104 patients with breast cancer, clinicopathologic features and incidence of uMMMT were compared between patients who underwent SERM treatment and those who did not. Of 92 uMMMT cases that occurred during the same period, incidence, dose, and duration of SERM treatment, as well as overall survival rate, were compared for patients with breast cancer who underwent SERM treatment and those who did not (S-uMMMT vs NS-uMMMT) and for patients without breast cancer (de novo-uMMMT). Histopathological findings and immunophenotypes for myogenin, desmin, p53, WT-1, estrogen receptor (ER) α, ERβ, progesterone receptor, and GATA-3 were compared between S-uMMMT and de novo-uMMMT. Results The incidence of S-uMMMT was significantly higher than that of NS-uMMMT (6.35-fold). All patients with SERM were postmenopausal and received daily 20–40 mg SERM. Cumulative SERM dose ranged from 21.9 to 73.0 g (mean, 46.0) over 39–192 months (mean, 107). Clinicopathologic features, such as International Federation of Gynecology and Obstetrics stage and overall survival, were not significantly different between patients with S-uMMMT and NS-uMMMT or between patients with S-uMMMT and de novo-uMMMT. All 11 S-uMMMT cases available for immunostaining exhibited strong overexpression/null expression of p53 protein and significantly increased ERβ expression in carcinomatous and sarcomatous components. Conclusions SERM therapy seemingly increases risk of S-uMMMT development; however, clinicopathologic features were similar in all uMMMTs from different backgrounds. p53 mutation and increased ERβ expression might be involved in the etiology of S-uMMMT.

Context.— Papillary immature metaplasia (PIM) is a known papillary cervical lesion associated with low-risk human papillomavirus (LR-HPV). Objective.— To evaluate additional clinicopathologic features and the HPV genotypes of PIM and discuss the presumptive cell of origin. Design.— A total of 26 PIM cases were evaluated by p16INK4a, cytokeratin (CK) 7, and CK17 immunohistochemical stainings. Human papillomavirus genotyping was performed, by using HPV DNA Chip, HPV polymerase chain reaction (PCR), and real-time PCR. Results.— Histologically, PIM forms either a papillary mass (n = 21 of 26, 81%) or a slightly elevated/flat plaque (n = 5, 19%). All cases contain variable amounts of mucinous epithelia within the lesions. Koilocytosis was identified in 15 of the 26 cases (58%). Sixteen cases (61%) were associated with LR-HPV (types 6, 11, or 42), but 3 cases (12%) with high-risk (HR) HPV (16, 16/18, and 33), 2 cases (8%) with mixed LR- and HR-HPV (6/16 and 11/58), while 2 cases (8%) were negative, but p16INK4a immunostaining showed nonblock positivity in all cases. Eight (31%) had high-grade squamous intraepithelial lesion (HSIL) in the adjacent mucosa, 4 (50%) of which showed direct continuity. Identical HPV subtypes were confirmed in separately microdissected cases from PIM and adjacent HSIL. Most lesions (n = 24, 92%) expressed CK17 (reserve cell marker) in a bottom-heavy pattern and CK7 (squamocolumnar junction [SCJ] marker) in a top-heavy pattern, while most cases of low-grade squamous intraepithelial lesion (LSIL) were negative for both markers. Conclusions.— Our results suggest that PIM is a distinct subset of LSIL showing a productive HPV infection, but PIM involves the transformation zone and is proximal to SCJ, while LSIL is mostly from ectocervix or distal to the SCJ.

Objective To determine the accuracy of frozen section diagnosis and factors associated with final pathological diagnosis upgrade in patients with mucinous ovarian tumors. Methods This study included 1,032 patients with mucinous ovarian tumors who underwent frozen section diagnosis during surgery. Sensitivity, specificity, and diagnostic accuracy of frozen section diagnosis was calculated. Univariate and multivariate regression analyses were performed to determine factors associated with diagnosis upgrade in the final pathology report. Results The sensitivity and specificity of frozen section diagnosis were 99.1% (95% confidence interval [CI]=98%–99.6%) and 82.2% (95% CI=77.9%–85.7%), respectively, for benign mucinous tumors; 74.6% (95% CI=69.1%–79.4%) and 96.7% (95% CI=95.2%–97.8%), respectively, for mucinous borderline ovarian tumors; and 72.5% (95% CI=62.9%–80.3%) and 98.8% (95% CI=97.9%–99.3%), respectively, for invasive mucinous carcinomas. The multivariate analysis revealed that mixed tumor histology (odds ratio [OR]=2.8; 95% CI=1.3–6.3; p=0.012), tumor size >12 cm (OR=2.5; 95% CI=1.5–4.3; p=0.001), multilocular tumor (OR=2.9; 95% CI=1.4–6.0; p=0.006), and presence of a solid component in the tumor (OR=3.1; 95% CI=1.8–5.1; p12 cm, multilocular tumor, and presence of a solid component in the tumor were independent risk factors for final pathological diagnosis upgrade based on frozen section diagnosis.

BACKGROUND Immature teratoma (IT) is a tumor containing immature neuroectodermal tissue, primarily in the form of neuroepithelial tubules. However, the diagnosis of tumors containing only cellular neuroglial tissue (CNT) without distinct neuroepithelial tubules is often difficult, since the histological characteristics of immature neuroectodermal tissues remain unclear. Here, we examined the significance of CNT and tried to define immature neuroectodermal tissues by comparing the histological features of neuroglial tissues between mature teratoma (MT) and IT. METHODS The histological features of neuroglial tissue, including the cellularity, border between the neuroglial and adjacent tissues, cellular composition, mitotic index, Ki-67 proliferation rate, presence or absence of tissue necrosis, vascularity, and endothelial hyperplasia, were compared between 91 MT and 35 IT cases. RESULTS CNTs with a cellularity grade of ≥ 2 were observed in 96% of IT cases and 4% of MT cases (p < .001); however, CNT with a cellularity grade of 3 in MT cases was confined to the histologically distinct granular layer of mature cerebellar tissue. Moreover, CNT in IT exhibited significantly higher rates of Ki-67 proliferation, mitoses, and necrosis than those in MT (p < .001). Furthermore, an infiltrative border of neuroglial tissue and glomeruloid endothelial hyperplasia were significantly more frequent in IT cases than in MT cases (p < .001). CONCLUSIONS Our results suggest that if CNT with a cellularity grade of ≥ 2 is not a component of cerebellar tissue, such cases should be diagnosed as IT containing immature neuroectodermal tissue, particularly if they exhibit an infiltrative border, mitoses, necrosis, and increased Ki-67 proliferation.

Objective To investigate the expression of androgen receptor (AR) and its correlation with disease status and survival outcome in uterine leiomyosarcoma with other hormone receptors. Methods The medical records and paraffin blocks of 42 patients were reviewed. The immunohistochemical expression of AR, estrogen receptor (ER), progesterone receptor (PR), gonadotropin releasing hormone (GnRH), and cytochrome P450, family 19, subfamily A, polypeptide 1 (CYP19A1) were assessed using tissue microarray. Results In total, AR expression was observed in 11 patients (26.2%). International Federation of Gynecology and Obstetrics (FIGO) stage and AR were independent factors for disease-free survival (DFS) in multivariate regression analysis (odds ratio [OR]=5.8; 95% confidence interval [CI]=1.2-28.4 and OR=0.2; 95% CI=0.05-0.90; p=0.029 and 0.032, respectively). There were no deaths in the AR expression group, whereas the 5-year overall survival (OS) was 54.8% in the no expression group (p=0.014). Co-expression of ER and/or PR with AR was associated with significantly better 5-year DFS and OS than those with negative AR (72.7% vs. 28.6% and 100% vs. 64.3%; p=0.020 and 0.036, respectively). AR may be an independent prognostic marker regardless of ER/PR. Conclusion AR can be a potential prognostic biomarker in uterine leiomyosarcoma.

Carcinosarcoma is an aggressive malignant neoplasm of the female genital tract that is biphasic and composed of carcinomatous and sarcomatous components. It was previously considered as a subtype of uterine sarcoma but is currently regarded as a type of metaplastic carcinoma. 1 Here, we report a case in which a carcinosarcoma forming a discrete mass in the peritoneal cavity was diagnosed concurrently with smaller bilateral ovarian masses showing unequivocal histologic features of high-grade serous carcinoma. Although there seems to be a close relationship between the two tumors in this case, firm evidence for the histopathologic determination of the primary site is lacking because primary carcinosarcomas have been described in many extragenital organs, including the peritoneum, in the literature. We demonstrated two tumors with different histologic findings at distant tumor locations but with a common origin in their pathogenetic mechanism, as suggested by their similar immunohistochemical overexpression of p53 protein and identical pattern TP53 mutation and microsatellites (the reference panel, the Bethesda markers) by molecular analysis.

Purpose The purpose of this study was to evaluate the feasibility, safety, and clinical effectiveness of ultrasound and fluoroscopy-guided percutaneous nephrostomy (PCN) placement in infants and young children. Materials and methods Between January 2000 and December 2015, 57 patients had a total of 66 fluoroscopically guided PCN placement procedures. There were 37 boys and 20 girls with a mean age 8.6 ± 15.3 (SD) months (range: 1 day–75.5 months). The most common underlying disease was upper-urinary-tract obstruction, including ureteropelvic-junction stenosis (27/66, 40.9%) and ureterovesical-junction stenosis (16/66, 24.2%). Technical success, complications, clinical effectiveness, and radiation exposure were retrospectively analyzed. Technical success was defined as completion of PCN catheter in the renal calyx or proximal ureter. Complications were graded in severity using the Common Terminology Criteria for Adverse Event (version 4.03). Clinical effectiveness was evaluated with presence of decompression of the hydronephrosis on follow-up ultrasonography. Results All PCN placement procedures were technically successful. A total of 37 complications were identified in 33/37 procedures (89.2%), with transient gross hematuria (n = 28) being most common (mean hematuria duration 2.2 ± 1.4 [range: 1–6] days), which were grade 1 Postprocedural fever occurred after eight procedures; four and three patients were graded 1 and 2, respectively. Complete hydronephrosis decompression was achieved in 35/53 kidneys (66%), incomplete hydronephrosis decompression in 17/55 kidneys (32.1%), and progression of hydronephrosis was noted in 1/55 kidney (1.9%). Dose-area-product (DAP) was 44.86 ± 89 (SD) (range: 3.7–464) μGy cm2 and cumulative dose was 10.3 ± 20.4 (SD) (range: 0.3–97.9) mGy. Conclusion PCN is a feasible and effective treatment option to relieve urinary obstruction, and can serve as a bridging procedure until definitive corrective surgery in pediatric patients.

Gestational choriocarcinomas are derived from placental trophoblast cells, with HLA-C being the only class I polymorphic molecule expressed. However, choriocarcinomas have not been profiled for endoplasmic reticulum aminopeptidase 2 (ERAP2) expression. ERAP2 trims peptides presented by human leukocyte antigens (HLA) that have shown to modulate immune response. Over 50% of choriocarcinomas we screened lack ERAP2 expression, which suggests that the absence of ERAP2 expression allows immune evasion of choriocarcinoma cells. We demonstrate that the ability of choriocarcinoma cells to activate lymphocytes was lowest with cells lacking ERAP2 (JEG-3) or HLA-C (JAr). This observation suggests that activation is dependent on expression of both ERAP2 and HLA-C molecules. In addition, an ERAP2 variant in which lysine is changed to asparagine (K392N) results in increased trimming activity (165-fold) for hydrophobic peptides and biologically never been detected. We hypothesize that homozygosity for the N392 ERAP2 variant is prohibited because it modulates the immune recognition of placental trophoblasts. We demonstrate that NK-cell activation and killing were significantly dependent on forced expression of the N392 ERAP2 isoform in JEG-3 cells. Cytotoxicity was confirmed by 7AAD killing assays showing that N392 ERAP2-isoform expressing JEG-3 cells had the highest percentage of apoptotic cells independent of the expression level of CD11a on lymphocytes. This is the first report showing that N392 ERAP2 promotes an immune clearance pathway for choriocarcinoma cells, and provides an explanation for why embryonic homozygosity for the N392 ERAP2 variant is not detected in any population.

Objective Most BRCA1/2 carriers do not undergo risk-reducing salpingo-oophorectomy (RRSO) by the recommended age. This study aimed to find the incidence of precursor lesions and cancer after RRSO. Methods We retrospectively reviewed breast cancer patients identified as BRCA mutation carriers who underwent RRSO at Asan Medical Center, Seoul, Korea, from 2010 to 2014. From 2013, all cases were examined according to the Sectioning and Extensively Examining the Fimbria (SEE/FIM) protocol and underwent immunohistochemically staining. RRSO was performed in 63 patients, 27 in 2010 to 2012 and 36 in 2013 to 2014. Results The median age at RRSO was 46.5 years (range, 32 to 73 years). Occult invasive cancer was detected in eight patients, of ovarian origin in five and of tubal origin in three. All occult invasive cancer cases with metastasis were detected in patients older than 40 years. Of the 36 patients from the 2013 to 2014 cohort, seven showed p53 overexpression, one showed Ki-67 overexpression, two showed serous tubal intraepithelial carcinoma, and three showed occult cancer. The detection rate of precursor lesions or cancer was 36.1% (13/36). In the analysis according to age, precursor lesions were more common in BRCA1 mutation carriers younger than 40 years old (66.7% vs. 20.0%). In BRCA2 mutation carriers, precursor lesions were only detected in those older than 40 years of age, indicating the possible faster occurrence of precursor lesions in BRCA1 mutation carriers. Conclusion Many patients still tend to delay RRSO until after they are 40 years old. Our findings support the significance of RRSO before the age of 40 in germline BRCA mutation carriers.

Objectives Primary small cell carcinoma of the endometrium is a rare disease that can only be diagnosed at an advanced stage, and thus has a poor prognosis. In this study, the clinicopathologic characteristics of endometrial small cell carcinoma are described and the survival outcomes are discussed. Materials and methods The data from six patients from a single medical institution who were diagnosed with endometrial small cell carcinoma in the past 20 years were retrospectively reviewed. Results The median age of the six patients was 60 years. Vaginal bleeding was the most common symptom. All six patients underwent complete staging surgery, including hysterectomy, bilateral salpingoophorectomy, and systematic lymphadenectomy. Three of the patients were diagnosed with early stage disease, [International Federation of Gynecology and Obstetrics (FIGO) stage I or II], and the other three were in an advanced stage (FIGO stage III). Pathologically, deep myometrial invasion was observed in five (83.3%) of the patients, and lymphovascular invasion in six. As adjuvant therapy, four (66.7%) patients received platinum-based chemotherapy and one (16.7%) underwent concurrent chemoradiotherapy. During the median follow-up period of 16.2 months, recurrence developed in four patients (66.7%). There were disseminated recurrences on the peritoneum and lymph nodes in two cases, and distant metastasis to the brain in the other two cases. The median time to recurrence was 7.5 months (range, 315 months). One patient died of disease. Conclusion Small cell carcinoma of the endometrium shows an aggressive clinical behavior, such as a disseminated disease and distant metastasis within a short time to recurrence. Initial active management with complete surgical resection and systemic chemotherapy might improve outcomes, although further large studies should be done to confirm this.

Pseudomyxoma peritonei (PMP) cases can be classified into the prognosis-related subtypes of disseminated peritoneal adenomucinosis (DPAM) and peritoneal mucinous carcinomatosis (PMCA). To investigate the mechanisms of mucinous invasion and the differing prognoses of these two subtypes, we examined the expression levels of proteins involved in cellular adhesion and invasion, including E-cadherin, vimentin, β-catenin, and S100A4, in single isolated tumor cells (SICs) and cohesive cellular strips within mucin pools isolated from DPAM (n = 31) and PMCA (n = 21) patients. In both PMCA and DPAM cases, SICs showed a complete loss of E-cadherin expression, whereas cells in cohesive cellular clusters retained E-cadherin expression. The frequency of high numbers of SICs (>8) in PMCA cases was significantly greater than that in DPAM cases (86% and 26%, respectively) and was correlated with poor progression-free survival (P = 0.019) in a univariate analysis. In both PMP subtypes, strong vimentin expression was identified in most of the SICs but not the cohesive cellular strips. The relatively slow progression of DPAM may be attributable to the smaller number of SICs that lack E-cadherin expression and have increased vimentin expression, whereas the rapid progression of PMCA may be due to larger numbers of these SICs.

Up-regulated expression of telomerase reverse transcriptase (TERT) and subsequent maintenance of telomere length are essential in tumour development. Recent studies have implicated somatic gain-of-function mutations at the TERT promoter as one of the mechanisms that promote transcriptional activation of TERT; however, it remains unclear whether this genetic abnormality is prevalent in gynaecological neoplasms. We performed mutational analysis in a total of 525 gynaecological cancers, and correlated TERT promoter mutations with clinicopathological features. With the exception of ovarian clear cell carcinomas, in which mutations were found in 37 (15.9%) of 233 cases, the majority of gynaecological malignancies were wild-type. TERT promoter mutation does not appear to be an early event during oncogenesis, as it was not detected in the contiguous endometriosis associated with ovarian clear cell carcinoma. Ovarian clear cell carcinoma cell lines with TERT promoter mutations exhibited higher TERT mRNA expression than those with wild-type sequences (p = 0.0238). TERT promoter mutation tended to be mutually exclusive with loss of ARID1A protein expression (p = 4.4 × 10(-9) ) and PIK3CA mutation (p = 0.0019) in ovarian clear cell carcinomas. No associations with disease-specific survival were observed for ovarian clear cell carcinoma. The above results, in conjunction with our previous report showing longer telomeres in ovarian clear cell carcinomas relative to other types of ovarian cancer, suggests that aberrations in telomere biology may play an important role in the pathogenesis of ovarian clear cell carcinoma.

Squamous cell carcinoma (SCC) involving the upper genital tract, including the endometrium, fallopian tubes, and ovarian surface, is extremely rare, with most patients described in single case reports.1-5 Its possible pathogenic mechanisms include 1) de novo carcinogenesis; 2) extensive squamous metaplasia (ichthyosis uteri) in the mucosa of the upper genital tract with subsequent malignant transformation; 3) endometrioid adenocarcinoma with predominantly squamous differentiation; and 4) mucosal spread from cervical SCC.6 Differentiating primary SCC arising in the upper genital tract from primary cervical SCC extending to the upper genital tract is clinically important for tumor staging and patient management, especially since the locoregional recurrence rate is higher and the disease-free survival rate is lower in cervical SCC patients with endometrial involvement than it is in patients without endometrial involvement.7 The diagnostic criteria for primary SCC of the endometrium include the absence of 1) coexisting endometrial adenocarcino adenocarcinoma; 2) a connection between endometrial SCC and the squamous epithelium of the cervix; and 3) a primary squamous lesion in the cervix, either in situ SCC or invasive carcinoma.8 We have found it difficult, however, to determine the primary sites of SCCs detected in a fallopian tube or ovary in patients who have undergone prior hysterectomy with insufficient histological examination of the uterine cervix at the time of surgery. Human papillomavirus (HPV) infection has been associated with the development of cervical SCC, and p16INK4a, a surrogate marker for HPV infection, is consistently positive in HPV-associated cervical SCCs and precancerous squamous intraepithelial lesions.9 However, the cause of disease and the utility of p16INK4a expression and HPV DNA status have not been clearly determined in patients with primary SCC of the upper genital tract. To determine the utility of p16INK4a expression and HPV DNA status in identifying the primary tumor site, we compared these markers as well as the histologic findings in four patients with primary SCCs of the upper genital tract and in five patients with cervical SCCs extending to the mucosa of the upper genital tract.

We describe an ovarian mucinous neoplasm that histologically resembles lobular endocervical glandular hyperplasia (LEGH) containing pyloric gland type mucin in a patient with Peutz-Jeghers syndrome (PJS). Although ovarian mucinous tumors rarely occur in PJS patients, their pyloric gland phenotype has not been clearly determined. The histopathologic features of the ovarian mucinous tumor were reminiscent of LEGH. The cytoplasmic mucin was stained with periodic acid-Schiff reaction after diastase treatment but was negative for Alcian blue pH 2.5, suggesting the presence of neutral mucin. Immunohistochemically, the epithelium expressed various gastric markers, including MUC6, HIK1083, and carbonic anhydrase-IX. Multiple ligation-dependent probe amplification detected a germline heterozygous deletion mutation at exons 1-7 of the STK11 gene (c.1-?_920+?del) in peripheral blood leukocytes and mosaic loss of heterozygosity in ovarian tumor tissue. Considering that LEGH and/or gastric-type cervical adenocarcinoma can be found in patients with PJS carrying germline and/or somatic STK11 mutations, our case indicates that STK11 mutations have an important role in the proliferation of pyloric-phenotype mucinous epithelium at various anatomical locations.

Endometrial stromal sarcoma (ESS) is a rare tumor with limited treatment options. Histone deacetylase (HDAC) is a potential therapeutic target in ESS showing a good rate of response in laboratory studies. In this study we investigated the expression of HDAC enzymes in 41 ESS patients.Immunohistochemical expression of HDACs was analyzed by tissue microarrays.Strong positive immunoreactivity was observed in 32 (78.0%), 23 (56.1%), 8 (19.5%), 36 (87.8%), 7 (17.1%), 30 (73.2%), 31 (75.6%), and 33 (80.5%) for HDACs 1-8, respectively. Although not statistically significant, HDAC 1, 4, 6, 7, and 8 exhibited a high frequency of strong immunoreactivity linked to a lower 10-year DFS (100.0% vs. 81.3%, p=0.202; 100.0% vs. 83.3%, p=0.393; 90.9% vs. 83.3%, p=0.579; 90.0% vs. 83.9%; and 100.0% vs. 81.8%, p=0.207; respectively).HDACs 1, 4, 6, 7, and 8, that showed an especially high frequency of strong immunoreactivity, may represent potential therapeutic targets for ESS.

Mucinous adenocarcinoma is an uncommon type of endometrial adenocarcinoma for which precursor lesions have yet to be clarified. During a review of noncancerous endometrial lesions in postmenopausal women, we found that mucinous endometrial glands showed variable degrees of epithelial changes that ranged from the formation of simple tubular glands to the formation of complex glands with papillary tufts, and some of the glands with papillary tufts were architecturally similar to low-grade mucinous adenocarcinomas. Based on histological similarities, we have postulated that mucinous metaplasia could be a precursor lesion of mucinous adenocarcinoma. To explain the pathogenetic significance of endometrial mucinous metaplasia, we analyzed the immunohistochemical expression of ER, PR, MKI67, PTEN, β-catenin, P16(INK4A), TP53, and PAX2 in 21 endometrial mucinous metaplasias, screened for KRAS (n=16) and PTEN (n=14) mutations, and compared expression patterns between samples with simple mucinous glands, those with complex glands having intraglandular papillary tufts, and endometrioid adenocarcinomas. Compared with the surrounding flat mucinous epithelium and simple mucinous metaplasia, the intraglandular papillary tufts associated with papillary mucinous metaplasia were characterized by selectively decreased expression of PAX2 (P=0.029) and PR (P

Development of an efficient cancer control program is essential, considering that the incidence of cancer is increasing in Korea. Cancer registration and cancer screening are important cancer control programs that are closely related to and influenced by each other. The hospital-based cancer registry started in 1980 with 47 training hospitals participating in the cancer control program in Korea. Currently, the registry includes 80-90% of cancer cases from more than 150 training hospitals. The details of the history, objectives, and activities of the Korea Central Cancer Registry (KCCR) have been documented in 2005 and 2011.1,2 Cancer cases are classified according to the International Classification of Diseases for Oncology, 3rd edition (ICD-O-3)3 and then converted according to the International Classification of Diseases, 10th edition (ICD-10).4 As discussed in our first proposal,5 the roles of pathologists are important for improving the quality of cancer statistics since they provide a correct diagnosis and classification of the cancer which is essential for the application of the ICD-O code, in particular the behavior code. In collaboration with the National Cancer Center, the Korean Society of Pathologists (KSP) has participated in confirmation of diagnostic terms, standardization of diagnostic formats, clarification and assessment of multiple primaries, primary sites and the ICD-O code, and education of the pathologists. In addition, the KSP has also contributed to the education of cancer registrars because they play a key role in entering the data in the cancer registry. We have previously noticed the differences in the diagnostic terms between pathologists and the ICD-O code book. It is likely that these differences may originate from numerous coexisting classification systems, synonyms, new entities, newly recognized tumor behavior, and time interval between identification of an entity and its application to the code book. Of these, clarification of the behavior code is important for the registry, because behavior code 2 (carcinoma in situ) and 3 (invasive carcinoma and sarcoma) must be registered and used for both cancer statistics and insurance reimbursement. It is noteworthy, however, that some tumors including microinvasive tumors of the breast and ovary are not included in the ICD-O code book.3 The Gastrointestinal Pathology Study Group of the KSP therefore proposed behavior codes for several gastrointestinal tumors in 2008.5 Whether a microinvasive tumor (especially diagnosed as ductal carcinoma in situ with microinvasion [DCISM]) of the breast should be treated as carcinoma in situ or invasive carcinoma has been an important issue. The behavior of microinvasive tumors remains undetermined. Therefore, there is a controversy regarding this matter even among specialists.6-14 In addition, some clinicians and pathologists don't have exact concept about this matter. Furthermore, there is even a controversy regarding how to abbreviate microinvasive tumor into DCISM or microinvasive carcinoma (MIC) between the pathologists. This poses a problem to the registrars when they should enter the data in the cancer registry. An appropriate behavior code can be assigned only when they understand the meaning of different pathologic terminology. It would therefore be necessary not only to standardize the pathologic terminologies but also to have an identical understanding of the biologic behavior of the tumor, which is essential for the registration of tumors. In addition, borderline serous or mucinous tumors are issues that remain unresolved in association with diagnostic criteria, diagnostic terminology, behavior and treatment.15-21 We have therefore made an additional proposal of behavior codes for microinvasive tumors of the breast and ovary based on our previous proposal. In addition, we have also focused on the clinically meaningful behavior code rather than diagnostic criteria. Given the above background, we made our second proposal. But this is not conclusive but subject to alterations with the accumulation of more experience and knowledge. However, reconsideration and understanding of the biological behavior of microinvasive tumors of the breast and ovary and sharing a common concept will be helpful in statistics and in changing after amending the rule. Thus, we would like to report a current progress on our second proposal.

Lymph node metastasis is an important prognostic factor in cervical cancer patients. We report THz imaging for detecting micro-metastatic foci in the lymph nodes of early-stage uterine cervical cancer patients. Five paraffin-embedded metastatic lymph nodes from two cervical cancer patients were imaged using a THz time-domain spectroscopy system in the reflection mode. The size and shape of the tumor regions were compared with those from histopathologic examinations. The metastatic portions of lymph nodes as small as 3 mm were well delineated by THz imaging. The reflected peak amplitudes were lower in metastatic portions than in the normal portions of lymph nodes, and the difference in their peak-to-peak amplitudes was ~5%.

The pathogenetic mechanism underlying the hydropic change in complete hydatidiform moles (CHMs) is poorly understood. A growing body of data suggests that pericytes play a role in vascular maturation. Since maturation of villous stromal vessels in CHMs is markedly impaired at early stages, we postulated that a defect in pericytes around stromal vessels in chorionic villi might cause vascular immaturity and subsequent hydropic change. To investigate this, we examined several markers of pericytes, namely, α-smooth muscle actin (α-SMA), platelet-derived growth factor receptor-β (PDGFR-β), and desmin, in 61 normally developing placentas and 41 CHMs with gestational ages of 4–12 weeks. The ultrastructure of villous stromal vessels was also examined. Mature blood vessels from normal placentas show patent vascular lumens and formed hematopoietic components in the villous stroma. α-SMA and PDGFR-β expression in the villous stroma gradually increased and extended from the chorionic plate to peripheral villous branches. The labeled cells formed a reticular network in the villous stroma and, after week 7, encircled villous stromal vessels. In comparison, α-SMA and PDGFR-β expression in the villous stroma and stromal vessels of CHMs was significantly lower (p

The role of human papilloma virus (HPV) infection in the development of cervical carcinoma is well established, however, the prevalence of HPV DNA in cervical adenocarcinoma varies from study to study. It appears to be caused by a number of factors, one of which is that cervical adenocarcinomas comprise a heterogeneous group of multiple subtypes. To clarify the impact of HPV infection on the development of cervical adenocarcinoma with diverse histological subtypes, we performed a population-based study in Korean women from 15 different institutes for the status of HPV infection in adenocarcinoma of uterine cervix. A total of 432 cervical adenocarcinomas from 1997 to 2001 were reviewed and classified according to the modified WHO classification. For 135 cases, HPV typing was performed with HPV DNA chip (82 cases) and PCR HPV typing (53 cases), using formalin-fixed, paraffin-embedded archival tissue. The overall prevalence of HPV infection in cervical adenocarcinoma was 90%. The infection of HPV 16 and/or HPV 18 accounted for 78% of HPV-positive adenocarcinomas. Multiple HPV types were found in 13% of the cases. The HPV DNA was rarely detected in minimal deviation adenocarcinoma. Interestingly, HPV 16 was a predominant type in endometrioid and villoglandular types, whereas HPV 16 and HPV 18 were detected with equal prevalence in other subtypes. In conclusion, HPV infection, mostly HPV 16 and HPV 18, is highly associated with most of the cervical adenocarcinomas, whereas endometrioid and villoglandular type have a different pattern of HPV infection status. Minimal deviation adenocarcinoma does not seem to be related with HPV infection.

Placenta cretas are defined as abnormal adherences or ingrowths of placental tissue, but their pathogenetic mechanism has not been fully explained. During histologic examination of postpartum uteri, we noticed that the number of implantation site intermediate trophoblasts was increased in the placental bed of placenta cretas. To validate our observation and to address the pathogenetic role of implantation site intermediate trophoblasts in placenta cretas, we examined postpartum uteri with placenta cretas (n=34) and noncretas (n=22), obtained from Cesarean or immediate postpartum hysterectomy specimens. Using antibody to CD146, a marker for implantation site intermediate trophoblasts, we found that placenta cretas had significantly thicker layer of implantation site intermediate trophoblasts (2300+/-1200 mum) than noncretas (1500+/-1200 microm, P0.025). We also observed that the confluent distribution of cells was more frequent in placenta cretas (97%) than noncretas samples (45%, P0.001), and that the total number of implantation site intermediate trophoblasts within the superficial myometrium of the placental bed was significantly higher in placenta cretas than noncretas. Using antibodies to Ki-67, Bcl-2 and cleaved caspase-3 to determine the proliferative index and apoptotic rates of implantation site intermediate trophoblasts, we found that they were close to zero in both groups and did not differ significantly. These findings suggest that the increased number of implantation site intermediate trophoblasts observed in placenta cretas may be related to the pathogenesis of placental ingrowth, but the mechanism by which the increase in implantation site intermediate trophoblasts causes placenta cretas remains to be clarified.

Malignant transformation of mature cystic teratoma is uncommon, and occurs in approximately 2%–4% of cases [1]. The most common tumor is squamous cell carcinoma, followed by mucinous carcinoma, carcinoid tumor, thyroid carcinoma, etc.; however, any of the tissues in mature teratoma may undergo malignant transformation [1]. Goblet cell carcinoid (mucinous carcinoid) is a distinctive neoplasm with features of both carcinoid tumor and adenocarcinoma. Most cases described in the literature have occurred in the appendix and rarely, in the ovary. Although mature cystic teratomas occur in many extragonadal areas including the mesentery [2] and greater omentum, occurrence of goblet cell carcinoid arising in extragonadal teratoma has been rarely described, with only a single case in mediastinum being reported in the English literature [3]. Moreover, a combination of mucinous adenocarcinoma, goblet cell carcinoid, carcinoid tumor, and mature teratoma in an extragenital organ has not been reported. Herein, we present a rare case of combined mucinous adenocarcinoma and goblet cell and typical carcinoid tumor arising in mature cystic teratoma of the mesentery in a 48-year-old woman.

Context.—The ability of intermediate trophoblasts to invade maternal tissue during placentation depends on how well they can degrade the extracellular matrix. Invasion into the extracellular matrix requires many complex proteases. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) is a novel family of secreted metalloproteinases. The ADAMTS-1, -4, -5, and -14 subtypes are known to be expressed in human placenta, but little is understood about their expression patterns.Objective.—To examine the expression patterns of ADAMTS-1, -4, -5, and -14 in specific human placenta cell types during gestation and in gestational trophoblastic diseases.Design.—Placental tissues were obtained from 25 pregnant women and 21 cases of gestational trophoblastic diseases (10 early complete moles, 3 placental site trophoblastic tumors, 4 invasive moles, and 4 choriocarcinomas). The expression of the 4 ADAMTS was analyzed by immunohistochemistry.Results.—ADAMTS-1, -4, -5, and -14 were differentially expressed by the human placenta throughout gestation in a time-specific and cell type–specific manner, as well as in gestational trophoblastic diseases. ADAMTS-1 showed gradually strong staining intensity in gestational trophoblastic diseases according to the invasive potential but showed consistent strong intensity throughout normal placenta. ADAMTS-4 and ADAMTS-5 exhibited higher and restricted expression in first-trimester intermediate trophoblasts. They also exhibited comparably strong expression in gestational trophoblastic diseases. However, ADAMTS-14 expression remained unchanged throughout gestation.Conclusions.—The restricted expression pattern of ADAMTS-4 and ADAMTS-5 and their increased expression in gestational trophoblastic diseases suggest that these 2 ADAMTS subtypes are associated with a biological phenotype of trophoblasts involved in human placentation and the development of gestational trophoblastic diseases.

BACKGROUND AND PURPOSE: An increased prevalence of disabilities is being observed as more preterm infants survive. This study was conducted to evaluate correlations between brain MR imaging measurements taken at a term-equivalent age and neurodevelopmental outcome at 2 years9 corrected age among very low–birth-weight infants. MATERIALS AND METHODS: Of the various brain MR imaging measurements obtained at term-equivalent ages, reproducible measurements of the transcerebellar diameter and anteroposterior length of the corpus callosum on sagittal images were compared with neurodevelopmental outcomes evaluated by the Bayley Scales of Infant Development (II) at 2 years9 corrected age (mean ± standard deviation, 16.1 ± 6.4 months of age). RESULTS: Ninety infants were enrolled. The mean gestational age at birth was 27 weeks and the mean birth weight was 805.5 g. A short corpus callosal length was associated with a Mental Developmental Index P = .047) and high-risk or diagnosed cerebral palsy ( P = .049). A small transcerebellar diameter was associated with a Psychomotor Developmental Index P = .003), Mental Developmental Index P = .004), and major neurologic disability ( P = .006). CONCLUSIONS: A small transcerebellar diameter and short corpus callosal length on brain MR imaging at a term-equivalent age are related to adverse neurodevelopmental outcomes at a corrected age of 2 years and could be a useful adjunctive tool for counseling parents about future developmental outcomes.

The TP53 mutations have been proved to be predominated in ovarian cancer in a study from The Cancer Genome Atlas (TCGA). However, the molecular characteristics of recurrent ovarian cancers following initial treatment have been poorly estimated. This study was to investigate the pattern of somatic point mutations in matched paired samples of primary and recurrent epithelial ovarian cancers, using the OncoMap mutation detection protocol. We have adapted a high-throughput genotyping platform to determine the mutation status of a large panel of known cancer genes. OncoMap v.4.4 was used to evaluate genomic DNA isolated from a set of 92 formalin-fixed, paraffin-embedded (FFPE) tumors, consisting of matched paired samples of initially diagnosed and recurrent tumors from 46 epithelial ovarian cancer (EOC) patients. Mutations were observed in 33.7% of the samples, with 29.3% of these samples having a single mutation and the remaining 4.3% having two or more mutations. Among the 41 genes analyzed, 35 mutations were found in four genes, namely, CDKN2A (2.2%), KRAS (6.5%), MLH1 (8.2%) and TP53 (20.7%). TP53 was the most frequently mutated gene, but there was no correlation between the presence of mutation in any gene and clinical prognosis. Furthermore, somatic mutations did not differ between primary and recurrent ovarian carcinomas. Every mutation present in recurrent samples was detected in the corresponding primary sample. In conclusion, these OncoMap data of Korean EOC samples provide that somatic mutations were found in CDKN2A, KRAS, MLH1, and TP53. No differences in mutational status between primary and recurrent samples were detected. To understand the biology of tumor recurrence in epithelial ovarian cancer, more studies are necessary, including epigenetic modifications or additional mutations in other genes.

DNA copy number changes were studied by comparative genomic hybridization on 10 tumor specimens of squamous cell carcinoma of cervix obtained from Korean patients. DNA was extracted from paraffin‐embedded sections after removal of non‐malignant cells by microdissection technique. Copy number changes were found in 8/10 tumors. The most frequent changes were chromosome 19 gains (n=6) and losses on chromosomes 4 (n=4), 5 (n=3), and 3p (n=3). A novel finding was amplification in chromosome arm 9p21‐pter in 2 cases. Gains in 1, 3q, 5p, 6p, 8q, 16p, 17, and 20q and losses at 2q, 6q, 8p, 9q, 10p, 11, 13, 16q, and 18q were observed in at least one of the cases.

Prenatal ultrasonography early in gestation allows diagnosis of posterior urethral valves. We report on a fetus with posterior urethral valves treated using vesicoamniotic shunting at 13 + 5 weeks' gestation. A double-basket catheter was used for shunting. A 2582-g male neonate was delivered at 33 weeks' gestation, and the infant continued to show normal renal function at 3 years of age. To the best of our knowledge this is the first report of successful vesicoamniotic shunt placement using a double-basket catheter in the first trimester of pregnancy. Copyright © 2005 ISUOG. Published by John Wiley & Sons, Ltd.

Up-regulated expression of telomerase reverse transcriptase (TERT) and subsequent maintenance of telomere length are essential in tumour development. Recent studies have implicated somatic gain-of-function mutations at the TERT promoter as one of the mechanisms that promote transcriptional activation of TERT; however, it remains unclear whether this genetic abnormality is prevalent in gynaecological neoplasms. We performed mutational analysis in a total of 525 gynaecological cancers, and correlated TERT promoter mutations with clinicopathological features. With the exception of ovarian clear cell carcinomas, in which mutations were found in 37 (15.9%) of 233 cases, the majority of gynaecological malignancies were wild-type. TERT promoter mutation does not appear to be an early event during oncogenesis, as it was not detected in the contiguous endometriosis associated with ovarian clear cell carcinoma. Ovarian clear cell carcinoma cell lines with TERT promoter mutations exhibited higher TERT mRNA expression than those with wild-type sequences (p = 0.0238). TERT promoter mutation tended to be mutually exclusive with loss of ARID1A protein expression (p = 4.4 × 10(-9) ) and PIK3CA mutation (p = 0.0019) in ovarian clear cell carcinomas. No associations with disease-specific survival were observed for ovarian clear cell carcinoma. The above results, in conjunction with our previous report showing longer telomeres in ovarian clear cell carcinomas relative to other types of ovarian cancer, suggests that aberrations in telomere biology may play an important role in the pathogenesis of ovarian clear cell carcinoma.

The features and regulation of uterine angiogenesis and vascular remodelling during pregnancy are poorly defined. Here we show that dynamic and variable decidual angiogenesis (sprouting, intussusception and networking), and active vigorous vascular remodelling such as enlargement and elongation of 'vascular sinus folding' (VSF) and mural cell drop-out occur distinctly in a spatiotemporal manner in the rapidly growing mouse uterus during early pregnancy - just after implantation but before placentation. Decidual angiogenesis is mainly regulated through VEGF-A secreted from the progesterone receptor (PR)-expressing decidual stromal cells which are largely distributed in the anti-mesometrial region (AMR). In comparison, P4 -PR-regulated VEGF-A-VEGFR2 signalling, ligand-independent VEGFR3 signalling and uterine natural killer (uNK) cells positively and coordinately regulate enlargement and elongation of VSF. During the postpartum period, Tie2 signalling could be involved in vascular maturation at the endometrium in a ligand-independent manner, with marked reduction of VEGF-A, VEGFR2 and PR expressions. Overall, we show that two key vascular growth factor receptors - VEGFR2 and Tie2 - strikingly but differentially regulate decidual angiogenesis and vascular remodelling in rapidly growing and regressing uteri in an organotypic manner.

PURPOSE: Inactivation of TP53, which occurs predominantly by missense mutations in exons 4-9, is a major genetic alteration in a subset of human cancer. In spite of growing evidence that gain-of-function (GOF) mutations of p53 also have oncogenic activity, little is known about the clinical relevance of these mutations. METHODS: The clinicopathological features of high-grade serous ovarian carcinoma (HGS-OvCa) patients with GOF p53 mutations were evaluated according to a comprehensive somatic mutation profile comprised of whole exome sequencing, mRNA expression, and protein expression profiles obtained from the Cancer Genome Atlas (TCGA). RESULTS: Patients with a mutant p53 protein (mutp53) with a GOF mutation showed higher p53 mRNA and protein expression levels than patients with p53 mutation with no evidence of GOF (NE-GOF). GOF mutations were more likely to occur within mutational hotspots, and at CpG sites, and resulted in mutp53 with higher functional severity (FS) scores. Clinically, patients with GOF mutations showed a higher frequency of platinum resistance (22/58, 37.9%) than patients with NE-GOF mutations (12/56, 21.4%) (p=0.054). Furthermore, patients with GOF mutations were more likely to develop distant metastasis (36/55, 65.5%) than local recurrence (19/55, 34.5%), whereas patients with NE-GOF mutations showed a higher frequency of locoregional recurrence (26/47, 55.3%) than distant metastasis (21/47, 44.7%) (p=0.035). There were no differences in overall or progression-free survival between patients with GOF or NE-GOF mutp53. CONCLUSION: This study demonstrates that patient with GOF mutp53 is characterized by a greater likelihood of platinum treatment resistance and distant metastatic properties in HGS-OvCa.

We describe two cases of postnatally diagnosed congenital diaphragmatic hernia (CDH) combined with pulmonary sequestration, both of which were diagnosed as isolated pulmonary sequestration on prenatal ultrasound. In these cases, prenatal ultrasonography demonstrated only a hyperechoic mass on the left lower lung and the diaphragm seemed intact. In each case both lungs showed otherwise normal development throughout pregnancy. Pulmonary sequestration may serve as a 'protector', preventing herniation of abdominal contents into the thoracic cavity. The co-occurrence of CDH may be obscured by a lung mass, especially on the left lower lung, and therefore it is necessary to deliver these infants at a tertiary center and parents should be counseled about the possibility of postnatal CDH.

Background MicroRNA (miRNA) expression is known to be deregulated in cervical carcinomas. However, no data is available about the miRNA expression pattern for the minimal deviation adenocarcinoma (MDA) of uterine cervix. We sought to detect deregulated miRNAs in MDA in an attempt to find the most dependable miRNA or their combinations to understand their tumorigenesis pathway and to identify diagnostic or prognostic biomarkers. We also investigated the association between those miRNAs and their target genes, especially Notch1 and Notch2. Methods We evaluated miRNA expression profiles via miRNA microarray and validated them using.real-time PCR assays with 24 formalin-fixed, paraffin-embedded tissue blocks of MDA and 11 normal proliferative endocervical tissues as control. Expression for Notch1 and 2 was assessed by immunohistochemistry. Results MiRNA-135a-3p, 192-5p, 194-5p, and 494 were up-regulated, whereas miR-34b-5p, 204-5p, 299-5p, 424-5p, and 136-3p were down-regulated in MDA compared with normal proliferative endocervical tissues (all P

Neoplasm of the vulva is a rare malignancy accounting for

Fibroepithelial stromal polyp (FSP) is a benign lesion that can occur at various sites, including the lower female genital tract. In rare cases, however, it may exhibit hypercellularity, bizarre cytomorphological features, and atypical mitoses resulting in an overdiagnosis as a malignant tumor despite its benign clinical course. Recently, we experienced one case of a 30-year-old pregnant woman with cellular pseudosarcomatous FSP that was initially diagnosed as a malignant fibrous histiocytoma at a primary clinic. In addition to describing the rare features of this case, we wish to increase awareness about this benign lesion which will be essential for avoiding unnecessary radical surgery or chemoradiation treatment.