Journal of Pathology and Translational Medicine

Original Article

Landscape of EGFR mutations in lung adenocarcinoma: a single institute experience with comparison of PANAMutyper testing and targeted next-generation sequencing: Jeonghyo Lee, Yeon Bi Han, Hyun Jung Kwon, Song Kook Lee, Hyojin Kim, Jin-Haeng Chung; J Pathol Transl Med. 2022;56(5):249-259. Published online September 13, 2022; DOI: https://doi.org/10.4132/jptm.2022.06.11

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Abstract PDF Supplementary Material: Background
Activating mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) are predictive biomarkers for response to EGFR–tyrosine kinase inhibitor (TKI) therapy in lung adenocarcinoma (LUAD). Here, we characterized the clinicopathologic features associated with EGFR mutations via peptide nucleic acid clamping-assisted fluorescence melting curve analysis (PANAMutyper) and evaluated the feasibility of targeted deep sequencing for detecting the mutations.
Methods
We examined EGFR mutations in exons 18 through 21 for 2,088 LUADs from July 2017 to April 2020 using PANAMutyper. Of these, we performed targeted deep sequencing in 73 patients and evaluated EGFR-mutation status and TKI clinical response.
Results
EGFR mutation was identified in 55.7% of LUADs by PANAMutyper, with mutation rates higher in females (69.3%) and never smokers (67.1%) and highest in the age range of 50 to 59 years (64.9%). For the 73 patients evaluated using both methods, next-generation sequencing (NGS) identified EGFR mutation–positive results in 14 of 61 patients (23.0%) who were EGFR-negative according to PANAMutyper testing. Of the 10 patients reportedly harboring a sensitizing mutation according to NGS, seven received TKI treatment, with all showing partial response or stable disease. In the 12 PANAMutyper-positive cases, NGS identified two additional mutations in exon 18, whereas a discordant negative result was observed in two cases.
Conclusions
Although PANAMutyper identified high frequencies of EGFR mutations, targeted deep sequencing revealed additional uncommon EGFR mutations. These findings suggested that appropriate use of NGS may benefit LUAD patients with otherwise negative screening test results.

Case Study

A case of concomitant EGFR/ALK alteration against a mutated EGFR background in early-stage lung adenocarcinoma: Ki-Chang Lee, Jiwon Koh, Doo Hyun Chung, Yoon Kyung Jeon; J Pathol Transl Med. 2021;55(2):139-144. Published online January 22, 2021; DOI: https://doi.org/10.4132/jptm.2020.12.16

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Rare cases of lung adenocarcinoma (LUAD) with concomitant epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) translocation have been reported. However, their clonal and evolutional relationship remains unclear. We report a case of early-stage EGFR-mutated LUAD with a focal concomitant EGFR/ALK alteration. A 63-year-old male underwent lobectomy to remove a 1.9-cm-sized lung nodule, which was diagnosed with EGFR-mutated LUAD. ALK immunohistochemistry (IHC) showed focal positivity within the part of the tumor characterized by lepidic pattern, also confirmed by fluorescence in-situ hybridization (FISH). Targeted next-generation sequencing was performed separately on the ALK IHC/FISH-positive and -negative areas. EGFR L833V/L858R mutations were detected in both areas, whereas EML4 (echinoderm microtubule-associated protein-like 4)-ALK translocations was confirmed only in the ALK IHC/FISH-positive area, suggesting the divergence of an EGFR/ALK co-altered subclone from the original EGFR-mutant clone. Our study suggests that concurrent alterations of EGFR and ALK can arise via divergent tumor evolution, even in the relatively early phases of tumorigenesis.

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Identification and validation of molecular subtype and prognostic signature for lung adenocarcinoma based on neutrophil extracellular traps
Yanhua Zuo, Guangyi Leng, Ping Leng
Pathology and Oncology Research.2023;[Epub] CrossRef
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Zuwei Li, Minzhang Guo, Wanli Lin, Peiyuan Huang
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Review

Current status and future perspectives of liquid biopsy in non-small cell lung cancer: Sunhee Chang, Jae Young Hur, Yoon-La Choi, Chang Hun Lee, Wan Seop Kim; J Pathol Transl Med. 2020;54(3):204-212. Published online April 15, 2020; DOI: https://doi.org/10.4132/jptm.2020.02.27

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Abstract PDF

With advances in target therapy, molecular analysis of tumors is routinely required for treatment decisions in patients with advanced non-small cell lung cancer (NSCLC). Liquid biopsy refers to the sampling and analysis of circulating cell-free tumor DNA (ctDNA) in various body fluids, primarily blood. Because the technique is minimally invasive, liquid biopsies are the future in cancer management. Epidermal growth factor receptor (EGFR) ctDNA tests have been performed in routine clinical practice in advanced NSCLC patients to guide tyrosine kinase inhibitor treatment. In the near future, liquid biopsy will be a crucial prognostic, predictive, and diagnostic method in NSCLC. Here we present the current status and future perspectives of liquid biopsy in NSCLC.

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Molecular biomarker testing for non–small cell lung cancer: consensus statement of the Korean Cardiopulmonary Pathology Study Group
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Original Article

Analysis of the molecular subtypes of preoperative core needle biopsy and surgical specimens in invasive breast cancer: Ye Sul Jeong, Jun Kang, Jieun Lee, Tae-Kyung Yoo, Sung Hun Kim, Ahwon Lee; J Pathol Transl Med. 2020;54(1):87-94. Published online November 13, 2019; DOI: https://doi.org/10.4132/jptm.2019.10.14

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Abstract PDF

Background
Accurate molecular classification of breast core needle biopsy (CNB) tissue is important for determining neoadjuvant systemic therapies for invasive breast cancer. The researchers aimed to evaluate the concordance rate (CR) of molecular subtypes between CNBs and surgical specimens.
Methods
This study was conducted with invasive breast cancer patients who underwent surgery after CNB at Seoul St. Mary’s Hospital between December 2014 and December 2017. Estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki67 were analyzed using immunohistochemistry. ER and PR were evaluated by Allred score (0–8). HER2 was graded from 0 to +3, and all 2+ cases were reflex tested with silver in situ hybridization. The labeling index of Ki67 was counted by either manual scoring or digital image analysis. Molecular subtypes were classified using the above surrogate markers.
Results
In total, 629 patients were evaluated. The CRs of ER, PR, HER2, and Ki67 were 96.5% (kappa, 0.883; p<.001), 93.0% (kappa, 0.824; p<.001), 99.7% (kappa, 0.988; p<.001), and 78.7% (kappa, 0.577; p<.001), respectively. Digital image analysis of Ki67 in CNB showed better concordance with Ki67 in surgical specimens (CR, 82.3%; kappa, 0.639 for digital image analysis vs. CR, 76.2%; kappa, 0.534 for manual counting). The CRs of luminal A, luminal B, HER2, and triple negative types were 89.0%, 70.0%, 82.9%, and 77.2%, respectively.
Conclusions
CNB was reasonably accurate for determining ER, PR, HER2, Ki67, and molecular subtypes. Using digital image analysis for Ki67 in CNB produced more accurate molecular classifications.

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Su Hwa Kim, Young Suk Lee, Sung Hak Lee, Yeoun Eun Sung, Ahwon Lee, Jun Kang, Jae-Sung Park, Sin Soo Jeun, Youn Soo Lee
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Jahnavi Kalvala, Ruth M Parks, Andrew R Green, Kwok‐Leung Cheung
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İnvaziv Meme Kanserinde Preoperatif Kor İğne Biyopsi ile Postoperatif Cerrahi Spesmenler Arasında ER, PR, HER2 ve Ki67 Açısından Karşılaştırma
Pınar CELEPLİ, Pelin Seher ÖZTEKİN, Salih CELEPLİ, İrem BİGAT, Sema HÜCÜMENOĞLU
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Case Study

Morule-like features in pulmonary adenocarcinoma associated with epidermal growth factor receptor mutations: two case reports with targeted next-generation sequencing analysis: Yoo Jin Lee, Harim Oh, Eojin Kim, Bokyung Ahn, Jeong Hyeon Lee, Youngseok Lee, Yang Seok Chae, Chul Hwan Kim; J Pathol Transl Med. 2020;54(1):119-122. Published online November 1, 2019; DOI: https://doi.org/10.4132/jptm.2019.09.30

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Abstract PDF

Morules, or morule-like features, can be identified in benign and malignant lesions in various organs. Morular features are unusual in pulmonary adenocarcinoma cases with only 26 cases reported to date. Here, we describe two cases of pulmonary adenocarcinoma with morule-like features in Korean women. One patient had a non-mucinous-type adenocarcinoma in situ and the other had an acinarpredominant adenocarcinoma with a micropapillary component. Both patients showed multiple intra-alveolar, nodular, whorled proliferative foci composed of atypical spindle cells with eosinophilic cytoplasm. Targeted next-generation sequencing was performed on DNA extracted from formalin-fixed paraffin-embedded samples of the tumors. Results showed unusual epidermal growth factor receptor (EGFR) mutations, which are associated with drug resistance to EGFR tyrosine kinase inhibitors, revealing the importance of identifying morule-like features in pulmonary adenocarcinoma and the need for additional study, since there are few reported cases.

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Mitsuteru Yosida, Mitsuru Tomita, Naoya Kawakita, Teruki Shimizu, Ryou Yamada, Hiromitsu Takizawa, Hisanori Uehara
Respiratory Medicine Case Reports.2024; 48: 102008. CrossRef
Clinicopathological, Radiological, and Molecular Features of Primary Lung Adenocarcinoma with Morule-Like Components
Li-Li Wang, Li Ding, Peng Zhao, Jing-Jing Guan, Xiao-Bin Ji, Xiao-Li Zhou, Shi-Hong Shao, Yu-Wei Zou, Wei-Wei Fu, Dong-Liang Lin, Dong Pan
Disease Markers.2021; 2021: 1. CrossRef

Review

Provisional Guideline Recommendation for EGFR Gene Mutation Testing in Liquid Samples of Lung Cancer Patients: A Proposal by the Korean Cardiopulmonary Pathology Study Group: Dong Hoon Shin, Hyo Sup Shim, Tae Jung Kim, Heae Surng Park, Yun La Choi, Wan Seop Kim, Lucia Kim, Sun Hee Chang, Joon Seon Song, Hyo jin Kim, Jung Ho Han, Chang Hun Lee, Geon Kook Lee, Se Jin Jang; J Pathol Transl Med. 2019;53(3):153-158. Published online February 28, 2019; DOI: https://doi.org/10.4132/jptm.2019.02.22

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Abstract PDF

Liquid biopsy for detection of mutation from circulating tumor DNA is a new technology which is attractive in that it is non-invasive. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) is an effective first line drug for advanced non-small cell lung cancer patients who harbor activating EGFR mutation. During the course of treatment, resistance against TKI arises which can be contributed to EGFR T790M mutation in about 50–60% of patients. Third generation TKI may overcome the resistance. In patients who cannot undergo tissue biopsy due to variable reasons, liquid biopsy is an excellent alternative for the detection of EGFR T790M mutation. However, this relatively novel method requires standardization and vigorous quality insurance. Thus, a standard set of guideline recommendations for liquid biopsy for EGFR mutation testing suitable for the Korean medical community is necessary. In this article, we propose a set of provisional guideline recommendations that was discussed and approved by the Cardiopulmonary Pathology Study Group of the Korean Society of Pathologists.

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Improving non-small-cell lung cancer survival through molecular characterization: Perspective of a multidisciplinary expert panel
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Molecular biomarker testing for non–small cell lung cancer: consensus statement of the Korean Cardiopulmonary Pathology Study Group
Sunhee Chang, Hyo Sup Shim, Tae Jung Kim, Yoon-La Choi, Wan Seop Kim, Dong Hoon Shin, Lucia Kim, Heae Surng Park, Geon Kook Lee, Chang Hun Lee
Journal of Pathology and Translational Medicine.2021; 55(3): 181. CrossRef
Current status and future perspectives of liquid biopsy in non-small cell lung cancer
Sunhee Chang, Jae Young Hur, Yoon-La Choi, Chang Hun Lee, Wan Seop Kim
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Prevalence of T790M mutation among TKI-therapy resistant Lebanese lung cancer patients based on liquid biopsy analysis: a first report from a major tertiary care center
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Original Articles

The EGFR Protein Expression and the Gene Copy Number Changes in Renal Cell Carcinomas.: Sangho Lee, Jungsuk An, Aeree Kim, Young Sik Kim, Insun Kim; Korean J Pathol. 2009;43(5):413-419.; DOI: https://doi.org/10.4132/KoreanJPathol.2009.43.5.413

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Abstract PDF

BACKGROUND
The epidermal growth factor receptor (EGFR) is known to be involved in many tumor promoting activities. EGFR inhibition has been tried as a therapeutic modality in many human malignancies.
METHODS
The expression of EGFR protein and the gene copy number changes were studied in 135 clear cell carcinomas and 16 papillary renal cell carcinomas (RCCs), and these tumors were diagnosed between 1995 and 1997.
RESULTS
An EGFR protein expression (2+ and 3+) was found in 54.1% of the clear cell RCCs and in 43.8% of the papillary RCCs. In the clear cell RCCs, its expression was associated with male gender, the tumor size (> or =4 cm) and high T stages (T2 and T3), with statistical significance. Trisomy and polysomy of the EGFR gene were found in 27 (25.7%) and 40 (38.1%) of 105 clear cell RCCs, respectively. Trisomy and polysomy were correlated with an EGFR protein expression and a high clinical T stage, with statistical significance. Among 15 papillary RCCs, 13 tumors showed trisomy (86.7%) and one showed polysomy (6.7%). Amplification was not found in both the clear cell and papillary type RCCs.
CONCLUSIONS
A considerable numbers of RCCs showed an overexpression of EGFR protein and increased EGFR gene copy numbers, yet the clinical significance of conducting a FISH study in RCC patients seems to be limited.

Citations

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EGFR protein overexpression correlates with chromosome 7 polysomy and poor prognostic parameters in clear cell renal cell carcinoma
Gordana Đorđević, Koviljka Matušan Ilijaš, Ita Hadžisejdić, Anton Maričić, Blaženka Grahovac, Nives Jonjić
Journal of Biomedical Science.2012;[Epub] CrossRef

Metaplastic Squamous Carcinoma of the Breast: Clinicopathologic Analysis of 17 Cases.: Sun Ah Lee, Kyung Eun Lee, Byung In Moon, Woon Sup Han, Sun Hee Sung; Korean J Pathol. 2009;43(1):20-25.; DOI: https://doi.org/10.4132/KoreanJPathol.2009.43.1.20

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Abstract PDF

BACKGROUND
Squamous cell carcinoma of the breast is very rare and it is considered to arise from metaplastic change of ductal carcinoma. Metaplastic squamous cell carcinoma (MSC) of the breast includes pure squamous cell carcinoma, metaplastic adenosquamous carcinoma and low grade adenosquamous carcinoma. Most of the cases of MSC of the breast were reported to have lymph node metastasis and this has a worse prognosis than that of conventional invasive ductal carcinoma.
METHODS
We collected 17 cases of MSC of the breast from 1,173 cases of breast cancer and analyzed the clinicopathological characteristics.
RESULTS
The age range was 31 to 69 years (mean age: 47.2). The mean tumor size was 3.6 cm. Twelve cases (70.6%) had a negative nodal status. The majority of the cases were of a high nuclear grade (grade III: 76.5%), and a high histologic grade (grade III: 88.2%). All the cases had no amplification of HER2, and they were negative for hormonal receptors, except for 2 cases with weak positivity. All the cases showed positivity for EGFR (3+: 14 cases, 1+: 3 cases). Clinical relapse was found in 3 patients on follow up and two of them expired due to lung and bone metastasis.
CONCLUSIONS
MSC is associated with high nuclear and histologic grades, a high EGFR expression and they are triple negative for ER, PR, and HER2. The EGFR immunopositivity of MSC suggests a basal-like subtype.

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Eccrine ductal and acrosyringeal metaplasia in breast carcinomas: report of eight cases
Tibor Tot
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Hanna Kang, Harin Cheong, Min Sun Cho, Heasoo Koo, Woon Sup Han, Kyung Eun Lee, Byung In Moon, Sun Hee Sung
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Correlation between Histopathologic Grade, Stage, and Degree of EGFR Expression in Transitional Cell Carcinoma of the Urinary Bladder.: Hyeon Ok Kim, Hwa Sun Lee, Kang Suek Suh; Korean J Pathol. 1996;30(9):784-791.

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Abstract PDF: This study was performed to estimate the correlation between the histopathological grade and the clinical stage, which are known as important prognostic factors, and EGFR expression status in 57 cases of transitional cell carcinoma of the urinary bladder. There was a significant correlation between the histopathological grade and clinical stage of transitional cell carcinoma of the urinary bladder and between expression grades of EGFR and histopathological grades, or clinical stages of transitional cell carcinoma of the urinary bladder. Therefore, the presence of a high intensity of EGFR staining in the transitional cell carcinoma of the urinary bladder was associated with poor differentiation and invasion. On the basis of the above results, it was suggested that the degree of EGFR expression is one of the objective and reliable prognostic factors in transitional cell carcinoma of the urinary bladder.

Epidermal Growth Factor Receptor Expression and Cell Proliferation in Renal Cell Carcinoma.: Ji Shin Lee, Jong Jae Jung, Min Cheol Lee, Chang Soo Park; Korean J Pathol. 2000;34(4):273-279.

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Abstract PDF: The epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein whose expression is a possible cause of increased tumor cell proliferation and has recently been proposed as a prognostic parameter in some tumors. Expression of EGFR was studied immunohistochemically in 62 cases of human renal cell carcinomas to evaluate their possible prognostic roles. We also examined the correlation between EGFR expression and cell proliferation by immunohistochemical staining for proliferating cell nuclear antigen (PCNA). Fifty-six cases (90.3%) expressed EGFR, with staining largely confined to the cell membrane and cytoplasm. Staining intensity of EGFR was directly correlated with nuclear grade (p=0.000) and TNM stage (p=0.015). PCNA index was significantly higher in EGFR-positive tumors than in EGFR- negative tumors. There was a statistically significant positive correlation between PCNA index and increasing staining intensity of EGFR (p=0.000). In univariate survival analysis, EGFR expression was significantly associated with shortened survival. However, EGFR expression was not an independent prognostic factor by multivariate analysis. These findings suggest that EGFR expression may be an important cause of tumor cell proliferation in renal cell carcinoma and further studies are needed to evaluate whether EGFR expression analysis provides independent prognostic information.

Epidermal Growth Factor Receptor Overexpression and the Tumor Response to Preoperative Radiochemotherapy for Patients with Advanced Rectal Cancer.: Jinyoung Yoo, Ju Won Chyung, Ji Han Jung, Hyun Joo Choi, Seok Jin Kang, Kyo Young Lee; Korean J Pathol. 2007;41(5):316-323.

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Abstract PDF: BACKGROUND
An association between the epidermal growth factor receptor (EGFR) signaling pathway and the response of cancer cells to ionizing radiation has been previously described. Preoperative radiochemotherapy (PRCT) has been administered for treating locally advanced rectal cancer to improve the outcomes, and to preserve the sphincter from lowlying tumor. However, the responses of tumors to PRCT are variable and there are currently no reliable markers that predict the therapeutic benefits. We studied the association between EGFR overexpression and the tumor response to PRCT in rectal cancer.
METHODS
The EGFR protein expression, as determined by immunohistochemistry, was analyzed in the pretreatment biopsy specimens from 120 patients with advanced rectal cancer. The tumor response was graded in the surgically resected specimens by using a three-scale grading system: no response (NR), partial remission (PR) and complete remission (CR).
RESULTS
NR was identified in 70 cases (58.3%). Fifty patients (41.7%) responded to PRCT; 27 (22.5%) achieved a PR and 23 (19.2%) achieved a CR. EGFR overexpression was detected in 78 (65%) cases. Seventy-eight percent (39/50) of the tumors with a CR/PR revealed EGFR reactivity, whereas 55.7% (39/70) of the tumors with NR showed an EGFR expression (p=0.048).
CONCLUSIONS
The EGFR protein expression might be a valuable marker for identifying those patients who are most likely to benefit from PRCT.

Expression of Epidermal Growth Factor Receptor Related Protein in Gallbladder Cancer: An Association with p53 Mutation.: Ho Sung Park, Kyu Yun Jang, Kyung Ryoul Kim, Hak Yong Lee, Andrzej S Tarnawski, Adhip P N Majumdar, Myoung Jae Kang, Dong Geun Lee, Woo Sung Moon; Korean J Pathol. 2005;39(6):385-390.

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Abstract PDF: BACKGROUND
It has been well demonstrated that the overexpression of epidermal growth factor receptor (EGFR) is associated with numerous gastrointestinal malignancies, including gallbladder carcinoma. However, the cellular events that regulate EGFR in cancer cells have not been fully elucidated. A novel negative regulator of EGFR that is referred to as EGFR related protein (ERRP) has recently been identified. The aim of this study was to investigate the expression and localization of ERRP in gallbladder carcinoma and to examine a possible role for ERRP.
METHODS
We examined the immunohistochemical expressions of ERRP, p53 and proliferating cell nuclear antigen labeling index (PCNA-LI) in formalin-fixed, paraffinembedded specimens of 43 cases of gallbladder carcinoma, 7 cases of adenoma and 3 cases of dysplasia.
RESULTS
In the normal mucosa, ERRP immunoreactivity was positive in over 64% of specimens. In contrast, the ERRP staining was positive in only 46% of the cancer specimens. The expression of ERRP in cancer cells was inversely correlated with tumor cell proliferation. The loss of ERRP expression correlated with the p53 overexpression.
CONCLUSIONS
Our data indicate that the down-regulation or loss of ERRP could play an important role in the progression of gallbladder carcinoma. The inverse relationship between the ERRP expression and PCNA-LI suggests that ERRP may play a role in the inhibition of tumor cell proliferation in gallbladder cancer.

Pathological Analysis of 15 Cases of Phyllodes Tumors of the Breast.: Sung Nam Kim, Woo Ho Kim, Sang Kook Lee; Korean J Pathol. 1993;27(1):19-26.

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Abstract PDF: Retrospective clinicopathologic analysis of 15 patients with the phyllodes tumors(PT) of the breast, diagnosed at SNUH over 6 years period, was done. By light microscopy, 8 cases were diagnosed as benign, and 7 cases were diagnosed as malignant. Mean ages o the patients were 37 and 34 years in malignant and benign, respectively. Most of those cases were presented with a palpable mass of the breast. None of the patients with malignant PT had distant metastasis, Local recurrences were experienced in 3 patients among the malignant PT, and one patient among the benign PT. One of 7 malignant PT was coexisted with simultaneous ipsilateral infiltrating duct carcinoma. The clinical course was not well correlated with pathologic features. The prognostic significances of several histopathologic parameters were assessed for possible correlation with local recurrence, metastasis and death; stromal cellularity, stromal cellular atypism, mitotic activity, tumor contour, necrosis, tumor size and heterologous stromal elements. Immunohistochemistry using antibody to vimentin, proliferating cell nuclear antigen(PCNA) and epidermal growth factor receptor(EGF-R) were analysed. In the 5 cases of benign PT, the stromal cells stained diffusely positive for vimentin and 3 cases of malignant tumors show similar staining for vimentin. The percentage of PCNA-positive cells were higher in the malignant PT than in the benign ones; they were 3.5% to 60% in malignancy, while they were less than 60% in all benign PT. The results of EGF-R staining were correlated with the histologic classification; only 2 cases out of 8 benign PT show diffusely positive staining of EGF-R in the cytoplasm, but 6 cases out of 7 malignant PT show positive findings.

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