Journal of Pathology and Translational Medicine

Original Articles

Usefulness of BRAF VE1 immunohistochemistry in non–small cell lung cancers: a multi-institutional study by 15 pathologists in Korea: Sunhee Chang, Yoon-La Choi, Hyo Sup Shim, Geon Kook Lee, Seung Yeon Ha; J Pathol Transl Med. 2022;56(6):334-341. Published online October 27, 2022; DOI: https://doi.org/10.4132/jptm.2022.08.22

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Background
Next-generation sequencing (NGS) is an approved test to select patients for BRAF V600E targeted therapy in Korea. However, the high cost, long turnaround times, and the need for sophisticated equipment and skilled personnel limit the use of NGS in daily practice. Immunohistochemistry (IHC) is a rapid and relatively inexpensive assay available in most laboratories. Therefore, in this study, we evaluate the usefulness of BRAF VE1 IHC in terms of predictive value and interobserver agreement in non–small cell lung cancers (NSCLCs).
Methods
A total of 30 cases with known BRAF mutation status were selected, including 20 cases of lung adenocarcinomas, six cases of colorectal adenocarcinomas, and four cases of papillary thyroid carcinomas. IHC for BRAF V600E was carried out using the VE1 antibody. Fifteen pathologists independently scored both the staining intensity and the percentage of tumor cell staining on whole slide images.
Results
In the lung adenocarcinoma subset, interobserver agreement for the percentage of tumor cell staining and staining intensity was good (percentage of tumor cell staining, intraclass correlation coefficient = 0.869; staining intensity, kappa = 0.849). The interobserver agreement for the interpretation using the cutoff of 40% was almost perfect in the entire study group and the lung adenocarcinoma subset (kappa = 0.815). Sensitivity, specificity, positive predictive value, and negative predictive value of BRAF VE1 IHC were 80.0%, 90.0%, 88.9%, and 81.8%, respectively.
Conclusions
BRAF VE1 IHC could be a screening test for the detection of BRAF V600E mutation in NSCLC. However, further studies are needed to optimize the protocol and to establish and validate interpretation criteria for BRAF VE1 IHC.

Citations

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Dedifferentiated Leiomyosarcoma of the Uterine Corpus with Heterologous Component: Clinicopathological Analysis of Five Consecutive Cases from a Single Institution and Comprehensive Literature Review
Suyeon Kim, Hyunsik Bae, Hyun-Soo Kim
Diagnostics.2024; 14(2): 160. CrossRef
Differentiating BRAF V600E- and RAS-like alterations in encapsulated follicular patterned tumors through histologic features: a validation study
Chankyung Kim, Shipra Agarwal, Andrey Bychkov, Jen-Fan Hang, Agnes Stephanie Harahap, Mitsuyoshi Hirokawa, Kennichi Kakudo, Somboon Keelawat, Chih-Yi Liu, Zhiyan Liu, Truong Phan-Xuan Nguyen, Chanchal Rana, Huy Gia Vuong, Yun Zhu, Chan Kwon Jung
Virchows Archiv.2024;[Epub] CrossRef
BRAF V600E Mutation of Non-Small Cell Lung Cancer in Korean Patients
Hyo Yeong Ahn, Chang Hun Lee, Min Ki Lee, Jung Seop Eom, Yeon Joo Jeong, Yeong Dae Kim, Jeong Su Cho, Jonggeun Lee, So Jeong Lee, Dong Hoon Shin, Ahrong Kim
Medicina.2023; 59(6): 1085. CrossRef
Reevaluating diagnostic categories and associated malignancy risks in thyroid core needle biopsy
Chan Kwon Jung
Journal of Pathology and Translational Medicine.2023; 57(4): 208. CrossRef

Interobserver diagnostic reproducibility in advanced-stage endometrial carcinoma: Ho Jin Jung, Soo Yeon Lee, Jin Hwa Hong, Yi Kyeong Chun; J Pathol Transl Med. 2021;55(1):43-52. Published online December 3, 2020; DOI: https://doi.org/10.4132/jptm.2020.10.04

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Abstract PDF

Background
The accurate pathologic diagnosis and subtyping of high-grade endometrial carcinoma are often problematic, due to its atypical and overlapping histopathological features.
Methods
Three pathologists reviewed 21 surgically resected cases of advancedstage endometrial carcinoma. The primary diagnosis was based only on hematoxylin and eosin stained slides. When a discrepancy arose, a secondary diagnosis was made by additional review of immunohistochemical (IHC) stains. Finally, three pathologists discussed all cases and rendered a consensus diagnosis.
Results
The primary diagnoses were identical in 13/21 cases (62%). The secondary diagnosis based on the addition of IHC results was concordant in four of eight discrepant cases. Among four cases with discrepancies occurring in this step, two cases subsequently reached a consensus diagnosis after a thorough discussion between three reviewers. Next-generation sequencing (NGS) study was performed in two cases in which it was difficult to distinguish between serous carcinoma and endometrioid carcinoma. Based on the sequencing results, a final diagnosis of serous carcinoma was rendered. The overall kappa for concordance between the original and consensus diagnosis was 0.566 (moderate agreement).
Conclusions
We investigated stepwise changes in interobserver diagnostic reproducibility in advanced-stage endometrial carcinoma. We demonstrated the utility of IHC and NGS study results in the histopathological diagnosis of advanced-stage endometrial carcinoma.

Citations

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Accuracy of endometrial sampling in the diagnosis of endometrial cancer: a multicenter retrospective analysis of the JAGO-NOGGO
Zaher Alwafai, Maximilian Heinz Beck, Sepideh Fazeli, Kathleen Gürtler, Christine Kunz, Juliane Singhartinger, Dominika Trojnarska, Dario Zocholl, David Johannes Krankenberg, Jens-Uwe Blohmer, Jalid Sehouli, Klaus Pietzner
BMC Cancer.2024;[Epub] CrossRef
Application of NGS molecular classification in the diagnosis of endometrial carcinoma: A supplement to traditional pathological diagnosis
Qunxian Rao, Jianwei Liao, Yangyang Li, Xin Zhang, Guocai Xu, Changbin Zhu, Shengya Tian, Qiuhong Chen, Hui Zhou, Bingzhong Zhang
Cancer Medicine.2023; 12(5): 5409. CrossRef
Risk Stratification of Endometrial Cancer Patients: FIGO Stage, Biomarkers and Molecular Classification
Jenneke C. Kasius, Johanna M. A. Pijnenborg, Kristina Lindemann, David Forsse, Judith van Zwol, Gunnar B. Kristensen, Camilla Krakstad, Henrica M. J. Werner, Frédéric Amant
Cancers.2021; 13(22): 5848. CrossRef

Interobserver Reproducibility of PD-L1 Biomarker in Non-small Cell Lung Cancer: A Multi-Institutional Study by 27 Pathologists: Sunhee Chang, Hyung Kyu Park, Yoon-La Choi, Se Jin Jang; J Pathol Transl Med. 2019;53(6):347-353. Published online October 28, 2019; DOI: https://doi.org/10.4132/jptm.2019.09.29

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Abstract PDF

Background
Assessment of programmed cell death-ligand 1 (PD-L1) immunohistochemical staining is used for treatment decisions in non-small cell lung cancer (NSCLC) regarding use of PD-L1/programmed cell death protein 1 (PD-1) immunotherapy. The reliability of the PD-L1 22C3 pharmDx assay is critical in guiding clinical practice. The Cardiopulmonary Pathology Study Group of the Korean Society of Pathologists investigated the interobserver reproducibility of PD-L1 staining with 22C3 pharmDx in NSCLC samples.
Methods
Twenty-seven pathologists individually assessed the tumor proportion score (TPS) for 107 NSCLC samples. Each case was divided into three levels based on TPS: <1%, 1%–49%, and ≥50%.
Results
The intraclass correlation coefficient for TPS was 0.902±0.058. Weighted κ coefficient for 3-step assessment was 0.748±0.093. The κ coefficients for 1% and 50% cut-offs were 0.633 and 0.834, respectively. There was a significant association between interobserver reproducibility and experience (formal PD-L1 training, more experience for PD-L1 assessment, and longer practice duration on surgical pathology), histologic subtype, and specimen type.
Conclusions
Our results indicate that PD-L1 immunohistochemical staining provides a reproducible basis for decisions on anti–PD-1 therapy in NSCLC.

Citations

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Xinran Wang, Jiankun He, Jinze Li, Chun Wu, Meng Yue, Shuyao Niu, Ying Jia, Zhanli Jia, Lijing Cai, Yueping Liu
Journal of Cancer Research and Clinical Oncology.2024;[Epub] CrossRef
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Hiroaki Ito, Akihiko Yoshizawa, Kazuhiro Terada, Akiyoshi Nakakura, Mariyo Rokutan-Kurata, Tatsuhiko Sugimoto, Kazuya Nishimura, Naoki Nakajima, Shinji Sumiyoshi, Masatsugu Hamaji, Toshi Menju, Hiroshi Date, Satoshi Morita, Ryoma Bise, Hironori Haga
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Angels Barberà, Juan González, Montserrat Martin, Jose L. Mate, Albert Oriol, Fina Martínez-Soler, Tomas Santalucia, Pedro Luis Fernández
Applied Immunohistochemistry & Molecular Morphology.2023; 31(9): 607. CrossRef
A practical approach for PD-L1 evaluation in gastroesophageal cancer
Valentina Angerilli, Matteo Fassan, Paola Parente, Irene Gullo, Michela Campora, Chiara Rossi, Maria Luisa Sacramento, Gianmaria Pennelli, Alessandro Vanoli, Federica Grillo, Luca Mastracci
Pathologica.2023; 115(2): 57. CrossRef
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Artificial intelligence-assisted system for precision diagnosis of PD-L1 expression in non-small cell lung cancer
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Immunohistochemistry as predictive and prognostic markers for gastrointestinal malignancies
Matthew W. Rosenbaum, Raul S. Gonzalez
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Sangjoon Choi, Sujin Park, Hyunjin Kim, So Young Kang, Soomin Ahn, Kyoung-Mee Kim
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Development and validation of a supervised deep learning algorithm for automated whole‐slide programmed death‐ligand 1 tumour proportion score assessment in non‐small cell lung cancer
Liesbeth M Hondelink, Melek Hüyük, Pieter E Postmus, Vincent T H B M Smit, Sami Blom, Jan H von der Thüsen, Danielle Cohen
Histopathology.2022; 80(4): 635. CrossRef
5-hmC loss is another useful tool in addition to BAP1 and MTAP immunostains to distinguish diffuse malignant peritoneal mesothelioma from reactive mesothelial hyperplasia in peritoneal cytology cell-blocks and biopsies
Ziyad Alsugair, Vahan Kepenekian, Tanguy Fenouil, Olivier Glehen, Laurent Villeneuve, Sylvie Isaac, Juliette Hommell-Fontaine, Nazim Benzerdjeb
Virchows Archiv.2022; 481(1): 23. CrossRef
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Sangjoon Choi, Soo Ick Cho, Minuk Ma, Seonwook Park, Sergio Pereira, Brian Jaehong Aum, Seunghwan Shin, Kyunghyun Paeng, Donggeun Yoo, Wonkyung Jung, Chan-Young Ock, Se-Hoon Lee, Yoon-La Choi, Jin-Haeng Chung, Tony S. Mok, Hyojin Kim, Seokhwi Kim
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Artificial Intelligence-Assisted Score Analysis for Predicting the Expression of the Immunotherapy Biomarker PD-L1 in Lung Cancer
Guoping Cheng, Fuchuang Zhang, Yishi Xing, Xingyi Hu, He Zhang, Shiting Chen, Mengdao Li, Chaolong Peng, Guangtai Ding, Dadong Zhang, Peilin Chen, Qingxin Xia, Meijuan Wu
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High interobserver and intraobserver reproducibility among pathologists assessing PD‐L1 CPS across multiple indications
Shanthy Nuti, Yiwei Zhang, Nabila Zerrouki, Charlotte Roach, Gudrun Bänfer, George L Kumar, Edward Manna, Rolf Diezko, Kristopher Kersch, Josef Rüschoff, Bharat Jasani
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Modifying factors of PD‐L1 expression on tumor cells in advanced non‐small‐cell lung cancer
Alejandro Avilés‐Salas, Diana Flores‐Estrada, Luis Lara‐Mejía, Rodrigo Catalán, Graciela Cruz‐Rico, Mario Orozco‐Morales, David Heredia, Laura Bolaño‐Guerra, Pamela Denisse Soberanis‐Piña, Edgar Varela‐Santoyo, Andrés F. Cardona, Oscar Arrieta
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Case Study

Encapsulated Papillary Thyroid Tumor with Delicate Nuclear Changes and a KRAS Mutation as a Possible Novel Subtype of Borderline Tumor: Kenji Ohba, Norisato Mitsutake, Michiko Matsuse, Tatiana Rogounovitch, Nobuhiko Nishino, Yutaka Oki, Yoshie Goto, Kennichi Kakudo; J Pathol Transl Med. 2019;53(2):136-141. Published online January 14, 2019; DOI: https://doi.org/10.4132/jptm.2018.12.07

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Abstract PDF

Although papillary thyroid carcinoma (PTC)–type nuclear changes are the most reliable morphological feature in the diagnosis of PTC, the nuclear assessment used to identify these changes is highly subjective. Here, we report a noninvasive encapsulated thyroid tumor with a papillary growth pattern measuring 23 mm at its largest diameter with a nuclear score of 2 in a 26-year-old man. After undergoing left lobectomy, the patient was diagnosed with an encapsulated PTC. However, a second opinion consultation suggested an alternative diagnosis of follicular adenoma with papillary hyperplasia. When providing a third opinion, we identified a low MIB-1 labeling index and a heterozygous point mutation in the KRAS gene but not the BRAF gene. We speculated that this case is an example of a novel borderline tumor with a papillary structure. Introduction of the new terminology “noninvasive encapsulated papillary RAS-like thyroid tumor (NEPRAS)” without the word “cancer” might relieve the psychological burden of patients in a way similar to the phrase “noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP).”

Citations

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The Asian Thyroid Working Group, from 2017 to 2023
Kennichi Kakudo, Chan Kwon Jung, Zhiyan Liu, Mitsuyoshi Hirokawa, Andrey Bychkov, Huy Gia Vuong, Somboon Keelawat, Radhika Srinivasan, Jen-Fan Hang, Chiung-Ru Lai
Journal of Pathology and Translational Medicine.2023; 57(6): 289. CrossRef
Whole Tumor Capsule Is Prognostic of Very Good Outcome in the Classical Variant of Papillary Thyroid Cancer
Carlotta Giani, Liborio Torregrossa, Teresa Ramone, Cristina Romei, Antonio Matrone, Eleonora Molinaro, Laura Agate, Gabriele Materazzi, Paolo Piaggi, Clara Ugolini, Fulvio Basolo, Raffaele Ciampi, Rossella Elisei
The Journal of Clinical Endocrinology & Metabolism.2021; 106(10): e4072. CrossRef
Evidence of Cooperation between Hippo Pathway and RAS Mutation in Thyroid Carcinomas
Thaise Nayane Ribeiro Carneiro, Larissa Valdemarin Bim, Vanessa Candiotti Buzatto, Vanessa Galdeno, Paula Fontes Asprino, Eunjung Alice Lee, Pedro Alexandre Favoretto Galante, Janete Maria Cerutti
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Capsular Invasion Matters Also in “Papillary Patterned” Tumors: A Study on 121 Cases of Encapsulated Conventional Variant of Papillary Thyroid Carcinoma
Dilara Akbulut, Ezgi Dicle Kuz, Nazmiye Kursun, Serpil Dizbay Sak
Endocrine Pathology.2021; 32(3): 357. CrossRef
Noninvasive encapsulated papillary RAS-like thyroid tumor (NEPRAS) or encapsulated papillary thyroid carcinoma (PTC)
Pedro Weslley Rosario
Journal of Pathology and Translational Medicine.2020; 54(3): 263. CrossRef
Updates in the Pathologic Classification of Thyroid Neoplasms: A Review of the World Health Organization Classification
Yanhua Bai, Kennichi Kakudo, Chan Kwon Jung
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Original Articles

Interobserver Variability of Ki-67 Measurement in Breast Cancer: Yul Ri Chung, Min Hye Jang, So Yeon Park, Gyungyub Gong, Woo-Hee Jung, The Korean Breast Pathology Ki- Study Group; J Pathol Transl Med. 2016;50(2):129-137. Published online February 15, 2016; DOI: https://doi.org/10.4132/jptm.2015.12.24

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Abstract PDF

Background
As measurement of Ki-67 proliferation index is an important part of breast cancer diagnostics, we conducted a multicenter study to examine the degree of concordance in Ki-67 counting and to find factors that lead to its variability. Methods: Thirty observers from thirty different institutions reviewed Ki-67–stained slides of 20 different breast cancers on whole sections and tissue microarray (TMA) by online system. Ten of the 20 breast cancers had hot spots of Ki-67 expression. Each observer scored Ki-67 in two different ways: direct counting (average vs. hot spot method) and categorical estimation. Intraclass correlation coefficient (ICC) of Ki-67 index was calculated for comparative analysis. Results: For direct counting, ICC of TMA was slightly higher than that of whole sections using average method (0.895 vs 0.858). The ICC of tumors with hot spots was lower than that of tumors without (0.736 vs 0.874). In tumors with hot spots, observers took an additional counting from the hot spot; the ICC of whole sections using hot spot method was still lower than that of TMA (0.737 vs 0.895). In categorical estimation, Ki-67 index showed a wide distribution in some cases. Nevertheless, in tumors with hot spots, the range of distribution in Ki-67 categories was decreased with hot spot method and in TMA platform. Conclusions: Interobserver variability of Ki-67 index for direct counting and categorical estimation was relatively high. Tumors with hot spots showed greater interobserver variability as opposed to those without, and restricting the measurement area yielded lower interobserver variability.

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Practical approaches to automated digital image analysis of Ki-67 labeling index in 997 breast carcinomas and causes of discordance with visual assessment
Ah-Young Kwon, Ha Young Park, Jiyeon Hyeon, Seok Jin Nam, Seok Won Kim, Jeong Eon Lee, Jong-Han Yu, Se Kyung Lee, Soo Youn Cho, Eun Yoon Cho, Irina V. Lebedeva
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Interobserver Variability in Diagnosing High-Grade Neuroendocrine Carcinoma of the Lung and Comparing It with the Morphometric Analysis: Seung Yeon Ha, Joungho Han, Wan-Seop Kim, Byung Seong Suh, Mee Sook Roh; Korean J Pathol. 2012;46(1):42-47. Published online February 23, 2012; DOI: https://doi.org/10.4132/KoreanJPathol.2012.46.1.42

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Abstract PDF

Background

Distinguishing small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC) of the lung is difficult with little information about interobserver variability.

Methods

One hundred twenty-nine cases of resected SCLC and LCNEC were independently evaluated by four pathologists and classified according to the 2004 World Health Organization criteria. Agreement was regarded as "unanimous" if all four pathologists agreed on the classification. The kappa statistic was calculated to measure the degree of agreement between pathologists. We also measured cell size using image analysis, and receiver-operating-characteristic curve analysis was performed to evaluate cell size in predicting the diagnosis of high-grade neuroendocrine (NE) carcinomas in 66 cases.

Results

Unanimous agreement was achieved in 55.0% of 129 cases. The kappa values ranged from 0.35 to 0.81. Morphometric analysis reaffirmed that there was a continuous spectrum of cell size from SCLC to LCNEC and showed that tumors with cells falling in the middle size range were difficult to categorize and lacked unanimous agreement.

Conclusions

Our results provide an objective explanation for considerable interobserver variability in the diagnosis of high-grade pulmonary NE carcinomas. Further studies would need to define more stringent and objective definitions of cytologic and architectural characteristics to reliably distinguish between SCLC and LCNEC.

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The Interobserver Variability for Diagnosing Pulmonary Carcinoid Tumor.: Chang Hun Lee, Hee Kyung Chang, Hyoun Wook Lee, Dong Hoon Shin, Mee Sook Roh; Korean J Pathol. 2010;44(3):267-271.; DOI: https://doi.org/10.4132/KoreanJPathol.2010.44.3.267

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Abstract PDF

BACKGROUND
Although the grade of pulmonary carcinoid tumor is routinely reported in pathology practice, there is a paucity of data on the level of agreement between pathologists.
METHODS
Data for 30 cases of surgically resected pulmonary tumors diagnosed as carcinoid tumors (19 typical carcinoids [TCs] and 11 atypical carcinoids [ACs]) were retrieved from four university hospitals. These cases were independently evaluated by five pathologists and were classified according to the 2004 World Health Organization (WHO) classification. Agreement was regarded as "unanimous" if all five pathologists agreed, and as a "majority" if four agreed. The kappa statistic was calculated to measure the degree of agreement between pathologists.
RESULTS
Unanimous agreement was achieved for 50.0% and a majority agreement for 83.3% of the 30 cases. The range of the kappa values extended from 0.37 to 0.89. After a consensus meeting, there was disagreement between the original diagnosis by each institute and the consensus diagnosis by the five pathologists for 40.0% of the 30 cases. Based on the consensus diagnosis, the agreement was greater for TCs than that for ACs.
CONCLUSIONS
Discriminating carcinoid tumors is subject to interobserver variability. This study indicates that there is a need for more careful standardization and application of diagnostic criteria for making the diagnosis of pulmonary carcinoid tumor.

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