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ASAKA Shiho

Academic OrganizationTEL
Education and Research OrganizationUniversity Hospital Laboratory MedicineFAX
PositionSenior Assistant ProfessorMail Address
Address3-1-1, Asahi, Matsumoto City 390-8621Web site

Profile

Research Field
Diagnostic Pathology
Human pathology
Keywords:Lung Cancer , Endometrial carcinoma , Ovarian Cancer , Molecular Oncology , Adenocarcinoma of the uterine cervix , Immunohistochemistry , Diagnostic Pathology
Academic Societies
Academic Societies
日本臨床細胞学会
日本臨床検査医学会
日本病理学会
Academic Background
Graduate School
Shinshu University , (Department of Laboratory Medicine , Graduate School of Medicine) , 2017
Shinshu University , (医学科 , School of Medicine) , 2007
Awards
2022 , 日本病理学会症例研究賞(B演説)
2020 , 松医会賞
2018 , 同門会賞
Research Career
Research Career
2014- , Assistant Professor

Overseas Education
2017-2020 , Johns Hopkins University

Research

Books, Articles, etc.
Articles
Mucosal damage in pancreaticobiliary maljunction is stronger in the gallbladder than in the bile duct.
Pathology, research and practice,253:155011-155011 2024(Jan.)
Author:Masato Kamakura; Takeshi Uehara; Takashi Muraki; Mai Iwaya; Shiho Asaka; Tomoyuki Nakajima; Yugo Iwaya; Tadanobu Nagaya; Takahiro Yoshizawa; Akira Shimizu; Yasuhiro Kuraishi; Hiroyoshi Ota; Takeji Umemura
Abstract:BACKGROUND: The frequency of gallbladder carcinoma is high in pancreaticobiliary maljunction (PBM), and the mechanism of carcinogenesis is not well understood. METHODS: The expression of γH2AX, the most sensitive marker for detecting DNA damage, was analyzed using immunohistochemistry in patients with PBM, in which the gallbladder and bile duct were simultaneously resected. Gallbladder and bile ducts were evaluated in non-neoplastic regions in 13 cases of PBM without cancer in the gallbladder and bile ducts. RESULTS: The median frequencies of γH2AX expression in the bile duct and gallbladder within the same case were 5.9% (range 1.7-12.05%) and 9.9% (range 2.8-25%), respectively, and were significantly higher in the gallbladder mucosa (P < 0.0004). γH2AX expression strongly correlated in the bile duct and gallbladder (r = 0.9436, P < 0.0001). PBM caused marked mucosal damage to the gallbladder. CONCLUSIONS: Mucosal damage may be involved in carcinogenesis, which may be useful for predicting malignant transformation.


Interleukin-6 Stromal Expression is Correlated with Epithelial-Mesenchymal Transition at Tumor Budding in Colorectal Cancer.
International journal of surgical pathology,:10668969231177705-10668969231177705 2023(Jun. 12)
Author:Takeshi Uehara; Koichi Sato; Mai Iwaya; Shiho Asaka; Tomoyuki Nakajima; Tadanobu Nagaya; Masato Kitazawa; Hiroyoshi Ota
Abstract:Background. Tumor budding is a poor prognostic factor in colorectal adenocarcinoma, but the underlying mechanism remains unclear. Interleukin-6 (IL6) is one of the main cytokines produced by cancer-associated fibroblasts. IL6 is linked with cancer progression and poor prognosis by activating cancer cells and modifying the cancer microenvironment. However, little is known about the expression of IL6 in tumor budding and its association with tumor budding in colorectal adenocarcinoma. Methods. The clinicopathological and prognostic significance of IL6 in tumor budding was examined using a tissue microarray consisting of 36 patient samples of tumor budding in colorectal adenocarcinoma. IL6 mRNA was detected by RNAscope. Patients were stratified into negative and positive IL6 expression groups. Results. IL6 expression was overwhelmingly observed in cancer stroma but was negligible in cancer cells. Tumor budding grade was higher in the IL6-positive group in cancer stroma than in the IL6-negative group (P = .0161), while the IL6-positive group significantly exhibited the epithelial-mesenchymal transition phenotype compared with the IL6-negative group in cancer stroma (P = .0301). There was no significant difference in overall survival between colorectal adenocarcinoma patients in the IL6-positive and -negative groups in cancer stroma. Conclusion. Tumor budding may be affected by IL6 expression, and IL6 expression in cancer stroma at tumor budding may be an important prognostic marker.


ARL4C is associated with epithelial-to-mesenchymal transition in colorectal cancer.
BMC cancer,23(1):478-478 2023(May 26)
Author:Ryo Kanai; Takeshi Uehara; Takahiro Yoshizawa; Masato Kamakura; Tomoyuki Nakajima; Yasuhiro Kinugawa; Mai Iwaya; Shiho Asaka; Masato Kitazawa; Tadanobu Nagaya; Hiroyoshi Ota
Abstract:BACKGROUND: ADP-ribosylation factor-like protein 4 C (ARL4C) is a member of the ARF small GTP-binding protein subfamily. The ARL4C gene is highly expressed in colorectal cancer (CRC). ARL4C protein promotes cell motility, invasion, and proliferation. METHODS: We investigated the characteristics of ARL4C by comparing its expression at the invasion front and relationships with clinicopathological data using RNAscope, a highly sensitive RNA in situ method. RESULTS: In all cases, ARL4C expression was observed in cancer stromal cells and cancer cells. ARL4C expression in cancer cells was localized at the invasion front. In cancer stromal cells, ARL4C expression was significantly stronger in cases with high-grade tumor budding than in cases with low-grade tumor budding (P = 0.0002). Additionally, ARL4C expression was significantly increased in patients with high histological grade compared with those with low histological grade (P = 0.0227). Furthermore, ARL4C expression was significantly stronger in lesions with the epithelial-to-mesenchymal transition (EMT) phenotype compared with the non-EMT phenotype (P = 0.0289). In CRC cells, ARL4C expression was significantly stronger in cells that had the EMT phenotype compared with those with a non-EMT phenotype (P = 0.0366). ARL4C expression was significantly higher in cancer stromal cells than in CRC cells (P < 0.0001). CONCLUSION: Our analysis reinforces the possibility that ARL4C expression worsens the prognosis of patients with CRC. Further elucidation of the function of ARL4C is desired.


IgG4 expression and IgG4/IgG ratio in the tumour invasion front predict long-term outcomes for patients with intrahepatic cholangiocarcinoma.
Pathology,55(4):508-513 2023(Feb. 03)
Author:Takahiro Yoshizawa; Takeshi Uehara; Mai Iwaya; Shiho Asaka; Tomoyuki Nakajima; Yasuhiro Kinugawa; Akira Shimizu; Koji Kubota; Tsuyoshi Notake; Hitoshi Masuo; Hiroki Sakai; Kiyotaka Hosoda; Hikaru Hayashi; Tadanobu Nagaya; Hiroyoshi Ota; Yuji Soejima
Abstract:IgG4-positive plasma cells are reportedly increased in the tumour microenvironment, and a high number of these cells in tumours is a poor prognostic factor in several cancers. However, there are no reported analyses of IgG4 expression in intrahepatic cholangiocarcinoma (ICC). This study aimed to analyse the correlations between prognosis-related clinicopathological features of patients with ICC and IgG4 expression. We identified 37 ICC patients who underwent surgical resection between January 2010 and December 2020. The number of IgG-positive and IgG4-positive plasma cells in the tumour, invasion front, and stroma near the tumour was analysed by immunostaining. Furthermore, we examined the association of prognosis-related clinicopathological data with the number of IgG4-positive plasma cells and IgG4/IgG ratio in ICC patients. The IgG4-positive plasma cell percentages for the intra-tumour area, invasion front, and non-cancerous area (NCA) near the tumour were 91.9%, 56.8%, and 81.1%, respectively. IgG-positive plasma cells were observed in each region for all cases, except for NCA tissue in one case. A high IgG4 expression level and IgG4/IgG ratio in the invasion front were significantly associated with poor overall survival (OS) (log-rank test p=0.0438 and p=0.0338, respectively). Multivariate analysis for OS revealed that high IgG4 expression (p=0.0140), lymph node metastasis (p=0.0205), and positive surgical margin (p=0.0009) or a high IgG4/IgG ratio (p=0.0051), lymph node metastasis (p=0.0280), and positive surgical margin (p=0.0009) were independent poor prognostic factors. In conclusion, a high IgG4 expression level and IgG4/IgG ratio in the invasion front are independent poor prognostic factors for ICC. Targeted therapy for IgG4 may improve the prognosis for patients with ICC.


High expression of LGR6 is a poor prognostic factor in esophageal carcinoma.
Pathology, research and practice,242:154312-154312 2023(Feb.)
Author:Takehito Ehara; Takeshi Uehara; Takahiro Yoshizawa; Yasuhiro Kinugawa; Tomoyuki Nakajima; Shota Kobayashi; Shiho Asaka; Mai Iwaya; Tadanobu Nagaya; Masato Kitazawa; Hiroyoshi Ota; Yuji Soejima
Abstract:BACKGROUND: Leucine-rich repeat-containing G-protein-coupled receptor 6 (LGR6) promotes carcinogenesis and progression in some cancer types. However, there are few reports of LGR6 expression in esophageal squamous cell carcinoma (ESCC). LGR6 expression and clinicopathological features in ESCC were investigated by RNAscope, a highly sensitive RNA in situ hybridization method. METHODS: Appropriate tumors were selected from 41 cases of ESCC from which tissue microarrays were generated, and LGR6 expression was identified by RNAscope. RESULTS: Thirty-seven patients had LGR6 expression. High LGR6 expression was observed in 17 cases and low LGR6 expression in 24 cases. LGR6 expression was significantly higher in high histological grade ESCC than in low histological grade ESCC (P = 0.0023). ESCC patients who received neoadjuvant chemotherapy had significantly higher LGR6 expression than those without neoadjuvant chemotherapy (P = 0.0109). Furthermore, high LGR6 expression showed a poorer prognosis than low LGR6 expression (log-rank test, P = 0.0365). CONCLUSIONS: LGR6 may be a prognostic factor and a potential new therapeutic target in ESCC.


ARID1A Regulates Progesterone Receptor Expression in Early Endometrial Endometrioid Carcinoma Pathogenesis
Modern Pathology 2023(Feb.)
Author:Shiho Asaka; Ying Liu; Zheng-Cheng Yu; Yohan Suryo Rahmanto; Motoki Ono; Ryoichi Asaka; Tsutomu Miyamoto; Ting-Tai Yen; Ayse Ayhan; Tian-Li Wang; Ie-Ming Shih


胎児型横紋筋腫類似の高分化異所性肉腫を有する卵巣癌肉腫の一例
日本病理学会会誌,111(2):106-106 2022(Oct.)
Author:成澤 友里; 浅香 志穂; 紺野 沙織; 布 麻里奈; 草間 由紀子; 村元 勤; 西澤 千津恵; 小林 弥生子; 大石 善丈; 上原 剛


PIM1 is a Poor Prognostic Factor for and Potential Therapeutic Target in Serous Carcinoma of the Endometrium.
International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists 2022(Apr. 12)
Author:Hodaka Takeuchi; Tsutomu Miyamoto; Chiho Fuseya; Ryoichi Asaka; Koichi Ida; Motoki Ono; Yasuhiro Tanaka; Manaka Shinagawa; Hirofumi Ando; Shiho Asaka; Tanri Shiozawa
Abstract: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.


Correlation of LGR5 expression and clinicopathological features in intrahepatic cholangiocarcinoma.
Pathology, research and practice,232:153832-153832 2022(Mar. 03)
Author:Takahiro Yoshizawa; Takeshi Uehara; Mai Iwaya; Shiho Asaka; Shota Kobayashi; Tomoyuki Nakajima; Yasuhiro Kinugawa; Tadanobu Nagaya; Masato Kamakura; Akira Shimizu; Koji Kubota; Tsuyoshi Notake; Hitoshi Masuo; Kiyotaka Hosoda; Hiroki Sakai; Hikaru Hayashi; Kentaro Umemura; Atsushi Kamachi; Takamune Goto; Hidenori Tomida; Shiori Yamazaki; Hiroyoshi Ota; Yuji Soejima
Abstract:Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a known cancer stem cell marker. However, there are no reported analyses of LGR5 mRNA expression in normal liver and liver cancer tissues. Here, we evaluated LGR5 expression by RNAscope, a newly developed RNA in situ hybridization technique, using a tissue microarray consisting of 25 samples of intrahepatic cholangiocarcinoma (ICC) selected from the medical archives at our hospital. LGR5 expression levels were divided into high and low expression groups by the five-grade scoring system, and clinicopathological features were analyzed. Low LGR5 expression was identified in some normal hepatocytes and bile duct cells. In addition, LGR5 expression was identified in all bile duct cancer samples except one case. Well-differentiated to moderately-differentiated adenocarcinoma tended to show higher LGR5 expression than poorly-differentiated adenocarcinoma (P = 0.0561), and the large duct type showed significantly higher LGR5 expression levels than the small duct type (P = 0.0225). Patients in the high LGR5 expression group tended to have good overall survival (OS) (P = 0.0623). The Cox proportional hazard regression model revealed that the high LGR5 expression group showed independently better OS for ICC (P = 0.0285). High LGR5 expression is possibly a good prognosis factor in ICC. However, the detailed mechanism of LGR5 in this disease remains unclear, and further analysis is warranted.


Usual Interstitial Pneumonia Pattern Interstitial Lung Disease Developed in a Patient with IgG4-related Chronic Sclerosing Sialadenitis: A Case Report.
Internal medicine (Tokyo, Japan),61(17):2637-2642 2022(Feb. 08)
Author:Hiroshi Yamamoto; Masamichi Komatsu; Kei Sonehara; Yuichi Ikuyama; Kazuhisa Urushihata; Kazunari Tateishi; Yoshiaki Kitaguchi; Atsuhito Ushuiki; Shiho Asaka; Takeshi Uehara; Satoshi Kawakami; Kentaro Mori; Kazutoshi Hamanaka; Kenichi Nishie; Akira Hebisawa; Masayuki Hanaoka
Abstract:A 69-year-old man was diagnosed with immunoglobulin (Ig) G4-related disease (IgG4-RD) at 62 years old. At that time, he had high serum IgG4 levels and bilateral submandibular gland swelling on CT; thus, a gland biopsy was performed. Because a reticular shadow was found on chest CT, a lung surgical biopsy was also performed. The specimens revealed usual interstitial pneumonia (UIP) pattern interstitial pneumonia with some IgG4-positive cells. The patient was subsequently followed up without treatment. His forced vital capacity and radiological findings progressively deteriorated, consistent with UIP pattern interstitial lung disease but different from a lung lesion of IgG4-RD.


LGR5 expression and clinicopathological features of the invasive front in the fat infiltration area of pancreatic cancer.
Diagnostic pathology,17(1):21-21 2022(Feb. 05)
Author:Masato Kamakura; Takeshi Uehara; Mai Iwaya; Shiho Asaka; Shota Kobayashi; Tomoyuki Nakajima; Yasuhiro Kinugawa; Tadanobu Nagaya; Takahiro Yoshizawa; Akira Shimizu; Hiroyoshi Ota; Takeji Umemura
Abstract:BACKGROUND: Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a strong cancer stem cell marker in colorectal cancer; however, there are many unclear aspects of LGR5 expression in pancreatic cancer. It has been reported that the interaction between tumor cells and stroma at the fat infiltration site has a significant effect on pancreatic cancer prognosis. Therefore, we report a clinicopathological study of LGR5 expression at the fat invasion front in pancreatic cancer. METHODS: LGR5 expression was analyzed in 40 pancreatic ductal adenocarcinoma cases with RNAscope, which is a newly developed high-sensitivity in situ hybridization method. Epithelial-mesenchymal transition (EMT) was analyzed by the expression of E-cadherin and vimentin via immunohistochemistry. RESULTS: LGR5-positive dots were identified in all cases, especially with glandular formation. In the fat invasion front, a high histological grade showed significantly reduced LGR5 expression compared with a low histological grade (p=0.0126). LGR5 expression was significantly higher in the non-EMT phenotype group than in EMT phenotype group (p=0.0003). Additionally, LGR5 expression was significantly lower in cases with high vascular invasion than in those with low vascular invasion (p=0.0244). CONCLUSIONS: These findings suggest that decreased LGR5 expression in the fat invasion front is associated with more aggressive biological behavior in pancreatic ductal adenocarcinoma, with higher tumor grade, EMT phenotype, and higher vascular invasion.


Syndrome of Inappropriate Antidiuretic Hormone Secretion as the Initial Presentation in a Patient with Stage I Small-cell Lung Cancer.
Internal medicine (Tokyo, Japan),61(5):709-713 2022
Author:Tomonobu Koizumi; Takashi Kobayashi; Shintaro Kanda; Toshirou Fukushima; Futoshi Muranaka; Kentaro Miura; Shiho Asaka
Abstract:A 67-year-old man with a history of esophageal cancer resection was referred to our hospital because of nausea and appetite loss. Laboratory findings showed severe hyponatremia and were compatible with syndrome of inappropriate antidiuretic hormone (SIADH) secretion. Chest computed tomography (CT) revealed a nodule measuring 13 mm in the lower lobe of the right lung. Right thoracotomy was performed, and the histopathological diagnosis was small-cell lung cancer (T1bN0M0; Stage 1b). Although SIADH is frequently associated with small-cell lung cancer, it is extremely rare as the initial clinical feature in stage I small-cell lung cancer.


Clinicopathological and prognostic significance of immunophenotypic characterization of endocervical adenocarcinoma using CLDN18, CDH17, and PAX8 in association with HPV status.
Virchows Archiv : an international journal of pathology,480(2):269-280 2021(Sep. 28)
Author:Shiho Asaka; Tomoyuki Nakajima; Koichi Ida; Ryoichi Asaka; Chinatsu Kobayashi; Masayuki Ito; Tsutomu Miyamoto; Takeshi Uehara; Hiroyoshi Ota
Abstract: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 Müllerian epithelial cells. We identified five immunophenotypes of endocervical adenocarcinoma: gastric (21%); intestinal (14%); gastrointestinal (11%); Müllerian (35%); and not otherwise specified (NOS) (20%). Adenocarcinomas with gastric immunophenotype, characterized by aging (p = 0.0050), infrequent HPV infection (p < 0.0001), concurrent lobular endocervical glandular hyperplasia (p = 0.0060), lymphovascular invasion (p = 0.0073), advanced clinical stage (p = 0.0001), and the poorest progression-free (p < 0.0001) and overall (p = 0.0023) survivals, were morphologically compatible with gastric-type adenocarcinoma of the WHO 2020 classification. Conversely, most adenocarcinomas with Müllerian (91%) and intestinal (89%) immunophenotypes were HPV associated and morphologically compatible with usual- or intestinal-type adenocarcinomas of the WHO 2020 classification. The morphology of adenocarcinomas with gastrointestinal immunophenotype was intermediate or mixed between those of gastric and intestinal immunophenotypes; 57% were HPV associated. Adenocarcinomas with NOS immunophenotype were mainly HPV associated (85%) and histologically poorly differentiated. Multivariate analysis revealed that gastric (p = 0.008), intestinal + gastrointestinal (p = 0.0103), and NOS (p = 0.009) immunophenotypes were independent predictors of progression-free survival. Immunophenotypes characterized by CLDN18, CDH17, and PAX8 exhibited clinicopathological relevance and may improve the diagnostic accuracy and prognostic value of conventional histological classification.


IL-6 expression helps distinguish Castleman's disease from IgG4-related disease in the lung.
BMC pulmonary medicine,21(1):219-219 2021(Jul. 10)
Author:Yasuhiro Kinugawa; Takeshi Uehara; Mai Iwaya; Shiho Asaka; Shota Kobayashi; Tomoyuki Nakajima; Masamichi Komatsu; Masanori Yasuo; Hiroshi Yamamoto; Hiroyoshi Ota
Abstract:BACKGROUND: It is difficult to distinguish between multicentric Castleman's disease (MCD) and IgG4-related lung disease (IgG4-LD), an IgG4-related disease (IgG4-RD) in the lung. METHODS: We focused on IL-6, which is elevated in MCD, to distinguish between MCD and IgG4-LD by RNAscope, a highly sensitive RNA in situ method. Six cases of MCD and four cases of IgG4-LD were selected. RESULTS: In all cases of MCD and IgG4-LD, 10 or more IgG4-positive cells were found in one high-power field. All MCD cases were inconsistent with the pathological IgG4-related comprehensive diagnostic criteria, but 2 of 6 cases had an IgG4/IgG ratio greater than 40%. In all IgG4-LD cases, histological features were consistent with the pathological IgG4-RD comprehensive diagnostic criteria. IL-6 expression was observed in all MCD and IgG4-LD cases except for one IgG4-LD biopsy. IL-6-expressing cells were mainly identified in the stroma. Sites of IL-6 expression were not characteristic and were sparse. IL-6 expression tended to be higher in MCD compared with IgG4-LD. A positive correlation was found between the IL-6 H-score and serum IL-6 level. CONCLUSION: Differences in IL-6 expression may help distinguish between MCD and IgG4-LD. In addition, the presence of high IL-6 levels may help elucidate the pathological mechanisms of IgG4-LD.


Genome-wide mutation analysis in precancerous lesions of endometrial carcinoma
JOURNAL OF PATHOLOGY,253(1):119-128 2021(Jan.)
Author:Lihong Li; Pinli Yue; Qianqian Song; Ting-Tai Yen; Shiho Asaka; Tian-Li Wang; Anna L. Beavis; Amanda N. Fader; Yuchen Jiao; Guangwen Yuan; Ie-Ming Shih; Yan Song
Abstract:Clinicopathological evidence supports endometrial atypical hyperplasia (AH) or endometrial intraepithelial neoplasia as the precursor of uterine endometrioid carcinoma (EC), the most common gynecologic malignancy. However, the pathogenic progression from AH to EC remains unclear. Here, we employed whole-exome sequencing to identify somatic mutations and copy number changes in micro-dissected lesions from 30 pairs of newly diagnosed AH and EC. We found that all but one pair of AHs shared the same DNA mismatch repair status as their corresponding ECs. The percentage of common mutations between AH lesions and corresponding ECs varied significantly, ranging from 0.1% to 82%. Microsatellite stable AHs had fewer cancer driver mutations than ECs (5 versus 7, p = 0.017), but among microsatellite unstable AHs and ECs there was no difference in mutational numbers (36 versus 38, p = 0.65). As compared to AH specimens, 19 (79%) of 24 microsatellite stable EC tumors gained new cancer driver mutations, most of which involved PTEN, ARID1A, PIK3CA, CTNNB1, or CHD4. Our results suggest that some AH lesions are the immediate precursor of ECs, and progression depends on acquisition of additional cancer driver mutations. However, a complex clonal relationship between AH and EC can also be appreciated, as in some cases both lesions diverge very early or arise independently, thus co-developing with distinct genetic trajectories. Our genome-wide profile of mutations in AH and EC shines new light on the molecular landscape of tumor progression. (c) 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Superiority of sucrase-isomaltase to CD10 for immunohistochemical detection of intestinal absorptive cell phenotype in differentiated-type gastric adenocarcinoma.
International journal of clinical and experimental pathology,14(10):1031-1037 2021
Author:Hiroyoshi Ota; Masayuki Ito; Chinatsu Kobayashi; Shiho Asaka; Mai Iwaya; Takeshi Uehara
Abstract:Gastric adenocarcinoma (GAC) can be divided immunophenotypically into gastric, intestinal, or mixed gastric and intestinal phenotypes. Cadherin 17 (CDH17) and CD10 have been used as comprehensive markers for intestinal epithelial cells and for small intestinal absorptive cells in GACs, respectively. Sucrase-isomaltase (SI) and CD10 are expressed in small intestinal absorptive cells and SI is more frequently expressed than CD10 in gastric intestinal metaplasia (IM). The aim of this study was to evaluate the potential of SI as a marker for intestinal absorptive cells compared to CD10 in differentiated-type (DT) GACs. We compared the immunohistochemical expression of CDH17, SI, and CD10 in IMs and tissue microarrays of 40 samples of DTGACs. In IMs and DTGACs, CDH17 showed a diffuse lateral cytoplasmic membrane staining both in columnar and goblet cells. SI and CD10 were expressed on the luminal surfaces of the columnar cells. In IMs, SI was positive both in both complete-type IMs and in incomplete-type IMs. CD10 was positive only in complete-type IMs. In DTGACs, CDH17, SI, and CD 10 were positive in 37 (92.5%), 22 (55%), and 11 (27.5%) cases, respectively. In SI-positive cases, the degrees of expression of SI were equal to (7 cases) or less than (15 cases) those of CDH17; the degrees of expression of SI were equal to (5 cases), more than (16 cases), or less than (1 case) those of CD10. In conclusion, SI is a more sensitive immunohistochemical marker for intestinal absorptive cells than CD10 in DTGACs.


Immunostaining With Immunoglobulin G Subclass Antibody Cocktail for Diagnosis of Type 1 Autoimmune Pancreatitis
INTERNATIONAL JOURNAL OF SURGICAL PATHOLOGY,28(8):844-849 2020(Dec.)
Author:Rie Nakata; Takeshi Uehara; Mai Iwaya; Shiho Asaka; Shota Kobayashi; Mitsutoshi Sugano; Kayoko Higuchi; Yukiko Kusama; Koh Nakazawa; Masato Nakaguro; Mikiko Kobayashi; Ayako Tateishi; Mutsuki Makino; Kenji Kawaguchi; Toshitaka Maejima; Keiko Ishii; Kenji Sano; Hisashi Shimojo; Atsushi Hori; Toshiaki Otsuki; Hideaki Hamano; Shigeyuki Kawa; Hiroyoshi Ota
Abstract:Background. Immunoglobulin (Ig) G4-related diseases (RDs) are systemic diseases in which serum IgG4 levels are frequently elevated. They can cause diffuse or focal tumor formation, organ swelling, and tissue thickening in organs infiltrated by IgG4 plasma cells. The diagnostic criteria for IgG4-RDs include an IgG4/IgG ratio >40%, but counting IgG(+) cells can be difficult because of the weakness of IgG staining density. We hypothesized that an antibody cocktail of mixed IgG1, IgG2, IgG3, and IgG4 (AC-IgG) might give immunohistochemistry results comparable with those of IgG in IgG4-RD. Methods. We compared AC-IgG reactivity with IgG expression in type 1 autoimmune pancreatitis (AIP), a representative IgG4-RD. We compared immunohistochemistry results using AC-IgG and IgG-only in 10 cases of AIP. The coefficient of variation (Cv) was used to analyze differences between AC-IgG and IgG findings in AIP by 13 board-certified pathologists. Results. Although mean values for IgG(+) cells did not significantly differ between AC-IgG (34.3; range = 27.4-37.1) and IgG (30.0; range = 23.0-45.6; P = .6254), Cv was lower for AC-IgG (33.4%) than for IgG (51.4%; regression equation; y[IgG] = 0.988x + 0.982; correlation coefficient = 0.907). The data showed that the results of both methods were largely consistent. Conclusion. AC-IgG could replace IgG to count IgG(+) cells because of its lower Cv.


Inhibition of the MYC-Regulated Glutaminase Metabolic Axis Is an Effective Synthetic Lethal Approach for Treating Chemoresistant Ovarian Cancers
CANCER RESEARCH,80(20):4514-4526 2020(Oct.)
Author:Yao-An Shen; Jiaxin Hong; Ryoichi Asaka; Shiho Asaka; Fang-Chi Hsu; Yohan Suryo Rahmanto; Jin-Gyoung Jung; Yu-Wei Chen; Ting-Tai Yen; Alicja Tomaszewski; Cissy Zhang; Nabeel Attarwala; Angelo M. DeMarzo; Ben Davidson; Chi-Mu Chuang; Xi Chen; Stephanie Gaillard; Anne Le; Ie-Ming Shih; Tian-Li Wang
Abstract:Amplification and overexpression of the MYC oncogene in tumor cells, including ovarian cancer cells, correlates with poor responses to chemotherapy. As MYC is not directly targetable, we have analyzed molecular pathways downstream of MYC to identify potential therapeutic targets. Here we report that ovarian cancer cells overexpressing glutaminase (GLS), a target of MYC and a key enzyme in glutaminolysis, are intrinsically resistant to platinum-based chemotherapy and are enriched with intracellular antioxidant glutathione. Deprivation of glutamine by glutamine-withdrawal, GLS knockdown, or exposure to the GLS inhibitor CB-839 resulted in robust induction of reactive oxygen species in high GLS-expressing but not in lowGLS-expressing ovarian cancer cells. Treatment with CB-839 rendered GLS(high) cells vulnerable to the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, and prolonged survival in tumor-bearing mice. These findings suggest consideration of applying a combined therapy of GLS inhibitor and PARP inhibitor to treat chemoresistant ovarian cancers, especially those with high GLS expression.Significance: Targeting glutaminase disturbs redox homeostasis and nucleotide synthesis and causes replication stress in cancer cells, representing an exploitable vulnerability for the development of effective therapeutics.


Limited frequency of malignant change in lobular endocervical glandular hyperplasia
INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER,30(10):1480-1487 2020(Oct.)
Author:Hisanori Kobara; Tsutomu Miyamoto; Hirofumi Ando; Ryoichi Asaka; Akiko Takatsu; Ayumi Ohya; Shiho Asaka; Tanri Shiozawa
Abstract:Introduction Although 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. Methods The 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. Results Of 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. Conclusion An 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.


Immunophenotype analysis using CLDN18, CDH17, and PAX8 for the subcategorization of endocervical adenocarcinomas in situ: gastric-type, intestinal-type, gastrointestinal-type, and Müllerian-type.
Virchows Archiv : an international journal of pathology,476(4):499-510 2020(Apr.)
Author:Shiho Asaka; Tomoyuki Nakajima; Kaori Kugo; Risako Kashiwagi; Nozomi Yazaki; Tsutomu Miyamoto; Takeshi Uehara; Hiroyoshi Ota
Abstract: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.


The Interstitial Lung Disease-Gender-Age-Physiology Index Can Predict the Prognosis in Surgically Resected Patients with Interstitial Lung Disease and Concomitant Lung Cancer
RESPIRATION,99(1):9-18 2020(Jan.)
Author:Fumika Ueno; Yoshiaki Kitaguchi; Takayuki Shiina; Shiho Asaka; Masanori Yasuo; Yosuke Wada; Takumi Kinjo; Akihiko Yoshizawa; Masayuki Hanaoka
Abstract:Background: The interstitial lung disease-gender-age-physiology (ILD-GAP) index and staging system have been reported as a clinical prognostic factor for ILD, including all ILD subtypes. Objectives: The purpose of this study was to clarify the association of various prognostic indices, including the ILD-GAP index, with the prognosis, the incidence of acute exacerbations of ILD (ILD-AE), and the use of long-term oxygen therapy (LTOT) after surgery in surgically resected patients with ILD and concomitant lung cancer, to provide additional information when considering whether it is safe to perform surgery. Methods: The medical records of patients with ILD and concomitant lung cancer who had undergone surgery at Shinshu University Hospital between August 2001 and September 2016 were retrospectively analyzed. Results: There were significant differences in survival between the ILD-GAP index: 0-1 and >= 4 groups (p = 0.0001) and between the ILD-GAP index: 2-3 and >= 4 groups (p = 0.0236). A higher ILD-GAP index was independently associated with the risk of death (hazard ratio [HR] 1.32030; p = 0.0059). A higher body mass index (BMI) and a higher serum C-reactive protein (CRP) level were independently associated with the incidence of ILD-AE (HR 1.28336; p = 0.0206 and HR 26.3943; p = 0.0165, respectively). A higher severity of ILD on chest high-resolution computed tomography (HRCT) was independently associated with the use of LTOT (HR 2.78670; p = 0.0313). Conclusions: The ILD-GAP index can predict the prognosis in surgically resected patients with ILD and concomitant lung cancer. The BMI and serum CRP levels were independent determinants that predicted the incidence of ILD-AE. The severity of ILD on chest HRCT was an independent determinant that predicted the use of LTOT.


αGlcNAc and its catalyst α4GnT are diagnostic and prognostic markers in uterine cervical tumor, gastric type.
Scientific reports,9(1):13043-13043 2019(Sep. 10)
Author:Koichi Ida; Kazuhiro Yamanoi; Shiho Asaka; Hodaka Takeuchi; Tsutomu Miyamoto; Tanri Shiozawa; Jun Nakayama
Abstract:Cervical adenocarcinoma, gastric type (GAS) is not associated with human papilloma virus (HPV) infection. GAS patients prognoses are significantly worse compared with cervical adenocarcinoma associated with HPV infection, as their tumors exhibit resistance to conventional chemotherapy and radiotherapy. GAS is often associated with lobular endocervical glandular hyperplasia (LEGH), which is regarded as a precursor to GAS in the latest WHO classification. Recently, we reported that a decrease in expression of terminal α1,4-linked N-acetylglucosamine (αGlcNAc) relative to that of MUC6 was already apparent in atypical LEGH in the LEGH-GAS sequence. Here, we analyzed expression of α1,4-N-acetylglucosaminyltransferase (α4GnT), the sole enzyme catalyzing αGlcNAc biosynthesis, and that of αGlcNAc and MUC6 in cases representing non-neoplastic endocervical gland (NNEG) (11 cases), LEGH (26 cases) and GAS (12 cases). α4GnT protein was detected in a "dot-like" pattern, indicating localization in the Golgi apparatus in all 26 LEGH cases and 5 of 12 GAS cases. α4GnT- and αGlcNAc-positive cells largely overlapped, suggesting that α4GnT gene expression regulates αGlcNAc biosynthesis. Interestingly, all NNEG cases were negative for α4GnT and αGlcNAc expression, but 7 of 11 NNEG and all LEGH cases were MUC6-positive. In GAS cases, patients whose tumors were α4GnT- and αGlcNAc-positive had more favorable prognosis than others. Multivariate analysis revealed that positive expressions of α4GnT and αGlcNAc were independent prognostic indicators. These results indicate that α4GnT and αGlcNAc could serve as useful markers not only to distinguish LEGH from NNEG but to evaluate prognoses of GAS patients.


Whole-exome sequencing of lobular endocervical glandular hyperplasia.
Oncology letters,18(3):2592-2597 2019(Sep.)
Author:Koichi Ida; Tsutomu Miyamoto; Akiko Takatsu; Hirofumi Ando; Ryoichi Asaka; Hodaka Takeuchi; Motoki Ono; Satoshi Yamada; Shiho Asaka; Tanri Shiozawa
Abstract: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.


Analysis of Telomere Lengths in p53 Signatures and Incidental Serous Tubal Intraepithelial Carcinomas Without Concurrent Ovarian Cancer.
The American journal of surgical pathology,43(8):1083-1091 2019(Aug.)
Author:Shiho Asaka; Christine Davis; Shiou-Fu Lin; Tian-Li Wang; Christopher M Heaphy; Ie-Ming Shih
Abstract:Telomere alterations represent one of the major molecular changes in the development of human cancer. We have previously reported that telomere lengths in most serous tubal intraepithelial carcinomas (STIC) are shorter than they are in ovarian high-grade serous carcinomas (HGSC) or in normal-appearing fallopian tube epithelium from the same patients. However, it remains critical to determine if similar telomere alterations occur in TP53-mutated but histologically unremarkable "p53 signature" lesions, as well as incidental STICs without concurrent HGSC. In this study, we quantitatively measured telomere lengths by performing telomere-specific fluorescence in situ hybridization in conjunction with p53 immunolabeling in 15 p53 signatures and 30 incidental STICs without concurrent HGSC. We compared these new results with our previous data in paired STICs and concurrent HGSCs. We found that most p53 signatures (80%) and incidental STICs without HGSC (77%) exhibited significant telomere shortening compared with adjacent normal-appearing fallopian tube epithelium (P<0.01). Interestingly, however, p53 signatures and incidental STICs without HGSC displayed longer telomeres and less cell-to-cell telomere length heterogeneity than STICs associated with HGSC (P<0.001). These findings indicate that telomere shortening occurs in p53 signatures, the earliest precancer lesion. Moreover, incidental STICs without concurrent HGSC are indeed similar to p53 signatures as they have less telomere shortening and less cell-to-cell telomere length heterogeneity than STICs associated with HGSC.


腹腔鏡下リスク低減卵管卵巣摘出術により両側卵管采に漿液性卵管上皮内病変が発見された遺伝性乳癌卵巣癌症候群の1例
信州医学雑誌,67(3):209-215 2019(Jun.)
Author:鹿島 大靖; 岡 賢二; 品川 真奈花; 山中 桜; 小野 元紀; 竹内 穂高; 井田 耕一; 樋口 正太郎; 山田 靖; 小原 久典; 菊地 範彦; 宮本 強; 橘 涼太; 福嶋 義光; 古庄 知己; 家里 明日美; 伊藤 研一; 浅香 志穂; 上原 剛; 塩沢 丹里
Abstract:症例は42歳女性で、41歳時に左乳癌と診断され、左乳房全摘術、センチネルリンパ節生検、乳房再建術が行われた。家族歴と若年での乳癌発症から遺伝性乳癌卵巣癌症候群が疑われたため、遺伝カウンセリングが行われた後に当科紹介となった。リスク低減卵管卵巣摘出術を腹腔鏡下手術で行った。子宮、膀胱子宮窩、ダグラス窩、骨盤腹膜、両側傍結腸溝、大網、肝表面、横隔膜下面に異常所見は認められず、骨盤内から腹腔洗浄細胞診を施行したが、腫瘍細胞は検出されなかった。術後経過は良好で、2日目に退院した。HE標本では両側の卵管采上皮に細胞の偽重層化した領域を認め、核異型はごく軽度であり、免疫染色ではp53強発現、Ki-67低陽性率であることから漿液性卵管上皮内病変と診断した。術後27ヵ月経過し、腹膜癌等の異常は認められていない。


腸管嚢腫様気腫症による腸重積の1例
日本臨床外科学会雑誌,80(6):1147-1151 2019(Jun.)
Author:片桐 忍; 和城 光庸; 北原 拓哉; 成田 淳; 浅香 志穂; 大塚 将之
Abstract:症例は28歳,男性.既往は特になし.急激な腹痛と血便がみられたため当院を受診.腹部CTでは,回腸末端の上行結腸内への嵌入像と,同部位に多発する嚢胞状気腫様陰影を認めた.腸管虚血の症状を伴ったため緊急手術を施行した.術中所見上盲腸に弾性軟の腫瘍を触知したため,悪性も否定し得ず,回盲部切除術を施行した.切除標本の肉眼所見では,盲腸粘膜に多発するポリープ性病変を認めた.病理組織検査所見では,病変部の粘膜下層に高度の間質の浮腫と大小多数の嚢胞化がみられ,粘膜固有層にはうっ血と出血を伴っていた.以上より,腸管嚢腫様気腫症(pneumatosis cystoides intestinalis:以下PCI)に伴う腸重積と診断した.PCIは腸管壁の粘膜下または漿膜下に含気性嚢胞状腫瘤が多発する疾患で,病因は解明されていない.また,PCIを重積の先進部とした症例の報告は稀である.若干の文献的考察を加えて報告する.(著者抄録)


T cell-inflamed phenotype and increased Foxp3 expression in infiltrating T-cells of mismatch-repair deficient endometrial cancers.
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc,32(4):576-584 2019(Apr.)
Author:Shiho Asaka; Ting-Tai Yen; Tian-Li Wang; Ie-Ming Shih; Stephanie Gaillard
Abstract:Mismatch repair-deficient endometrial cancers have a high somatic mutation burden, suggesting that patients with these tumors may benefit from immunotherapy. Elucidating the immune suppressive mechanisms of mismatch repair-deficient endometrial cancers is fundamental to developing future immune-based interventions. This study aimed to determine the immune cell populations associated with mismatch repair-deficient endometrial cancers, especially focusing on targetable regulatory pathways of the immune response. A total of 76 endometrial cancer hysterectomy specimens were evaluated for tumor-infiltrating immune cells by immunohistochemistry. Immune specific markers were used to evaluate each specimen for the number of CD8 + cytotoxic T lymphocytes, forkhead-box P3 (FoxP3) + regulatory T cells, CD68 + tumor-associated macrophages, as well as programmed death-1 (PD-1) + immune cells, and the percentage of programmed death ligand-1 (PD-L1) + immune cells. Mismatch repair-deficient tumors exhibited a significantly higher number of CD8 + cytotoxic T lymphocytes (p = 0.0006), FoxP3 + regulatory T cells (p = 0.0003), PD-1 + immune cells (p = 0.0069), and a higher percentage of PD-L1 + immune cells (p = 0.0007) occupying the tumor compared to mismatch repair-proficient endometrial cancers. There was no significant difference in CD68 + tumor-associated macrophages infiltration between the two groups. Endometrial cancers with tumor PD-L1 expression also showed significantly increased infiltration of CD8 + cytotoxic T lymphocytes (p = 0.0002), FoxP3 + regulatory T cells (p = 0.0003), PD-1 + immune cells (p < 0.0001), and PD-L1 + immune cells (p < 0.0001). Endometrial cancers showing mismatch repair-deficiency and PD-L1 expression in tumor cells exhibit a prominent T cell-inflamed phenotype. More importantly, the increased number of FoxP3 + regulatory T cells in mismatch repair-deficient endometrial cancers suggests that combination therapy by targeting both regulatory T cells and immune checkpoints may be warranted to improve clinical efficacy.


Long Interspersed Nuclear Element 1 Retrotransposons Become Deregulated during the Development of Ovarian Cancer Precursor Lesions
AMERICAN JOURNAL OF PATHOLOGY,189(3):513-520 2019(Mar.)
Author:Thomas R. Pisanic; Shiho Asaka; Shiou-Fu Lin; Ting-Tai Yen; Hanru Sun; Ash Bahadirli-Talbott; Tza-Huei Wang; Kathleen H. Burns; Tian-Li Wang; Ie-Ming Shih
Abstract:There is growing evidence that most high-grade serous ovarian carcinomas likely arise from local dissemination of precursor lesions of the fallopian tube. Evolution of these lesions from early p53 signatures to latter-stage, serous tubal intraepithelial carcinomas (STICs) is characterized by cytologic atypia, accumulation of somatic mutations, and genomic instability, the etiologies of which remain unclear. Long interspersed element 1 (LINE-1) retrotransposon is expressed in many carcinomas, including high-grade serous ovarian carcinoma, where it contributes to genomic instability; however, the timing of LINE-1 activation during this evolution has yet to be elucidated. In this study, we assessed LINE-1 open reading frame 1 protein expression in 12 p53 signature lesions, 32 STICs, and 112 various types of ovarian cancers via immunohistochemical staining and examined LINE-1 promoter methylation in representative cases. We found that 78% and 57% of STICs, with and without concurrent ovarian carcinomas, respectively, exhibited intense LINE-1 immunoreactivity compared with adjacent, normal-appearing fallopian tube epithelium. Hypomethylation of the LINE-1 promoter was found in all STICs exhibiting overexpression. None of the 12 p53 signatures demonstrated significant LINE-1 expression. In ovarian cancer, 84 (75 /a) of 112 ovarian carcinomas overexpressed LINE-1. Our results indicate that LINE-1 retrotransposons often become deregulated during progression of ovarian cancer precursor lesions from the p53 signature to STIC stages and remain highly expressed in carcinoma.


Trefoil factor family 2 protein: a potential immunohistochemical marker for aiding diagnosis of lobular endocervical glandular hyperplasia and gastric-type adenocarcinoma of the uterine cervix.
Virchows Archiv : an international journal of pathology,474(1):79-86 2019(Jan.)
Author:Shiho Asaka; Tomoyuki Nakajima; Masanobu Momose; Tsutomu Miyamoto; Takeshi Uehara; Hiroyoshi Ota
Abstract: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.


Gastric gland mucin-specific O-glycan expression decreases as tumor cells progress from lobular endocervical gland hyperplasia to cervical mucinous carcinoma, gastric type
VIRCHOWS ARCHIV,473(3):305-311 2018(Sep.)
Author:Kazuhiro Yamanoi; Keiko Ishii; Michihiko Tsukamoto; Shiho Asaka; Jun Nakayama
Abstract:Gastric gland mucin-specific O-glycans are unique in having alpha 1,4-linked N-acetylglucosamine (alpha GlcNAc) attached to MUC6. We previously reported decreased expression of alpha GlcNAc relative to MUC6 in gastric and pancreatic neoplasms, but its significance in cervical glandular lesions remained unclear. Here, we analyzed MUC5AC, MUC6, alpha GlcNAc, and p16 expression in 9 lesions of mucinous carcinoma, gastric type with minimal deviation adenocarcinoma (GAS-MDA), 5 of GAS with nonMDA (GAS-nonMDA), 14 of typical lobular endocervical gland hyperplasia (LEGH), and 5 of atypical LEGH (33 total lesions). All 33 were MUC5AC-positive. Moreover, all 14 typical LEGH, 5 atypical LEGH, 8 of 9 GAS-MDA, and 3 of 5 GAS-nonMDA were MUC6-positive. All 14 typical LEGH, 2 of 5 atypical LEGH, 3 of 9 GAS-MDA, and 1 of 5 GAS-nonMDA were alpha GlcNAc-positive. The proportion of alpha GlcNAc-positive atypical LEGH or GAS-MDA or GAS-nonMDA lesions was significantly smaller than that seen in typical LEGH lesions (P < 0.001 and P < 0.01, respectively). Of 33 lesions, 32 were p16-negative. Furthermore, when we evaluated MUC6 and alpha GlcNAc immunoreactivity semi-quantitatively in all 33 lesions, in typical LEGH and GAS-MDA, the immunohistochemical score for alpha GlcNAc was significantly lower than that for MUC6 (P < 0.01). We did not observe significantly decreased alpha GlcNAc expression relative to MUC6 in typical LEGH lesions. These studies suggest that alpha GlcNAc expression decreases as typical LEGH progresses to GAS. Given the difficulty in distinguishing MDA and atypical LEGH from typical LEGH in H.E. staining, we propose that immunohistochemical analysis of alpha GlcNAc and MUC6 could be useful.


Loss of ARID1A expression in endometrial samplings is associated with the risk of endometrial carcinoma
GYNECOLOGIC ONCOLOGY,150(3):426-431 2018(Sep.)
Author:Ting-Tai Yen; Tsutomu Miyamoto; Shiho Asaka; M. Herman Chui; Yeh Wang; Shiou-Fu Lin; Rebecca L. Stone; Amanda N. Fader; Ryoichi Asaka; Hiroyasu Kashima; Tanri Shiozawa; Tian-Li Wang; Ie-Ming Shih; Edward J. Tanner
Abstract:Objectives. 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 ARIDIA loss during tumor progression from CAH to EEC and to assess its role as a predictive cancer biomarker.Methods. 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.Results. 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.Conclusions. 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. (C) 2018 Elsevier Inc. All rights reserved.


Rapid point-of-care testing for epidermal growth factor receptor gene mutations in patients with lung cancer using cell-free DNA from cytology specimen supernatants.
International journal of oncology,52(6):2110-2118 2018(Jun.)
Author:Shiho Asaka; Akihiko Yoshizawa; Kazusa Saito; Yukihiro Kobayashi; Hiroshi Yamamoto; Tatsuya Negishi; Rie Nakata; Kazuyuki Matsuda; Akemi Yamaguchi; Takayuki Honda
Abstract:Epidermal growth factor receptor (EGFR) mutations are associated with responses to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small-cell lung cancer (NSCLC). Our previous study revealed a rapid point-of-care system for detecting EGFR mutations. This system analyzes cell pellets from cytology specimens using droplet-polymerase chain reaction (d-PCR), and has a reaction time of 10 min. The present study aimed to validate the performance of the EGFR d-PCR assay using cell-free DNA (cfDNA) from supernatants obtained from cytology specimens. Assay results from cfDNA supernatant analyses were compared with those from cell pellets for 90 patients who were clinically diagnosed with, or suspected of having, lung cancer (80 bronchial lavage fluid samples, nine pleural effusion samples and one spinal fluid sample). EGFR mutations were identified in 12 and 15 cases using cfDNA supernatants and cell pellets, respectively. The concordance rates between cfDNA-supernatant and cell‑pellet assay results were 96.7% [kappa coefficient (K)=0.87], 98.9% (K=0.94), 98.9% (K=0.79) and 98.9% (K=0.79) for total EGFR mutations, L858R, E746_A750del and T790M, respectively. All 15 patients with EGFR mutation-positive results, as determined by EGFR d-PCR assay using cfDNA supernatants or cell pellets, also displayed positive results by conventional EGFR assays using tumor tissue or cytology specimens. Notably, EGFR mutations were even detected in five cfDNA supernatants for which the cytological diagnoses of the corresponding cell pellets were 'suspicious for malignancy', 'atypical' or 'negative for malignancy.' In conclusion, this rapid point-of-care system may be considered a promising novel screening method that may enable patients with NSCLC to receive EGFR-TKI therapy more rapidly, whilst also reserving cell pellets for additional morphological and molecular analyses.


Uterine cervical adenocarcinoma associated with lobular endocervical glandular hyperplasia: Radiologic-pathologic correlation
JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH,44(2):312-322 2018(Feb.)
Author:Ayumi Ohya; Shiho Asaka; Yasunari Fujinaga; Masumi Kadoya
Abstract:AimWe aimed to identify the radiologic features of uterine cervical adenocarcinoma associated with lobular endocervical glandular hyperplasia (LEGH).MethodsWe retrospectively analyzed magnetic resonance (MR) images and pathologic findings of eight patients who underwent preoperative MR imaging followed by surgical resection and who were pathologically diagnosed with adenocarcinoma (except for adenocarcinoma in situ) associated with LEGH. We assessed the following MR findings: multicystic component (MC), solid component (SC), signal intensity of SC on diffusion-weighted imaging (DWI) and the apparent diffusion coefficient (ADC) map, and radiological stage (r-stage) based on the FIGO classification. A pathologist reevaluated the pathological stage (p-stage) according to the FIGO classification. We correlated the MR findings with the pathologic features.ResultsEight patients were classified into the following three types based on the MR findings: type A, MC and SC; type B, only SC; and type C, only MC. In the five patients with type A, diffusion restriction (DR) was seen on DWI and the ADC map. In 80% of type A cases, the r-stage matched the p-stage. In the one patient with type B, DR was not seen on DWI or the ADC map, and the r-stage matched the p-stage. In the remaining type C cases, DR was not seen on DWI or the ADC map, and the r-stage was underestimated compared with the p-stage.ConclusionOn MR imaging, the most common type of adenocarcinoma with LEGH is type A; type C is difficult to diagnose as carcinoma.


Utility of bronchial lavage fluids for epithelial growth factor receptor mutation assay in lung cancer patients: Comparison between cell pellets, cell blocks and matching tissue specimens.
Oncology letters,15(2):1469-1474 2018(Feb.)
Author:Shiho Asaka; Akihiko Yoshizawa; Rie Nakata; Tatsuya Negishi; Hiroshi Yamamoto; Takayuki Shiina; Shohei Shigeto; Kazuyuki Matsuda; Yukihiro Kobayashi; Takayuki Honda
Abstract:The detection of epidermal growth factor receptor (EGFR) mutations is necessary for the selection of suitable patients with non-small cell lung cancer (NSCLC) for treatment with EGFR tyrosine kinase inhibitors. Cytology specimens are known to be suitable for EGFR mutation detection, although tissue specimens should be prioritized; however, there are limited studies that examine the utility of bronchial lavage fluid (BLF) in mutation detection. The purpose of the present study was to investigate the utility of BLF specimens for the detection of EGFR mutations using a conventional quantitative EGFR polymerase chain reaction (PCR) assay. Initially, quantification cycle (Cq) values of cell pellets, cell-free supernatants and cell blocks obtained from three series of 1% EGFR mutation-positive lung cancer cell line samples were compared for mutation detection. In addition, PCR analysis of BLF specimens obtained from 77 consecutive NSCLC patients, detecting EGFR mutations was validated, and these results were compared with those for the corresponding formalin-fixed paraffin-embedded (FFPE) tissue specimens obtained by surgical resection or biopsy of 49 of these patients. The Cq values for mutation detection were significantly lower in the cell pellet group (average, 29.58) compared with the other groups, followed by those in cell-free supernatants (average, 34.15) and in cell blocks (average, 37.12) for all three series (P<0.05). Mutational status was successfully analyzed in 77 BLF specimens, and the results obtained were concordant with those of the 49 matching FFPE tissue specimens. Notably, EGFR mutations were even detected in 10 cytological specimens that contained insufficient tumor cells. EGFR mutation testing with BLF specimens is therefore a useful and reliable method, particularly when sufficient cancer cells are not obtained.


A case of pure-type ovarian squamous cell carcinoma producing granulocyte-colony stimulating factor
GYNECOLOGIC ONCOLOGY REPORTS,22:89-91 2017(Nov.)
Author:Hisanori Kobara; Hiroyasu Kashima; Tsutomu Miyamoto; Yasushi Yamada; Shiho Asaka; Tanri Shiozawa
Abstract:•Pure-type ovarian squamous cell carcinoma (POSCC) is extremely rare.•This is the first report of G-CSF-producing POSCC.•This case was successfully treated with primary surgery and standard chemotherapy.•A tumor with uninfected neutrophilia may be a G-CSF-producing tumor.•18F-FDG-PET/CT and MRI may be useful for diagnosing G-CSF-producing tumors.


Clinical significance of preoperative serum albumin level for prognosis in surgically resected patients with non-small cell lung cancer Comparative study of normal lung, emphysema, and pulmonary fibrosis
LUNG CANCER,111:88-95 2017(Sep.)
Author:Kentaro Miura; Kazutoshi Hamanaka; Tomonobu Koizumi; Yoshiaki Kitaguchi; Yukihiro Terada; Daisuke Nakamura; Hirotaka Kumeda; Hiroyuki Agatsuma; Akira Hyogotani; Satoshi Kawakami; Akihiko Yoshizawa; Shiho Asaka; Ken-ichi Ito
Abstract:Objectives: This study was performed to clarify whether preoperative serum albumin level is related to the prognosis of non-small cell lung cancer patients undergoing surgical resection, and the relationships between serum albumin level and clinicopathological characteristics of lung cancer patients with emphysema or pulmonary fibrosis.Materials and methods: We retrospectively evaluated 556 patients that underwent surgical resection for non small cell lung cancer. The correlation between preoperative serum albumin level and survival was evaluated. Patients were divided into three groups according to the findings on chest high-resolution computed tomography (normal lung, emphysema, and pulmonary fibrosis), and the relationships between serum albumin level and clinicopathological characteristics, including prognosis, were evaluated.Results: The cut-off value of serum albumin level was set at 4.2 g/dL. Patients with low albumin levels (albumin < 4.2) had significantly poorer prognosis than those with high albumin levels (albumin >= 4.2) with regard to both overall survival and recurrence-free survival. Serum albumin levels in the emphysema group (n = 48) and pulmonary fibrosis group (it = 45) were significantly lower than that in the normal lung group (n = 463) (p = 0.009 and < 0.001, respectively). Low serum albumin level was a risk factor in normal lung and pulmonary fibrosis groups, but not in the emphysema group.Conclusion: Preoperative serum albumin level was an important prognostic factor for overall survival and recurrence-free survival in patients with resected non-small cell lung cancer. Divided into normal lung, emphysema, and pulmonary fibrosis groups, serum albumin level showed no influence only in patients in the emphysema group.


Expression of Mucin 1 in Mycosis Fungoides Tumour Cells: A Case Report
ACTA DERMATO-VENEREOLOGICA,97(6):747-748 2017(Jun.)
Author:Takushi Shirai; Yukiko Kiniwa; Shiho Asaka; Yasuyo Shimojo; Fuminao Kamijo; Ryuhei Okuyama


Human intestinal spirochetosis in Japanese patients aged less than 20 years: Histological analysis of colorectal biopsy and surgical specimens obtained from 479 patients.
Pathology international,67(6):302-305 2017(Jun.)
Author:Shojiro Ichimata; Akihiko Yoshizawa; Mai Kusakari; Yoshiko Nakayama; Shiho Asaka; Tatsuya Negishi; Eriko Kasuga; Takehisa Matsumoto; Takayuki Honda
Abstract:Human intestinal spirochetosis (HIS) is a condition in which spirochetes attach to and colonize the colorectal epithelium. To our knowledge, no comprehensive studies of HIS in young patient have been published in a developed country. This study aimed to determine the incidence and clinicopathological manifestations of HIS in Japanese patients aged less than 20 years. We retrospectively reviewed 3605 biopsy and 92 surgical specimens obtained from 479 patients admitted to Shinshu University Hospital between 1997 and 2014. All slides were reviewed independently by two pathologists to confirm the histological presence of spirochetes. Among 387 patients who underwent biopsy, the most common pathologic diagnosis was ulcerative colitis (12.6%, n = 49). Additionally, about half of the biopsy specimens showed non-specific, mildly inflamed mucosa (50.6%, n = 196); only one of these cases was HIS. On the other hand, among the surgical specimens, we found no cases of HIS. We concluded that the incidence of HIS in Japanese young patients was 0.2% (1/479 cases). The incidence of HIS in Japanese young patients was very low, and one HIS case was associated with colitis with abdominal pain.


Two patients with TAFRO syndrome exhibiting strikingly similar anterior mediastinal lesions with predominantly fat attenuation on chest computed tomography
RESPIRATORY INVESTIGATION,55(2):176-180 2017(Mar.)
Author:Yoko Ozawa; Hiroshi Yamamoto; Masanori Yasuo; Hidekazu Takahashi; Kazunari Tateishi; Atsuhito Ushiki; Satoshi Kawakami; Yasunari Fujinaga; Shiho Asaka; Kenji Sano; Hiroshi Takayama; Hiroshi Imamura; Masayuki Hanaoka
Abstract:We herein report on two middle-aged men with TAFRO Lthrombocytopenia, anasarca, fever, reticulin fibrosis or renal failure, and organomegaly) syndrome, a unique clinicopathological variant of multicentric Castleman's disease recently proposed in Japan. Strikingly similar anterior mediastinal fat swellings with soft tissue density were observed in the patients on chest computed tomography. In TAFRO syndrome, bilateral pleural effusion and slight lymph node swelling are common in the thoracic region; however, anterior mediastinal lesions have not been previously observed. Although the mechanisms of anterior mediastinal lesions have not been defined, these lesions seem to have a close relationship with TAFRO syndrome. (C) 2016 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.


子宮頸部・内膜スメアtwo-color patternの解析
日本臨床細胞学会雑誌,56(2):85-91 2017(Mar.)
Author:石井 恵子; 浅香 志穂; 堀川 美栄子; 小林 幸弘; 下條 康代; 百瀬 正信; 仲田 梨恵; 中嶋 智之
Abstract:目的:子宮頸部および内膜スメアにおいて粘液の色調異常を認めた症例の臨床病理学的検討を行った。方法:子宮頸部・内膜スメアで、two-color pattern(TCP)あるいは黄色調粘液を認めた54例につき臨床所見および組織像を含めた追跡調査を行った。成績:54例中4例は頸部・内膜の両方、うち1例は初回、内膜のみに黄色調粘液細胞が認められた。多くは頸部多発嚢胞や水様帯下等の自・他覚症状があったが、無症状でスクリーニングされた症例が12例あった。54例中49例でHIK陽性であった。胃型粘液確認後、摘出材料にて分葉状頸管腺過形成(LEGH)と診断された症例は11例、異型LEGH4例、悪性腺腫(MDA)3例、MDAを伴った胃型腺癌1例であった。胃型腺癌やMDAでは、色調異常に加え腺細胞異型もみられた。結論:子宮頸部・内膜スメアにおける粘液のTCPは、胃型粘液の存在を鋭敏に反映しており、注意深く色調を観察することによってLEGHやMDAなどの胃型腺系病変の早期診断に貢献できる。TCPがみられず黄色調粘液のみが観察される症例ももちろん胃型腺系病変の可能性があるため、腺細胞異常としスクリーニングすべきである。(著者抄録)


A novel, rapid point-of-care test for lung cancer patients to detect epidermal growth factor receptor gene mutations by using real-time droplet-PCR and fresh liquid cytology specimens.
Oncology reports,37(2):1020-1026 2017(Feb.)
Author:Shiho Asaka; Akihiko Yoshizawa; Kazuyuki Matsuda; Akemi Yamaguchi; Hiroshi Yamamoto; Takayuki Shiina; Rie Nakata; Kaoru Ogawa; Meng Zhang; Takayuki Honda
Abstract:Epidermal growth factor receptor gene (EGFR) mutations are associated with response to tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). We developed a novel, rapid EGFR mutation assay using a real-time droplet-polymerase chain reaction machine (EGFR d-PCR assay). The purpose of this study was to validate the performance of the EGFR d-PCR assay using fresh liquid cytology specimens. We analyzed three major EGFR mutations (L858R in exon 21, E746_A750del in exon 19 and T790M in exon 20) in 80 fresh liquid cytology specimens of adenocarcinoma (ADC) or NSCLC-not otherwise specified (NOS) via the EGFR d-PCR assay and conventional real-time PCR assay using the therascreen® EGFR RGQ PCR kit (Therascreen assay). In addition, we performed sensitivity assays using cell lines with EGFR mutations. The EGFR d-PCR assay detected 16 L858Rs, 8 E746_A750dels and 1 T790M mutation and the Therascreen assay detected 16 L858Rs, 11 deletions in exon 19 and 1 T790M mutation. The results were concordant between the two assays. The reaction time of the EGFR d-PCR assay was 8 min and 10 sec, but that of the Therascreen assay was 1 h and 45 min. Sensitivity, as assessed by the detection limit of the EGFR d-PCR assay was 0.5, 0.05 and 0.5% for L858R, E746_A750del and T790M, respectively. The EGFR d-PCR assay markedly reduced the detection time of major EGFR mutations with high sensitivity compared with the conventional Therascreen assay and is expected to expedite EGFR-TKI therapy for lung cancer patients, especially those in advanced stages.


Trefoil Factor Family 2 Protein: A Promising Immunohistochemical Marker for Diagnosing Lobular Endocervical Glandular Hyperplasia and Gastric-Type Adenocarcinoma of Uterine Cervix
Modern Pathology,30 2017
Author:Asaka, Shiho; Ota, Hiroyoshi


Angioimmunoblastic T-cell Lymphoma Associated with IgA Nephropathy
Internal Medicine,56(1):85-89 2017
Author:Harada, Yukinori; Sakai, Kei; Asaka, Shiho; Nakayama, Kazutaka
Abstract:

Few cases of IgA nephropathy with angioimmunoblastic T-cell lymphoma (AITL) have been reported. We herein present the case of a 79-year-old Japanese man with AITL and IgA nephropathy. The patient presented with generalized edema, fatigue, and fever. Laboratory investigations revealed polyclonal gammopathy with a high level of IgA, microscopic hematuria, proteinuria, and some other immunological abnormalities. Computed tomography revealed generalized lymphadenopathy. A diagnosis of AITL and IgA nephropathy was made based on inguinal lymph node and renal biopsies. Following chemotherapy for AITL, the patient's edema, microscopic hematuria, and proteinuria were alleviated. These findings indicate that IgA nephropathy may occur in AITL patients.




The Preoperative Composite Physiologic Index May Predict Mortality in Lung Cancer Patients with Combined Pulmonary Fibrosis and Emphysema
RESPIRATION,94(2):198-206 2017
Author:Fumika Ueno; Yoshiaki Kitaguchi; Takayuki Shiina; Shiho Asaka; Kentaro Miura; Masanori Yasuo; Yosuke Wada; Akihiko Yoshizawa; Masayuki Hanaoka
Abstract:Background: It remains unclear whether the preoperative pulmonary function parameters and prognostic indices that are indicative of nutritional and immunological status are associated with prognosis in lung cancer patients with combined pulmonary fibrosis and emphysema (CPFE) who have undergone surgery. Objective: The aim of this study is to identify prognostic determinants in these patients. Methods: The medical records of all patients with lung cancer associated with CPFE who had undergone surgery at Shinshu University Hospital were retrospectively reviewed to obtain clinical data, including the results of preoperative pulmonary function tests and laboratory examinations, chest highresolution computed tomography (HRCT), and survival. Results: Univariate Cox proportional hazards regression analysis showed that a high pathological stage of the lung cancer, a higher preoperative serum carcinoembryonic antigen level, and a higher preoperative composite physiologic index (CPI) were associated with a high risk of death. Multivariate analysis showed that a high pathological stage of the lung cancer (HR: 1.579; p = 0.0305) and a higher preoperative CPI (HR: 1.034; p = 0.0174) were independently associated with a high risk of death. In contrast, the severity of fibrosis or emphysema on chest HRCT, the individual pulmonary function parameters, the prognostic nutritional index, the neutrophil- to-lymphocyte ratio, and the platelet-to-lymphocyte ratio were not associated with prognosis. In the Kaplan-Meier analysis, the log-rank test showed significant differences in survival between the high-CPI and the low-CPI group (p = 0.0234). Conclusion: The preoperative CPI may predict mortality and provide more powerful prognostic information than individual pulmonary function parameters in lung cancer patients with CPFE who have undergone surgery. (C) 2017 S. Karger AG, Basel


The histological characteristics and clinical outcomes of lung cancer in patients with combined pulmonary fibrosis and emphysema
CANCER MEDICINE,5(10):2721-2730 2016(Oct.)
Author:Meng Zhang; Akihiko Yoshizawa; Satoshi Kawakami; Shiho Asaka; Hiroshi Yamamoto; Masanori Yasuo; Hiroyuki Agatsuma; Masayuki Toishi; Takayuki Shiina; Kazuo Yoshida; Takayuki Honda; Ken-ichi Ito
Abstract:Combined pulmonary fibrosis and emphysema (CPFE) is an important risk factor for lung cancer (LC), because most patients with CPFE are smokers. However, the histological characteristics of LC in patients with CPFE (LC-CPFE) remain unclear. We conducted this study to explore the clinicopathological characteristics of LC-CPFE. We retrospectively reviewed data from 985 patients who underwent resection for primary LC, and compared the clinicopathological characteristics of patients with LC-CPFE and non-CPFE LC. We identified 72 cases of LC-CPFE, which were significantly associated with squamous cell carcinoma (SqCC) histology (n = 46, P < 0.001) and higher tumor grade (n = 44, P < 0.001), compared to non-CPFE LC. Most LC-CPFE lesions were contiguous with fibrotic areas around the tumor (n = 59, 81.9%), and this association was independent of tumor location. Furthermore, dysplastic epithelium was identified in the fibrotic area for 31 (52.5%) LC-CPFE lesions. Moreover, compared to patients with pulmonary fibrosis alone in the non-CPFE group (n = 31), patients with CPFE were predominantly male (P = 0.008) and smokers (P < 0.001), with LC-CPFE predominantly exhibiting SqCC histology (P = 0.010) and being contiguous with the tumor-associated fibrotic areas (P < 0.001). Multivariate analysis revealed that CPFE was an independent predictor of overall survival (hazard ratio: 1.734; 95% confidence interval: 1.060-2.791; P = 0.028). Our results indicate that LC-CPFE has a distinct histological phenotype, can arise from the dysplastic epithelium in the fibrotic area around the tumor, and is associated with poor survival outcomes.


A case of pulmonary Mycobacterium avium infection in an immunocompetent patient who showed a huge consolidation with a high FDG uptake on PET/CT.
Respiratory medicine case reports,19:49-52 2016
Author:Akane Kato; Hiroshi Yamamoto; Mariko Ikeda; Kazunari Tateishi; Atsuhito Ushiki; Masanori Yasuo; Satoshi Kawakami; Shiho Asaka; Kazuhiro Oguchi; Masayuki Hanaoka
Abstract:We encountered a middle-aged afebrile immunocompetent woman with a slight cough. Positron emission tomography (PET)/computed tomography (CT) revealed a broad left upper-lobe consolidation without cavity lesions, small nodules, or bronchiectasis showing a positive fluorodeoxyglucose (FDG) uptake with a maximum standardized uptake value (SUVmax) of 26.9. Percutaneous needle lung biopsy specimens showed caseous granulomas without atypical cells and Mycobacterium avium was cultured from left pleural effusion, which developed after the biopsy. The consolidation significantly decreased following combination chemotherapy for approximately 2 years. Clinicians should remember that pulmonary M. avium infection could result in a large consolidation without other typical radiological findings.


Clinicopathological Characteristics of Lung Cancer with Combined Pulmonary Fibrosis and Emphysema
JOURNAL OF THORACIC ONCOLOGY,10(9):S456-S457 2015(Sep.)
Author:Akihiko Yoshizawa; Meng Zhang; Shiho Asaka; Takayuki Shiina; Kazuo Yoshida


A Case of Pulmonary Squamous Cell Carcinoma Revealed Ground Glass Opacity on Computed Tomography
JOURNAL OF THORACIC ONCOLOGY,10(8):1229-1230 2015(Aug.)
Author:Takao Sakaizawa; Akihiko Yoshizawa; Hideki Nishimura; Takaaki Arimura; Nobutaka Kobayashi; Keisuke Ozawa; Shiho Asaka; Kazuo Yoshida; Kazuya Hirai; Noriko Hosaka


A Case of Vulval Extramammary Paget Disease With Dermal Invasion Showing Mucinous Carcinoma.
International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists,34(4):396-400 2015(Jul.)
Author:Shiho Asaka; Akihiko Yoshizawa; Kenji Sano; Hisashi Uhara; Takayuki Honda; Hiroyoshi Ota
Abstract:We report a case of vulval extramammary Paget disease (EMPD) with dermal invasion showing mucinous carcinoma (MC). An 80-year-old woman presented with vulvar itching and pain. A physical examination showed a pigmented vulvar, perianal erythematous plague, and a subcutaneous nodule in the left major labia. No internal malignancy, such as colorectal or genitourinary carcinoma, was identified in any of the clinical examinations. A histological examination of the resected specimen revealed Pagetoid tumor cells that had spread widely through the epidermis and invaded the dermis forming a solid nest with mucous lake-like MC. Immunohistochemical examination revealed that the tumor cells in the epidermis and dermis were positive for CK7, CEA, GCDFP-15, MUC5AC, and MUC2, but negative for CK20, MUC6, and CDX2. Only the invasive component showed overexpression of p53. A diagnosis of primary EMPD with dermal invasion showing MC of the vulva was made. This is an extremely rare diagnosis, and we suggest that immunohistochemical evaluations in addition to systemic work-ups are helpful in distinguishing between these cases and those involving vulvar or perianal skin invasion of underlying colorectal or genitourinary carcinomas, which are referred to as secondary EMPD.


[UNDIFFERENTIATED CARCINOMA OF THE URETER WITH FETAL CLINICAL COURSE: A CASE REPORT].
Nihon Hinyokika Gakkai zasshi. The japanese journal of urology,106(2):103-8 2015(Apr.)
Author:Hiroaki Hara; Tomonori Minagawa; Takahiro Yamagishi; Midori Ichino; Teruyuki Ogawa; Yoshiki Kurizaki; Haruaki Kato; Osamu Ishizuka; Masayuki Furuhata; Shiho Asaka; Osamu Nishizawa
Abstract:Undifferentiated carcinoma of ureter is rare neoplastic lesion, and the natural history of undifferentiated carcinoma of ureter has not been known well yet. We hereby presented an autopsy case of undifferentiated carcinoma of the ureter with rapid progression from the initial stage. A 62-year-old male visited the local urologist complaining of asymptomatic gross hematuria. Cystoscopy revealed the outflow of hematuria from the right ureteral orifice. Abdominal CT showed the right hydronephrosis with atrophic change of the renal parenchyma and the stenosis of upper ureter. He was referred to our hospital on suspicion of a right ureteral tumor. Magnetic resonance imaging and retrograde ureterography did not reveal a tumor in the right ureter. He complained of low back pain 4 months after the initial hematuria, and CT revealed the diffuse enlargement of the right kidney, swelling of the abdominal lymph nodes, and lung nodules. Renal biopsy was done, and only undifferentiated cells were revealed histopathologically without any specific findings to diagnose the primary organ. The tumor increased progressively, and he died about 6 months after the initial gross hematuria. Autopsy was performed, and urothelial carcinoma was found in the right ureter as the primary lesion. The ureteral tumor infiltrated to the right kidney, right adrenal gland, liver, duodenum, and pancreas with undifferentiation. Undifferentiated tumor cells were also found in distant metastatic lesion including the abdominal lymph nodes, left adrenal gland, liver, lung, pleura, and peritoneum.


A case of MUC5AC-positive intraductal neoplasm of the pancreas classified as an intraductal tubulopapillary neoplasm?
PATHOLOGY RESEARCH AND PRACTICE,211(12):1034-1039 2015
Author:Takashi Muraki; Takeshi Uehara; Kenji Sano; Hiroyoshi Oota; Akihiko Yoshizawa; Shiho Asaka; Ayako Tateishi; Toshiaki Otsuki; Kunihiko Shingu; Hisanori Matoba; Shota Kobayashi; Shojiro Ichimata; Takayuki Watanabe; Tetsuya Itou; Eiji Tanaka
Abstract:This report describes a unique case of intraductal tubulopapillary neoplasm (ITPN) of the pancreas in order to clarify its oncogenesis and more precisely classify pancreatic intraductal neoplasms. A 74-year-old man visited our institution for follow-up of acute pancreatitis. Imaging examinations revealed a hypovascular intraductal mass in the head of the pancreas with progressive dilation of the pancreatic duct, atrophy of the pancreatic parenchyma, and a non-mucinous appearance. A pancreatoduodenectomy was performed to identify this pancreatic intraductal neoplasm. Macroscopically, the tumor was a solid nodular mass with no visibly secreted mucin obstructing the dilated ducts. Histologically, it had a homogeneous appearance with nodules of back-to-back tubular glands and occasional papillary elements, and there were no apparent transitions to areas with less marked cytoarchitectural atypia. Although the intraductal neoplastic growth corresponded to an ITPN, immunohistochemical staining revealed partial positivity for MUC5AC, for which ITPNs are characteristically negative. Somatic mutations in KRAS, GNAS, BRAF, and PIK3CA were not detected. A loss of MUC5AC expression and mutations in KRAS and GNAS are key elements in the diagnosis of ITPN. Thus, it was difficult to distinguish the present case as a pancreatobiliary-type (PB-type) intraductal papillary mucinous neoplasm (IPMN) or a phenotypic variant of ITPN. As it is possible that some cases of PB-type IPMN and ITPN overlap, the precise classification of these rare lesions may require re-evaluation. (C) 2015 Elsevier GmbH. All rights reserved.


肉眼的血尿を認めてから半年の経過で死亡した未分化型尿路上皮癌の一例
泌尿器外科,27(臨増):779-779 2014(May)
Author:原 寛彰; 皆川 倫範; 山岸 貴裕; 市野 みどり; 小川 輝之; 栗崎 功己; 加藤 晴朗; 石塚 修; 西沢 理; 古畑 誠之; 浅香 志穂; 吉澤 明彦


Lipoleiomyosarcoma of the Uterine Corps: a report of 2 cases with fluorescence in situ hybridisation analysis
Virchows Archiv,465 2014
Author:Asaka, S.; Yoshizawa, A.; Sano, K.; Shingu, K.; Matoba, H.; Han-Seung, Y.; Honda, T.


An Intrathoracic Low-Grade Fibromyxoid Sarcoma Arising from the Chest Wall with Massive Pleural Effusion
ANNALS OF THORACIC AND CARDIOVASCULAR SURGERY,20:509-512 2014
Author:Yoshiaki Tominaga; Takashi Eguchi; Takayuki Shiina; Kazutoshi Hamanaka; Jun Amano; Shiho Asaka; Kazuo Yoshida
Abstract:We herein report a case of an intrathoracic low-grade fibromyxoid sarcoma arising from the chest wall and associated with massive pleural effusion. A 70-year-old man presented with a persistent cough. A chest computed tomography scan revealed a large mass in the right pleural cavity with massive pleural effusion. No malignant cells were recognized in the pleural effusion by thoracentesis. A malignant soft tissue tumor was suspected, and surgery was performed. The tumor arose from the posterior chest wall and was resected with the connected chest wall. The definitive diagnosis was a low grade fibromyxoid sarcoma. Because the posterior margin of the chest wall was microscopically tumor positive, postoperative irradiation was performed. The patient has now been followed up for 30 months with no evidence of recurrence.


Structural Valve Deterioration of Porcine Bioprosthesis Soon after Mitral Valve Repair and Replacement
ANNALS OF THORACIC AND CARDIOVASCULAR SURGERY,20:717-719 2014
Author:Tamaki Takano; Tatsuichiro Seto; Shiho Asaka; Takamitsu Terasaki; Noburou Ohashi; Daisuke Fukui; Jun Amano
Abstract:An 81-year-old woman, who had undergone mitral valve replacement (MVR) with a porcine bioprosthesis after mitral valve repair, presented with hemolysis 4 years and 6 months after MVR. Transthoracic echocardiography (TTE) revealed trivial mitral regurgitation, which was diagnosed based on the observed perivalvular leakage. Hemolysis gradually increased, and she developed dyspnea and edema 2 years after the appearance of mitral regurgitation. We performed a reoperation. Intraoperative transesophageal echocardiography (TEE) after intubation showed no perivalvular leakage of the mitral prosthesis, but transvalvular leakage through a leaflet perforation was present. The leaflets of the bioprosthesis had slit-shaped perforations at their hinges. There was no sign of infection on the leaflet or annulus. We implanted a new bioprosthesis after removal of the deteriorated valve. The postoperative course was uneventful. Microscopic examination verified collagen degeneration, histiocyte infiltration, and hyalinization. It is important to perform TEE to rule out structural valve deterioration (SVD) even when regurgitation occurs soon after valve replacement.


Tumor size and computed tomography attenuation of pulmonary pure ground-glass nodules are useful for predicting pathological invasiveness.
PloS one,9(5):e97867 2014
Author:Takashi Eguchi; Akihiko Yoshizawa; Satoshi Kawakami; Hirotaka Kumeda; Tetsuya Umesaki; Hiroyuki Agatsuma; Takao Sakaizawa; Yoshiaki Tominaga; Masayuki Toishi; Masahiro Hashizume; Takayuki Shiina; Kazuo Yoshida; Shiho Asaka; Mina Matsushita; Tomonobu Koizumi
Abstract:OBJECTIVES: Pulmonary ground-glass nodules (GGNs) are occasionally diagnosed as invasive adenocarcinomas. This study aimed to evaluate the clinicopathological features of patients with pulmonary GGNs to identify factors predictive of pathological invasion. METHODS: We retrospectively evaluated 101 pulmonary GGNs resected between July 2006 and November 2013 and pathologically classified them as adenocarcinoma in situ (AIS; n = 47), minimally invasive adenocarcinoma (MIA; n = 30), or invasive adenocarcinoma (I-ADC; n = 24). The age, sex, smoking history, tumor size, and computed tomography (CT) attenuation of the 3 groups were compared. Receiver operating characteristic (ROC) curve analyses were performed to identify factors that could predict the presence of pathologically invasive adenocarcinomas. RESULTS: Tumor size was significantly larger in the MIA and I-ADC groups than in the AIS group. CT attenuation was significantly greater in the I-ADC group than in the AIS and MIA groups. In ROC curve analyses, the sensitivity and specificity of tumor size (cutoff, 11 mm) were 95.8% and 46.8%, respectively, and those for CT attenuation (cutoff, -680 HU) were 95.8% and 35.1%, respectively; the areas under the curve (AUC) were 0.75 and 0.77, respectively. A combination of tumor size and CT attenuation (cutoffs of 11 mm and -680 HU for tumor size and CT attenuation, respectively) yielded in a sensitivity and specificity of 91.7% and 71.4%, respectively, with an AUC of 0.82. CONCLUSIONS: Tumor size and CT attenuation were predictive factors of pathological invasiveness for pulmonary GGNs. Use of a combination of tumor size and CT attenuation facilitated more accurate prediction of invasive adenocarcinoma than the use of these factors independently.


A mediastinal liposarcoma resected using a double approach with a thoracoscope.
The Thoracic and cardiovascular surgeon reports,2(1):46-9 2013(Dec.)
Author:Shiho Asaka; Kazuo Yoshida; Mashiro Hashizume; Ken-Ichi Ito
Abstract:We report a case of a 45-year-old woman who underwent a complete resection of a liposarcoma using thoracoscopic and cervical approaches. General checkup and computed tomography revealed a large mediastinal tumor occupying the thoracic outlet, which had reached the posterior thyroid region, and another small tumor at a subcarina. A cervical method for evaluating a neck lesion and a thoracoscopic (video-assisted thoracic surgery) approach for assessing a mediastinal lesion were performed. This double approach provided excellent visualization and enabled us to perform fine manipulation even within the narrow thoracic outlet region. The patient was disease free at 11 months after surgery.


Xp11.2およびt(6;11)(p21:q12)転座型腎細胞癌との鑑別を要した腎類上皮型血管筋脂肪腫の1例
診断病理,30(1):23-27 2013(Jan.)
Author:浅香 志穂; 福島 万奈; 下条 久志; 太田 浩良; 黒田 直人; 本田 孝行
Abstract:症例は40代女性、左腎に発生した径4cm大の類上皮型血管筋脂肪腫の一例を報告する。本症例では、腫瘍が多形性に富む上皮様細胞のみから構成される点、免疫染色で上皮マーカー陰性、メラノサイトマーカー陽性を示す点からは、Xp11.2およびt(6;12)(p21:q12)転座型腎細胞癌との鑑別が問題になった。しかし、腫瘍が明らかな乳頭状あるいは胞巣状の増殖様式を示さず、免疫染色にて平滑筋細胞への分化が認められたこと、TFE3およびTFEBが陰性であったことが鑑別に有用であった。(著者抄録)


術前に肝細胞癌と診断された肝Reactive lymphoid hyperplasiaの1例
日本消化器外科学会雑誌,45(4):400-409 2012(Apr.)
Author:鈴木 史恭; 横山 隆秀; 秋田 眞吾; 清水 明; 中田 岳成; 小林 聡; 浅香 志穂; 宮川 眞一
Abstract:症例は65歳の女性で,腹部CTで肝S4の腫瘍性病変を指摘され当院へ紹介された.腹部CTでは早期相でenhanceされ,後期相でwashoutされる径10mm大の腫瘍を認めた.腹部MRIではT1強調像でlow intensity,T2強調像でhigh intensityであり,腹部血管造影では辺縁優位の濃染像を認めた.腫瘍マーカーは正常であったが,画像検査からは肝細胞癌が疑われ,腹腔鏡補助下肝S4部分切除術を施行した.肝腫瘍は灰白色の結節であり,病理組織学的検査所見で肝Reactive lymphoid hyperplasiaと診断された.肝Reactive lymphoid hyperplasiaは術前に悪性腫瘍と診断され切除術後に確定診断がなされる症例が多い.そのため辺縁優位にenhanceされる肝臓の小腫瘍の鑑別診断として念頭におく必要があると考えられた.(著者抄録)


MISC
特発性全身性後天性無汗症は汗腺暗細胞の脱顆粒が顕著に生じ、血清のCEAが上昇する(AIGA demonstrates marked degranulation of dark cells in eccrine gland and elevated CEA in serum)
日本病理学会会誌,106(1):476-476 2017(Mar.)
Author:佐野 健司; 上原 剛; 浅香 志穂; 荒木 信之; 朝比奈 正人


Validation of a Rapid Point-of-Care Test to Detect Epidermal Growth Factor Receptor Gene Mutations in Patients with Lung Cancer by Using Cell-Free DNA Supernatants
MODERN PATHOLOGY,30:472A-472A 2017(Feb.)
Author:Shiho Asaka; Akihiko Yoshizawa


IgA腎症と腎病変の合併を認めた血管免疫芽球性T細胞リンパ腫(AITL)の1例
日本腎臓学会誌,57(6):985-985 2015(Aug.)
Author:酒井 慧; 原田 侑典; 浅香 志穂


A Novel High-Speed Droplet-Polymerase Chain Reaction Can Detect Epidermal Growth Factor Receptor Gene Mutation in Non-Small Cell Lung Cancer in Less Than 10 Minutes
MODERN PATHOLOGY,28:471A-472A 2015(Feb.)
Author:Shiho Asaka; Akihiko Yoshizawa; Kazuyuki Matsuda; Akemi Yamaguchi; Yukihiro Kobayashi; Rie Nakata; Zhang Meng; Mitsutoshi Sugano; Takayuki Honda


胸腔内に進展した胸壁原発low grade fibromyxoid sarcomaの1切除例
日本臨床外科学会雑誌,71(増刊):720-720 2010(Oct.)
Author:奥村 征大; 江口 隆; 小林 宣隆; 齋藤 学; 兵庫谷 章; 濱中 一敏; 椎名 隆之; 藏井 誠; 吉田 和夫; 天野 純; 浅香 志穂; 福島 万奈; 上原 剛


術前に肝細胞癌と診断された肝reactive lymphoid hyperplasiaの1例
ENDOSCOPIC FORUM for digestive disease,26(1):87-87 2010(Jun.)
Author:鈴木 史恭; 横山 隆秀; 秋田 眞吾; 内川 裕司; 本山 博章; 清水 明; 中田 岳成; 小林 聡; 三輪 史郎; 黒住 昌弘; 浅香 志穂; 福島 万奈; 宮川 眞一


結核性腹膜炎として発症し、急速な経過で死亡した粟粒結核の1剖検例
日本病理学会会誌,99(1):335-335 2010(Mar.)
Author:浅香 志穂; 福島 万奈; 増本 純也; 遠藤 真紀; 佐野 健司; 金井 信一郎; 中山 淳; 本田 孝行


上皮内扁平上皮癌病巣へのPagetoid spreadを伴った食道内分泌細胞癌の1例
日本病理学会会誌,99(1):258-258 2010(Mar.)
Author:福島 万奈; 浅香 志穂; 遠藤 真紀; 浅野 功治; 小林 実喜子; 上原 剛; 下条 久志; 佐野 健司; 太田 浩良; 本田 孝行