Preoperative Magnetic Resonance Imaging versus Intraoperative Frozen Section Diagnosis for Predicting the Deep Myometrial Invasion in Endometrial Cancer: Our Experience and Literature Review.

AIM: The present study was designed to directly compare the diagnostic performance of preoperative magnetic resonance imaging (MRI) and intraoperative frozen section (FS) diagnoses in predicting deep myometrial invasion (MI) of endometrial cancer. METHODS: Using MRI findings and FS diagnoses, 194 patients with surgically staged endometrial cancer were evaluated for deep MI between 2006 and 2018. Definitive histological diagnosis of paraffin sections of excised tissues was used as the gold standard approach. RESULTS: Of 194 cases, 53 (27.3%) cases were finally diagnosed as having deep MI (≥50%). There was 82% total agreement between MRI and FS diagnoses in predicting deep MI, with a kappa value of 0.54 (95% confidence interval [CI] = 0.40-0.67, moderate agreement). The sensitivity of FS diagnosis (0.66, 95% CI = 0.52-0.78) for predicting deep MI was lower than that of MRI (0.77, 95% CI = 0.63-0.87; p = 0.21), while the specificity of FS (0.98, 95% CI = 0.93-0.99) was significantly higher than that of MRI (0.88, 95% CI = 0.81-0.93; p = 0.001). Overall, the accuracy of FS (0.89, 95% CI = 0.84-0.93) was higher than that of MRI (0.85, 95% CI = 0.79-0.90), although the difference did not reach statistical significance (p = 0.23). The accuracy (0.95, 95% CI = 0.90-0.97) was very high in cases with concordant MRI and FS results. CONCLUSIONS: MRI and FS showed different diagnostic characteristics for predicting deep MI, with a higher specificity observed for FS and the greatest accuracy obtained in concordant cases. Thus, our findings recommend the addition of FS diagnosis, either alone or in conjunction with MRI, to MI evaluation.

Diagnostic yield of fourth-generation endocytoscopy for esophageal squamous lesions using a modified endocytoscopic classification.

OBJECTIVES: Endocytoscopy (EC) is an ultra-high magnification endoscopy designed to provide in vivo histologic assessment. This study aimed to evaluate the diagnostic yield of the newly developed fourth-generation EC for esophageal squamous lesions by using a modified EC classification. METHODS: A total of 2548 EC images of 57 esophageal targeted areas between June 2015 and October 2017 were retrospectively collected. Two lesions with low-quality images were excluded. Only EC images were independently reviewed by two expert and two non-expert endoscopists. The lesions were classified according to a three-tier modified EC classification. We used a multilevel logistic regression to analyze the data. RESULTS: The sensitivity and specificity of diagnosing non-squamous cell cancer (SCC) vs SCC were 82.5% and 83.0% by the experts; 90.1% and 75.0% by non-experts. The interobserver agreement among the four raters was good (kappa statistic 0.59). The diagnostic accuracy of experts and non-experts was similar (P = 0.16 for specificity and P = 0.20 for sensitivity). The sensitivity and specificity of EC for non-neoplasia vs neoplasia were 88.7% and 74.6% by experts; 90.3 and 52.1% by non-experts. The interobserver agreement among the four raters was moderate (kappa statistic 0.44). The specificity of experts was higher compared to non-experts, although the difference did not reach statistical significance (P = 0.08 for specificity and P = 0.93 for sensitivity). CONCLUSIONS: Fourth-generation EC offers acceptable diagnostic accuracy and reliability in both experts and non-experts, especially when diagnosing SCC lesions.

Ultrasound-based logistic regression model LR2 versus magnetic resonance imaging for discriminating between benign and malignant adnexal masses: a prospective study.

BACKGROUND: The diagnostic performances of the International Ovarian Tumor Analysis (IOTA) ultrasound-based logistic regression model (LR2) and magnetic resonance imaging (MRI) in discriminating between benign and malignant adnexal masses have not been directly compared in a single study. METHODS: Using the IOTA LR2 model and subjective interpretation of MRI findings by experienced radiologists, 265 consecutive patients with adnexal masses were preoperatively evaluated in two hospitals between February 2014 and December 2015. Definitive histological diagnosis of excised tissues was used as a gold standard. RESULTS: From the 265 study subjects, 54 (20.4%) tumors were histologically diagnosed as malignant (including 11 borderline and 3 metastatic tumors). Preoperative diagnoses of malignant tumors showed 91.7% total agreement between IOTA LR2 and MRI, with a kappa value of 0.77 [95% confidence interval (CI), 0.68-0.86]. Sensitivity of IOTA LR2 (0.94, 95% CI, 0.85-0.98) for predicting malignant tumors was similar to that of MRI (0.96, 95% CI, 0.87-0.99; P = 0.99), whereas specificity of IOTA LR2 (0.98, 95% CI, 0.95-0.99) was significantly higher than that of MRI (0.91, 95% CI, 0.87-0.95; P = 0.002). Combined IOTA LR2 and MRI results gave the greatest sensitivity (1.00, 95% CI, 0.93-1.00) and had similar specificity (0.91, 95% CI, 0.86-0.94) to MRI. CONCLUSIONS: The IOTA LR2 model had a similar sensitivity to MRI for discriminating between benign and malignant tumors and a higher specificity compared with MRI. Our findings suggest that the IOTA LR2 model, either alone or in conjunction with MRI, should be included in preoperative evaluation of adnexal masses.

Successful treatment of uterine artery pseudoaneurysm with laparoscopic temporary clamping of bilateral uterine arteries, followed by hysteroscopic surgery.

Surgical strategies for the treatment of uterine artery pseudoaneurysm (UAP) include transarterial embolization and ultrasound-guided low-dose thrombin injection. Such strategies, however, have limitations and include the risk of ischemic damage to the uterus. We report a case of UAP treated with a new hysteroscopic and laparoscopic technique. A 29-year-old G1P0 woman with spontaneous abortion was transferred to the present institution because of hemorrhagic shock. We diagnosed ruptured UAP on transvaginal ultrasound with color Doppler. Emergency laparoscopic temporary clamping of the bilateral uterine arteries was done to reduce the bleeding, and transcervical resection to stop the hemorrhaging and to collect the pseudoaneurysm tissue. After surgery, blood flow to the myometrium was monitored on ultrasound. By postoperative day 48, normal menstruation had restarted, and no intrauterine adhesions were observed. On pathology of the UAP, a dilated spiral artery without its characteristic elastic fibers was identified. This surgical approach may help preserve fertility and allow for pathological diagnosis of UAP.

[Testicular tumor with opposite inguinal lymph node metastasis in a patient with prior orchiopexy for undescended testis].

The patient was a 54-year-old man. At age 6 years, he had undergone orchiopexy for left undescended testis. Six months prior to the current presentation, he visited our hospital with a chief complaint of painless enlargement of the left testis. Left high orchiectomy was performed under a diagnosis of left testicular tumor. Histopathological examination determined the tumor to be a seminoma (pT2). Postoperatively, the patient was placed on surveillance without preventive radiation treatment. He visited our hospital six months after surgery due to a painless mass in the right inguinal region. All tumor markers (AFP, HCG-ß, and LDH) were within normal ranges. However, based on ultrasound and CT scan findings, lymph node metastasis was suspected and a right inguinal lymph node excision was thus performed. Histopathological examination led to the diagnosis of seminoma.

Rare case of peritoneal complete hydatidiform mole.

A 23-year-old woman, gravida 1, para 1, was transferred to our hospital with acute lower abdominal pain and vital signs consistent with shock. Her urine concentration of human chorionic gonadotrophin was 8000 mIU/mL. Transvaginal ultrasound revealed an echo-free space with mosaic echo pattern in the right adnexal area and no gestational sac in the uterus. With a preoperative diagnosis of ruptured ectopic pregnancy, emergency laparotomy was performed. The rectouterine pouch was filled with many clots containing small amounts of villous tissue. After removal of the conceptus, which was infiltrating into the peritoneum of the Pouch of Douglas, bleeding was controlled by Argon laser. Histological examination of the conceptus by immunohistochemical staining with p57(kip2) showed features of complete hydatidiform mole. This case demonstrates that the peritoneum in the Pouch of Douglas is a possible site of ectopic complete hydatidiform mole occurrence and that immunohistochemical stain is useful to confirm the diagnosis of ectopic complete hydatidiform mole.

Mixed mucin-producing and squamous differentiated tumor of the uterine cervix: a report of a case as adenosquamous carcinoma in situ.

We report a non-invasive mixed mucin-producing and squamous differentiated tumor of the uterine cervix. This tumor was composed of two cell types: mucin-producing cells and non-mucin-producing cells. These cells were intimately mixed with each other, and showed intraepithelial spreading. The mucin-producing cells showed signet-ring or columnar shapes, and were localized to the lower-to-upper epithelial layer. The non-mucin-producing cells had eosinophilic cytoplasms with a monotonous appearance through the epithelium. Mitosis was sometimes observed in both cell types. Immunohistochemically, both cell types were positive for p16(INK4A) . The non-mucin-producing cells were positive for p63 and 34ßE12, suggesting squamous differentiation. Although most mucin-producing cells were p63(-) , a few of them were p63(+) and many 34ßE12 immunoreactive cells were found in the mucin-producing cells. This tumor was adenosquamous carcinoma in situ.

Determination of esophageal squamous cell carcinoma and gastric adenocarcinoma on raw tissue using Raman spectroscopy.

BACKGROUND: Cancer detection is a global research focus, and novel, rapid, and label-free techniques are being developed for routine clinical practice. This has led to the development of new tools and techniques from the bench side to routine clinical practice. In this study, we present a method that uses Raman spectroscopy (RS) to detect cancer in unstained formalin-fixed, resected specimens of the esophagus and stomach. Our method can record a clear Raman-scattered light spectrum in these specimens, confirming that the Raman-scattered light spectrum changes because of the histological differences in the mucosal tissue. AIM: To evaluate the use of Raman-scattered light spectrum for detecting endoscop-ically resected specimens of esophageal squamous cell carcinoma (SCC) and gastric adenocarcinoma (AC). METHODS: We created a Raman device that is suitable for observing living tissues, and attempted to acquire Raman-scattered light spectra in endoscopically resected specimens of six esophageal tissues and 12 gastric tissues. We evaluated formalin-fixed tissues using this technique and captured shifts at multiple locations based on feasibility, ranging from six to 19 locations 200 microns apart in the vertical and horizontal directions. Furthermore, a correlation between the obtained Raman scattered light spectra and histopathological diagnosis was performed. RESULTS: We successfully obtained Raman scattered light spectra from all six esophageal and 12 gastric specimens. After data capture, the tissue specimens were sent for histopathological analysis for further processing because RS is a label-free methodology that does not cause tissue destruction or alterations. Based on data analysis of molecular-level substrates, we established cut-off values for the diagnosis of esophageal SCC and gastric AC. By analyzing specific Raman shifts, we developed an algorithm to identify the range of esophageal SCC and gastric AC with an accuracy close to that of histopathological diagnoses. CONCLUSION: Our technique provides qualitative information for real-time morphological diagnosis. However, further in vivo evaluations require an excitation light source with low human toxicity and large amounts of data for validation.

Does daily alcohol and/or cigarette consumption cause low-grade dysplasia, a precursor of esophageal squamous cell carcinoma?

BACKGROUND: Cigarette smoking and alcohol consumption are well-known risk factors for esophageal squamous cell carcinoma (ESCC), which has a very poor prognosis. Successful screening strategies for precursor lesions that can be targets for early detection and treatment are required to prevent ESCC. METHODS: This is a prospectively cross-sectional study. To clarify whether daily smoking and/or alcohol consumption are risk factors for dysplasia, which is the initial lesion leading to ESCC. Lugol chromoendoscopy was performed in 1,345 eligible individuals. Six hundred ninety individuals had daily smoking and/or alcohol consumption; 655 individuals did not smoke and drink alcohol. The effects of smoking and alcohol consumption among high-grade dysplasia (HGD), low-grade dysplasia (LGD), and controls without dysplasia were evaluated using multiple logistic regression analysis. RESULTS: Among 1,345 individuals, 17 HGD and 23 LGD lesions were confirmed histologically. The prevalence of both smoking and drinking consumption was significantly higher in HGD than in LGD individuals (age and sex adjusted odds ratio; 113.0, 95% confidence interval; 6.26), whereas no significant difference was seen in both consumption between LGD individuals and controls (odds ratio; 1.29, 95% confidence interval; 0.33-6.37). Approximately 70% of HGD individuals, but only 13% of LGD individuals, both smoked and consumed alcohol. CONCLUSIONS: Daily cigarette and alcohol consumption were not the risk factors for LGD, however, consumption of both were high-risk factors for HGD. We suggest that documenting the difference of risk factors for LGD and HGD can assist in the development of effective screening, early detection, and prevention strategies for ESCC.

Transition from low-grade endometrial stromal sarcoma to high-grade endometrial stromal sarcoma.

We report on a case of a primary low-grade endometrial stromal sarcoma (ESS) that progressed to a secondary high-grade ESS. In the secondary tumor, the immunohistochemical profile and focal tumor cell proliferation pattern suggested that this tumor was not truly undifferentiated, but possessed features of endometrial stroma. Low-grade ESS of our patient's primary tumor showed p53 protein overexpression, which is unusual in low-grade ESS, and her secondary high-grade ESS showed more prominent p53 immunoreactivity. This indicates that low-grade ESS that shows p53 immunoreactivity might progress to high-grade ESS, and it is considered that such cases of low-grade ESS should pay attention to the prognosis. Immunoreactivity for epidermal growth factor receptor was observed in both tumors, suggesting a relationship between the primary and secondary tumors in our case. Further study requires more immunohistochemical data for cases in which low-grade ESS transitions to high-grade ESS; in particular, data on epidermal growth factor receptor expression are necessary to define new therapeutic strategies for ESS.

Highly accurate colorectal cancer prediction model based on Raman spectroscopy using patient serum.

BACKGROUND: Colorectal cancer (CRC) is an important disease worldwide, accounting for the second highest number of cancer-related deaths and the third highest number of new cancer cases. The blood test is a simple and minimally invasive diagnostic test. However, there is currently no blood test that can accurately diagnose CRC. AIM: To develop a comprehensive, spontaneous, minimally invasive, label-free, blood-based CRC screening technique based on Raman spectroscopy. METHODS: We used Raman spectra recorded using 184 serum samples obtained from patients undergoing colonoscopies. Patients with malignant tumor histories as well as those with cancers in organs other than the large intestine were excluded. Consequently, the specific diseases of 184 patients were CRC (12), rectal neuroendocrine tumor (2), colorectal adenoma (68), colorectal hyperplastic polyp (18), and others (84). We used the 1064-nm wavelength laser for excitation. The power of the laser was set to 200 mW. RESULTS: Use of the recorded Raman spectra as training data allowed the construction of a boosted tree CRC prediction model based on machine learning. Therefore, the generalized R 2 values for CRC, adenomas, hyperplastic polyps, and neuroendocrine tumors were 0.9982, 0.9630, 0.9962, and 0.9986, respectively. CONCLUSION: For machine learning using Raman spectral data, a highly accurate CRC prediction model with a high R 2 value was constructed. We are currently planning studies to demonstrate the accuracy of this model with a large amount of additional data.

Expression of the fluoropyrimidine-metabolizing enzymes in bladder cancers as measured by the Danenberg tumor profile.

5-Fluorouracil (5-FU) and its prodrugs are used to treat various cancers. Response to 5-FU-based chemotherapy and expression of 5-FU-related enzymes differ among cancers. The objective of the present study was to investigate the relationship between the expression of 5-FU-related enzymes and clinicopathologic factors in bladder cancer. Formalin-fixed, paraffin-embedded sections of 44 bladder cancers and 27 normal bladders were included in this study. After laser capture microdissection, "Danenberg tumor profile," was performed for the measurement of 5-FU-related enzymes. There was no significant difference between dihydropyrimidine hydrogenase (DPD) mRNA expression in bladder cancer and in normal bladder. On the contrary, mRNA expressions of orotate phosphoribosyltransferase (OPRT), thymidylate synthase (TS), and thymidine phosphorylase (TP) in bladder cancer were higher than those in normal bladder. Compared with previously reported DPD mRNA expressions in other types of cancer, DPD mRNA expression in bladder cancer was relatively low. The 5-FU-related enzymatic condition of bladder cancer is favorable for 5-FU.

Observational Studies on the Association Between Post-diagnostic Metformin Use and Survival in Ovarian Cancer: A Systematic Review and Meta-Analysis.

Objectives: To summarize and quantify the relationship between post-diagnostic metformin use and ovarian cancer (OC) survival. Methods: We systematically conducted an updated meta-analysis based on observational studies published up to December 31, 2018, identified from PubMed and Web of Science. Two team members independently extracted data and assessed the quality of each study. Summary Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using a random-effects model. Results: Five cohort studies including 3,582 OC patients were included. All studies were graded as low risk of bias according to the Newcastle-Ottawa quality assessment scale. Post-diagnostic metformin use was associated with improved overall survival (summarized HR = 0.42, 95% CI = 0.31-0.56; I 2 = 0%, P = 0.842) and progression-free survival (summarized HR = 0.69, 95% CI = 0.45-1.07; I 2 = 61.9%, P = 0.049) of OC patients. For OC patients with diabetes, post-diagnostic metformin use was associated with improved overall survival (summarized HR = 0.51, 95% CI = 0.28-0.95; I 2 = 47.6%, P = 0.149) and progression-free survival (summarized HR = 0.38, 95% CI = 0.27-0.55; I 2 = 0%, P = 0.594). No significant publication bias was detected in these analyses. Conclusions: Post-diagnostic metformin use is consistently associated with better survival of OC patients regardless of diabetes status. Studies with larger sample sizes and prospective designs are required to confirm these findings and obtain detailed information, including standardized references for comparison, intensity and dose of metformin use, and further adjustment for potential confounders.

Intrahepatic status of regulatory T cells in autoimmune liver diseases and chronic viral hepatitis.

AIM: Regulatory T cells (Tregs) maintain immunological tolerance and suppress autoreactive immune responses. We evaluated the intrahepatic status of Tregs in patients with autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), chronic hepatitis C (CH-C), or chronic hepatitis B (CH-B). METHODS: We analyzed 85 patients (20 AIH, 22 PBC, 27 CH-C, and 16 CH-B) and 14 controls. Using liver tissue samples obtained by needle biopsy or from marginal parts of resected metastatic liver tumors in the controls, immunohistochemical analyses of forkhead box P3(+), which is a specific marker for Tregs, CD4(+), and CD8(+) cells were performed. RESULTS: Intrahepatic Tregs were significantly more infiltrated in patients with liver diseases than in the controls. There were significantly fewer intrahepatic Tregs in the AIH patients than in the PBC patients (P = 0.037). Patients with alow frequency of intrahepatic Tregs were detected significantly more in the AIH and CH-B groups than in the PBC and CH-C groups (P < 0.05). In addition, the frequency of Tregs decreased in the liver of PBC patients as the pathological stage of the disease advanced. We found significantly less infiltration of CD4(+) T cells in AIH than in other diseases (P < 0.05). Liver-infiltrating CD8(+) T cells were detected more frequently in the CH-B group than in other groups (P < 0.003). CONCLUSION: Intrahepatic Tregs were increased in both patients with autoimmune liver diseases and those with viral hepatitis. In autoimmune liver diseases, intrahepatic Tregs were fewer in the AIH patients than in the PBC patients.

Lobular endocervical glandular hyperplasia might become a precursor of adenocarcinoma with pyloric gland features.

We report a case of adenocarcinoma with pyloric gland features, which appears to have originated from lobular endocervical glandular hyperplasia (LEGH). Hematoxylin and eosin staining, as well as histochemical and immunohistochemical stainings were performed on formalin-fixed and paraffin-embedded specimens. LEGH was observed in the conization specimens. In the hysterectomy specimens, LEGH, atypical LEGH, and mucinous adenocarcinoma coexisted. The adenocarcinoma was located at a site distant from the transition zone. p16(INK4a) immunopositivity was extremely rare. Front formation was observed, and a transition from benign-looking columnar cells of LEGH to adenocarcinoma was recognized. These findings suggested that the adenocarcinoma with pyloric gland features arose from LEGH. LEGH is no longer regarded as a pseudoneoplastic lesion, and it is necessary to consider that LEGH is able to transform into a precursor lesion and to develop into an adenocarcinoma with pyloric gland features.

Clear cell adenocarcinoma arising from a giant cystic adenomyosis: a case report with immunohistochemical analysis of laminin-5 gamma2 chain and p53 overexpression.

We report a case of a clear cell adenocarcinoma arising from a giant cystic adenomyosis, with immunohistochemical analysis of p53 and laminin-5 gamma2 chain overexpression. Microscopically, not only clear cell adenocarcinoma showing myometrial invasion but also single-layered clear cell adenocarcinoma cells lining the cyst wall were observed. Transition from these single-layered tumor cells to papillary proliferative lesions of various degrees was recognized. Moreover, these tumor cells were continuous with minimal atypical cells. Although the tumor cells within the uterus showed a low positive cell ratio for p53, the metastatic foci showed a remarkable p53 overexpression. Laminin-5 gamma2 chain expression was low in papillary proliferation and high in myometrial invasion and metastatic foci. The single-layered tumor cells showing non-invasive proliferation also contained laminin-5 gamma2 chain-positive cells. When non-invasive tumor cells were considered to be at an early stage in tumor progression, some tumor cells had already acquired an invasive feature. p53 overexpression was not related to expression of the laminin-5 gamma2 chain.

Sequential changes in rat femoral artery blood flow and tissue degeneration after exposure to high-intensity focused ultrasound.

PURPOSE: The purpose of this study was to investigate the sequential changes in rat artery blood flow and tissue degeneration after exposure to high-intensity focused ultrasound (HIFU) in vivo. METHODS: HIFU was applied through the skin to the femoral artery of Sprague-Dawley rats. The peak intensities used were 530, 1080, 2750, and 4300 W/cm(2). After exposure, we measured the peak systolic velocity (PSV) in the artery every 1 min until the velocity stabilized. The vessel was resected and examined histologically 7 days after exposure. RESULTS: PSV was not significantly affected by HIFU exposure at 530 W/cm(2). PSV increased immediately after HIFU exposure at intensities of 1080 and 2750 W/cm(2). PSV after HIFU exposure at 1080 W/cm(2) fell to the control level within minutes; however, PSV increased immediately after HIFU exposure at 2750 W/cm(2) and then decreased slowly but remained at a higher level than the control for 15 min. On HIFU exposure at 4300 W/cm(2), the target artery was completely occluded. Histological studies 7 days after HIFU exposure demonstrated that exposure at 530 and 1080 W/cm(2) induced vacuolar degeneration in the tunica media of the femoral artery in rats; exposure to HIFU at 2750 and 4300 W/cm(2) resulted in strong necrotic degeneration in the tunica media. These histological changes were more marked than those found immediately after HIFU exposure. Organized thrombus formation was observed only for HIFU exposure at 4300 W/cm(2). CONCLUSION: Sequential changes in arterial blood flow after HIFU exposure vary with the intensity, and the histological changes in arterial tissue progress over time. These phenomena should be considered when HIFU is clinically applied to achieve arterial occlusion.

Raman spectroscopy for the diagnosis of unlabeled and unstained histopathological tissue specimens.

AIM: To investigate the possibility of diagnosing gastric cancer from an unstained pathological tissue using Raman spectroscopy, and to compare the findings to those obtained with conventional histopathology. METHODS: We produced two consecutive tissue specimens from areas with and without cancer lesions in the surgically resected stomach of a patient with gastric cancer. One of the two tissue specimens was stained with hematoxylin and eosin and used as a reference for laser irradiation positioning by the spectroscopic method. The other specimen was left unstained and used for Raman spectroscopy analysis. RESULTS: A significant Raman scattering spectrum could be obtained at all measurement points. Raman scattering spectrum intensities of 725 cm-1 and 782 cm-1, are associated with the nucleotides adenine and cytosine, respectively. The Raman scattering spectrum intensity ratios of 782 cm-1/620 cm-1, 782 cm-1/756 cm-1, 782 cm-1/1250 cm-1, and 782 ​​cm-1/1263 cm-1 in the gastric adenocarcinoma tissue were significantly higher than those in the normal stomach tissue. CONCLUSION: The results of this preliminary experiment suggest the feasibility of our spectroscopic method as a diagnostic tool for gastric cancer using unstained pathological specimens.