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Lobular endocervical glandular hyperplasia (LEGH) is a multicystic proliferative disorder of the uterine cervix. The aim of this review was to clarify the current understanding of this unique tumor.This article reviews the chronological progress of research regarding clinico-pathological and genetic aspects of LEGH and related cervical cystic diseases such as Nabothian cyst and adenocarcinoma of gastric type (GAS), using the literature and data from our institute. We also describe clinical management including preoperative diagnosis and adequate surgical/expectant treatment based on the biological features.Recent studies revealed several unique aspects of LEGH, that is, (i) production of gastric mucin, (ii) symptomatic and histological similarity with minimal deviation adenocarcinoma (MDA), and (iii) frequent association with GAS, including MDA. These findings indicated that LEGH is a gastric metaplasia, as well as pre-cancerous neoplasia. For the preoperative diagnosis of LEGH, the combination of "cosmos" sign on magnetic resonance imaging, detection of gastric mucin, and lack of nuclear atypia on cytology is important. Cone biopsy is effective for pathological diagnosis. Simple hysterectomy is indicated as surgical treatment for LEGH; however, meticulous follow-up is also an option, especially for young patients, because the rate of malignant transformation was reported to be 1%-2%. For LEGH patients who selected follow-up, a worsening cytology and increase in lesion size were important signs of malignant change of LEGH for safe follow-up.Proper understanding of the characteristics of LEGH is important for adequate management.

In 2020, the WHO published a new system for classifying invasive endocervical adenocarcinoma based on histological features and high-risk human papillomavirus (HPV) infection. However, immunophenotypes of each histological subtype require further investigation. We immunohistochemically analyzed 66 invasive endocervical adenocarcinomas using three cell-lineage–specific markers: claudin 18 (CLDN18) for gastric, cadherin 17 (CDH17) for intestinal, and PAX8 for Mullerian epithelial cells. We identified five immunophenotypes of endocervical adenocarcinoma: gastric (21%); intestinal (14%); gastrointestinal (11%); Mullerian (35%); and not otherwise specified (NOS) (20%). Adenocarcinomas with gastric immunophenotype, characterized by aging (p = 0.0050), infrequent HPV infection (p

Serous carcinoma (SC) is an aggressive histologic type of endometrial carcinoma (EMC) with a poor prognosis. The development of novel therapeutics for SC is an important issue. PIM1 is a serine/threonine kinase involved in various cellular functions, such as cell cycle progression, apoptosis, and transcriptional activation via the phosphorylation of many target proteins, including MYC. PIM1 is overexpressed in several cancers and has been associated with the treatment-resistance. We investigated the expression and function of PIM1 in EMC, particularly SC. Immunohistochemical analysis in 133 EMC cases [103 endometrioid carcinomas (EC) and 30 SC] revealed the significantly stronger expression of PIM1 in SC than in EC and significantly shorter survival of patients with the overexpression of PIM1 in all EMC cases, as well as in only SC cases. A multivariate analysis identified the overexpression of PIM1 as an independent prognostic factor. The knockdown of PIM1 by siRNA in the SC cell line, ARK1, decreased the expression of phosphorylated MYC and reduced proliferation, migration, and invasion. The PIM1 inhibitor, SGI-1776, reduced cell viability in SC cell lines (ARK1, ARK2, and SPAC1L) with IC50 between 1 and 5 µM. SGI-1776 also reduced the migration and invasion of ARK1 cells. Moreover, the oral administration of SGI-1776 significantly suppressed subcutaneous ARK1 xenograft tumor growth in nude mice without impairing health. These results indicate that PIM1 is involved in the acquisition of aggressiveness and suggest the potential of PIM1 as a novel therapeutic target and SGI-1776 as a therapeutic agent for SC.

IntroductionAlthough lobular endocervical glandular hyperplasia is a benign disorder of the uterine cervix, its potential as a precursor of minimal deviation adenocarcinoma has been reported. However, the natural history of the disease and the frequency of malignant change are not fully understood. We evaluated the frequency of malignant change of clinical lobular endocervical glandular hyperplasia and explored useful parameters indicating malignant change.MethodsThe clinical courses of 175 patients with cervical multi-cystic lesions who visited Shinshu University Hospital between June 1995 and June 2019 were retrospectively analyzed. We examined the results of follow-up and outcomes of the patients diagnosed with lobular endocervical glandular hyperplasia and investigated the frequency of malignant transformation.ResultsOf the 175 patients, 15, 84, and 76 were clinically diagnosed with suspected malignancy, suspected lobular endocervical glandular hyperplasia, and suspected nabothian cyst, respectively. Of these patients, 69 patients with suspected lobular endocervical glandular hyperplasia were followed, and 12 underwent hysterectomy after a mean follow-up of 57.1 (range: 3–154) months due to lesion enlargement (increase in tumor diameter of >20%) and/or worsening cytology. Of these 12 patients, two had lobular endocervical glandular hyperplasia with atypia and one had minimal deviation adenocarcinoma. Of 69 patients, the rate of malignant change was 1.4% (1/69). The growth rates of the lesions for these three patients during follow-up were significantly higher than those of nine patients who underwent surgery with lobular endocervical glandular hyperplasia without atypia and 48 follow-up cases of suspected lobular endocervical glandular hyperplasia. The cut-off value of the growth rate suggesting malignant transformation was 38.1% (84.6% sensitivity and 100% specificity). Tumor size and cytology did not change in the remaining 57 cases continuing follow-up.ConclusionAn increase in tumor size and worsening cytology are important parameters for detecting malignant transformation of lobular endocervical glandular hyperplasia during follow-up. However, the frequency of malignant change of this disease may be limited. These results suggest that conservative management may be an option for clinical lobular endocervical glandular hyperplasia.

In order to identify genes involved in the pathogenesis of clear cell carcinoma of the ovary (CCC), functional screening using a cDNA expression library was performed. We extracted mRNA from a CCC cell line (RMG-1), established a cDNA library using a retroviral vector, transfected that library into mouse NIH3T3 cells and sequenced the resultant foci. The tissue-type specific expression of isolated genes and their transforming activities were evaluated. Seven genes were isolated. Of these genes, the mRNA expression of SEC61B and DVL1 is significantly stronger in CCC than in other histological types (

A classification system for invasive endocervical adenocarcinoma (ECA) focusing on high-risk human papillomavirus (HPV) detection has been recently developed. However, precursor lesions of each ECA subtype and immunohistochemical markers that effectively subcategorize ECAs with gastric and intestinal differentiation have not been fully described. Here, we aimed to subcategorize endocervical adenocarcinoma in situ (AIS) by immunophenotype and to characterize the histopathology of each AIS subtype. We immunohistochemically analyzed 36 AIS and 25 lobular endocervical glandular hyperplasia (LEGH) samples using three cell lineage-specific markers (CLDN18, gastric epithelial cells; CDH17, intestinal epithelial cells; and PAX8, Müllerian epithelial cells). The AISs were immunophenotypically classified as gastric-type (G-AIS; n = 2), intestinal-type (I-AIS; n = 10), gastrointestinal-type (GI-AIS; n = 3), Müllerian-type (M-AIS; n = 18), and AIS, not otherwise specified (AIS-NOS; n = 3). All 25 LEGHs were categorized as gastric-type. G-AIS had pale eosinophilic or clear cytoplasm with a small amount of apical mucin and fewer mitotic bodies. I-AIS comprised various numbers of goblet cell-type tumor cells. GI-AIS showed intermediate or mixed features of G-AIS and I-AIS. M-AIS, as with the usual-type ECA, was typically characterized by mucin depletion; however, several lesions had abundant cytoplasmic mucin. High-risk HPV was detected in most AISs but was negative in 100% (2/2) of G-AIS, 10% (1/10) of I-AIS, and 6% (1/18) of M-AIS lesions. In summary, the AIS subtypes defined by immunophenotype had distinct histopathological and etiological characteristics. Thus, immunophenotyping with CLDN18, CDH17, and PAX8 might improve the diagnostic accuracy of histopathological classifications of ECAs.

Endometrial stromal sarcoma (ESS) is a rare uterine malignancy that requires accurate pathological diagnosis for proper treatment. This study aimed to clarify the discrepancies in the pathological diagnosis of ESS and obtain practical clues to improve diagnostic accuracy. Between 2002 and 2015, 148 patients with low-grade ESS (LGESS), high-grade ESS (HGESS), undifferentiated endometrial sarcoma (UES), or undifferentiated uterine sarcoma (UUS) diagnosed at 31 institutions were included. We performed immunohistochemistry, real-time polymerase chain reaction for JAZF1-SUZ12 and YWHAE-NUTM2A/B, and break-apart fluorescent in situ hybridization for JAZF1, PHF1, and YWHAE. Central pathology review (CPR) was performed by six pathologists. After CPR, LGESS, HGESS, UES/UUS, and other diagnoses were confirmed in 72, 25, 16, and 31 cases, respectively. Diagnostic discrepancies were observed in 19.6% (18/92) of LGESS and 34% (18/53) of HGESS or UUS/UES. Adenosarcomas, endometrial carcinomas, carcinosarcomas, and leiomyosarcomas were common diagnostic pitfalls. JAZF1-SUZ12 transcript, PHF1 split signal, and YWHAE-NUTM2A/B transcript were mutually exclusively detected in 23 LGESS, 3 LGESS, and 1 LGESS plus 3 HGESS, respectively. JAZF1-SUZ12 and YWHAE-NUTM2A/B transcripts were detected only in cases with CPR diagnosis of LGESS or HGESS. The CPR diagnosis of LGESS, HGESS, and UUS was a significant prognosticator, and patients with LGESS depicted a favorable prognosis, while those with UUS showed the worst prognosis. Pathological diagnosis of ESS is often challenging and certain tumors should be carefully considered. The accurate pathological diagnosis with the aid of molecular testing is essential for prognostic prediction and treatment selection.

To analyze the clinical behavior of neuroendocrine tumors (NETs) of the uterine cervix, we conducted a multicenter, retrospective study of 193 patients.We evaluated the prognosis of NETs according to the new International Federation of Gynecology and Obstetrics (FIGO) staging system, compared the clinical response to different chemotherapy regimens, and compared different histological subtypes of NETS.Diagnoses of the subjects were atypical carcinoid tumor (ACT, n = 37), small cell neuroendocrine carcinoma (SCNEC, n = 126), large cell neuroendocrine carcinoma (LCNEC, n = 22), and NET, not elsewhere classified (n = 8), according to central pathological review. According to FIGO 2018, 69, 17, 74, and 33 patients were at stage I, II, III, or IV, respectively. Five-year survival was 64.5%, 50.1%, 30.2%, and 3.4% for patients at stage I, II, III and IV. About 40% of patients with stage IIIC1 survived5 years. On multivariate analyses, locally-advanced disease, para-aortic node metastasis, distant metastasis, and4 cycles of chemotherapy were associated with poor survival. Histological subtype and pelvic node metastasis had no prognostic significance. Response rates to etoposide-platinum (EP) or irinotecan-platinum (CPT-P) regimens were 43.8% (28/64), but only 12.9% to a taxane-platinum (TC) regimen (4/31). The response rate for ACT was 8.7% (2/23), significantly less than the 36.6% for high-grade neuroendocrine carcinomas (HGNEC: both SCNEC and LCNEC, 41/111).Locally-advanced, extra-pelvic disease and insufficient chemotherapy were independent prognostic factors for cervical NET. HGNEC showed good responses to EP or CPT-P but not TC. Chemotherapy was less effective for ACT, which had a prognosis identical to HGNEC.

Gastric-type mucinous carcinoma (GAS) is a novel variant of uterine cervix mucinous carcinoma. GAS is a distinct entity that can be distinguished from typical endocervical adenocarcinoma (UEA). In Japan, postoperative adjuvant therapy for cervical cancer includes not only radiation therapy (RT) or concurrent chemoradiotherapy (CCRT) but also chemotherapy in many cases. However, no previous studies have analyzed adjuvant therapy for GAS. In the present study, we investigated the efficacy of adjuvant therapy for GAS.This was a preplanned secondary analysis of a dataset from previous nationwide, retrospective, observational study. The study population comprised women with stage I-II GAS who underwent surgery. Progression-free survival (PFS) and overall survival (OS) were compared among patients who did and did not receive adjuvant therapy using the Kaplan-Meier method.Data were analyzed for a total of 102 enrolled patients, who were classified as low- (17 patients), intermediate- (37 patients), or high risk (48 patients) based on the risk of postoperative cervical cancer recurrence. In the intermediate-risk group, median survival could not be assessed due to a lack of sufficient events, but the no-adjuvant and RT groups tended to exhibit better prognoses. In contrast, within the high-risk group, patients in the RT subgroup exhibited a trend towards better PFS and OS than those in the CCRT and chemotherapy groups.The prognosis of GAS was confirmed to be poor, even in cases of early-stage cancer and following surgical resection. Chemotherapy strategies, including CCRT as postoperative adjuvant therapy, tend to have a poor prognosis.

Gastric-type mucinous carcinoma (GAS) is a novel variant of mucinous carcinoma of the uterine cervix. As shown in the original Japanese group description, in recent studies, GAS represents a more aggressive disease than the usual-type endocervical adenocarcinoma (UEA). Detailed clinicopathological features of this variant remain to be elucidated in a larger series of patients.Patients were enrolled by the Gynecologic Cancer Study Group of the Japan Clinical Oncology Group after receiving the approval of each Institutional Review Board. The study population comprised of women with stage I to II endocervical adenocarcinomas who underwent surgery between 2000 and 2009. Representative slides were evaluated by central pathological review (CPR), categorized into either GAS or UEA, and correlated with clinicopathological features and outcome.Among the 393 enrolled patients with endocervical adenocarcinoma, 328 patients met the criteria for CPR and the study eligibility criteria and were included in further analysis. A total of 95 of the 328 tumors were classified as GAS. Compared with UEA, GAS was more significantly associated with bulky mass, deep stromal invasion, lymphovascular space invasion, parametrial invasion, ovarian metastasis, positive ascitic fluid cytology, pelvic lymph node metastasis, and pathological (p) T stage but was not related to the degree of histological differentiation. Disease-free survival (P 0.0001) and overall survival (P 0.0001) were poorer in patients with GAS than in those with UEA.GAS showed aggressive behavior with ominous histopathological predictors as well as decreased survival. GAS is therefore considered a distinct entity that should be distinguished from UEA.UMIN Clinical Trials Registry: UMIN000007987.

Organoid cultures are widely used because they preserve many features of cancer cells in vivo. Here, we developed high-throughput oil-in-water droplet microtechnology to generate highly uniform, small-volume, multi-compartment organoids. Each organoid culture features a microenvironmental architecture that mimics both the basement membrane and stromal barriers. This matrix architecture, which allows accessing both proliferative and invasive features of cancer cells in a single platform, has profound effect on observed drug responsiveness and tumor progression that correlate well with in vivo and clinical outcomes. The method was tested on multiple types of cancer cells including primary cells and immortalized cell lines, and we determined our platform is suitable even for cells of poor organoid-forming ability. These new organoids also allow for direct orthotopic mouse implantation of cancer cells with unprecedented success.

Background Mutations in the Wilms tumor 1 gene cause a spectrum of podocytopathy ranging from diffuse mesangial sclerosis to focal segmental glomerulosclerosis. In a considerable fraction of patients with Wilms tumor 1 mutations, the distinctive histology of immune-complex-type glomerulonephritis has been reported. However, the clinical relevance and etiologic mechanisms remain unknown. Case presentation A 5-year-old child presented with steroid-resistant nephrotic range proteinuria. Initial renal biopsy revealed predominant diffuse mesangial proliferation with a double-contour and coexisting milder changes of focal segmental glomerulosclerosis. Immunofluorescence and electron microscopy revealed a full-house-pattern deposition of immune complexes in the subendothelial and paramesangial areas. Serial biopsies at 6 and 8 years of age revealed that more remarkable changes of focal segmental glomerulosclerosis had developed on top of the initial proliferative glomerulonephritis. Identification of a de novo Wilms tumor 1 splice donor-site mutation in intron 9 (NM_024426.6:c.1447 + 4C > T) and 46,XY-gonadal dysgenesis led to the diagnosis of Frasier syndrome. Conclusions Our findings, together with those of others, point to the importance of heterogeneity in clinicopathological phenotypes caused by Wilms tumor 1 mutations and suggest that immune-complex-mediated membranoproliferative glomerulopathy should be considered as a histological variant.

AIM To evaluate the usefulness of the 'cosmos pattern' (CP) on magnetic resonance (MR) images for differentiating between gastric-type mucin-positive lesions (GMPL) and gastric-type mucin-negative lesions (GMNL). METHODS This study included 131 patients with clinical suspicion of lobular endocervical glandular hyperplasia (LEGH) who underwent pelvic MR imaging and a Pap smear and/or latex agglutination assay. Differences in MR findings, such as cyst and solid component patterns, cervical location and T1-weighted image (T1WI) signal intensity, were compared between GMPL and GMNL. The diagnostic performances of the findings were assessed. RESULTS The frequencies of CP (63.1%), upper part (UP) lesions (72.3%) and hypointense area compared with the cervical stroma on T1WI (61.3%) were significantly greater in GMPL than in GMNL (P

Gastric-type adenocarcinoma (GA) is an aggressive subtype of cancer of the uterine cervix. Several immunohistochemical markers for gastric mucins, such as mucin 6 (MUC6) and N-acetylglucosamine α1 → 4galactose → R (αGlcNAc-R), which is recognized by HIK1083 antibody, have been introduced for diagnosis of GA and lobular endocervical glandular hyperplasia (LEGH). However, MUC6 is also expressed in normal endocervical glands and HIK1083 antibody has limited availability. Trefoil factor family 2 protein (TFF2) is secreted by gastric, but not normal endocervical glands. Here, we evaluated TFF2 immunostaining for detection of a gastric immunophenotype in endocervical glandular lesions. We compared TFF2, αGlcNAc-R, and MUC6 expression in 103 endocervical glandular lesions: LEGH (n = 23), adenocarcinoma in situ/microinvasive adenocarcinoma (AIS-MIA) (n = 29), and invasive adenocarcinoma (usual type [UA], n = 26; GA, n = 11; intestinal type [IA], n = 2; signet ring cell type [Sig], n = 2; and mucinous adenocarcinoma not otherwise specified [NOS], n = 10). TFF2 and αGlcNAc-R expression was completely concordant in each subtype: LEGH (100%), AIS-MIA (44.8%), UA (26.9%), GA (90.9%), IA (100%), Sig (0%), and NOS (20%). TFF2 staining scores were significantly correlated with those of αGlcNAc-R in these lesions. TFF2 and αGlcNAc-R immunoreactivity was present in cytoplasmic mucins and luminal secretions. TFF2 and αGlcNAc-R were not expressed in the normal endocervical glands. MUC6 was frequently expressed in normal endocervical glands and endocervical glandular lesions. Endocervical adenocarcinomas sometimes stained only for MUC6. TFF2 is a promising immunohistochemical marker and its identification in uterine cervical secretion is a potentially useful diagnostic test for endocervical glandular lesions with gastric differentiation.

In order to understand the role of gene mutations in endometrial carcinogenesis, whole exome sequencing via laser microdissection was performed in the normal endometrium, atypical endometrial hyperplasia and endometrial carcinoma in the same patient. A total of 4046 and 5746 mutations with amino acid substitution were detected in endometrial hyperplasia and endometrial carcinoma, respectively; 2252 were common in both tissues and might play crucial roles in early carcinogenesis. These common mutations included polymerase epsilon (POLE) and DNA mismatch repair (MMR) genes, indicating that an ultra-mutated phenotype, and also included PTEN and PIK3CA. The mutation-prone environment evoked by mutations in the POLE and MMR genes associated with the activated phosphatidylinositol-3 kinase pathway played a pivotal role in this case.

Sirtuin 1 (SIRT1), originally identified as a longevity gene, regulates DNA repair and metabolism by deacetylating target proteins such as p53. SIRT1 plays a key role in the pathophysiology of metabolic diseases and neurodegenerative disorders, and is considered to protect against age-related diseases including cancer. In contrast, SIRT1 may be oncogenic because its overexpression has been detected in many cancers. The aim of the present study was to clarify the expression and the role of SIRT1 in ovarian carcinoma (OvCa). The expression of SIRT1 was evaluated immunohistochemically in 16 cases of normal ovaries, 35 cases of endometriosis with/without carcinoma, and 68 cases of OvCa (endometrioid, 16; clear cell, 20; mucinous, 16; serous, 16). Staining results were evaluated semiquantitatively by the Immunoreactive Scoring System, and the relationships with clinicopathologic features and outcomes of patients were analyzed. The expression of SIRT1 was higher in endometrioid, mucinous, and clear-cell carcinomas than in the inclusion cysts of normal ovaries, but not in serous carcinoma (P=0.038). The expression of SIRT1 on OvCa did not correlate with age, stage, location of metastasis, or capsular penetration. However, elevated SIRT1 expression was a significant predictor of shorter survival in univariate (P=0.038) and multivariate (P=0.037) survival analyses, regardless of the tumor stage. Results of the present study suggest a positive role for SIRT1 in the development of OvCa and its potential as a novel therapeutic target.

Lobular endocervical glandular hyperplasia (LEGH) was first reported as a benign proliferative disorder of the uterine cervix. However, it currently remains unclear whether it has the biological characteristics of pyloric metaplasia or precursor of minimal deviation adenocarcinoma (MDA)/gastric-type mucinous cervical adenocarcinoma (GAS). Therefore, in the present study we performed whole-exome sequencing on three cases of LEGH collected by laser-microdissection from the frozen tissue sections of surgically removed uteri. Analysis of the results identified 50 somatic variants. After several filtering processes, we identified 13 functional variants, including 12 missense and one insertion-deletion variants. Of these mutations, keratinocyte proline-rich protein, olfactory receptor M4 and zinc finger protein 645 mutations were found in the Catalogue Of Somatic Mutations In Cancer but were not related to carcinogenic diseases. We did not detect any significant copy number alterations or signatures. Although this was a limited case series, we did not identify any variants relevant to the tumorigenesis of LEGH to MDA/GAS, suggesting a metaplastic aspect of LEGH.

To increase diagnostic efficiency and cost-effectiveness, we performed an exploratory genetic test using a newly designed panel containing 28 actionable and druggable genes, alterations in which are frequently reported in gynecological cancers (TANRE-G, Targeted variants ANalysis RElated to Gynecological cancers). Samples consisted of the formalin-fixed, paraffin-embedded tissue of endometrial (4 cases), cervical (3 cases), and ovarian (4 cases) carcinomas. The sequencing procedure was performed using Ion PGM in our institute with related sequencing kits, and data were analyzed using ClinVar. The present system achieved more than 2500 reads in all tumor samples, and enabled a copy number variation analysis. Results showed that actionable and druggable mutations were detected in 82% (9/11) and 64% (7/11) of cases, respectively, which was similar to other commercially available genetic tests. The amplification of MYC and KRAS was also detected. The analysis cost for each sample was JPY 94,000 (USD 850). These results demonstrate the potential of the TANRE-G panel as an effective tool for examining genetic alterations in gynecological cancers.

Somatic inactivating mutations of ARID1A, a SWI/SNF chromatin remodeling gene, are prevalent in human endometrium-related malignancies. To elucidate the mechanisms underlying how ARID1A deleterious mutation contributes to tumorigenesis, we establish genetically engineered murine models with Arid1a and/or Pten conditional deletion in the endometrium. Transcriptomic analyses on endometrial cancers and precursors derived from these mouse models show a close resemblance to human uterine endometrioid carcinomas. We identify transcriptional networks that are controlled by Arid1a and have an impact on endometrial tumor development. To verify findings from the murine models, we analyze ARID1AWT and ARID1AKO human endometrial epithelial cells. Using a system biology approach and functional studies, we demonstrate that ARID1A-deficiency lead to loss of TGF-β tumor suppressive function and that inactivation of ARID1A/TGF-β axis promotes migration and invasion of PTEN-deleted endometrial tumor cells. These findings provide molecular insights into how ARID1A inactivation accelerates endometrial tumor progression and dissemination, the major causes of cancer mortality., ARID1A, which is often mutated in human endometrial cancer, is a component of the SWI/SNF chromatin remodelling complex. Here, the authors show that Arid1a mutations in the mouse endometrium and primary human endometrial epithelial cells cause widespread reprogramming of gene transcription and result in a loss of response to TGFβ.

Endometrial carcinoma (EC) often expresses estrogen receptors (ER), and the growth of EC is stimulated by estrogen. Therefore, EC is considered to be an estrogen-dependent tumor. However, the role of estrogen in endometrial carcinogenesis is somewhat unclear because the majority of EC occurs at peri- or post menopause when serum estrogen levels are generally decreased. In this article, we describe the double-edged role of estrogen in the genesis of EC, especially in terms of mismatch repair functions in vitro and in vivo, i.e. when serum estradiol (E2) levels are relatively low (approximately less than 90 pg/ml), and E2 enhance the carcinogenesis, whereas high E2 levels may suppress the carcinogenesis. This will deepen mechanistic insight into unopposed estrogen.

Background The sawtooth fetal heart rate pattern is rare, and has been reported as a possible indicator of neurological sequelae in newborns. However, we observed this fetal heart rate pattern in an infant with normal neurological function. Case presentation A 29-year-old primigravida Japanese woman presented to our hospital at 40 weeks and 1 day of gestation with marked vaginal bleeding. Since admission, fetal heart rate tracing consistently demonstrated a sawtooth-like pattern. There were 3–4 oscillations per minute, and their amplitude was 30–40 beats per minute. An emergency cesarean section was performed because of non-reassuring fetal status. Evidence of placental abruption was not observed. The newborn was a male weighing 2936 g, with an Apgar score of 1 and 3 at 1 minute and 5 minutes, respectively. The infant received brain cooling, but was discharged uneventfully. A follow-up examination at age 3 years demonstrated no developmental restriction. Conclusion Although the Apgar score of the newborn was low, the infant had no neurological sequelae. Thus, the sawtooth fetal heart rate pattern may not be linked to in utero irreversible fetal central nervous system injury.

Aim The proper preoperative diagnosis and management of cervical proliferative disorders presenting with multiple cysts, including minimal deviation adenocarcinoma (MDA), lobular endocervical glandular hyperplasia (LEGH), and nabothian cyst (NC), have not been fully established. We previously proposed a management protocol comprising a diagnostic approach using cytology, magnetic resonance imaging, and gastric-type mucin and subsequent treatment. We herein evaluate the usefulness of this protocol and implications of GNAS mutations in LEGH. Methods The clinical courses of 94 patients with cervical multicystic lesions who visited our hospital between June 1995 and September 2014 were retrospectively analyzed. GNAS mutations were investigated in 10 LEGH, five LEGH with atypia, and two MDA cases. Results Of the 94 patients, the conditions of 10, 59, and 25 were clinically diagnosed as suspicious of MDA or carcinoma (S/O MDA-Ca), suspicious of LEGH (S/O LEGH), and NC, respectively. Ten patients each with S/O MDA-Ca and S/O LEGH underwent hysterectomy, and the correct ratio for diagnosis was 90% (18/20). Of the 42 S/O LEGH cases followed-up for more than 12 months, three showed an increase in tumor size. After hysterectomy, two were LEGH with atypia while one was NC. The GNAS mutation was detected in two cases of LEGH with atypia, one of which showed an increase in tumor size during follow-up. Conclusion The management protocol we propose herein will be useful. An increase in tumor size is important to detect potentially malignant LEGH. GNAS mutations may be involved in the tumorigenesis of potentially malignant LEGH.

Sirtuin 1 (SIRT1), originally identified as a longevity gene, is induced by caloric restriction, and regulates various cellular functions including DNA repair, cell survival and metabolism via the deacetylation of target proteins such as histone and p53. These functions are considered to act dualistically as preventing or facilitating cancer. This study aimed to clarify the expression and role of SIRT1 in endometrial carcinoma. Because a high-calorie diet was a well-known risk factor for endometrial carcinoma, we first hypothesized that SIRT1 might be downregulated in normal endometrial glandular cells of obese women. However, no correlation was observed between the expression of SIRT1 and body mass index (BMI). In contrast, regardless of BMI, the immunohistochemical expression of SIRT1 was significantly higher in endometrial carcinoma (108 cases) than in normal endometria (60 cases) (P

Highlights • We report a case of MDA arising from clinical LEGH during 5 years of follow-up. • The first sign suggesting MDA was cellular atypia in endocervical cytology, and was followed by an increase in tumor size. • MDA lesion lacked in stromal reaction and MRI failed to detected MDA. • Worsening cytology and lesion enlargement are important signs for malignant change of LEGH during follow-up.

Objectives Cell senescence is irreversible cell cycle arrest. The human placenta is a unique organ that grows and matures during pregnancy until 40 weeks of gestation. However, the role of senescence in placental villi, particularly in the two types of trophoblast, has not yet been elucidated in detail. Therefore, we herein investigated the expression of cell senescence-related markers in trophoblast. Methods Seventy normal placental tissues were used. The expression of senescence-associated beta-galactosidase (SA-β-gal), cell senescence-related markers (p16, p21, and promyelocytic leukemia; PML), and a growth marker (MCM2) was immunohistochemically examined. The expression of these markers in BeWo cells before and after cell fusion using forskolin was also investigated. Results The expression of MCM2 is detected in cytotrophoblast (CT). The expression of SA-β-gal in CT is strong in the first and second trimesters, but weaker in the third trimester. Syncytiotrophoblast (ST) are negative in the first and second trimesters, but become positive in the third trimester. The immunohistochemical expression of p16, p21, and PML is stronger in CT than in ST throughout pregnancy. Furthermore, the expression of these markers in ST significantly increases as pregnancy advances. The expression of SA-β-gal, PML, and p21 in BeWo cells is stronger after than before cell fusion. Conclusions The proliferation and senescence of CT occurred in early to mid-pregnancy in association with syncytial fusion, while senescence was observed in ST in late pregnancy. This coordinated trophoblastic senescence may be essential for maintaining placental function.

Inactivating somatic mutations of ARID1A, a chromatin remodeling gene, are common in endometrioid endometrial carcinoma (EEC) but rare in complex atypical hyperplasia (CAH). Our objectives were to determine the clinical significance of ARID1A loss during tumor progression from CAH to EEC and to assess its role as a predictive cancer biomarker.In cohort A, ARID1A immunoreactivity was evaluated in endometrial sampling (biopsy/curettage) specimens showing CAH to determine whether ARID1A expression correlates with the presence of EEC at subsequent hysterectomy. In cohort B, ARID1A immunoreactivity was evaluated in the hysterectomy specimens with concurrent CAH and EEC to assess for the concordance of ARID1A expression in both components.In cohort A, loss of ARID1A immunoreactivity was identified in the endometrial sampling specimen of 31% of patients undergoing hysterectomy for a preoperative diagnosis of CAH. EEC was identified in the hysterectomy specimen of 94% of patients with loss of ARID1A in the endometrial sampling specimen while only 15% of patients with retained ARID1A expression (P 0.0001). No association was observed between ARID1A expression and demographic characteristics. In cohort B, 14 (31%) of 45 patients with concurrent CAH/EEC in their hysterectomy specimens had complete loss of ARID1A expression in the EEC components. Among these 14 patients, 50% also had loss of ARID1A immunoreactivity in the CAH component.ARID1A immunostaining may correlate with malignant transformation and the presence of concurrent EEC in patients with CAH identified at pre-hysterectomy endometrial sampling. Further investigation to determine the potential utility of ARID1A expression as a tissue biomarker is warranted.

Objectives Molecular markers associated with tumor progression in uterine carcinoma are poorly defined. In this study, we determine whether upregulation of LAMC1, a gene encoding extracellular matrix protein, laminin γ1, is associated with various uterine carcinoma subtypes and stages of tumor progression. Methods An analysis of the immunostaining patterns of laminin γ1 in normal endometrium, atypical hyperplasia, and a total of 150 uterine carcinomas, including low-grade and high-grade endometrioid carcinomas, uterine serous and clear cell carcinoma, was performed. Clinicopathological correlation was performed to determine biological significance. The Cancer Genome Atlas (TCGA) data set was used to validate our results. Results As compared to normal proliferative and secretory endometrium, for which laminin γ1 immunoreactivity was almost undetectable, increasing laminin C1 staining intensity was observed in epithelial cells from atypical hyperplasia to low-grade endometrioid to high-grade endometrioid carcinoma, respectively. Laminin γ1 expression was significantly associated with FIGO stage, myometrial invasion, cervical/adnexal involvement, angiolymphatic invasion and lymph node metastasis. Similarly, analysis of the endometrial carcinoma data set from TCGA revealed that LAMC1 transcript levels were higher in high-grade than those in low-grade endometrioid carcinoma. Silencing LAMC1 expression by siRNAs in a high-grade endometrioid carcinoma cell line did not affect its proliferative activity but significantly suppressed cell motility and invasion in vitro . Conclusions These data suggest that laminin γ1 may contribute to the development and progression of uterine carcinoma, likely through enhancing tumor cell motility and invasion. Laminin γ1 warrants further investigation regarding its role as a biomarker and therapeutic target in uterine carcinoma.

Catechol estrogens, such as 4-hydroxyestradiol (4-OHE2), are estrogen metabolites that form DNA adducts and may induce mutations and subsequent cell transformation in mammary cells; however, little is known about their roles in endometrial carcinogenesis. Furthermore, it remains unclear whether 4-OHE2 is able to induce DNA damage on specific genes involved in carcinogenesis or a ‘pro’-mutation status such as microsatellite instability (MSI). Therefore, we modified terminal transferase-dependent PCR by the application of a capillary sequencer to detect DNA damage at the single base level. Using this method, we demonstrated that 4-OHE2 directly induced DNA damage on codon 130/131 in exon 5 of PTEN, which is a mutation hot spot for PTEN in endometrial carcinoma. Whereas, both estradiol and 4-OHE2 treatment did not affect MSI status in immortalized endometrial glandular cells. 4-OHE2 might contribute to endometrial carcinogenesis by inducing PTEN mutation on codon 130/131.

Idiopathic interstitial pneumonias (IIPs) typically occur in the fifth and sixth decades, and thus are uncommon in the child-bearing age group. We herein report an extremely rare case of a pregnant woman with IIP accompanied by secondary pulmonary hypertension that had a successful cesarean delivery. A 36-year-old primigravida woman was referred to our Obstetrics department at 6 weeks of gestation. Seven years ago, she had a dry cough and moderate dyspnea, and was diagnosed with non-specific interstitial pneumonia (NSIP), a subtype of IIP. At 11 weeks of gestation, spirometry showed a vital capacity of 1.89 L (60% of predicted). An arterial blood gas analysis showed PaO2 of 77.2 mmHg and oxygen saturation of 95% in breathing room air at rest. An echocardiogram revealed mild pulmonary hypertension; systolic pulmonary artery blood pressure (PABP) of 44 mmHg. Fetal growth and amniotic fluid volume were normal. Our management plan was to maintain oxygen saturation at more than 95% of oxygen saturation and systolic PABP at less than 50 mmHg. Oxygen therapy was initiated at 13 weeks of gestation because of dyspnea at rest. At 28 weeks of gestation, an echocardiogram showed severe pulmonary hypertension with systolic PABP of 64 mmHg. Therefore, we performed cesarean section at 30 weeks of gestation. The newborn was a male weighing 1.452 g with Apgar scores of 6 and 7 at 1 min and 5 min, respectively. Although the patient’s post-operative course was uneventful, she was discharged on a regimen of oxygen therapy. The effects of pregnancy on IIPs remain unclear because of its extreme rarity. In the management of pregnant women with IIPs accompanied by secondary pulmonary hypertension, the maintenance of systolic PABP of less than 50 mmHg on an echocardiogram may be effective.

Objective: Although estrogen has been regarded as a risk factor for endometrial carcinoma, its concentrationdependent carcinogenetic effects remain unclear, because most endometrial carcinomas occur in post-menopausal women, whose serum estrogen levels are relatively low. We previously reported that high levels of estradiol (E2) may suppress endometrial carcinogenesis by up-regulating DNA mismatch repair (MMR) in vitro. The present study was undertaken to further examine the carcinogenetic role of estrogen at various concentrations in vivo. Methods: N-methyl-N-nitrosourea (MNU) was injected into the uterine cavity of 29 mice, and E2 was administered by pellets or orally. Uteri were removed for histological examinations 24 weeks later, and serum E2 levels were measured. The immunohistochemical expression of MMR proteins in uterine epithelia was investigated. Results: Of 29 mice, 8, 8, 8, and 5 showed atrophic, normal, hyperplastic, and carcinomatous endometria, respectively. The mean E2 levels of each group were 0.2 pg/ml, 3.8 pg/ml, 190.0 pg/ml, and 6.7 pg/ml, with significant differences. The expression of the MMR proteins was stronger in mice with elevated E2. Conclusion: Elevated E2 levels preferentially induced endometrial hyperplasia rather than carcinoma, and this may be mediated by MMR proteins. These results indicate that modest E2 is needed, whereas elevated E2 levels are not necessarily advantageous for carcinogenesis, suggesting the importance of low-chronic (un-opposed) estrogen in human endometrial carcinogenesis.

Polypoid endometriosis is a rare type of endometriosis. We report a case of polypoid endometriosis of the ovary mimicking ovarian carcinoma with peritoneal dissemination. Computed tomography and magnetic resonance imaging showed a left ovarian endometriotic cyst containing several nodules in the cystic wall that displayed enhancement, and pelvic nodules on the right ovary. A preoperative or intraoperative diagnosis to avoid the unnecessary extended operation is important for such disease. Retrospective magnetic resonance imaging analysis identified a peculiar finding for polypoid endometriosis: all solid nodules had a round and smooth shape and displayed a low-signal-intense marginal edge on T2-weighted images, suggesting that this is an important finding for differentiating polypoid endometriosis from ovarian carcinoma arising from endometriosis.