Journal of Pathology and Translational Medicine

Volume 55(5); September 2021

Original Articles

SMARCA4/BRG1 protein-deficient thoracic tumors dictate re-examination of small biopsy reporting in non–small cell lung cancer: Anurag Mehta, Divya Bansal, Rupal Tripathi, Ankush Jajodia; J Pathol Transl Med. 2021;55(5):307-316. Published online June 21, 2021; DOI: https://doi.org/10.4132/jptm.2021.05.11

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Background
SMARCA4/BRG1 protein–deficient lung adenocarcinomas and thoracic sarcoma are recently described entities that lack distinctive histological features, transcription termination factor 1 (TTF1) reactivity, and actionable driver mutations. The current diagnostic path for small lung biopsies as recommended by the World Health Organization (WHO, 2015) is likely to categorize these as non– small cell carcinoma–not otherwise specified (NSCC-NOS). The present study attempts to define the subtle but distinctive clinicopathologic features of SMARCA4/BRG1 protein-deficient thoracic tumors; highlight their unique biology; and addresses the unmet need to segregate these using a new, tissue-proficient diagnostic pathway.
Methods
All lung biopsies and those from metastatic sites in patients with suspected advanced lung cancer and classified as NSCC-NOS as per WHO (2015) guidelines were subjected to BRG1 testing by immunohistochemistry. SMARCA4/BRG1 protein–deficient thoracic tumors were evaluated by an extended immunohistochemistry panel. Predictive biomarker and programmed death–ligand 1 testing was conducted in all cases.
Results
Of 110 cases, nine were found to be SMARCA4/BRG1 protein-deficient; six were identified as SMARCA4/BRG1 protein–deficient lung adenocarcinomas, and three were SMARCA4/BRG1 protein-deficient thoracic sarcomas. The histology ranged from poorly differentiated to undifferentiated to rhabdoid. None of the cases showed significant expression of TTF1 or p40, and no actionable mutation was identified.
Conclusions
It is difficult to separate BRG1-deficient lung adenocarcinomas and thoracic sarcomas based on morphology alone. We propose a diagnostic pathway for small biopsies of thoracic tumors to segregate these distinct entities so that they can be studied more efficaciously for new biomarkers and therapeutic options.

Citations

Citations to this article as recorded by

Clinicopathologic and genomic analyses of SMARCA4-mutated non-small cell lung carcinoma implicate the needs for tailored treatment strategies
Bokyung Ahn, Deokhoon Kim, Wonjun Ji, Sung-Min Chun, Goeun Lee, Se Jin Jang, Hee Sang Hwang
Lung Cancer.2025; 201: 108445. CrossRef
SMARCA4-deficient non-small cell lung cancer with metastasis to the sigmoid colon: a case report
Rong Xiao, Guang Fu, Xinglan Li, Tao Lu
World Journal of Surgical Oncology.2025;[Epub] CrossRef
Unravelling switch/sucrose non-fermentable (SWI-SNF) complex-deficient thoracic tumours: a clinicopathological comparative on undifferentiated tumours and non-small cell lung carcinomas with BRG1 and BRM deficiency
Ridhi Sood, Arshi Tandon, Warisa Khatoon, Jayashimman Vasanthraman, Aruna Nambirajan, Anant Mohan, Prabhat Singh Malik, Deepali Jain
Journal of Clinical Pathology.2024; : jcp-2024-209619. CrossRef
Case report: The first account of undifferentiated sarcoma with epithelioid features originating in the pleura
Ling-Xi Xiao, Li Liu, Wang Deng
Frontiers in Medicine.2024;[Epub] CrossRef
SMARCA4-deficient central nervous system metastases: A case series and systematic review
Meaghan Morris, Kerime Ararat, Hannah Cutshall, Murat Gokden, Analiz Rodriguez, Lisa Rooper, Matthew Lindberg, James Stephen Nix
Journal of Neuropathology & Experimental Neurology.2024; 83(8): 638. CrossRef
Chemotherapy and Immune Checkpoint Inhibitors in a Case of SMARCA4-dUT: A Case Report and Review of Literature
Akriti Pokhrel, Ruchi Yadav, Kapil Kumar Manvar, Richard Wu, Vijay Jaswani, Carrie Brooke Wasserman, Jen C. Wang
Journal of Investigative Medicine High Impact Case Reports.2023;[Epub] CrossRef
TTF1-positive SMARCA4/BRG1 deficient lung adenocarcinoma
Anurag Mehta, Himanshi Diwan, Divya Bansal, Manoj Gupta
Journal of Pathology and Translational Medicine.2022; 56(1): 53. CrossRef
Delineation of a SMARCA4-specific competing endogenous RNA network and its function in hepatocellular carcinoma
Lei Zhang, Ting Sun, Xiao-Ye Wu, Fa-Ming Fei, Zhen-Zhen Gao
World Journal of Clinical Cases.2022; 10(29): 10501. CrossRef
Artificial intelligence platform, RADR®, aids in the discovery of DNA damaging agent for the ultra-rare cancer Atypical Teratoid Rhabdoid Tumors
Joseph McDermott, Drew Sturtevant, Umesh Kathad, Sudhir Varma, Jianli Zhou, Aditya Kulkarni, Neha Biyani, Caleb Schimke, William C. Reinhold, Fathi Elloumi, Peter Carr, Yves Pommier, Kishor Bhatia
Frontiers in Drug Discovery.2022;[Epub] CrossRef

Proto-oncogene Pokemon in thyroid cancer: a potential promoter of tumorigenesis in papillary thyroid carcinoma: Kyungseek Chang, Sung-Im Do, Kyungeun Kim, Seoung Wan Chae, In-gu Do, Hyun Joo Lee, Dong Hoon Kim, Jin Hee Sohn; J Pathol Transl Med. 2021;55(5):317-323. Published online August 9, 2021; DOI: https://doi.org/10.4132/jptm.2021.06.28

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Abstract PDF Supplementary Material

Background
Pokemon is an oncogenic transcription regulator that plays a critical role in cellular differentiation. Although it has been found to be overexpressed in several types of cancer involving different organs, its role in thyroid gland has yet to be reported. The objective of this study was to evaluate the expression of Pokemon in papillary thyroid carcinoma (PTC) based on clinicopathological parameters.
Methods
Tissue microarray samples derived from patients with PTC or benign thyroid disease were used to evaluate Pokemon expression based on immunohistochemical analysis. Correlations of its expression with various clinicopathological parameters were then analyzed.
Results
Pokemon expression was observed in 22.0% of thyroid follicular cells from the normal group, 44.0% from the group with benign thyroid diseases, and 92.1% from the group with PTC (p < .001). The intensity of Pokemon expression was markedly higher in the PTC group. Pokemon expression level and PTC tumor size showed an inverse correlation. T1a tumors showed strong expression levels of Pokemon. However, larger tumors showed weak expression (p = .006).
Conclusions
Pokemon expression is associated with tumorigenesis of PTC, with expression showing an inverse correlation with PTC tumor size. This might be related to the negative regulation of aerobic glycolysis by Pokemon.

Citations

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ZBTB7A as a therapeutic target for cancer
Ying Zhou, Xisha Chen, Xuyu Zu
Biochemical and Biophysical Research Communications.2024; 736: 150888. CrossRef
Knockdown of FBI-1 Inhibits the Warburg Effect and Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Molecular Targeted Agents via miR-3692/HIF-1α
Juan Liu, Chao Yang, Xiao-Mei Huang, Pan-Pan Lv, Ya-Kun Yang, Jin-Na Zhao, Si-Yuan Zhao, Wan-Jun Sun
Frontiers in Oncology.2021;[Epub] CrossRef

Robust home brew fragment sizing assay for detection of MET exon 14 skipping mutation in non–small cell lung cancer patients in resource constrained community hospitals: Anurag Mehta, Shrinidhi Nathany, Aanchal Chopra, Sakshi Mattoo, Dushyant Kumar, Manoj Kumar Panigrahi; J Pathol Transl Med. 2021;55(5):324-329. Published online September 2, 2021; DOI: https://doi.org/10.4132/jptm.2021.07.15

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Abstract PDF

Background
A mutation/deletion involving donor or acceptor sites for exon 14 results in splicing out of exon 14 of the mesenchymal epithelial transition (MET) gene and is known as “MET exon 14 skipping” (ΔMET14). The two recent approvals with substantial objective responses and improved progression-free survival to MET inhibitors namely capmatinib and tepotinib necessitate the identification of this alteration upfront. We herein describe our experience of ΔMET14 detection by an mRNA-based assay using polymerase chain reaction followed by fragment sizing.
Methods
This is a home brew assay which was developed with the concept that the transcripts from true ΔMET14 will be shorter by ~140 bases than their wild type counterparts. The cases which were called MET exon 14 skipping positive on next-generation sequencing (NGS) were subjected to this assay, along with 13 healthy controls in order to establish the validity for true negatives.
Results
Thirteen cases of ΔMET14 mutation were detected on NGS using RNA-based sequencing. Considering NGS as a gold standard, the sizing assay using both gel and capillary electrophoresis that showed 100% specificity for both with concordance rates of 84.6% and 88.2% with NGS, respectively, were obtained.
Conclusions
Owing to the cost-effective nature and easy to use procedures, this assay will prove beneficial for small- and medium-sized laboratories where skilled technical personnel and NGS platforms are unavailable.

Citations

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MET
Shrinidhi Nathany, Ullas Batra
Cancer Research, Statistics, and Treatment.2022; 5(2): 284. CrossRef

Upward trend in follicular lymphoma among the Korean population: 10-year experience at a large tertiary institution: Meejeong Kim, Hee Sang Hwang, Hyungwoo Cho, Dok Hyun Yoon, Cheolwon Suh, Chan Sik Park, Heounjeong Go, Jooryung Huh; J Pathol Transl Med. 2021;55(5):330-337. Published online September 2, 2021; DOI: https://doi.org/10.4132/jptm.2021.07.25

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Abstract PDF Supplementary Material

Background
Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma (NHL) in Western countries. However, it is relatively rare in Asia. This study examined epidemiologic characteristics of FL in South Korea, with an emphasis on recent trends of increase in cases.
Methods
We retrospectively examined 239 cases of newly diagnosed FL at a large tertiary institution in Korea (Asan Medical Center, Seoul, Republic of Korea) between 2008 and 2017. Age-adjusted incidence rates and clinicopathological variables were analyzed, and joinpoint regression analysis was used to identify the changes.
Results
The age-adjusted incidence of FL significantly increased during the study period (p = .034), and the ratio of (relative incidence) patients with FL to patients with NHL increased from 4.28% to 9.35% in the same period. Over the 10-year study assessment duration, the proportion of patients with stage III/IV FL (p = .035) and expression of BCL2 (p = .022) or BCL6 (p = .039) significantly increased. From 2013–2017, the proportion of patients with highrisk Follicular Lymphoma International Prognostic Index (FLIPI) score increased (21.5% to 28.7%), whereas that of low-risk FLIPI decreased (55.4% to 38.6%), although those results were not statistically significant (p = .066).
Conclusions
We found an increasing incidence of FL, with a disproportionate increase in the incidence of high-stage disease and recent changes in the clinicopathologic features of the Korean patient population.

Citations

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Incidence Trend of Follicular Lymphoma in Taiwan Compared to Japan and Korea, 2001–2019
Liang-Chun Chiu, Chih-Wen Lin, Hung-Ju Li, Jian-Han Chen, Fu-Cheng Chuang, Sheng-Fung Lin, Yu Chang, Yu-Chieh Su
Journal of Clinical Medicine.2023; 12(4): 1417. CrossRef
A Case Report on the Complete Response of a Patient with Recurrent Follicular Lymphoma Treated with Integrative Medicine
Kyung-dug Park, Jisoo Kim, Yoona Oh, Beom-Jin Jeong, Yu-jin Jung, Sunhwi Bang
The Journal of Internal Korean Medicine.2023; 44(3): 585. CrossRef
Recent Updates on Diagnosis and Treatment of Follicular Lymphoma
Ga-Young Song, Deok-Hwan Yang
The Korean Journal of Medicine.2023; 98(5): 231. CrossRef
Classical Hodgkin lymphoma following follicular lymphoma: a case report
Bomi Kim
Journal of Yeungnam Medical Science.2023; 40(Suppl): S113. CrossRef
Incidence, clinicopathological features and genetics of in‐situ follicular neoplasia: a comprehensive screening study in a Japanese cohort
Naoki Oishi, Takahiro Segawa, Kunio Miyake, Kunio Mochizuki, Tetsuo Kondo
Histopathology.2022; 80(5): 820. CrossRef

Prognostic significance of viable tumor size measurement in hepatocellular carcinomas after preoperative locoregional treatment: Yoon Jung Hwang, Youngeun Lee, Hyunjin Park, Yangkyu Lee, Kyoungbun Lee, Haeryoung Kim; J Pathol Transl Med. 2021;55(5):338-348. Published online September 2, 2021; DOI: https://doi.org/10.4132/jptm.2021.07.26

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Abstract PDF Supplementary Material

Background
Preoperative locoregional treatment (LRT) for hepatocellular carcinoma (HCC) often induces intratumoral necrosis without affecting the overall tumor size, and residual viable tumor size (VTS) on imaging is an important clinical parameter for assessing post-treatment response. However, for surgical specimens, it is unclear whether the VTS would be more relevant to prognosis compared to total tumor size (TTS).
Methods
A total of 142 surgically resected solitary HCC cases were retrospectively reviewed. The TTS and VTS were assessed by applying the modified Response Evaluation Criteria in Solid Tumors method to the resected specimens, and correlated with the clinicopathological features and survival.
Results
As applying VTS, 13/142 cases (9.2%) were down-staged to ypT1a. Although the survival analysis results for overall survival according to TTS or VTS were similar, VTS was superior to predict disease-free survival (DFS; p = .023) compared to TTS (p = .08). In addition, multivariate analysis demonstrated VTS > 2 cm to be an independent predictive factor for decreased DFS (p = .001). In the subpopulation of patients with LRT (n = 54), DFS in HCCs with TTS or VTS > 2 cm were significantly shorter than those with TTS or VTS ≤ 2 cm (p = .047 and p = .001, respectively). Interestingly, HCCs with TTS > 2 cm but down-staged to VTS ≤ 2 cm after preoperative LRT had similar survival to those with TTS ≤ 2 cm.
Conclusions
Although the prognostic impact of tumor size was similar regardless of whether TTS or VTS was applied, reporting VTS may help to increase the number of candidates for surgery in HCC patients with preoperative LRT.

Citations

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PET-Assessed Metabolic Tumor Volume Across the Spectrum of Solid-Organ Malignancies: A Review of the Literature
Anusha Agarwal, Chase J. Wehrle, Sangeeta Satish, Paresh Mahajan, Suneel Kamath, Shlomo Koyfman, Wen Wee Ma, Maureen Linganna, Jamak Modaresi Esfeh, Charles Miller, David C. H. Kwon, Andrea Schlegel, Federico Aucejo
Biomedicines.2025; 13(1): 123. CrossRef
Measures for response assessment in HCC treatment
Fereshteh Yazdanpanah, Omar Al-Daoud, Moein Moradpour, Stephen Hunt
Hepatoma Research.2024;[Epub] CrossRef
Machine Learning for Dynamic Prognostication of Patients With Hepatocellular Carcinoma Using Time-Series Data: Survival Path Versus Dynamic-DeepHit HCC Model
Lujun Shen, Yiquan Jiang, Tao Zhang, Fei Cao, Liangru Ke, Chen Li, Gulijiayina Nuerhashi, Wang Li, Peihong Wu, Chaofeng Li, Qi Zeng, Weijun Fan
Cancer Informatics.2024;[Epub] CrossRef
Construction and validation of a novel signature based on epithelial-mesenchymal transition–related genes to predict prognosis and immunotherapy response in hepatocellular carcinoma by comprehensive analysis of the tumor microenvironment
Biao Gao, Yafei Wang, Shichun Lu
Functional & Integrative Genomics.2023;[Epub] CrossRef
Cellular senescence affects energy metabolism, immune infiltration and immunotherapeutic response in hepatocellular carcinoma
Biao Gao, Yafei Wang, Shichun Lu
Scientific Reports.2023;[Epub] CrossRef

Case Studies

Appendiceal actinomycosis mimicking appendiceal tumor, appendicitis or inflammatory bowel disease: You-Na Sung, Jihun Kim; J Pathol Transl Med. 2021;55(5):349-354. Published online June 26, 2020; DOI: https://doi.org/10.4132/jptm.2020.05.17

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Abstract PDF

Appendiceal actinomycosis is very rare and its diagnosis is often difficult even in surgically resected specimens. Here we report two cases of appendiceal actinomycosis confirmed by pathologic examination of surgically resected specimens. Characteristic histologic features included transmural chronic inflammation with Crohn-like lymphoid aggregates and polypoid mucosal protrusion into cecal lumen through fibrous expansion of the submucosa. Chronic active inflammation involved the mucosa of the appendix and cecum around the appendiceal orifice. Crohn’s disease with predominant cecal involvement and inflammatory pseudotumor were considered as differential diagnoses. Careful examination revealed a few actinomycotic colonies in the mucosa, confirming the diagnosis. A high index of suspicion with awareness of the characteristic histologic features might prompt careful inspection for the actinomycotic colonies, leading to the appropriate diagnosis of this rare disease.

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Appendicular actinomycosis: The first reported case of an uncommon finding of a common ailment from Nepal
Sujan Bohara, Manoj Khadka, Pawan Singh Bhat, Prajwal Syangtang, Badal Karki, Bhagawan Shrestha, Shoshan Arja Acharya, Khusbhu Khetan, Jyoti Rayamajhi, Sushil Bahadur Rawal
Clinical Case Reports.2023;[Epub] CrossRef
Abdominopelvic actinomycosis: An unexpected diagnosis in an elderly female with a destructive-appearing soft tissue mass
Elise Hyser, Drashti Antala, Harvey Friedman, Jonathan Stake
IDCases.2022; 28: e01479. CrossRef

Primary hepatic mixed germ cell tumor in an adult: Hyun-Jung Sung, Jihun Kim, Kyu-rae Kim, Shinkyo Yoon, Jae Hoon Lee, Hyo Jeong Kang; J Pathol Transl Med. 2021;55(5):355-359. Published online August 3, 2021; DOI: https://doi.org/10.4132/jptm.2021.06.16

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Abstract PDF

Primary hepatic mixed germ cell tumor (GCT) is very rare, and less than 10 cases have been reported. We report a case of mixed GCT composed of a choriocarcinoma and yolk sac tumor, which occurred in the liver of a 40-year-old woman. A large mass was detected by computed tomography solely in the liver. Serum β-human chorionic gonadotropin (hCG) was highly elevated, otherwise, other serum tumor markers were slightly elevated or within normal limits. For hepatic choriocarcinoma, neoadjuvant chemotherapy was administered, followed by right lobectomy. Histologic features of the resected tumor revealed characteristic choriocarcinoma features with diffuse positivity for hCG in the syncytiotrophoblasts and diffuse positivity for α-fetoprotein and Sal-like protein 4 in the yolk sac tumor components. Primary malignant GCT in the liver is associated with a poor prognosis and requires specific treatment. Therefore, GCT should be considered during a differential diagnosis of a rapidly growing mass in the liver.

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Mesenchymal Tumors of the Liver: An Update Review
Joon Hyuk Choi, Swan N. Thung
Biomedicines.2025; 13(2): 479. CrossRef
Testicular Seminoma in Prostate: Case Report and Review of Literature
Peter Lesko, Jana Obertova, Karol Kajo, Katarina Rejlekova, Zuzana Orszaghova, Viera Lehotska, Martina Ondrusova, Michal Chovanec, Dalibor Ondrus, Michal Mego
Clinical Genitourinary Cancer.2024; 22(2): 210. CrossRef

Metastatic leiomyosarcoma of the thyroid gland: cytologic findings and differential diagnosis: Jiyeon Lee, Yunjoo Cho, Kyue Hee Choi, Inwoo Hwang, Young Lyun Oh; J Pathol Transl Med. 2021;55(5):360-365. Published online August 13, 2021; DOI: https://doi.org/10.4132/jptm.2021.06.23

3,962 View
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Abstract PDF

Metastatic leiomyosarcoma to the thyroid is an extremely rare occurrence, and only 18 cases have been reported. Here, we report a case of a 37-year-old woman who presented with multiple masses on the scalp. Excisional biopsy was done and the mass revealed fascicles of smooth muscle fibers which showed positive staining for smooth muscle actin, thus confirming the diagnosis of leiomyosarcoma. The patient was also found to have a 0.9 cm mass within the left thyroid. Fine-needle aspiration was done and the cytological smear showed hypercellular spindle cell clusters with hyperchromatic and large nuclei. Normal thyroid follicular cells were found within or around tumor cells. In this report, we present the cytologic findings of metastatic leiomyosarcoma to the thyroid and offer differential diagnoses of the aspirated spindle cells.

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A Rare Case of Metastatic Uterine Leiomyosarcoma to the Thyroid Gland
R. Sathish Kumar, H. Akshaykumar, C. Ramesan, J. Dipin
Indian Journal of Otolaryngology and Head & Neck Surgery.2024; 76(1): 1365. CrossRef
Cytological Features and Mimickers of Thyroid Gland Sarcomas: A Case-Based Study
Poorvi Mathur, Shipra Agarwal, Chanchal Rana
International Journal of Surgical Pathology.2024;[Epub] CrossRef
Neck Surgery for Non-Well Differentiated Thyroid Malignancies: Variations in Strategy According to Histopathology
Fernando López, Abir Al Ghuzlan, Mark Zafereo, Vincent Vander Poorten, K. Thomas Robbins, Marc Hamoir, Iain J. Nixon, Ralph P. Tufano, Gregory Randolph, Pia Pace-Asciak, Peter Angelos, Andrés Coca-Pelaz, Avi Khafif, Ohad Ronen, Juan Pablo Rodrigo, Álvaro
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Mesonephric-like Adenocarcinoma of the Ovary: Clinicopathological and Molecular Characteristics
Hyun Hee Koh, Eunhyang Park, Hyun-Soo Kim
Diagnostics.2022; 12(2): 326. CrossRef
Alveolar Soft Part Sarcoma of the Uterus: Clinicopathological and Molecular Characteristics
Yurimi Lee, Kiyong Na, Ha Young Woo, Hyun-Soo Kim
Diagnostics.2022; 12(5): 1102. CrossRef

Newsletter

What’s new in gynecologic pathology 2021: ovary and fallopian tube: Gulisa Turashvili, Ricardo Lastra; J Pathol Transl Med. 2021;55(5):366-367. Published online September 15, 2021; DOI: https://doi.org/10.4132/jptm.2021.07.28

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Abstract PDF

The 5th edition of the World Health Organization (WHO) Classification of Female Genital Tumors was published in 2020. Although the classification of ovarian and fallopian tube neoplasms is largely unchanged from the prior (4th) edition, this newsletter compiles the most important refinements in these organ sites, including serous and non-serous epithelial tumors, and sex cord-stromal tumors.

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MR Imaging of Epithelial Ovarian Neoplasms Part II
Limin Xu, Susanna I. Lee, Aoife Kilcoyne
Magnetic Resonance Imaging Clinics of North America.2023; 31(1): 53. CrossRef
Current Trends on Bioengineering Approaches for Ovarian Microenvironment Reconstruction
Gustavo Henrique Doná Rodrigues Almeida, Rebeca Piatniczka Iglesia, Jaqueline de Carvalho Rinaldi, Mikaelly Kiemy Murai, Celso Vitor Alves Queiroz Calomeno, Leandro Norberto da Silva Junior, Bianca de Oliveira Horvath-Pereira, Letícia Beatriz Mazo Pinho,
Tissue Engineering Part B: Reviews.2023; 29(3): 260. CrossRef

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