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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.

Currently, the indications for progestin therapy are limited to endometrioid adenocarcinoma that are International Federation of Gynecology and Obstetrics (FIGO) grade 1, FIGO stage IA, and confined to the endometrium. However, there have been attempts to broaden the indications of progestin therapy to patients with higher FIGO grades and/or with superficial myometrial invasion. We experienced a case with myoinvasive endometrioid adenocarcinoma treated with oral progestin, whose follow-up endometrial curettage specimen showed an apparent complete histologic regression; however, the final hysterectomy specimen disclosed myoinvasive endometrioid adenocarcinoma within the superficial myometrium, with absence of residual tumor in the endometrium. We describe this case to demonstrate that complete histologic regression of the endometrial lesion in a follow-up curettage specimen after progestin treatment does not guarantee histologic regression of the carcinoma within the myometrium. Our case indicates that current indications for progestin treatment should not be broadened to patients with superficial myometrial invasion.

The epithelial-mesenchymal transition (EMT) is known to be associated with carcinoma invasion and metastasis. Previous studies have demonstrated that the expression of EMT-related proteins in carcinoma cells in many organs is associated with a higher histologic grade and a poor prognosis. However, the clinical significance of EMT in ovarian cancers is controversial. Formalin-fixed and paraffin-embedded tumor samples of 198 high-grade serous carcinomas (HGSCs) and 13 serous borderline tumors or low-grade serous carcinomas (SBT/LGSCs) of the ovary were analyzed. EMT phenotype marker expression, including claudin 4, E-cadherin, N-cadherin, α-smooth muscle actin (α-SMA) and vimentin, and EMT related transition factor expression, including paired-related homeobox 1 (PRRX1), SLUG, SNAI1, and TWIST1, were evaluated by immunohistochemistry. EMT phenotype was classified into three groups including complete EMT phenotype, incomplete EMT phenotype, and epithelial phenotype according to epithelial and mesenchymal marker expression. EMT phenotypes varied in HGSC (Complete phenotype, 32.3%; Incomplete phenotype, 42.9%; epithelial phenotype, 24.7%) compared with SBT/LGSC. EMT phenotype and each EMT phenotype markers were not significantly associated with patient survival of HGSCs in multivariate analysis. However transition factor, SLUG expression, correlated with advanced disease and SLUG expression was an independent predictor of poor overall survival in HGSC. EMT related transition factor expression like SLUG is more important in association with clinical outcome than EMT phenotype itself in HGSC.

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.

Background: Undifferentiated endometrial sarcoma (UES) is a very rare subtype of uterine sarcoma, which has no consensus on the treatment. We investigated the expression of potential new therapeutic targets in UES to improve its aggressive clinical course and poor survival outcome. Methods: The immunohistochemical expressions of vascular endothelial growth factor (VEGF), c-KIT, c-ABL, platelet derived growth factor receptor (PDGFR), protein kinase B (AKT1), mammalian target of rapamycin, epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER2), Wilms tumor (WT1), aromatase inhibitor (CYP19A1), and histone deacetylase (HDAC) series in 10 UES patients were assessed using tissue microarrays. Results: Strongly positive immunoreactivities were observed for VEGF, AKT1, and HDAC2/7 in 8 (80.0%) tumors; for CYP19A1 and HDAC6 in 9 (90%) tumors; and for HDAC1/4/8 in 10 (100%) tumors. Strong expression of CYP19A1 and HDAC6 was associated with distant recurrence (p = 0.030, both), and expression of WT1 indicated a more advanced stage (p = 0.033). UES treated with adjuvant therapy showed better disease-free and overall survivals (both 0 vs. 33.3%, p = 0.003). Conclusion: VEGF, AKT1, CYP19A1, and the HDAC1/2/4/6/7/8 series show an especially high frequency of strong immunoreactivity in UES and can be considered potential therapeutic targets.

Objective Genomic characteristics of gestational trophoblastic neoplasm (GTN) are mostly unknown. This study reveals the molecular features of malignant GTN, including choriocarcinoma (CC), epithelioid trophoblastic tumor (ETT), and placental site trophoblastic tumor (PSTT), by whole transcriptome sequencing analysis. Methods Data obtained from the total RNA sequencing of 2 CC, 4 ETT, and 4 PSTT were evaluated for differential gene expression, pathway alteration, fusion gene, infiltrating immune cell type, PD-L1 and PTEN expression level, and mutation analysis was performed. Results The transcriptome data were correlated with known biomarkers, including HDS3B1, p63, hCG, and hPL for all tumor types. ETT and PSTT were more closely clustered compared with CC in clustering analysis using gene expression; however, ETT showed various altered signaling pathways, including PI3K-Akt-mTOR, with frequent loss of PTEN protein expression. This finding was both well correlated with PIK3CA c.3140A > G pathogenic mutation, detected in 1 ETT, and further confirmed using the MassARRAY method. PSTT showed an overexpressed gene cluster associated with muscle contraction and G protein-coupled receptor activity. No significant fusion gene was seen in all 10 cases. In tumor-infiltrating immune cell profiles, CD4 memory T cell and macrophage signature were relatively high in ETT and PSTT. PD-L1 mRNA expression level was high in all cases, which was significantly correlated with the PD-L1 level by immunohistochemistry (p = 0.03) with positivity in all 10 cases. Conclusions ETT and PSTT were similar at the transcriptome level, with a high level of PD-L1 expression in all tumor types; however, specific pathways, such as PI3K signaling, were altered in ETT.

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.

Aims: We investigated the prognosis of patients with small-cell neuroendocrine carcinoma of the uterine cervix (SCNEC) in relation to treatment modalities. Methods: We retrospectively reviewed the medical records and pathological reports of 102 patients who were histologically diagnosed with SCNEC at 5 different institutes. Time to progression (TTP) and overall survival (OS) were analyzed for each treatment modality. Results: Of the patients with early-stage [International Federation of Obstetrics and Gynecology (FIGO) stage IB2 or below] SCNEC, 57.8 and 79.3% underwent radical hysterectomy followed by adjuvant therapy. In advanced-stage SCNEC, concurrent chemoradiation therapy was given to 51.4% of the patients. The overall recurrence rate was 51.6%. In early- and advanced-stage SCNEC, the TTP was not different (22.3 vs. 13.3 months, p = 0.104), but the OS was different (40.7 vs. 21.4 months, p = 0.029). Parametrial involvement and lymph vascular space invasion were found to be associated with an unfavorable prognosis. Interestingly, survival was the most unfavorable in patients with early-stage SCNEC who had never received chemotherapy. FIGO stage and use of chemotherapy were identified as independent prognostic factors in SCNEC patients. Conclusions: SCNEC requires systemic chemotherapy as part of the initial treatment, along with surgery or radiation, even in patients with early-stage disease.

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.

This report describes a rare case of invasive extramammary Paget disease of the vulva with signet ring cell morphology in a 58-yr-old woman with a history of signet ring cell carcinoma of the stomach. This case was initially misinterpreted as a metastatic gastric carcinoma to the vulva because an initial small, superficial biopsy specimen showed infiltration of signet ring cells in the dermis without intraepidermal Paget cells. However, a surgically resected specimen showed concordant immunophenotypes in both intraepidermal Paget cells and intradermal signet ring cell components with immunoreactivity to cytokeratin (CK) 7, CEA, and gross cystic disease fluid protein-15, and immunonegativity for CK20, MUC5AC, and MUC6. Gastric signet ring cell carcinoma showed immunoreactivity to CK7, CEA, MUC5AC, and MUC6, and immunonegativity for gross cystic disease fluid protein-15 and CK20. The diagnosis of primary invasive extramammary Paget disease of the vulva was also supported by a long interval after gastrectomy (7.5 yr), the solitary involvement of the vulva, and the absence of lymphovascular invasion. This case demonstrates that invasive extramammary Paget disease may have a signet ring cell morphology and immunohistochemical profile similar to those of gastric signet ring cell carcinoma, but the addition of gross cystic disease fluid protein-15 immunostain in the panel of markers is helpful in the differential diagnosis.

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.

Mucinous adenocarcinoma is one of the least common histologic types of endometrial carcinoma, comprising less than 10% (range 1–9%) of these tumors (Fujiwara and Longacre in Am J Surg Pathol 35:537–544, 2011 [1]; Ross et al. in Am J Surg Pathol 7:715–729, 1983 [2], Melhem and Tobon in Int J Gynecol Pathol 6:347–355, 1987 [3]).While focal mucinous differentiation is a common finding in usual endometrioid endometrial adenocarcinoma (Ross et al. in Am J Surg Pathol 7:715–729, 1983 [2]), mucinous endometrial adenocarcinoma is diagnosed when more than 50% of the tumor cells contain intracytoplasmic mucin (Zaino et al. in Tumours of the uterine corpus. WHO press, Geneva [4]). The diagnosis of endometrial adenocarcinoma in general is based on a combination of cytologic and architectural criteria. For mucinous adenocarcinoma, however, the usual diagnostic criteria cannot always be applied uniformly as cytologic atypia is rarely more than minimal to moderate, and architectural complexity is often the only diagnostic clue. Moreover, rare cases of mucinous adenocarcinoma are histologically similar to non-neoplastic endocervical epithelium or adenocarcinoma of cervical origin. For these reasons, establishing a diagnosis of mucinous adenocarcinoma sometimes poses a diagnostic challenge (Vang and Tavassoli in Int J Surg Pathol 11:261–270, 2003 [5]), requiring immunohistochemical and molecular genetic tests as useful adjuncts. The discussion that follows summarizes the clinical, histopathologic, and molecular genetic characteristics, and the possible precursors of endometrial mucinous adenocarcinoma.

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.

Aims To identify histopathological and immunohistochemical findings that aid diagnosis of metastatic endometrial stromal sarcoma (ESS) in small biopsy specimens of the lung. Methods and results We reviewed the histology of 46 lung nodules from 10 cases of pulmonary metastatic ESS. Biopsy sections were analysed by immunohistochemistry to highlight blood and lymphatic vasculature, and for expression of CD10 and oestrogen receptor (ER). Various histological changes were identified that could mislead in making a diagnosis on small biopsy samples: haemangiopericytomatous blood vessels (39%), absence of characteristic spiral arteriole-like vasculature (26%), intratumoral cysts formed by dilatation of airways (22%) or intratumoral myxoid change (11%), prominent interstitial collagen deposits (48%), foam cell infiltration (4%) and smooth muscle differentiation (2%). Peribronchial/peribronchiolar distribution of tumour cells with juxtaepithelial growth was a frequent feature, observed in 59% of nodules. In two very small nodules the lesion was barely recognizable histologically; tumour cells were detected only by expression of ER and CD10. Conclusions Combined staining for ER and CD10 can be helpful in avoiding an erroneous diagnosis. As lymphatics are not normally present in the juxtaepithelial bronchial/bronchiolar wall, juxtaepithelial tumour growth beneath the bronchial epithelium in early metastatic lesions indicates a haematogenous metastastic route through the bronchial artery.

Background and objective CD8+ cell infiltration and apoptosis of airway epithelial cells are increased in chronic obstructive pulmonary disease (COPD). CD8+ T cells induce apoptosis by releasing granzymes, which can also cause extracellular matrix degradation and remodelling. Granzyme B levels and T cells expressing granzyme B are increased in bronchoalveolar lavage fluid of COPD patients, which suggests that granzyme B may contribute to the pathogenesis of COPD. This study provides quantitation of granzyme B-positive cells in relation to CD8+ cells in the small airway walls of emphysema. Methods Antibodies against CD8 and granzyme B were used to identify CD8+ and granzyme B+ cells. Volume fraction (Vv) of CD8+ and granzyme B+ cells were quantitated by the point counting method in the small airways of 13 non-smoker control subjects and 46 emphysema patients (14 panlobular emphysema (PLE) and 32 centrilobular emphysema (CLE) lungs). Immunohistochemical detection of macrophage scavenger receptor was also performed in randomly selected cases. Results The Vv of CD8+ and granzyme B+ cells in CLE was greater than those in control and PLE (both P

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.

Borderline ovarian malignancies account for 10–15% of all the ovarian tumours, affect younger age groups as compared to its invasive counterpart, have a better prognosis, and are limited to Stage I...

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 purpose of this study was to assess clinical outcomes with respect to the extent of stromal invasion in patients with stage I ovarian mucinous adenocarcinoma (MAC) of the intestinal type. We retrospectively reviewed the medical records and pathologic slides of 113 patients with stage I ovarian MACs who were treated at the Asan Medical Center from January 1994 to July 2009. According to the recent histopathologic criteria, MACs were classified into 3 groups: intraepithelial carcinoma without invasion (IEC), intraepithelial carcinoma with microinvasion (IECMI), and mucinous adenocarcinoma with extensive invasion (MACEI). Stromal invasion was confined to the tumors showing severe cytologic atypia in the invasive foci. Therefore, cases showing mucin granulomas composed only of macrophages without malignant cells were excluded from the definition of invasion. Of the 113 patients, 54 (47.8%) had IEC, 15 (13.3%) had IECMI, and 44 (38.9%) had MACEI. There were no differences among groups in age, menopausal status, CA-125 level, surgical procedures, stage, capsular and lymphovascular space invasion. The 5-year disease-free-survival rates in the IEC, IECMI, and MACEI groups were 97.7%, 77.3%, and 79.9%, respectively (IEC vs IECMI, P = 0.004; IEC vs MACEI, P = 0.012; IECMI vs MACEI, P = 0.555). Prognosis was significantly poorer for patients with IECMI than for those with IEC, but not different between patients with IECMI and MACEI. Stromal microinvasion in ovarian MAC is a significant prognostic factor. Therefore, diligent search for “stromal microinvasion” with adequate sampling of tumor tissue are important at the time of histopathologic diagnosis, and patients with IECMI should no longer be treated identically to those with IEC.

Primary extragonadal germ cell tumors are rare and mostly occur in young men with predominance of nonseminomatous histology. We report an undescribed case of primary retroperitoneal dysgerminoma presenting as an adrenal tumor in a 17-year-old girl. Surgery was performed on a 10 × 9.5 cm sized adrenal gland tumor and the resected tumor showed unequivocal histological features of dysgerminoma. The diagnosis was confirmed by the tumor's germ cell immunophenotype. Postoperative ultrasonography, CT and PET over a 6-month period revealed no evidence of ovarian lesion. The patient is stable, but with a suspicious residual tumor after adjuvant chemotherapy.