Journal of Pathology and Translational Medicine

Original Articles

Correlation between HER2 gene copy number and immunohistochemistry categories in HER2-negative breast cancer: diagnostic utility for differentiating HER2-null, ultralow, and low tumors: Min Chong Kim, Young Kyung Bae; Received September 1, 2025 Accepted November 7, 2025 Published online February 25, 2026; DOI: https://doi.org/10.4132/jptm.2025.11.07 [Epub ahead of print]

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Abstract PDF: Background
The recent recognition of human epidermal growth factor receptor 2 (HER2)–low and HER2-ultralow breast cancers (BCs) has expanded the therapeutic relevance of HER2 testing in the antibody-drug conjugate era. However, the biological continuum of HER2 expression measured by immunohistochemistry (IHC) and its relationship with the HER2 gene copy number remain unclear. Methods: We retrospectively analyzed 135 HER2-negative invasive BCs and reclassified them as HER2-null (IHC 0), HER2-ultralow (0+), or HER2-low (1+ or 2+ without amplification). HER2 gene copy number was determined using silver-enhanced in situ hybridization. Statistical analyses were performed to compare HER2 copy number among IHC categories and evaluate the discriminatory value of HER2 copy number for distinguishing IHC subgroups. Results: The mean HER2 copy number increased stepwise across IHC categories: 1.95 ± 0.54 (null), 2.03 ± 0.43 (ultralow), 2.25 ± 0.65 (low, 1+), and 3.29 ± 1.05 (low, 2+). Significant differences were observed between the ultralow and low groups (p = .003) and between the null and low groups (p < .001), but not between the null and ultralow groups or between the ultralow and 1+ groups. Conclusions: HER2 gene copy number was positively correlated with protein expression as reflected by IHC categories. Although HER2 gene copy number was statistically higher in HER2-low than in HER2-null tumors, the substantial overlap in copy number ranges likely limits its utility in distinguishing HER2-low from HER2- null BCs.

Prevalence of HER2-ultralow breast cancer in South Korea: a multicenter study by reassessment of HER2-zero cases: Min Chong Kim, Eun Yoon Cho, Hee Jin Lee, Ji Shin Lee, Jee Yeon Kim, Wan Seop Kim, Chungyeul Kim, Sun-Young Jun, Hye Jeong Choi, So Mang Lee, Ahrong Kim, Ji-Young Kim, Jeong Yun Shim, Gyungyub Gong, Young Kyung Bae; Received September 17, 2025 Accepted October 21, 2025 Published online February 23, 2026; DOI: https://doi.org/10.4132/jptm.2025.10.22 [Epub ahead of print]

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Abstract PDF Supplementary Material: Background
This study aimed to determine the prevalence of human epidermal growth factor receptor 2 (HER2)–ultralow breast cancer among cases initially classified as HER2 immunohistochemistry (IHC) 0 and assess interobserver variability in interpreting low-level HER2 expression. Methods: In this multicenter retrospective study, all invasive breast cancer cases diagnosed between January and December 2022 across 10 Korean institutions were retrieved. Institutional pathologists reexamined HER2 IHC slides originally reported as IHC 0 according to the 2018 American Society of Clinical Oncology/College of American Pathologists guidelines and reclassified them as HER2-null (0), HER2-ultralow (0+), or HER2-low (1+). Slides from 10% of HER2-null and HER2-ultralow cases were digitized for central review and independently assessed by two pathologists, with discrepancies resolved by consensus. Results: Among 8,026 cases, 2,836 cases (35.5%) were initially reported as IHC 0. Upon re-review, 1,673 (59.0%), 1,139 (40.2%), and 24 (0.8%) cases were reclassified as HER2-null, HER2-ultralow, and HER2-low, respectively. The prevalence of HER2-ultralow breast cancer varied considerably across institutions (23.7%–78.1%). Central review of 268 digitized cases showed concordance in 193 cases (72.0%). Among the 75 discordant cases, 54 tumors (72.0%) were upgraded from HER2-null to HER2-ultralow, and 18 (24.0%) tumors were upgraded from HER2-ultralow to HER2-low. Furthermore, two tumors (2.7%) were downgraded from HER2-ultralow to HER2-null. Conclusions: Approximately 40% of cases initially categorized as IHC 0 were reclassified as HER2-ultralow. The substantial inter-institutional variability observed in interpreting low-level HER2 expression highlights the need for standardized training and quality assurance to ensure accurate identification of patients eligible for HER2-targeted antibody–drug conjugates.

Review Article

The evolving role of TRPS1 in dermatopathology: insights from the past 4 years: Mokhtar H. Abdelhammed, Woo Cheal Cho; Received September 11, 2025 Accepted November 25, 2025 Published online January 29, 2026; DOI: https://doi.org/10.4132/jptm.2025.11.25 [Epub ahead of print]

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Abstract PDF: Over the past 4 years, trichorhinophalangeal syndrome type 1 (TRPS1) has rapidly gained attention among practicing pathologists, with numerous studies emerging that both support and question its diagnostic utility. Initially regarded as a highly specific marker for tumors of mammary origin, TRPS1 is now recognized to have broader expression patterns, including in a variety of cutaneous neoplasms. This is likely due to embryologic parallels between breast tissue and skin adnexal structures, an overlap that was underappreciated in early investigations. Although TRPS1 lacks absolute specificity—even among cutaneous neoplasms—it can still offer meaningful diagnostic value when interpreted alongside conventional immunohistochemical markers and within the appropriate morphologic context. Noteworthy diagnostic applications include mammary Paget disease, primary extramammary Paget disease, rare adnexal neoplasms such as endocrine mucin-producing sweat gland carcinoma and primary cutaneous NUT adnexal carcinoma, and cutaneous metastases from breast carcinoma. In this review, we present the most comprehensive and up-to-date evaluation of the utility and limitations of TRPS1 immunohistochemistry in dermatopathology. Our aim is to deepen understanding of this emerging marker and provide practical guidance on its optimal integration with established immunohistochemical panels to enhance diagnostic accuracy in routine practice.

Original Articles

Spectrum of thyroiditis types: clinical, cytomorphological, and radiological findings: Anam Singh, Indrajeet Kundu; J Pathol Transl Med. 2025;59(6):421-433. Published online November 6, 2025; DOI: https://doi.org/10.4132/jptm.2025.08.13

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Abstract PDF: Background
Thyroiditis encompasses a range of inflammatory conditions affecting the thyroid gland. Lymphocytic thyroiditis (LT) is a common form of thyroiditis, with acute suppuration of the thyroid, while tuberculous thyroiditis is relatively rare. Fine-needle aspiration cytology (FNAC) remains a safe and cost-effective tool for diagnosing thyroid-related diseases, especially when paired with ultrasound (US) and clinical examination. Methods: This is a cross-sectional study including 21 cases. The cases were reported as thyroiditis on US and FNAC, and the findings were correlated with patient clinical history, symptoms during presentation, and serological profiles. Results: The cases of thyroiditis encompassed the more common forms, LT and subacute granulomatous thyroiditis (SAT), as well as relatively rare forms like tuberculous thyroiditis and thyroid abscess. Cases of follicular neoplasms (FN) arising in the context of LT also are included in this study. The case of tuberculous thyroiditis presented as a bulky thyroid gland that appeared heterogeneous on US with extensive necrosis on FNAC. The cases of thyroid abscess and SAT presented with painful neck swellings, with granulomas in the latter cases. US features of LT showed an array of appearances ranging from pseudonodular to an atrophic thyroid gland. All cases of FN showed a lymphocytic background. Conclusions: Thyroiditis is a commonly encountered condition that needs to be sub-categorized accurately into acute, subacute, and chronic types for appropriate clinical management, as they can sometimes show overlapping features. Though rare, acute suppurative and tuberculous thyroiditis are often encountered and warrant immediate care and treatment.

Low Ki-67 labeling index is a clinically useful predictive factor for recurrence-free survival in patients with papillary thyroid carcinoma: Takashi Masui, Katsunari Yane, Ichiro Ota, Kennichi Kakudo, Tomoko Wakasa, Satoru Koike, Hirotaka Kinugawa, Ryuji Yasumatsu, Tadashi Kitahara; J Pathol Transl Med. 2025;59(2):115-124. Published online February 18, 2025; DOI: https://doi.org/10.4132/jptm.2024.11.08

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Abstract PDF

Background
We report a new risk stratification of invasive stage papillary thyroid carcinomas (PTCs) by combining invasive status, using extrathyroid invasion (Ex) status, and tumor growth speed using the Ki-67 labeling index (LI). Methods: We examined tumor recurrence in 167 patients with PTC who were surgically treated at the Kindai University Nara Hospital between 2010 and 2022. The patients were classified according to the degree of invasion [negative (Ex0) or positive (Ex1, Ex2, and Ex3)] and tumor growth speed expressed with Ki-67 LI, as low (<5%) or high (>5%). This study confirmed previous findings that the disease-free survival (DFS) rate in PTCs significantly differed between patients with a high and low Ki-67 index. Results: When combining Ex status (negative or positive) and Ki-67 proliferation status (low or high), the DFS rate of invasion in the negative, low Ki-67 LI group was only 1.1%, while that of invasion in the positive, high Ki-67 LI was 44.1%. This study reports for the first time that recurrence risks can be stratified accurately when combining carcinoma’s essential two features of extrathyroid invasion status and tumor growth speed. Conclusions: We believe the evidence for low tumor recurrence risk may contribute to use of more conservative treatment options for invasive-stage PTCs and help alleviate patient anxiety about tumor recurrence and death.

Citations

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Research Progress on the Correlation between Three Biomarkers, Ki-67, CAIX and VEGF and Clear Cell Renal Cell Carcinoma
锦容马
Advances in Clinical Medicine.2025; 15(09): 326. CrossRef
Immunophenotypic Panel for Comprehensive Characterization of Aggressive Thyroid Carcinomas
Mihail Ceausu, Mihai Alin Publik, Dana Terzea, Carmen Adina Cristea, Dumitru Ioachim, Dana Manda, Sorina Schipor
Cells.2025; 14(19): 1554. CrossRef
High Ki-67 labeling index correlates with aggressive clinicopathological features in papillary thyroid carcinoma: a retrospective study
Defi Nurlia Erdian, Maria Francisca Ham, Dina Khoirunnisa, Agnes Stephanie Harahap
Thyroid Research.2025;[Epub] CrossRef

Reviews

Post-transplant liver biopsies: a concise and practical approach for beginners: Mohamad Besher Ourfali, David Hirsch, Marianna Scranton, Tony El Jabbour; J Pathol Transl Med. 2025;59(1):1-10. Published online January 15, 2025; DOI: https://doi.org/10.4132/jptm.2024.11.15

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Abstract PDF

Exposure to post-transplant liver biopsies varies among pathology residencies and largely depends on the institution's training program, particularly if the hospital has a liver transplant program. The interpretation of biopsies from transplanted livers presents its own set of challenges, even for those with a solid understanding of non-transplant medical liver biopsies. In this review, we aim to provide a succinct, step-by-step approach to help you interpret liver transplant biopsies. This article may be beneficial for residents interested in liver pathology, gastrointestinal and liver pathology fellows in the early stages of training, clinical gastroenterology and hepatology fellows, hepatologists and general pathologists who are curious about this niche.

Citations

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Histological and Molecular Evaluation of Liver Biopsies: A Practical and Updated Review
Joon Hyuk Choi
International Journal of Molecular Sciences.2025; 26(16): 7729. CrossRef

Cervical intraepithelial neoplasia and cervical cytology in pregnancy: Ji-Young Kim, Jeong Yun Shim; J Pathol Transl Med. 2024;58(6):283-290. Published online November 7, 2024; DOI: https://doi.org/10.4132/jptm.2024.10.17

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Abstract PDF

Cervical cancer screening during pregnancy presents unique challenges for cytologic interpretation. This review focuses on pregnancy-associated cytomorphological changes and their impact on diagnosis of cervical intraepithelial neoplasia (CIN) and cervical cancer. Pregnancy-induced alterations include navicular cells, hyperplastic endocervical cells, immature metaplastic cells, and occasional decidual cells or trophoblasts. These changes can mimic abnormalities such as koilocytosis, adenocarcinoma in situ, and high-grade squamous intraepithelial lesions, potentially leading to misdiagnosis. Careful attention to nuclear features and awareness of pregnancy-related changes are crucial for correct interpretation. The natural history of CIN during pregnancy shows higher regression rates, particularly for CIN 2, with minimal risk of progression. Management of abnormal cytology follows modified risk-based guidelines to avoid invasive procedures, with treatment typically deferred until postpartum. The findings reported in this review emphasize the importance of considering pregnancy status in cytological interpretation, highlight potential problems, and provide guidance on differentiating benign pregnancy-related changes from true abnormalities. Understanding these nuances is essential for accurate diagnosis and proper management of cervical abnormalities in pregnant women.

Citations

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The significance of biological samples from pregnant women in cervical intraepithelial neoplasia
Xue Mi, Maharjan Rashmi, Zangyu Pan, Di Wu, Jinwei Miao
Frontiers in Medicine.2025;[Epub] CrossRef
Oncologic and pregnancy outcomes of cervical high-grade intraepithelial lesions and delivery mode
Olga P. Matylevich, Ilya A. Tarasau, Sviatlana Y. Shelkovich, Aliaksandr F. Martsinkevich
Academia Oncology.2025;[Epub] CrossRef

Original Article

The combination of CDX2 expression status and tumor-infiltrating lymphocyte density as a prognostic factor in adjuvant FOLFOX-treated patients with stage III colorectal cancers: Ji-Ae Lee, Hye Eun Park, Hye-Yeong Jin, Lingyan Jin, Seung Yeon Yoo, Nam-Yun Cho, Jeong Mo Bae, Jung Ho Kim, Gyeong Hoon Kang; J Pathol Transl Med. 2025;59(1):50-59. Published online October 24, 2024; DOI: https://doi.org/10.4132/jptm.2024.09.26

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Abstract PDF Supplementary Material: Background
Colorectal carcinomas (CRCs) with caudal-type homeobox 2 (CDX2) loss are recognized to pursue an aggressive behavior but tend to be accompanied by a high density of tumor-infiltrating lymphocytes (TILs). However, little is known about whether there is an interplay between CDX2 loss and TIL density in the survival of patients with CRC.
Methods
Stage III CRC tissues were assessed for CDX2 loss using immunohistochemistry and analyzed for their densities of CD8 TILs in both intraepithelial (iTILs) and stromal areas using a machine learning-based analytic method.
Results
CDX2 loss was significantly associated with a higher density of CD8 TILs in both intraepithelial and stromal areas. Both CDX2 loss and a high CD8 iTIL density were found to be prognostic parameters and showed hazard ratios of 2.314 (1.050–5.100) and 0.378 (0.175–0.817), respectively, for cancer-specific survival. A subset of CRCs with retained CDX2 expression and a high density of CD8 iTILs showed the best clinical outcome (hazard ratio of 0.138 [0.023–0.826]), whereas a subset with CDX2 loss and a high density of CD8 iTILs exhibited the worst clinical outcome (15.781 [3.939–63.230]).
Conclusions
Altogether, a high density of CD8 iTILs did not make a difference in the survival of patients with CRC with CDX2 loss. The combination of CDX2 expression and intraepithelial CD8 TIL density was an independent prognostic marker in adjuvant chemotherapy-treated patients with stage III CRC.

Case Study

Malignant potential of neuroendocrine microtumor of the pancreas harboring high-grade transformation: lesson learned from a patient with von Hippel-Lindau syndrome: Jongwon Lee, Kyung Jin Lee, Dae Wook Hwang, Seung-Mo Hong; J Pathol Transl Med. 2024;58(2):91-97. Published online March 13, 2024; DOI: https://doi.org/10.4132/jptm.2024.02.13

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Pancreatic neuroendocrine microtumor (PNEMT) is a neuroendocrine tumor (NET) < 0.5 cm in diameter, and it is considered benign. We report a PNEMT with high-grade transformation (HGT). A man in his 60s with von Hippel-Lindau syndrome underwent surgical resection of a NET. A second sub-centimeter nodule with a nodule-in-nodule pattern was discovered. The 0.4 cm outer nodule contained clear columnar cells with round nuclei and indistinct nucleoli, while the 0.1 cm inner nodule had eosinophilic cells with an increased nuclear to cytoplasmic ratio, vesicular nuclei, and prominent nucleoli. Tumor cells in the outer and inner nodules were synaptophysin and chromogranin positive. Only the inner nodule was p53 positive, while the outer nodule was exclusively positive for carbonic anhydrase 9 and vimentin. The Ki-67 labeling indices for the outer and inner nodules were 2.1% (grade 1) and 44.3% (grade 3), respectively. This nodule was determined to be a PNEMT with HGT. Our findings suggest that a PNEMT may not always be benign and can undergo HGT.

Citations

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Decoding Pancreatic Neuroendocrine Tumors: Molecular Profiles, Biomarkers, and Pathways to Personalized Therapy
Linda Galasso, Federica Vitale, Gabriele Giansanti, Giorgio Esposto, Raffaele Borriello, Irene Mignini, Alberto Nicoletti, Lorenzo Zileri Dal Verme, Antonio Gasbarrini, Maria Elena Ainora, Maria Assunta Zocco
International Journal of Molecular Sciences.2025; 26(16): 7814. CrossRef
Pancreatic neuroendocrine microtumors in the elderly: A retrospective study using cadaveric pancreatic tissue
Ting Yang, Ke Ren, Xiang-Quan Chen, Taku Toriumi, Yutaro Natsuyama, Jun Li, Aoi Sukeda, Toshitaka Nagao, Shuang-Qin Yi
World Journal of Gastrointestinal Oncology.2025;[Epub] CrossRef
Molecular Basis of Pancreatic Neuroendocrine Tumors
Alesia Maluchenko, Denis Maksimov, Zoia Antysheva, Julia Krupinova, Ekaterina Avsievich, Olga Glazova, Natalia Bodunova, Nikolay Karnaukhov, Ilia Feidorov, Diana Salimgereeva, Mark Voloshin, Pavel Volchkov
International Journal of Molecular Sciences.2024; 25(20): 11017. CrossRef

Original Articles

Identification of invasive subpopulations using spatial transcriptome analysis in thyroid follicular tumors: Ayana Suzuki, Satoshi Nojima, Shinichiro Tahara, Daisuke Motooka, Masaharu Kohara, Daisuke Okuzaki, Mitsuyoshi Hirokawa, Eiichi Morii; J Pathol Transl Med. 2024;58(1):22-28. Published online January 10, 2024; DOI: https://doi.org/10.4132/jptm.2023.11.21

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Abstract PDF

Background
Follicular tumors include follicular thyroid adenomas and carcinomas; however, it is difficult to distinguish between the two when the cytology or biopsy material is obtained from a portion of the tumor. The presence or absence of invasion in the resected material is used to differentiate between adenomas and carcinomas, which often results in the unnecessary removal of the adenomas. If nodules that may be follicular thyroid carcinomas are identified preoperatively, active surveillance of other nodules as adenomas is possible, which reduces the risk of surgical complications and the expenses incurred during medical treatment. Therefore, we aimed to identify biomarkers in the invasive subpopulation of follicular tumor cells.
Methods
We performed a spatial transcriptome analysis of a case of follicular thyroid carcinoma and examined the dynamics of CD74 expression in 36 cases.
Results
We identified a subpopulation in a region close to the invasive area, and this subpopulation expressed high levels of CD74. Immunohistochemically, CD74 was highly expressed in the invasive and peripheral areas of the tumor.
Conclusions
Although high CD74 expression has been reported in papillary and anaplastic thyroid carcinomas, it has not been analyzed in follicular thyroid carcinomas. Furthermore, the heterogeneity of CD74 expression in thyroid tumors has not yet been reported. The CD74-positive subpopulation identified in this study may be useful in predicting invasion of follicular thyroid carcinomas.

Citations

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Carbonic Anhydrase 12 as a Novel Prognostic Biomarker and Therapeutic Target for High‐Risk Follicular Thyroid Carcinoma
Masashi Tanida, Tsuyoshi Takashima, Shinichiro Tahara, Masaharu Kohara, Haruka Kanai, Masami Suzuki, Motoyuki Suzuki, Mitsuyoshi Hirokawa, Ayana Suzuki, Shinya Sato, Daisuke Okuzaki, Satoshi Nojima, Takahiro Matsui, Hidenori Inohara, Eiichi Morii
Cancer Science.2026; 117(1): 257. CrossRef
An emerging role of CD74 in thyroid follicular cells in Hashimoto´s thyroiditis
Pablo Sacristán-Gómez, Ana Serrano-Somavilla, Nuria Sánchez de la Blanca, Andrea Álvarez-Rodríguez, Eduardo Martínez-Parra, Miguel Sampedro-Nuñez, Fernando Sebastián-Valles, Mónica Marazuela, Rebeca Martínez-Hernández
Biomedicine & Pharmacotherapy.2026; 194: 118945. CrossRef
Diagnosis of invasive encapsulated follicular variant papillary thyroid carcinoma by protein-based machine learning
Truong Phan-Xuan Nguyen, Minh-Khang Le, Sittiruk Roytrakul, Shanop Shuangshoti, Nakarin Kitkumthorn, Somboon Keelawat
Journal of Pathology and Translational Medicine.2025; 59(1): 39. CrossRef
Spatial Transcriptomics in Thyroid Cancer: Applications, Limitations, and Future Perspectives
Chaerim Song, Hye-Ji Park, Man S. Kim
Cells.2025; 14(12): 936. CrossRef
A New Tool to Decrease Interobserver Variability in Biomarker Annotation in Solid Tumor Tissue for Spatial Transcriptomic Analysis
Sravya Palavalasa, Emily Baker, Jack Freeman, Aditri Gokul, Weihua Zhou, Dafydd Thomas, Wajd N. Al-Holou, Meredith A. Morgan, Theodore S. Lawrence, Daniel R. Wahl
Current Issues in Molecular Biology.2025; 47(7): 531. CrossRef

Tumor-infiltrating T lymphocytes evaluated using digital image analysis predict the prognosis of patients with diffuse large B-cell lymphoma: Yunjoo Cho, Jiyeon Lee, Bogyeong Han, Sang Eun Yoon, Seok Jin Kim, Won Seog Kim, Junhun Cho; J Pathol Transl Med. 2024;58(1):12-21. Published online January 10, 2024; DOI: https://doi.org/10.4132/jptm.2023.11.02

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Abstract PDF

Background
The implication of the presence of tumor-infiltrating T lymphocytes (TIL-T) in diffuse large B-cell lymphoma (DLBCL) is yet to be elucidated. We aimed to investigate the effect of TIL-T levels on the prognosis of patients with DLBCL.
Methods
Ninety-six patients with DLBCL were enrolled in the study. The TIL-T ratio was measured using QuPath, a digital pathology software package. The TIL-T ratio was investigated in three foci (highest, intermediate, and lowest) for each case, resulting in TIL-T–Max, TIL-T–Intermediate, and TIL-T–Min. The relationship between the TIL-T ratios and prognosis was investigated.
Results
When 19% was used as the cutoff value for TIL-T–Max, 72 (75.0%) and 24 (25.0%) patients had high and low TIL-T–Max, respectively. A high TIL-T–Max was significantly associated with lower serum lactate dehydrogenase levels (p < .001), with patient group who achieved complete remission after RCHOP therapy (p < .001), and a low-risk revised International Prognostic Index score (p < .001). Univariate analysis showed that patients with a low TIL-T–Max had a significantly worse prognosis in overall survival compared to those with a high TIL-T–Max (p < .001); this difference remained significant in a multivariate analysis with Cox proportional hazards (hazard ratio, 7.55; 95% confidence interval, 2.54 to 22.42; p < .001).
Conclusions
Patients with DLBCL with a high TIL-T–Max showed significantly better prognosis than those with a low TIL-T–Max, and the TIL-T–Max was an independent indicator of overall survival. These results suggest that evaluating TIL-T ratios using a digital pathology system is useful in predicting the prognosis of patients with DLBCL.

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Do Pre‐Treatment Biopsy Characteristics Predict Early Tumour Progression in Feline Diffuse Large B Cell Nasal Lymphoma Treated With Radiotherapy?
Valerie J. Poirier, Valeria Meier, Michelle Turek, Neil Christensen, Jacqueline Bowal, Matthew D. Ponzini, Stefan M. Keller
Veterinary and Comparative Oncology.2025; 23(1): 82. CrossRef
Comprehensive Analysis of Tumor Microenvironment and PD-L1 Expression Associations with Clinicopathological Features and Prognosis in Diffuse Large B-Cell Lymphoma
Yun-Li Xie, Long-Feng Ke, Wen-Wen Zhang, Fu Kang, Shu-Yi Lu, Chen-Yu Wu, Huan-Huan Zhu, Jian-Chao Wang, Gang Chen, Yan-Ping Chen
Blood and Lymphatic Cancer: Targets and Therapy.2025; Volume 15: 167. CrossRef
Metabolic-immune axis in the tumor microenvironment: a new strategy for prognostic assessment and precision therapy in DLBCL and FL
Chengqian Chen, Wei Guo, Haotian Wang, Luming Cao, Ou Bai
Frontiers in Immunology.2025;[Epub] CrossRef
Integrative analysis of a novel immunogenic PANoptosis‑related gene signature in diffuse large B-cell lymphoma for prognostication and therapeutic decision-making
Ming Xu, Ming Ruan, Wenhua Zhu, Jiayue Xu, Ling Lin, Weili Li, Weirong Zhu
Scientific Reports.2024;[Epub] CrossRef

Case Studies

A rare goblet cell adenocarcinoma arising from Barrett’s esophagus: the first reported case in the esophagus: Chi Eun Oh, Sung Eun Kim, Sun-Ju Oh; J Pathol Transl Med. 2024;58(2):81-86. Published online January 8, 2024; DOI: https://doi.org/10.4132/jptm.2023.12.26

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Abstract PDF: Goblet cell adenocarcinoma (GCA) is a rare and distinctive amphicrine tumor comprised of goblet-like mucinous cells and neuroendocrine cells. It is believed to originate from pluripotent stem cells located at the base of crypts. GCA predominantly arises from the appendix, with a few reported cases in extra-appendiceal locations such as the colorectum, small intestine, and stomach. In this case report, we present a unique instance of a 64-year-old male who initially received a diagnosis of neuroendocrine carcinoma in the distal esophagus based on biopsy but, following resection, was subsequently re-diagnosed with GCA arising from Barrett’s esophagus.

Intravascular NK/T-cell lymphoma: a case report and literature review: Ji Min Na, Wookjae Jung, Minhye Kim, Yun-Hong Cheon, Jong Sil Lee, Dae Hyun Song, Jung Wook Yang; J Pathol Transl Med. 2023;57(6):332-336. Published online November 14, 2023; DOI: https://doi.org/10.4132/jptm.2023.10.30

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Abstract PDF

Intravascular lymphoma is characterized by an exclusively intravascular distribution of tumor cells. Intravascular natural killer/T-cell lymphoma (IVNKTL) is extremely rare, highly aggressive, commonly Epstein-Barr virus (EBV)–positive, and predominantly affects the skin and central nervous system. Here we report a case of IVNKTL diagnosed in a 67-year-old female, presenting with persistent intermittent fever and skin rashes throughout the body. Incisional biopsy of an erythematous lesion on the chest exhibited aggregation of medium to large-sized atypical lymphoid cells confined to the lumen of small vessels that were positive for CD3, granzyme B, and CD56 on immunohistochemistry and EBV-encoded RNA in situ hybridization. EBV DNA was also detected in serum after diagnosis. With a review of 26 cases of IVNKTL to date, we suggest that active biopsy based on EBV DNA detection may facilitate early diagnosis of IVNKTL.

Citations

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Mimicry in the vasculature: a review of diagnostic clues in cutaneous intravascular lymphoid proliferations
MA Faraz, S Tu Zahra, F Ocampo-Gonzalez, SC Shalin, Aadil Ahmed
Diagnostic Histopathology.2026; 32(3): 155. CrossRef
Intravascular Lymphoma: A Unique Pattern Underlying a Protean Disease
Mario Della Mura, Joana Sorino, Filippo Emanuele Angiuli, Gerardo Cazzato, Francesco Gaudio, Giuseppe Ingravallo
Cancers.2025; 17(14): 2355. CrossRef
Cutaneous Intravascular Hematolymphoid Entities: A Review
Emily Hatheway Marshall, Bethany Brumbaugh, Allison Holt, Steven T. Chen, Mai P. Hoang
Diagnostics.2024; 14(7): 679. CrossRef
CD30- and CD56-positive atypical intravascular lymphocytes of the uterine cervix, mimicking intravascular lymphoma: A case report and review of the literature
Daisuke Yamashita, Munemichi Otani, Hayato Maruoka, Takuya Aoki, Shigeo Hara
Journal of Clinical and Experimental Hematopathology.2024; 64(4): 328. CrossRef

Original Article

Establishing molecular pathology curriculum for pathology trainees and continued medical education: a collaborative work from the Molecular Pathology Study Group of the Korean Society of Pathologists: Jiwon Koh, Ha Young Park, Jeong Mo Bae, Jun Kang, Uiju Cho, Seung Eun Lee, Haeyoun Kang, Min Eui Hong, Jae Kyung Won, Youn-La Choi, Wan-Seop Kim, Ahwon Lee; J Pathol Transl Med. 2023;57(5):265-272. Published online September 15, 2023; DOI: https://doi.org/10.4132/jptm.2023.08.26

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Abstract PDF

Background
The importance of molecular pathology tests has increased during the last decade, and there is a great need for efficient training of molecular pathology for pathology trainees and as continued medical education.
Methods
The Molecular Pathology Study Group of the Korean Society of Pathologists appointed a task force composed of experienced molecular pathologists to develop a refined educational curriculum of molecular pathology. A 3-day online educational session was held based on the newly established structure of learning objectives; the audience were asked to score their understanding of 22 selected learning objectives before and after the session to assess the effect of structured education.
Results
The structured objectives and goals of molecular pathology was established and posted as a web-based interface which can serve as a knowledge bank of molecular pathology. A total of 201 pathologists participated in the educational session. For all 22 learning objectives, the scores of self-reported understanding increased after educational session by 9.9 points on average (range, 6.6 to 17.0). The most effectively improved items were objectives from next-generation sequencing (NGS) section: ‘NGS library preparation and quality control’ (score increased from 51.8 to 68.8), ‘NGS interpretation of variants and reference database’ (score increased from 54.1 to 68.0), and ‘whole genome, whole exome, and targeted gene sequencing’ (score increased from 58.2 to 71.2). Qualitative responses regarding the adequacy of refined educational curriculum were collected, where favorable comments dominated.
Conclusions
Approach toward the education of molecular pathology was refined, which would greatly benefit the future trainees.

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Presence of RB1 or Absence of LRP1B Mutation Predicts Poor Overall Survival in Patients with Gastric Neuroendocrine Carcinoma and Mixed Adenoneuroendocrine Carcinoma
In Hye Song, Bokyung Ahn, Young Soo Park, Deok Hoon Kim, Seung-Mo Hong
Cancer Research and Treatment.2025; 57(2): 492. CrossRef

Case Study

Intrathyroidal metastasis of tonsillar squamous cell carcinoma masquerading as a primary thyroid tumor: Jai-Hyang Go; J Pathol Transl Med. 2023;57(4):242-245. Published online July 11, 2023; DOI: https://doi.org/10.4132/jptm.2023.06.16

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Abstract PDF

Intrathyroidal metastasis of tonsillar squamous cell carcinoma is rare. To date, only six cases have been reported in the literature. This case was unusual and presented with thyromegaly before the diagnosis of the primary tumor. A 55-year-old male patient was suspected to have a primary thyroid tumor with nodal metastasis. The thyroid gland was diffusely enlarged, with no discernible mass. Histologically, the thyroid parenchyma revealed extensive endolymphatic tumor emboli, which were positive for p40 and p16 in a background of chronic lymphocytic thyroiditis. Positron emission tomography–computed tomography revealed hypermetabolic activity in the right tonsillar region. Tonsillar biopsy revealed human papillomavirus–positive squamous cell carcinoma. The present case is the first reported case of intrathyroidal metastasis of tonsillar squamous cell carcinoma with an initial clinical presentation of thyroid enlargement before the primary tumor of tonsillar cancer was diagnosed.

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Reviews

Trouble-makers in cytologic interpretation of the uterine cervix: Eunah Shin, Jaeeun Yu, Soon Won Hong; J Pathol Transl Med. 2023;57(3):139-146. Published online May 15, 2023; DOI: https://doi.org/10.4132/jptm.2023.04.25

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Abstract PDF

The development and standardization of cytologic screening of the uterine cervix has dramatically decreased the prevalence of squamous cell carcinoma of the uterine cervix. Advances in the understanding of biology of human papillomavirus have contributed to upgrading the histologic diagnosis of the uterine cervix; however, cytologic screening that should triage those that need further management still poses several difficulties in interpretation. Cytologic features of high grade intraepithelial squamous lesion (HSIL) mimics including atrophy, immature metaplasia, and transitional metaplasia, and glandular lesion masquerades including tubal metaplasia and HSIL with glandular involvement are described with accentuation mainly on the differential points. When the cytologic features lie in a gray zone between the differentials, the most important key to the more accurate interpretation is sticking to the very basics of cytology; screening the background and cellular architecture, and then scrutinizing the nuclear and cytoplasmic details.

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Perspectives on single-nucleus RNA sequencing in different cell types and tissues: Nayoung Kim, Huiram Kang, Areum Jo, Seung-Ah Yoo, Hae-Ock Lee; J Pathol Transl Med. 2023;57(1):52-59. Published online January 10, 2023; DOI: https://doi.org/10.4132/jptm.2022.12.19

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Abstract PDF

Single-cell RNA sequencing has become a powerful and essential tool for delineating cellular diversity in normal tissues and alterations in disease states. For certain cell types and conditions, there are difficulties in isolating intact cells for transcriptome profiling due to their fragility, large size, tight interconnections, and other factors. Single-nucleus RNA sequencing (snRNA-seq) is an alternative or complementary approach for cells that are difficult to isolate. In this review, we will provide an overview of the experimental and analysis steps of snRNA-seq to understand the methods and characteristics of general and tissue-specific snRNA-seq data. Knowing the advantages and limitations of snRNA-seq will increase its use and improve the biological interpretation of the data generated using this technique.

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Single-cell and spatial sequencing application in pathology: Yoon-Seob Kim, Jinyong Choi, Sug Hyung Lee; J Pathol Transl Med. 2023;57(1):43-51. Published online January 10, 2023; DOI: https://doi.org/10.4132/jptm.2022.12.12

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Abstract PDF

Traditionally, diagnostic pathology uses histology representing structural alterations in a disease’s cells and tissues. In many cases, however, it is supplemented by other morphology-based methods such as immunohistochemistry and fluorescent in situ hybridization. Single-cell RNA sequencing (scRNA-seq) is one of the strategies that may help tackle the heterogeneous cells in a disease, but it does not usually provide histologic information. Spatial sequencing is designed to assign cell types, subtypes, or states according to the mRNA expression on a histological section by RNA sequencing. It can provide mRNA expressions not only of diseased cells, such as cancer cells but also of stromal cells, such as immune cells, fibroblasts, and vascular cells. In this review, we studied current methods of spatial transcriptome sequencing based on their technical backgrounds, tissue preparation, and analytic procedures. With the pathology examples, useful recommendations for pathologists who are just getting started to use spatial sequencing analysis in research are provided here. In addition, leveraging spatial sequencing by integration with scRNA-seq is reviewed. With the advantages of simultaneous histologic and single-cell information, spatial sequencing may give a molecular basis for pathological diagnosis, improve our understanding of diseases, and have potential clinical applications in prognostics and diagnostic pathology.

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Original Articles

The proteomic landscape shows oncologic relevance in cystitis glandularis: Jun Yong Kim, Dohyun Han, Hyeyoon Kim, Minsun Jung, Han Suk Ryu; J Pathol Transl Med. 2023;57(1):67-74. Published online December 22, 2022; DOI: https://doi.org/10.4132/jptm.2022.10.24

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Abstract PDF

Background
The relationship between cystitis glandularis (CG) and bladder malignancy remains unclear.
Methods
We identified the oncologic significance of CG at the molecular level using liquid chromatography-tandem mass spectrometry-based proteomic analysis of 10 CG, 12 urothelial carcinoma (UC), and nine normal urothelium (NU) specimens. Differentially expressed proteins (DEPs) were identified based on an analysis of variance false discovery rate < 0.05, and their functional enrichment was analyzed using a network model, Gene Set Enrichment Analysis, and Gene Ontology annotation.
Results
We identified 9,890 proteins across all samples and 1,139 DEPs among the three entities. A substantial number of DEPs overlapped in CG/NU, distinct from UC. Interestingly, we found that a subset of DEP clusters (n = 53, 5%) was differentially expressed in NU but similarly between CG and UC. This “UC-like signature” was enriched for reactive oxygen species (ROS) and energy metabolism, growth and DNA repair, transport, motility, epithelial-mesenchymal transition, and cell survival. Using the top 10 shortlisted DEPs, including SOD2, PRKCD, CYCS, and HCLS1, we identified functional elements related to ROS metabolism, development, and transport using network analysis. The abundance of these four molecules in UC/CG than in NU was consistent with the oncologic functions in CG.
Conclusions
Using a proteomic approach, we identified a predominantly non-neoplastic landscape of CG, which was closer to NU than to UC. We also confirmed a small subset of common DEPs in UC and CG, suggesting that altered ROS metabolism might imply potential cancerous risks in CG.

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Quantitative proteomics and immunohistochemistry uncover NT5DC2 as a diagnostic biomarker for papillary urothelial carcinoma
Jun Yong Kim, Jae Seok Lee, Dohyun Han, Ilias P. Nikas, Hyeyoon Kim, Minsun Jung, Han Suk Ryu
Heliyon.2024; 10(15): e35475. CrossRef
KRT18 as a Novel Biomarker of Urothelial Papilloma while Evaluating Low-Grade Papillary Urothelial Neoplasms: Bi-Center Analysis
Minsun Jung, Bohyun Kim, Jae Seok Lee, Jun Yong Kim, Dohyun Han, Kwangsoo Kim, Sunah Yang, Eun Na Kim, Hyeyooon Kim, Ilias P. Nikas, Sohyeon Yang, Kyung Chul Moon, Hyebin Lee, Han Suk Ryu
Pathobiology.2024; : 1. CrossRef

Evaluation of the characteristics of multiple human papillomavirus (HPV) infections identified using the BD Onclarity HPV assay and comparison with those of single HPV infection: Jinhee Kim, Moonsik Kim, Ji Young Park; J Pathol Transl Med. 2022;56(5):289-293. Published online September 13, 2022; DOI: https://doi.org/10.4132/jptm.2022.08.02

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Abstract PDF Supplementary Material

Background
Human papillomavirus (HPV) infection is a major cause of cervical cancer and associated precursor lesions. Multiple HPV genotype infections have been reported. However, their clinicopathological characteristics still remain elusive.
Methods
For this study, 814 consecutive patients who had undergone colposcopy and HPV genotyping test using BD Onclarity HPV assay were retrospectively selected. Clinicopathological parameters of multiple HPV infections were compared with those of single HPV infection.
Results
Multiple HPV infections were found in 110 out of 814 cases (13.5%). Multiple HPV infections were associated with a significantly higher incidence of high-grade intraepithelial lesions (HSILs) compared with single HPV infection. Other high-risk HPV genotypes, in addition to HPV 16, were found more frequently in the multiple HPV infections group; these included HPV 51, 52, 33/58, 56/59/66, and 35/39/68. No specific coinfection pattern was not identified. Additionally, the number of HPV genotypes in multiple HPV infections was not associated with the progression to HSIL or squamous cell carcinoma.
Conclusions
Multiple HPV infections have distinct clinicopathological characteristics (compared with single HPV infection). As their biological behavior is uncertain, close and frequent follow-up is warranted.

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Case Study

TTF1-positive SMARCA4/BRG1 deficient lung adenocarcinoma: Anurag Mehta, Himanshi Diwan, Divya Bansal, Manoj Gupta; J Pathol Transl Med. 2022;56(1):53-56. Published online November 16, 2021; DOI: https://doi.org/10.4132/jptm.2021.09.16

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Abstract PDF

SMARCA4/BRG1-deficient lung adenocarcinoma (SD-LUAD) is being recognized as a distinct subtype based on subtle differences in its clinical, morphological, and immunophenotypic attributes compared to other non–small cell lung carcinomas. We present here a case of SD-LUAD with curious thyroid transcription factor 1 (TTF1) expression in a morphologically heterogenous lung adenocarcinoma. The better differentiated area showed preservation of TTF1 expression, and a poorly differentiated tumor had loss of TTF1 expression with universal BRG1 loss.

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Tao Liu, Hengshan Ji, Siyuan Jiang, Rongxin Qi, Xiaodie Zhou, Jingjing Sun, Jiang Wu
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Lei Zhang, Ting Sun, Xiao-Ye Wu, Fa-Ming Fei, Zhen-Zhen Gao
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Novel germline SMARCA4 mutation in Small Cell Carcinoma of the Ovary, Hypercalcemic Type
Anurag Mehta, Himanshi Diwan, Diksha Karki, Divya Bansal, Meenakshi Kamboj, Anila Sharma, Shrinidhi Nathany, Sakshi Mattoo, Dushyant Kumar
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Original Articles

Association of PTTG1 expression with invasiveness of non-functioning pituitary adenomas: Su Jung Kum, Hye Won Lee, Soon Gu Kim, Hyungsik Park, Ilseon Hwang, Sang Pyo Kim; J Pathol Transl Med. 2022;56(1):22-31. Published online October 15, 2021; DOI: https://doi.org/10.4132/jptm.2021.08.31

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Abstract PDF

Background
Pituitary tumor transforming gene 1 (PTTG1), paired-like homeodomain 2 (PITX2), and galectin-3 have been widely studied as predictive biomarkers for various tumors and are involved in tumorigenesis and tumor progression. We evaluated the usefulness of PTTG1, PITX2, and galectin-3 as predictive biomarkers for invasive non-functioning pituitary adenomas (NFPAs) by determining the relationship between the expressions of these three proteins and the invasiveness of the NFPAs. We also investigated whether PTTG1, E-cadherin, and Ki-67, which are known to be related to each other, show a correlation with NFPA features.
Methods
A retrospective study was conducted on 87 patients with NPFAs who underwent surgical removal. The NFPAs were classified into three groups based on magnetic resonance imaging findings of suprasellar extension and cavernous sinus invasion. Immunohistochemical staining for PTTG1, PITX2, galectin-3, E-cadherin, and Ki-67 was performed on tissue microarrays.
Results
PTTG1 expression showed a statistically significant correlation with the invasiveness of NFPAs, whereas PITX2 and galectin-3 did not have a relationship with the invasiveness of NFPAs. Moreover, there was no association among PTTG1, E-cadherin, and Ki-67 expression.
Conclusions
PTTG1 has the potential to serve as a predictive biomarker for invasive NFPA. Furthermore, this study may serve as a reference for the development of PTTG1-targeted therapeutic agents.

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Immunohistochemical expression of programmed death-ligand 1 and CD8 in glioblastomas: Dina Mohamed El Samman, Manal Mohamed El Mahdy, Hala Sobhy Cousha, Zeinab Abd El Rahman Kamar, Khaled Abdel Karim Mohamed, Hoda Hassan Abou Gabal; J Pathol Transl Med. 2021;55(6):388-397. Published online October 14, 2021; DOI: https://doi.org/10.4132/jptm.2021.08.04

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Background
Glioblastoma is the most aggressive primary malignant brain tumor in adults and is characterized by poor prognosis. Immune evasion occurs via programmed death-ligand 1 (PD-L1)/programmed death receptor 1 (PD-1) interaction. Some malignant tumors have responded to PD-L1/PD-1 blockade treatment strategies, and PD-L1 has been described as a potential predictive biomarker. This study discussed the expression of PD-L1 and CD8 in glioblastomas.
Methods
Thirty cases of glioblastoma were stained immunohistochemically for PD-L1 and CD8, where PD-L1 expression in glioblastoma tumor tissue above 1% is considered positive and CD-8 is expressed in tumor infiltrating lymphocytes. The expression of each marker was correlated with clinicopathologic parameters. Survival analysis was conducted to correlate progression-free survival (PFS) and overall survival (OS) with PD-L1 and CD8 expression.
Results
Diffuse/fibrillary PD-L1 was expressed in all cases (mean expression, 57.6%), whereas membranous PD-L1 was expressed in six of 30 cases. CD8-positive tumor-infiltrating lymphocytes (CD8⁺ TILs) had a median expression of 10%. PD-L1 and CD8 were positively correlated (p = .001). High PD-L1 expression was associated with worse PFS and OS (p = .026 and p = .001, respectively). Correlation of CD8⁺ TILs percentage with age, sex, tumor site, laterality, and outcomes were statistically insignificant. Multivariate analysis revealed that PD-L1 was the only independent factor that affected prognosis.
Conclusions
PD-L1 expression in patients with glioblastoma is robust; higher PD-L1 expression is associated with lower CD8+ TIL expression and worse prognosis.

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Expression of Programmed Cell Death-Ligand 1 (PD-L1) in Astrocytic Tumors and Its Correlation With Histopathological Grade and Proliferative Index (Ki-67): A Cross-Sectional Study
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Immune intrinsic escape signature stratifies prognosis, characterizes the tumor immune microenvironment, and identifies tumorigenic PPP1R8 in glioblastoma multiforme patients
Ran Du, Lijun Jing, Denggang Fu
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Programmed death-ligand 1 expression and tumor-infiltrating lymphocytes in non-small cell lung cancer: association with clinicopathologic parameters: Gaurav Garg, Kuruswamy Thurai Prasad, Navneet Singh, Parul Gupta, Valliappan Muthu, Ashim Das, Amanjit Bal; J Pathol Transl Med. 2021;55(6):398-405. Published online October 6, 2021; DOI: https://doi.org/10.4132/jptm.2021.08.08

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Abstract PDF Supplementary Material

Background
Data on the prevalence of programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs) in non–small cell lung cancer (NSCLC) and their clinical significance in Indian patients are limited.
Methods
Newly diagnosed NSCLC cases (adenocarcinoma or squamous cell carcinoma [SqCC] histology) were included in the present study. The TILs were evaluated based on morphology on hematoxylin and eosin–stained slides. PD-L1 expression in tumors was assessed using immunohistochemistry with rabbit monoclonal antibody (SP263) on the Ventana automated immunostainer. Tumors with PD-L1 expression > 50% on tumor cells were considered PD-L1–positive. Tumors in which TILs occupy > 25% of stroma were considered to have high TILs. The association of PD-L1 expression and TILs with various clinical parameters including overall survival (OS) was investigated.
Results
The present study included 128 cases of NSCLC (67 adenocarcinoma, 61 SqCC). PD-L1 positivity was observed in 17.2% of the patients with NSCLC. Baseline characteristics of PD-L1–positive subjects were similar to PD-L1–negative subjects except for a higher prevalence of liver metastasis (18.2% vs. 2.8%; p = .018) and a higher probability of diagnosis from extrapulmonary biopsies. High TILs were observed in 26.6% of the subjects. However, PD-L1 expression and high TIL did not affect OS.
Conclusions
PD-L1 positivity and high TILs were observed in 20% and 25% of the patients with NSCLC, respectively, however, neither were predictors of survival in SqCC.

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Mohammad Tanvir Ahamed, Jenny Forshed, Adrian Levitsky, Janne Lehtiö, Amanj Bajalan, Maria Pernemalm, Lars E. Eriksson, Björn Andersson
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Correlation of TTF-1 immunoexpression and EGFR mutation spectrum in non–small cell lung carcinoma: Tripti Nakra, Varsha Singh, Aruna Nambirajan, Prabhat Singh Malik, Anant Mohan, Deepali Jain; J Pathol Transl Med. 2021;55(4):279-288. Published online July 8, 2021; DOI: https://doi.org/10.4132/jptm.2021.05.10

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Abstract PDF

Background
Thyroid transcription factor (TTF-1) is a diagnostic marker expressed in 75%–85% of primary lung adenocarcinomas (ACs). Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene is the most common targetable driver alteration in lung AC. Previous studies have shown a positive correlation between TTF-1 and EGFR mutation status. We aimed to determine the predictive value of TTF-1 immunoexpression for underlying EGFR mutation status in a large Indian cohort.
Methods
This retrospective designed study was conducted with medical record data from 2011 to 2020. All cases of primary lung AC and non–small cell lung carcinoma not otherwise specified (NSCLC, NOS) with known TTF-1 expression diagnosed by immunohistochemistry using 8G7G3/1 antibodies and EGFR mutation status diagnosed by quantitative polymerase chain reaction were retrieved, reviewed, and the
results
were analyzed. Results: Among 909 patient samples diagnosed as lung AC and NSCLC, NOS, TTF-1 was positive in 76.8% cases (698/909) and EGFR mutations were detected in 29.6% (269/909). A strong positive correlation was present between TTF-1 positivity and EGFR mutation status (odds ratio, 3.61; p < .001), with TTF-1 positivity showing high sensitivity (90%) and negative predictive value (87%) for EGFR mutation. TTF-1 immunoexpression did not show significant correlation with uncommon/dual EGFR mutations (odds ratio, 1.69; p = .098). EGFR–tyrosine kinase inhibitor therapy was significantly superior to chemotherapy among EGFR mutant cases irrespective of TTF-1 status; however, no significant differences among survival outcomes were observed.
Conclusions
Our study confirms a strong positive correlation between TTF-1 expression and common EGFR mutations (exon 19 deletion and exon 21 L858R) in advanced lung AC with significantly high negative predictive value of TTF-1 for EGFR mutations.

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Reviews

Liquid biopsy using extracellular vesicle–derived DNA in lung adenocarcinoma: In Ae Kim, Jae Young Hur, Hee Joung Kim, Seung Eun Lee, Wan Seop Kim, Kye Young Lee; J Pathol Transl Med. 2020;54(6):453-461. Published online October 8, 2020; DOI: https://doi.org/10.4132/jptm.2020.08.13

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Abstract PDF

Blood liquid biopsy has emerged as a way of overcoming the clinical limitations of repeat biopsy by testing for the presence of acquired resistance mutations to therapeutic agents. Despite its merits of repeatability and non-invasiveness, this method is currently only used as a supplemental test due to a relatively low sensitivity rate of 50%–60%, and cannot replace tissue biopsy. The circulating tumor DNAs used in blood liquid biopsies are passive products of fragmented DNA with a short half-life released following tumor cell death; the low sensitivity seen with liquid blood biopsy results from this instability, which makes increasing the sensitivity of this test fundamentally difficult. Extracellular vesicles (EVs) are ideal carriers of cancer biomarkers, as cancer cells secret an abundance of EVs, and the contents of tumor cell-originated EVs reflect the molecular and genetic composition of parental cells. In addition, EV-derived DNAs (EV DNAs) consist of large-sized genomic DNAs and tumor-specific oncogenic mutant DNAs. For these reasons, liquid biopsy using EV DNA has the potential to overcome issues arising from tissue shortages associated with small biopsies, which are often seen in lung cancer patients, and the biopsy product can be used in other diagnostic methods, such as epidermal growth factor receptor (EGFR) mutation testing and next-generation sequencing (NGS). A higher sensitivity can be achieved when EV DNAs obtained from bronchoalveolar lavage fluid (BALF) are used rather than those from blood. BALF, when obtained close to the tumor site, is a promising liquid biopsy tool, as it enables the gathering of both cellular and non-cellular fractions of the tumor microenvironment, and provides increased diagnostic sensitivity when compared to blood.

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Pathologic interpretation of endoscopic ultrasound–guided fine needle aspiration cytology/biopsy for pancreatic lesions: Haeryoung Kim, Kee-Taek Jang; J Pathol Transl Med. 2020;54(5):367-377. Published online August 31, 2020; DOI: https://doi.org/10.4132/jptm.2020.07.21

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Abstract PDF

Pathologic interpretation of endoscopic ultrasound–guided fine needle aspiration (EUS-FNA) cytology/biopsy specimens is one of the most challenging tasks in cytology and surgical pathology practice, as the procedure often yields minimal amounts of diagnostic material and contains contaminants, such as blood cells and normal intestinal mucosa. EUS-FNA cytology/biopsy will nevertheless become a more popular procedure for evaluation of various pancreatic lesions because they are difficult to approach with conventional endoscopic procedures. Pathologists should understand the structural differences and limitations of EUS-FNA that make pathologic diagnosis difficult. Ancillary tests are available for differential diagnosis of EUS-FNA for various pancreatic lesions. Immunostains are the most commonly used ancillary tests, and pathologists should able to choose the necessary panel for differential diagnosis. Pathologists should review clinical history and radiologic and/or EUS findings before selecting an immunostain panel and making a pathologic diagnosis. In addition, one’s threshold of malignancy should be adjusted according to the appropriate clinical setting to avoid under-evaluation of pathologic diagnoses. Clinico-pathologic correlation is essential in pathologic evaluation of EUS-FNA for pancreatic lesions. Pathologists can reduce errors by correlating clinical and radiologic findings when evaluating EUS-FNA. Some molecular tests can be applied in differential diagnosis of pancreatic neoplastic and cystic lesions. Molecular data should be used as supportive evidence of a specific disease entity, rather than direct evidence, and should be correlated with clinico-pathologic findings to avoid errors in pathologic diagnosis.

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Case Studies

Renal intravascular large B cell lymphoma: the first case report in Korea and a review of the literature: Moonsik Kim, Haerim Chung, Woo Ick Yang, Hyeon Joo Jeong; J Pathol Transl Med. 2020;54(5):426-431. Published online August 13, 2020; DOI: https://doi.org/10.4132/jptm.2020.06.18

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Herein, we describe the first case of renal intravascular large B cell lymphoma in Korea occurring in a 66-year-old female. She presented with mild fever and dyspnea. On physical and laboratory evaluations, hemophagocytic lymphohistiocytosis was suspected, but the bone marrow biopsy results were unremarkable. During the work-up, massive proteinuria developed, which led to a renal biopsy. The renal architecture was relatively well-preserved, but the glomeruli were hypercellular with the infiltration of atypical, large lymphoid cells with increased nucleus-cytoplasm ratio and clumped chromatin. Similar cells were also present in the peritubular capillaries. The tumor cells exhibited membranous staining for CD20 and CD79a. After the diagnosis of intravascular large B cell lymphoma, the patient received rituximab-based chemotherapy under close follow-up.

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Pediatric granular cell tumor in the posterior wall of the larynx extending to the trachea: Jungsuk Ahn, Na Rae Kim, Yong Han Sun; J Pathol Transl Med. 2020;54(4):336-339. Published online April 15, 2020; DOI: https://doi.org/10.4132/jptm.2020.02.28

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Abstract PDF

Granular cell tumor (GCT) is a slow-growing benign neoplasm that can be found in any organ. Pediatric laryngotracheal GCT is rare. We experienced a 6-year-old boy suffering from a barking cough and symptoms of stridor and croup for one month. Head and neck computed tomography revealed a protruding mass that occluded 60% of the airway lumen. Under the impression of hemangioma or papilloma, excision revealed a submucosal non-encapsulated mass. Histologically, the mass was composed of sheets of large polyhedralshaped tumor cells containing plump eosinophilic granular cytoplasm and centrally placed, small, bland-appearing nuclei. The tumor cells were positive for S-100 protein, and voluminous eosinophilic cytoplasm was stained by diastase-resistant periodic acid-Schiff. The present report describes a unique case of a huge pediatric laryngeal GCT extending to the subglottic trachea. We also review the clinical course of pediatric laryngotracheal GCT and emphasize the importance of diagnosing GCT in children.

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Pediatric granular cell tumor of the larynx: A case report and literature review
Jing Ke, Junwei Xiong, Juhong Zhang, Haiyu Ma, Wei Yuan
Journal of Cancer Research and Therapeutics.2023; 19(4): 1070. CrossRef

Original Article

Adjunctive markers for classification and diagnosis of central nervous system tumors: results of a multi-center neuropathological survey in Korea: Yoon Jin Cha, Se Hoon Kim, Na Rae Kim; J Pathol Transl Med. 2020;54(2):165-170. Published online February 20, 2020; DOI: https://doi.org/10.4132/jptm.2020.02.04

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Abstract PDF Supplementary Material

Background
The revised 4th 2016 World Health Organization (WHO) classification of tumors of the central nervous system (CNS) classification has adopted integrated diagnosis encompassing the histology and molecular features of CNS tumors. We aimed to investigate the immunohistochemistry, molecular testing, and testing methods for diagnosis of CNS tumors in pathological labs of tertiary centers in Korea, and evaluate the adequacy of tests for proper diagnosis in daily practice.
Methods
A survey, composed of eight questions concerning molecular testing for diagnosis of CNS tumors, was sent to 10 neuropathologists working in tertiary centers in Korea.
Results
For diagnosis of astrocytic and oligodendroglial tumors, all 10 centers performed isocitrate dehydrogenase mutations testing and 1p/19q loss of heterozygosity. For glioneuronal tumors, immunohistochemistry (IHC) assays for synaptophysin (n = 9), CD34 (n = 7), BRAF(VE1) (n = 5) were used. For embryonal tumors, particularly in medulloblastoma, four respondents used IHC panel (growth factor receptor bound protein 2-associated protein 1, filamin A, and yes-associated protein 1) for molecular subclassification. Regarding meningioma, all respondents performed Ki-67 IHC and five performed telomerase reverse transcriptase promoter mutation.
Conclusions
Most tertiary centers made proper diagnosis in line with 2016 WHO classification. As classification of CNS tumors has evolved to be more complex and more ancillary tests are required, these should be performed considering the effect of necessity and justification.

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Exploring the role of epidermal growth factor receptor variant III in meningeal tumors
Rashmi Rana, Vaishnavi Rathi, Kirti Chauhan, Kriti Jain, Satnam Singh Chhabra, Rajesh Acharya, Samir Kumar Kalra, Anshul Gupta, Sunila Jain, Nirmal Kumar Ganguly, Dharmendra Kumar Yadav, Timir Tripathi
PLOS ONE.2021; 16(9): e0255133. CrossRef

Case Study

Inconspicuous longitudinal tears of the intracranial vertebral artery in traumatic basal subarachnoid hemorrhage: Seongho Kim; J Pathol Transl Med. 2020;54(2):179-183. Published online November 8, 2019; DOI: https://doi.org/10.4132/jptm.2019.10.15

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Abstract PDF

Blunt force trauma to the head or neck region can cause traumatic basal subarachnoid hemorrhage (TBSAH), which can result in rapid loss of consciousness and death; however, detecting such a vascular injury is difficult. Posterior neck dissection was performed to investigate the bleeding focus in TBSAH cases 2018 and 2019. In all four cases, autopsies revealed a longitudinal tear in the midsection of the vertebral artery’s intracranial portion. The midportion of the intracranial vertebral artery appears to be most vulnerable to TBSAH. Interestingly, three of the cases showed only a vaguely visible longitudinal fissure in the artery without a grossly apparent tear; rupture was confirmed by microscopic examination. Longitudinal fissures of the intracranial vertebral artery, which are difficult to identify without detailed examination, may be overlooked in some cases of TBSAH. Thus, careful gross and microscopic examination of the vertebral artery is recommended in cases of TBSAH.

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Effect of Ginseng Extract Ginsenoside Rg1 on Mice with Intracerebral Injury
Zixin Zhuang, Jinman Chen, Hao Xu, Yongjun Wang, Qianqian Liang
Chinese Medicine and Culture.2023;[Epub] CrossRef

Review

Tumor immune response and immunotherapy in gastric cancer: Yoonjin Kwak, An Na Seo, Hee Eun Lee, Hye Seung Lee; J Pathol Transl Med. 2020;54(1):20-33. Published online November 1, 2019; DOI: https://doi.org/10.4132/jptm.2019.10.08

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Abstract PDF

Remarkable developments in immuno-oncology have changed the landscape of gastric cancer (GC) treatment. Because immunotherapy intervenes with tumor immune response rather than directly targeting tumor cells, it is important to develop a greater understanding of tumor immunity. This review paper summarizes the tumor immune reaction and immune escape mechanisms while focusing on the role of T cells and their co-inhibitory signals, such as the immune checkpoint molecules programmed death-1 and programmed deathligand 1 (PD-L1). This paper also describes past clinical trials of immunotherapy for patients with GC and details their clinical implications. Strong predictive markers are essential to improve response to immunotherapy. Microsatellite instability, Epstein-Barr virus, PD-L1 expression, and tumor mutational burden are now regarded as potent predictive markers for immunotherapy in patients with GC. Novel immunotherapy and combination therapy targeting new immune checkpoint molecules such as lymphocyte-activation gene 3, T cell immunoglobulin, and mucin domain containing-3, and indoleamine 2,3-dioxygenase have been suggested, and trials are ongoing to evaluate their safety and efficacy. Immunotherapy is an important treatment option for patients with GC and has great potential for improving patient outcome, and further research in immuno-oncology should be carried out.

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Original Articles

Reclassification of Mongolian Diffuse Gliomas According to the Revised 2016 World Health Organization Central Nervous System Tumor Classification: Enkhee Ochirjav, Bayarmaa Enkhbat, Tuul Baldandorj, Gheeyoung Choe; J Pathol Transl Med. 2019;53(5):298-307. Published online August 2, 2019; DOI: https://doi.org/10.4132/jptm.2019.07.15

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110 Download
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Abstract PDF

Background
The 2016 World Health Organization (WHO) classification of central nervous system (CNS) tumors has been modified to incorporate the IDH mutation and 1p/19q co-deletion in the diagnosis of diffuse gliomas. In this study, we aimed to evaluate the feasibility and prognostic significance of the revised 2016 WHO classification of CNS tumors in Mongolian patients with diffuse gliomas.
Methods
A total of 124 cases of diffuse gliomas were collected, and tissue microarray blocks were made. IDH1 mutation was tested using immunohistochemistry, and 1p/19q co-deletion status was examined using fluorescence in situ hybridization analysis.
Results
According to the 2016 WHO classification, 124 cases of diffuse brain glioma were reclassified as follows: 10 oligodendroglioma, IDH^mut and 1p/19q co-deleted; three anaplastic oligodendroglioma, IDH^mut and 1p/19q co-deleted; 35 diffuse astrocytoma, IDH^mut, 11 diffuse astrocytoma, IDH^wt, not otherwise specified (NOS); 22 anaplastic astrocytoma, IDH^mut, eight anaplastic astrocytoma, IDH^wt, NOS; and 35 glioblastoma, IDH^wt, NOS, respectively. The 2016 WHO classification presented better prognostic value for overall survival in patients with grade II tumors than traditional histological classification. Among patients with grade II tumors, those with oligodendroglioma IDH^mut and 1p/19q co-deleted and diffuse astrocytoma IDH^mut showed significantly higher survival than those with diffuse astrocytoma IDH^wt, NOS (p<.01).
Conclusions
Mongolian diffuse gliomas could be reclassified according to the new 2016 WHO classification. Reclassification revealed substantial changes in diagnosis of both oligodendroglial and astrocytic entities. We have confirmed that the revised 2016 WHO CNS tumor classification has prognostic significance in Mongolian patients with diffuse gliomas, especially those with grade II tumors.

Citations

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Targeted next‐generation sequencing of adult gliomas for retrospective prognostic evaluation and up‐front diagnostics
J. K. Petersen, H. B. Boldt, M. D. Sørensen, S. Blach, R. H. Dahlrot, S. Hansen, M. Burton, M. Thomassen, T. Kruse, F. R. Poulsen, L. Andreasen, H. Hager, B. P. Ulhøi, S. Lukacova, G. Reifenberger, B. W. Kristensen
Neuropathology and Applied Neurobiology.2021; 47(1): 108. CrossRef

Progressive Familial Intrahepatic Cholestasis in Korea: A Clinicopathological Study of Five Patients: Hyo Jeong Kang, Soon Auck Hong, Seak Hee Oh, Kyung Mo Kim, Han-Wook Yoo, Gu-Hwan Kim, Eunsil Yu; J Pathol Transl Med. 2019;53(4):253-260. Published online May 16, 2019; DOI: https://doi.org/10.4132/jptm.2019.05.03

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Abstract PDF

Background
Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal recessive liver diseases that present as neonatal cholestasis. Little is known of this disease in Korea.
Methods
The records of five patients histologically diagnosed with PFIC, one with PFIC1 and four with PFIC2, by liver biopsy or transplant were reviewed, and ATP8B1 and ABCB11 mutation status was analyzed by direct DNA sequencing. Clinicopathological characteristics were correlated with genetic mutations.
Results
The first symptom in all patients was jaundice. Histologically, lobular cholestasis with bile plugs was the main finding in all patients, whereas diffuse or periportal cholestasis was identified only in patients with PFIC2. Giant cells and ballooning of hepatocytes were observed in three and three patients with PFIC2, respectively, but not in the patient with PFIC1. Immunostaining showed total loss of bile salt export pump in two patients with PFIC2 and focal loss in two. Lobular and portal based fibrosis were more advanced in PFIC2 than in PFIC1. ATP8B1 and ABCB11 mutations were identified in one PFIC1 and two PFIC2 patients, respectively. One PFIC1 and three PFIC2 patients underwent liver transplantation (LT). At age 7 months, one PFIC2 patient was diagnosed with concurrent hepatocellular carcinoma and infantile hemangioma in an explanted liver. The patient with PFIC1 developed steatohepatitis after LT. One patient showed recurrence of PFIC2 after 10 years and underwent LT.
Conclusions
PFIC is not rare in patients with neonatal cholestasis of unknown origin. Proper clinicopathologic correlation and genetic testing can enable early detection and management.

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International Journal of Hepatology.2023; 2023: 1. CrossRef
Next-generation sequencing panel test results in pediatric patients with progressive familial intrahepatic cholestasis: a single-center experience
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Sagar Mehta, Karunesh Kumar, Ravi Bhardwaj, Smita Malhotra, Neerav Goyal, Anupam Sibal
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Liver transplantation in pediatric patients with progressive familial intrahepatic cholestasis: Single center experience of seven cases
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Case Study

Frozen Cytology of Meningeal Malignant Solitary Fibrous Tumor/Hemangiopericytoma: Myunghee Kang, Na Rae Kim, Dong Hae Chung, Gie-Taek Yie; J Pathol Transl Med. 2019;53(3):192-197. Published online April 11, 2019; DOI: https://doi.org/10.4132/jptm.2019.03.20

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Abstract PDF

A 51-year-old woman presented with severe dizziness. The brain magnetic resonance image revealed a 5.5 cm multiloculated mass with a thick rim in the left temporal lobe. Cytological examination of frozen diagnosis of the mass showed hypercellular sheets of round and rhabdoid cells in a hemorrhagic background, and two mitotic figures were observed. Histologically, the excised dura-based mass consisted of predominantly round cells with small foci of rhabdoid tumor cells in a pseudoalveolar pattern in a hemorrhagic background, and the cells showed nuclear positivity for signal transducer and activator of transcription 6 as well as frequent mitosis. The mass was diagnosed as a grade 3 solitary fibrous tumor (SFT)/hemangiopericytoma (HPC). The cytological diagnosis of SFT/HPC is challenging because of the heterogeneous cytological findings, such as histological heterogeneity, and because there are no standardized cytological criteria for malignant SFT/HPC. Cytological findings, such as singly scattered small cells, hypercellularity, rare ropy collagen, and round and rhabdoid cells with pseudoalveolar pattern, may assist in the diagnosis of malignant SFT/HPC.

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Original Articles

Association between p53 Expression and Amount of Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer: Miseon Lee, In Ah Park, Sun-Hee Heo, Young-Ae Kim, Gyungyub Gong, Hee Jin Lee; J Pathol Transl Med. 2019;53(3):180-187. Published online March 11, 2019; DOI: https://doi.org/10.4132/jptm.2019.02.08

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Abstract PDF

Background
Most triple-negative breast cancers (TNBCs) have a high histologic grade, are associated with high endoplasmic stress, and possess a high frequency of TP53 mutations. TP53 missense mutations lead to the production of mutant p53 protein and usually show high levels of p53 protein expression. Tumor-infiltrating lymphocytes (TILs) accumulate as part of the anti-tumor immune response and have a strong prognostic and predictive significance in TNBC. We aimed to elucidate the association between p53 expression and the amount of TILs in TNBC.
Methods
In 678 TNBC patients, we evaluated TIL levels and expression of endoplasmic stress molecules. Immunohistochemical examination of p53 protein expression was categorized into three groups: no, low, and high expression.
Results
No, low, and high p53 expression was identified in 44.1% (n = 299), 20.1% (n = 136), and 35.8% (n = 243) of patients, respectively. Patients with high p53 expression showed high histologic grade (p < .001), high TIL levels (p = .009), and high expression of endoplasmic reticulum stress-associated molecules (p-eIF2a, p = .013; XBP1, p = .007), compared to patients with low p53 expression. There was no significant difference in disease-free (p = .406) or overall survival rates (p = .444) among the three p53 expression groups.
Conclusions
High p53 expression is associated with increased expression of endoplasmic reticulum stress molecules and TIL influx.

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Correlating p53 immunostaining patterns with somatic TP53 mutation and functional properties of mutant p53 in triple‐negative breast cancer
Meejeong Kim, Miseon Lee, Ahwon Lee, Byung‐Ock Choi, Woo‐Chan Park, Sung Hun Kim, Jieun Lee, Jun Kang
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GD3 synthase drives resistance to p53-induced apoptosis in breast cancer by modulating mitochondrial function
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Prognostic benefit of TILs independent of clinicopathological and molecular factors
Koen Brummel, Anneke L. Eerkens, Marco de Bruyn, Hans W. Nijman
British Journal of Cancer.2023; 129(5): 737. CrossRef
Dihydroartemisinin-Transferrin Adducts Enhance TRAIL-Induced Apoptosis in Triple-Negative Breast Cancer in a P53-Independent and ROS-Dependent Manner
Xinyu Zhou, Abel Soto-Gamez, Fleur Nijdam, Rita Setroikromo, Wim J. Quax
Frontiers in Oncology.2022;[Epub] CrossRef
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Andrii Puzyrenko, Chandler S Cortina, Julie M Jorns
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Shengnan Sha, Luyi Si, Xinrui Wu, Yuanbiao Chen, Hui Xiong, Ying Xu, Wangrui Liu, Haijun Mei, Tao Wang, Mei Li
Frontiers in Immunology.2022;[Epub] CrossRef
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Ai-Yan Xing, Long Liu, Ke Liang, Bin Wang
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Crosstalk between Immune Checkpoint Modulators, Metabolic Reprogramming and Cellular Plasticity in Triple-Negative Breast Cancer
Arpita Poddar, Sushma R. Rao, Prashanth Prithviraj, George Kannourakis, Aparna Jayachandran
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Natsuki Furukawa, Vered Stearns, Cesar A. Santa-Maria, Aleksander S. Popel
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Intraoperative Frozen Cytology of Central Nervous System Neoplasms: An Ancillary Tool for Frozen Diagnosis: Myunghee Kang, Dong Hae Chung, Na Rae Kim, Hyun Yee Cho, Seung Yeon Ha, Sangho Lee, Jungsuk An, Jae Yeon Seok, Gie-Taek Yie, Chan Jong Yoo, Sang Gu Lee, Eun Young Kim, Woo Kyung Kim, Seong Son, Sun Jin Sym, Dong Bok Shin, Hee Young Hwang, Eung Yeop Kim, Kyu Chan Lee; J Pathol Transl Med. 2019;53(2):104-111. Published online January 14, 2019; DOI: https://doi.org/10.4132/jptm.2018.11.10

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Abstract PDF

Background
Pathologic diagnosis of central nervous system (CNS) neoplasms is made by comparing light microscopic, immunohistochemical, and molecular cytogenetic findings with clinicoradiologic observations. Intraoperative frozen cytology smears can improve the diagnostic accuracy for CNS neoplasms. Here, we evaluate the diagnostic value of cytology in frozen diagnoses of CNS neoplasms.
Methods
Cases were selected from patients undergoing both frozen cytology and frozen sections. Diagnostic accuracy was evaluated.
Results
Four hundred and fifty-four cases were included in this retrospective single-center review study covering a span of 10 years. Five discrepant cases (1.1%) were found after excluding 53 deferred cases (31 cases of tentative diagnosis, 22 cases of inadequate frozen sampling). A total of 346 cases of complete concordance and 50 cases of partial concordance were classified as not discordant cases in the present study. Diagnostic accuracy of intraoperative frozen diagnosis was 87.2%, and the accuracy was 98.8% after excluding deferred cases. Discrepancies between frozen and permanent diagnoses (n = 5, 1.1%) were found in cases of nonrepresentative sampling (n = 2) and misinterpretation (n = 3). High concordance was observed more frequently in meningeal tumors (97/98, 99%), metastatic brain tumors (51/52, 98.1%), pituitary adenomas (86/89, 96.6%), schwannomas (45/47, 95.8%), high-grade astrocytic tumors (47/58, 81%), low grade astrocytic tumors (10/13, 76.9%), non-neoplastic lesions (23/36, 63.9%), in decreasing frequency.
Conclusions
Using intraoperative cytology and frozen sections of CNS tumors is a highly accurate diagnostic ancillary method, providing subtyping of CNS neoplasms, especially in frequently encountered entities.

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Intraoperative Integrated Diagnostic System for Malignant Central Nervous System Tumors
Takahiro Hayashi, Kensuke Tateishi, Shinichiro Matsuyama, Hiromichi Iwashita, Yohei Miyake, Akito Oshima, Hirokuni Honma, Jo Sasame, Katsuhiro Takabayashi, Kyoka Sugino, Emi Hirata, Naoko Udaka, Yuko Matsushita, Ikuma Kato, Hiroaki Hayashi, Taishi Nakamur
Clinical Cancer Research.2024; 30(1): 116. CrossRef
A multicenter proof-of-concept study on deep learning-based intraoperative discrimination of primary central nervous system lymphoma
Xinke Zhang, Zihan Zhao, Ruixuan Wang, Haohua Chen, Xueyi Zheng, Lili Liu, Lilong Lan, Peng Li, Shuyang Wu, Qinghua Cao, Rongzhen Luo, Wanming Hu, Shanshan lyu, Zhengyu Zhang, Dan Xie, Yaping Ye, Yu Wang, Muyan Cai
Nature Communications.2024;[Epub] CrossRef
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Ali A. Mohamed, Emma Sargent, Cooper Williams, Zev Karve, Karthik Nair, Brandon Lucke-Wold
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Unveiling the potential application of intraoperative brain smear for brain tumor diagnosis in low-middle-income countries: A comprehensive systematic review
Muhammad Shakir, Ahmed Altaf, Hawra Hussain, Syed Muhammad Aqeel Abidi, Zoey Petitt, Mahnoor Tariq, Ahmed Gilani, S. Ather Enam
Surgical Neurology International.2023; 14: 325. CrossRef
A Comparative Study of Squash Smear Cytology Diagnosis and Radiological Diagnosis with Histopathology in Central Nervous System Lesions
B N Kumarguru, G Santhipriya, S Kranthi Kumar, R Ramesh Kumar, A S Ramaswamy, P Janakiraman
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Intraoperative squash cytology provides a qualitative intraoperative diagnosis for cases in which frozen section yields a diagnosis of equivocal brain tumour
Hirotaka Fujita, Takuma Tajiri, Tomohisa Machida, Nozomi Nomura, Suguru Toguchi, Hitoshi Itoh, Shinichiro Hiraiwa, Tomoko Sugiyama, Masaaki Imai, Shinri Oda, Masami Shimoda, Naoya Nakamura
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Quilty Lesions in the Endomyocardial Biopsies after Heart Transplantation: Haeyon Cho, Jin-Oh Choi, Eun-Seok Jeon, Jung-Sun Kim; J Pathol Transl Med. 2019;53(1):50-56. Published online December 26, 2018; DOI: https://doi.org/10.4132/jptm.2018.11.30

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Abstract PDF Supplementary Material

Background
The aim of this study was to investigate the clinical significance of Quilty lesions in endomyocardial biopsies (EMBs) of cardiac transplantation patients.
Methods
A total of 1190EMBs from 117 cardiac transplantation patients were evaluated histologically for Quilty lesions,acute cellular rejection, and antibody-mediated rejection. Cardiac allograft vasculopathy wasdiagnosed by computed tomography coronary angiography. Clinical information, including thepatients’ survival was retrieved by a review of medical records.
Results
Eighty-eight patients(75.2%) were diagnosed with Quilty lesions, which were significantly associated with acute cellularrejection, but not with acute cellular rejection ≥ 2R or antibody-mediated rejection. In patientsdiagnosed with both Quilty lesions and acute cellular rejection, the time-to-onset of Quilty lesionsfrom transplantation was longer than that of acute cellular rejections. We found a significant associationbetween Quilty lesions and cardiac allograft vasculopathy. No significant relationship wasfound between Quilty lesions and the patients’ survival.
Conclusions
Quilty lesion may be an indicator of previous acute cellular rejection rather than a predictor for future acute cellular rejection.

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Andrea Fernandez Valledor, Cathrine M. Moeller, Adi Hertz, Daniel Oren, Ilan Richter, Boaz Elad, Julia Baranowska, Salwa Rahman, Carolyn Hennecken, Afsana Rahman, Dor Lotan, David Bae, Adil Yunis, Justin A. Fried, Ersilia M. DeFilippis, David T. Majure, J
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PLAG1, SOX10, and Myb Expression in Benign and Malignant Salivary Gland Neoplasms: Ji Hyun Lee, Hye Ju Kang, Chong Woo Yoo, Weon Seo Park, Jun Sun Ryu, Yuh-Seog Jung, Sung Weon Choi, Joo Yong Park, Nayoung Han; J Pathol Transl Med. 2019;53(1):23-30. Published online November 14, 2018; DOI: https://doi.org/10.4132/jptm.2018.10.12

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Abstract PDF

Background
Recent findings in molecular pathology suggest that genetic translocation and/oroverexpression of oncoproteins is important in salivary gland tumorigenesis and diagnosis. Weinvestigated PLAG1, SOX10, and Myb protein expression in various salivary gland neoplasm tissues.
Methods
A total of 113 cases of surgically resected salivary gland neoplasms at the NationalCancer Center from January 2007 to March 2017 were identified. Immunohistochemical stainingof PLAG1, SOX10, and Myb in tissue samples was performed using tissue microarrays.
Results
Among the 113 cases, 82 (72.6%) were benign and 31 (27.4%) were malignant. PLAG1 showednuclear staining and normal parotid gland was not stained. Among 48 cases of pleomorphicadenoma, 29 (60.4%) were positive for PLAG1. All other benign and malignant salivary glandneoplasms were PLAG1-negative. SOX10 showed nuclear staining. In normal salivary gland tissuesSOX10 was expressed in cells of acinus and intercalated ducts. In benign tumors, SOX10 expressionwas observed in all pleomorphic adenoma (48/48), and basal cell adenoma (3/3), but not inother benign tumors. SOX10 positivity was observed in nine of 31 (29.0%) malignant tumors.Myb showed nuclear staining but was not detected in normal parotid glands. Four of 31 (12.9%)malignant tumors showed Myb positivity: three adenoid cystic carcinomas (AdCC) and onemyoepithelial carcinoma with focal AdCC-like histology.
Conclusions
PLAG1 expression is specificto pleomorphic adenoma. SOX10 expression is helpful to rule out excretory duct origin tumor,but its diagnostic value is relatively low. Myb is useful for diagnosing AdCC when histology isunclear in the surgical specimen.

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Loss of Human Leukocyte Antigen Class I Expression Is Associated with Poor Prognosis in Patients with Advanced Breast Cancer: Hong Sik Park, Uiju Cho, So Young Im, Chang Young Yoo, Ji Han Jung, Young Jin Suh, Hyun Joo Choi; J Pathol Transl Med. 2019;53(2):75-85. Published online November 14, 2018; DOI: https://doi.org/10.4132/jptm.2018.10.11

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Abstract PDF

Background
Human leukocyte antigen class I (HLA-I) molecules play important roles in regulating immune responses. Loss or reduction of HLA-I expression has been shown to be associated with prognosis in several cancers. Regulatory T-cells (Tregs) also play critical functions in immune response regulation. Evaluation of HLA-I expression status by the EMR8-5 antibody and its clinical impact in breast cancer have not been well studied, and its relationship with Tregs remains unclear.
Methods
We evaluated HLA-I expression and Treg infiltration by immunohistochemistry in 465 surgically resected breast cancer samples. We examined the correlation between HLA-I expression and Treg infiltration and clinicopathologic characteristics and survival analyses were performed.
Results
Total loss of HLA-I expression was found in 84 breast cancer samples (18.1%). Univariate survival analysis revealed that loss of HLA-I expression was significantly associated with worse disease-specific survival (DSS) (p = .029). HLA-I was not an independent prognostic factor in the entire patient group, but it was an adverse independent prognostic factor for DSS in patients with advanced disease (stage II–IV) (p = .031). Treg numbers were significantly higher in the intratumoral stroma of HLA-I–positive tumors than in HLA-I–negative tumors (median 6.3 cells/high power field vs 2.1 cells/high power field, p < .001). However, Tregs were not an independent prognostic factor in our cohort.
Conclusions
Our findings suggest that the loss of HLA-I expression is associated with poor prognosis in breast cancer patients, highlighting the role of HLA-I alterations in immune evasion mechanisms of breast cancer. HLA-I could be a promising marker that enables the application of more effective and precise immunotherapies for patients with advanced breast cancer.

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Case Studies

Primary Peripheral Gamma Delta T-Cell Lymphoma of the Central Nervous System: Report of a Case Involving the Intramedullary Spinal Cord and Presenting with Myelopathy: Jeemin Yim, Seung Geun Song, Sehui Kim, Jae Won Choi, Kyu-Chong Lee, Jeong Mo Bae, Yoon Kyung Jeon; J Pathol Transl Med. 2019;53(1):57-61. Published online October 1, 2018; DOI: https://doi.org/10.4132/jptm.2018.08.21

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Abstract PDF

Primary central nervous system lymphoma of T-cell origin (T-PCNSL) is rare, and its clinicopathological features remain unclear. Peripheral T-cell lymphoma of γδ T-cell origin is an aggressive lymphoma mainly involving extranodal sites. Here, we report a case of γδ T-PCNSL involving the intramedullary spinal cord and presenting with paraplegia. A 75-year-old Korean woman visited the hospital complaining of back pain and lower extremity weakness. Magnetic resonance imaging revealed multifocal enhancing intramedullary nodular lesions in the thoracic and lumbar spinal cord. An enhancing nodular lesion was observed in the periventricular white matter of the lateral ventricle in the brain. There were no other abnormalities in systemic organs or skin. Laminectomy and tumor removal were performed. The tumor consisted of monomorphic, medium-to-large atypical lymphocytes with pale-to-eosinophilic cytoplasm. Immunohistochemically, the tumor cells were CD3(+), TCRβF1(-), TCRγ(+), CD30(-), CD4(-), CD8(-), CD56(+), TIA1(+), granzyme B(+), and CD103(+). Epstein-Barr virus in situ was negative. This case represents a unique T-PCNSL of γδ T-cell origin involving the spinal cord.

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Hyalinizing Trabecular Tumor of the Thyroid Gland, a Diagnostic Challenge in Fine-Needle Aspiration Cytology: Case Report: Ye-Young Rhee, Hong Kyu Jung, Se Hoon Kim, Soo Hee Kim; J Pathol Transl Med. 2018;52(4):252-256. Published online June 11, 2018; DOI: https://doi.org/10.4132/jptm.2018.04.28

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Abstract PDF

Hyalinizing trabecular tumor (HTT) is a rare thyroid tumor with low to minimal malignant potential. HTT is often misinterpreted as other thyroid tumors, including papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma (MTC), on fine-needle aspiration (FNA) cytology, because of its overlapping cytologic features, such as nuclear grooves and intranulcear pseudoinclusions. Although cytopathologists cannot definitely conclude HTT by FNA cytology, suspicion of HTT is necessary to avoid misdiagnosing HTT as PTC or MTC and to avoid unnecessary aggressive treatment. Here, we report a case of HTT with novel cytologic features in CellPrep liquid based cytology that was diagnosed as suspicious for papillary carcinoma by FNA and finally diagnosed as HTT in the surgical specimen.

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Abstract PDF

Primary cutaneous mucinous carcinoma (PCMC) is an uncommon tumor of the sweat gland origin. The occurrence of PCMC is mostly in middle-aged and older patients, with a slight male predominance. Most cases of PCMC arise on the head, with a preference for eyelids. The histogenesis of PCMC, whether eccrine or apocrine, remains controversial. We report a rare case of PCMC with secondary extramammary Paget’s disease in the groin of a 75-year-old man, which favored an apocrine origin. Furthermore, based on a review of the literature, we provide several histologic clues that can be used to differentiate PCMC from metastatic mucinous carcinoma.

Citations

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Review

Extracellular Vesicles and the Promise of Continuous Liquid Biopsies: Don Armstrong, Derek E. Wildman; J Pathol Transl Med. 2018;52(1):1-8. Published online January 15, 2018; DOI: https://doi.org/10.4132/jptm.2017.05.21

19,223 View
339 Download
72 Web of Science
68 Crossref

Abstract PDF

The rapid and accurate diagnosis of patients with minimally invasive procedures was once only found in science fiction. However, the discovery of extracellular vesicles (EVs) and their near ubiquity in body fluids, coupled with the advent of inexpensive next generation sequencing techniques and EV purification protocols, promises to make science fiction a reality. Purifying and sequencing the RNA content of EV from routine blood draws and urine samples are likely to enable pathologists and physicians to diagnose and track the progress of diseases in many inaccessible tissues in the near future. Here we present the evolutionary background of EV, summarize the biology of EV formation and cargo selection, and discuss the current barriers to making continuous liquid biopsies through the use of EV a science reality.

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Case Study

Aggressive Supratentorial Ependymoma, RELA Fusion-Positive with Extracranial Metastasis: A Case Report: Seong-Ik Kim, Yoojin Lee, Seung Ki Kim, Hyoung Jin Kang, Sung-Hye Park; J Pathol Transl Med. 2017;51(6):588-593. Published online November 15, 2017; DOI: https://doi.org/10.4132/jptm.2017.08.10

12,791 View
231 Download
15 Web of Science
18 Crossref

Abstract PDF

Ependymoma is the third most common pediatric primary brain tumor. Ependymomas are categorized according to their locations and genetic abnormalities, and these two parameters are important prognostic factors for patient outcome. For supratentorial (ST) ependymomas, RELA fusion-positive ependymomas show a more aggressive behavior than YAP1 fusion-positive ependymomas. Extracranial metastases of intra-axial neuroepithelial tumors are extremely rare. In this paper, we report a case of aggressive anaplastic ependymoma arising in the right frontoparietal lobe, which had genetically 1q25 gain, CDKN2A homozygous deletion, and L1CAM overexpression. The patient was a 10-year-old boy who underwent four times of tumor removal and seven times of gamma knife surgery. Metastatic loci were scalp and temporalis muscle overlying primary operation site, lung, liver, buttock, bone, and mediastinal lymph nodes. He had the malignancy for 10 years and died. This tumor is a representative case of RELA fusion-positive ST ependymoma, showing aggressive behavior.

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Review

Thyroid Cytology: The Japanese System and Experience at Yamashita Thyroid Hospital: Shinya Satoh, Hiroyuki Yamashita, Kennichi Kakudo; J Pathol Transl Med. 2017;51(6):548-554. Published online October 11, 2017; DOI: https://doi.org/10.4132/jptm.2017.09.29

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Abstract PDF

In Japan, fine-needle aspiration (FNA) cytology is the most important diagnostic modality for triaging patients with thyroid nodules. A clinician (endocrinologist, endocrine surgeon, or head and neck surgeon) generally performs FNA cytology at the outpatient clinic, and ultrasound (US)-guided FNA is widespread because US is extremely common and most clinicians are familiar with it. Although almost all FNA thyroid samples are examined by certified cytopathologists and pathologists, some clinicians assess cytological specimens themselves. In Japan, there are two clinical guidelines regarding the management of thyroid nodules. One is the General Rules for the Description of Thyroid Cancer (GRDTC) published by the Japanese Society of Thyroid Surgery (JSTS) in 2005, and the other is the national reporting system for thyroid FNA cytology published by the Japan Thyroid Association in 2013 (Japanese system). Although the Bethesda System for Reporting Thyroid Cytopathology (Bethesda system) is rarely used in Japan, both the GRDTC and Japanese system tried to incorporate the Bethesda system so that the cytological diagnoses would be compatible with each other. The essential point of the Japanese system is stratification of follicular neoplasm (FN) into three subgroups based on cytological features in order to reduce unnecessary diagnostic thyroidectomy, and this system has been successful in stratifying the risk of malignancy in FN patients at several high-volume thyroid surgery centers. In Japan, the measurement of thyroglobulin and/or calcitonin in FNA needle washings is often used as an adjunct for diagnosis of possible cervical lymph node metastasis when FNA cytology is performed.

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Mohannad Rajab, Richard J. Payne, Véronique-Isabelle Forest, Marc Pusztaszeri
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Impact of Molecular Testing on the Management of Indeterminate Thyroid Nodules Among Western and Asian Countries: a Systematic Review and Meta-analysis
Hanh Thi Tuyet Ngo, Truong Phan Xuan Nguyen, Trang Huyen Vu, Chan Kwon Jung, Lewis Hassell, Kennichi Kakudo, Huy Gia Vuong
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The Incidence of Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features: A Meta-Analysis Assessing Worldwide Impact of the Reclassification
Chanchal Rana, Huy Gia Vuong, Thu Quynh Nguyen, Hoang Cong Nguyen, Chan Kwon Jung, Kennichi Kakudo, Andrey Bychkov
Thyroid.2021;[Epub] CrossRef
Ultrasound-guided Fine Needle Aspiration Cytological Examination of Thyroid Nodules: A Practical Guideline (2019 edition)

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Huy Gia Vuong, Hanh Thi Tuyet Ngo, Andrey Bychkov, Chan Kwon Jung, Trang Huyen Vu, Kim Bach Lu, Kennichi Kakudo, Tetsuo Kondo
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Exploring the Inter-observer Agreement Among the Members of the Italian Consensus for the Classification and Reporting of Thyroid Cytology
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Case Study

An Autopsy Case of Epstein-Barr Virus–Associated Diffuse Large B-Cell Lymphoma of the Central Nervous System in an Immunocompromised Host: Sun-Young Park, Seong Ik Kim, Hannah Kim, Yoojin Lee, Sung-Hye Park; J Pathol Transl Med. 2018;52(1):51-55. Published online August 4, 2017; DOI: https://doi.org/10.4132/jptm.2017.01.23

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174 Download
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1 Crossref

Abstract PDF

Lymphomas arising in the central nervous system (CNS) of immunocompromised hosts are most commonly non-Hodgkin’s lymphomas and are highly associated with Epstein-Barr virus (EBV). Here we report an autopsy case of EBV-associated CNS diffuse large B-cell lymphoma (DLBCL) in a host suffering from systemic lupus erythematosus who underwent immunosuppressive therapy. After autopsy, EBV-associated CNS DLBCL as well as pulmonary mixed aspergillosis and Pneumocystis jirovecii pneumonia were added to the cause of clinical manifestations of complicated pneumonia and cerebral hemorrhage in this immunocompromised patient. In conclusion, complex disease processes were revealed by autopsy in this case, indicating that the clinicopathological correlations observed through autopsy can improve our understanding of disease progression and contribute to the management of similar patients in the future.

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Primary central nervous system lymphoma in neuropsychiatric systemic lupus erythematosus: case-based review
Takanori Ichikawa, Yasuhiro Shimojima, Dai Kishida, Tomoki Kaneko, Yoshiki Sekijima
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Review

Molecular Testing of Lymphoproliferative Disorders: Current Status and Perspectives: Yoon Kyung Jeon, Sun Och Yoon, Jin Ho Paik, Young A Kim, Bong Kyung Shin, Hyun-Jung Kim, Hee Jeong Cha, Ji Eun Kim, Jooryung Huh, Young-Hyeh Ko; J Pathol Transl Med. 2017;51(3):224-241. Published online May 10, 2017; DOI: https://doi.org/10.4132/jptm.2017.04.09

22,375 View
712 Download
14 Web of Science
16 Crossref

Abstract PDF

Molecular pathologic testing plays an important role for the diagnosis, prognostication and decision of treatment strategy in lymphoproliferative disease. Here, we briefly review the molecular tests currently used for lymphoproliferative disease and those which will be implicated in clinical practice in the near future. Specifically, this guideline addresses the clonality test for B- and T-cell proliferative lesions, molecular cytogenetic tests for malignant lymphoma, determination of cell-of-origin in diffuse large B-cell lymphoma, and molecular genetic alterations incorporated in the 2016 revision of the World Health Organization classification of lymphoid neoplasms. Finally, a new perspective on the next-generation sequencing for diagnostic, prognostic, and therapeutic purpose in malignant lymphoma will be summarized.

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Original Articles

An Experimental Infarct Targeting the Internal Capsule: Histopathological and Ultrastructural Changes: Chang-Woo Han, Kyung-Hwa Lee, Myung Giun Noh, Jin-Myung Kim, Hyung-Seok Kim, Hyung-Sun Kim, Ra Gyung Kim, Jongwook Cho, Hyoung-Ihl Kim, Min-Cheol Lee; J Pathol Transl Med. 2017;51(3):292-305. Published online May 10, 2017; DOI: https://doi.org/10.4132/jptm.2017.02.17

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Abstract PDF

Background
Stroke involving the cerebral white matter (WM) has increased in prevalence, but most experimental studies have focused on ischemic injury of the gray matter. This study was performed to investigate the WM in a unique rat model of photothrombotic infarct targeting the posterior limb of internal capsule (PLIC), focusing on the identification of the most vulnerable structure in WM by ischemic injury, subsequent glial reaction to the injury, and the fundamental histopathologic feature causing different neurologic outcomes.
Methods
Light microscopy with immunohistochemical stains and electron microscopic examinations of the lesion were performed between 3 hours and 21 days post-ischemic injury.
Results
Initial pathological change develops in myelinated axon, concomitantly with reactive change of astrocytes. The first pathology to present is nodular loosening to separate the myelin sheath with axonal wrinkling. Subsequent pathologies include rupture of the myelin sheath with extrusion of axonal organelles, progressive necrosis, oligodendrocyte degeneration and death, and reactive gliosis. Increase of glial fibrillary acidic protein (GFAP) immunoreactivity is an early event in the ischemic lesion. WM pathologies result in motor dysfunction. Motor function recovery after the infarct was correlated to the extent of PLIC injury proper rather than the infarct volume.
Conclusions
Pathologic changes indicate that the cerebral WM, independent of cortical neurons, is highly vulnerable to the effects of focal ischemia, among which myelin sheath is first damaged. Early increase of GFAP immunoreactivity indicates that astrocyte response initially begins with myelinated axonal injury, and supports the biologic role related to WM injury or plasticity. The reaction of astrocytes in the experimental model might be important for the study of pathogenesis and treatment of the WM stroke.

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Neuroglia and immune cells play different roles in neuroinflammation and neuroimmune response in post-stroke neural injury and repair
Hui Guo, Wen-cao Liu, Yan-yun Sun, Xin-chun Jin, Pan-pan Geng
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Animal models of focal ischemic stroke: brain size matters
Blazej Nowak, Piotr Rogujski, Raphael Guzman, Piotr Walczak, Anna Andrzejewska, Miroslaw Janowski
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Motor Cortex Plasticity During Functional Recovery Following Brain Damage
Noriyuki Higo
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Tatiana Anan’ina, Alena Kisel, Marina Kudabaeva, Galina Chernysheva, Vera Smolyakova, Konstantin Usov, Elena Krutenkova, Mark Plotnikov, Marina Khodanovich
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Marina Y Khodanovich, Alena A Kisel, Andrey E Akulov, Dmitriy N Atochin, Marina S Kudabaeva, Valentina Y Glazacheva, Michael V Svetlik, Yana A Medvednikova, Lilia R Mustafina, Vasily L Yarnykh
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Dominik Michalski, Anna L. Keck, Jens Grosche, Henrik Martens, Wolfgang Härtig
Frontiers in Cellular Neuroscience.2018;[Epub] CrossRef
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Xiaohui Wang, Rongwen Li, Alex Zacharek, Julie Landschoot-Ward, Fengjie Wang, Kuan-Han Hank Wu, Michael Chopp, Jieli Chen, Xu Cui
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A Small Case Series of Intravascular Large B-Cell Lymphoma with Unexpected Findings: Subset of Cases with Concomitant Extravascular Central Nervous System (CNS) Involvement Mimicking Primary CNS Lymphoma: Kate Poropatich, Dave Dittmann, Yi-Hua Chen, Kirtee Raparia, Kristy Wolniak, Juehua Gao; J Pathol Transl Med. 2017;51(3):284-291. Published online April 17, 2017; DOI: https://doi.org/10.4132/jptm.2017.02.16

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Abstract PDF

Background
Intravascular large B-cell lymphoma (IVLBCL) is a rare type of extranodal lymphoma with growth mainly in the lumina of vessels. We studied a small series of IVLBCL and focused on its central nervous system (CNS) involvement.
Methods
Searching the medical records of Northwestern Memorial Hospital, we identified five cases of IVLBCL from January 2007 to January 2015. Clinical information, hematoxylin and eosin stained histologic slides and immunohistochemistry studies were reviewed for all cases. Polymerase chain reaction (PCR) analysis for the immunoglobulin (Ig) heavy and light chain gene rearrangement was performed on all five cases.
Results
Three of the five cases of IVLBCL were autopsies. Patients’ age ranged from 56 to 84. CNS involvement was present in two cases—in both patients, the CNS involvement showed an extravascular pattern with confluent sheet-like formation. PCR analysis confirmed that in one case the systemic intravascular and CNS extravascular components were clonally identical.
Conclusions
In a small case series of IVLBCL, we observed that CNS involvement by IVLBCL often has an extravascular morphology, but is clonally identical to the intravascular counterpart by PCR analysis. As IVLBCL can have a rapidly progressing poor outcome, it should be kept in the differential diagnoses for patients presenting with lymphoma of the CNS. The presence of extravascular growth patterns in the CNS should not exclude IVLBCL as a diagnosis.

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