Journal of Pathology and Translational Medicine

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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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.

Citations

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Original Articles

Histologic Parameters Predicting Survival of Patients with Multiple Non-small Cell Lung Cancers.: Joo Young Kim, Hee Jin Lee, Jun Kang, Se Jin Jang; Korean J Pathol. 2011;45(5):506-515.; DOI: https://doi.org/10.4132/KoreanJPathol.2011.45.5.506

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Abstract PDF: BACKGROUND
In multiple lung cancers (MLCs), distinction between intrapulmonary metastases and multiple primary tumors is important for staging and prognosis. In this study, we have investigated histopathologic prognostic factors of patients with MLCs.
METHODS
Histologic subtype, size differences, lobar location, lymphovascular invasion (LVI), size of the largest tumor, nodal status, number of tumors, morphology of tumor periphery, and immunohistochemical profiles using eight antibodies, were analyzed in 65 patients with MLCs.
RESULTS
There was no significant difference in the survivals of patients with multiple primary tumors and intrapulmonary metastases, as determined by the Martini-Melamed criteria (p=0.654). Risk grouping by four histologic parameters, LVI, margin morphology, size differences, and lobar locations of paired tumors were prognostic. The patients with one or two of aforementioned parameters had significantly longer survival than those with three or four parameters (p=0.017). In patients with largest mass (< or =5 cm), the risk grouping was found to be an independent prognostic factor (p=0.022). However, differences in immunohistochemical staining were not related to patients' survival.
CONCLUSIONS
A risk grouping of MLC patients by using combinations of histologic parameters can be a useful tool in evaluating the survival of patients with MLCs, and may indicate clonal relationship between multiple tumors.

Expression Pattern of the Rb Protein and its Correlation with Prognosis in Primary Lung Cancer.: Hea Kyoung Hur, Seo Hee Rha, Sook Hee Hong; Korean J Pathol. 1997;31(2):152-161.

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Abstract PDF: An immunohistochemical stain for the Rb tumor suppressor gene product was performed in pathologic specimens from 72 primary lung cancer patients to study the correlation between its expression and histologic type, cancer differentiation, clinical stage and survival rate. The expression of the Rb protein was positive in 34 cases(47.2%) and negative in 38 cases(52.8%). The Rb protein was not expressed in 16 of 42 cases(38.1%) in squamous cell carcinoma, in 17 of 23 cases(73.9%) in adenocarcinoma, in one of three cases(33.3%) in undifferentiated large cell carcinoma, in two of two cases(100%) in small cell carcinoma, in one of one case(100%) in an adenosquamous carcinoma and in one of one case(100%) in an atypical carcinoid. There were significant difference of the Rb protein expression between squamous cell carcinoma and adenocarcinoma(p<0.05). The expression of Rb protein was not correlated with degree of cancer cell differentiation and clinical stage of the lung cancer(p>0.05). The two year survival rate for patients with the Rb positive was 65% compared with 37% for those with the Rb negative which was significant(p<0.05). This result suggests that an altered or the absence of the Rb protein in cancer cells can be a valuable prognostic factor in the lung cancer.

Loss of Heterozygosity of Chromosome 3p in Squamous Cell Carcinomas and Adenocarcinomas of the Lung.: Gyeong Shin Park, Young Shin Kim, Kyo Young Lee, Chang Suk Kang, Sang In Shim, Byung Kee Kim; Korean J Pathol. 1999;33(3):151-157.

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Abstract PDF: We evaluated the frequency of genetic alteration of chromosome 3p in lung cancer, and analyzed the patterns of genetic alterations between two distinct histologic types, squamous cell carcinomas (SCC) and adenocarcinomas (AC). PCR-LOH analysis for 40 Korean non-small cell lung cancer including 20 SCC and 20 AC was performed using microsatellite markers, D3S1300, D3S1029 and D3S1038. These markers represented the loci of FHIT gene (3p14), mismatch repair gene hMLH1 (3p21) and VHL gene (3p25), respectively. For SCC, the frequency of LOH at D3S1300, D3S1029 and D3S1038 was 78.6%, 61.5% and 64.3%, and for AC, was 62.5%, 62.5% and 46.7%, and for total 40 cases of SCC and AC, was 70.0%, 62.1% and 55.2%, respectively. Among 27 cases showing heterozygosity at three examined loci, 7 cases (25.9%) revealed LOH at only one locus and 16 cases (59.3%) revealed LOH at two or three loci. The differences of incidence of LOH and the patterns of genetic alterations at chromosome 3p between two distinct histologic types of lung cancer were not significant. The genetic deletion of relatively broad area, including more than two loci, was more frequent than that of small area, including only one locus.

Protein Expression and Gene Amplification of Epidermal Growth Factor Receptor in Non-Small Cell Lung Cancer: Correlation with the Response to Gefitinib Therapy.: Jinyoung Yoo, Kyungji Lee, Ji Han Jung, Byoung Yong Shim, Sung Hwan Kim, Deog Gon Cho, Myeong Im Ahn, Chi Hong Kim, Kyu Do Cho, Hoon Kyo Kim, Seok Jin Kang; Korean J Pathol. 2008;42(1):1-8.

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Abstract PDF: BACKGROUND
Gefitinib is an EGFR tyrosine kinase inhibitor that has shown dramatic effectiveness in a subset of non-small cell lung cancer (NSCLC) patients. We evaluated the response rate to gefitinib, and the significance of the EGFR and HER2/neu status as predictive markers of the tumor response.
METHODS
The EGFR and HER2/neu protein expressions, as determined by immunohistochemistry (IHC) and gene amplification via chromogenic in situ hybridization (CISH), were analyzed in biopsy specimens from 46 patients with advanced NSCLC. After their failure with the first-line treatment, all the patients had received gefitinib treatment.
RESULTS
A partial response (PR) was achieved in 8 patients (17.4%). An EGFR overexpression was detected in 80.4% (37/46) of the tumors, and this was observed exclusively in patients with a PR (100% vs 75.3%, respectively; p=0.076). EGFR gene amplification was present in 47.8% of the tumors (22/46). HER2/neu was overexpressed in 13%(6/46) and it was amplified in 17% (7/46). The overall survival was prolonged in the female patients (p=0.007), and in patients with T1 and T2 disease (p=0.039), adenocarcinoma (p=0.010), a PR (p=0.022), an EGFR IHC+ status (p=0.033), an EGFR IHC+/CISH+ status (p=0.010), or an EGFR+/HER2/neu+ status (p=0.030). On multivariate analysis, gender, T disease and EGFR IHC/CISH remained the significant predictors of survival.
CONCLUSIONS
Gefitinib showed a modest effect for the patients with chemotherapy-refractory advanced NSCLC. A combination of EGFR IHC and CISH might be important for identifying those patients who are most likely to benefit from gefitinib therapy.

Expression of p53 and nm23 Proteins in Non-Small Cell Lung Cancer.: Mi Seon Kwon, Won Il Kim, Kyo Young Lee, Young Shin Kim, Chang Suk Kang, Sang In Shim; Korean J Pathol. 1997;31(6):499-507.

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Abstract PDF: To elucidate the role of p53 and nm23 in the development, progression, and metastasis of non-small cell lung cancer, we studied 91 paraffin sections of the primary non-small-cell lung cancers and the 34 paraffin sections of their metastatic lymph nodes using the immunohistochemical method. The results are as follows: 1) The incidence of p53 protein expression was positively correlated with the staging of lung cancers (p<0.025). 2) The incidence of p53 protein expression was higher in the lung cancers with lymph node metastasis than in those without lymph node metastasis (p=0.009). 3) The incidence of nm23 protein expression was lower in the adenocacinomas than in the squamous cell carcinomas (p=0.032). 4) The incidence of nm23 protein expression was lower in the lung cancers with lymph node metastasis than in those without lymph node metastasis (p=0.026). The expression of nm23 protein between the primary lung cancers and corresponding metastatic lymph nodes showed positive correlation (Kendall's Tau-b correlation coefficient=0.47140, p=0.0068). 5) The expression of p53 was not correlated with the expression of nm23 protein (Kendall's Tau-b correlation coefficient=0.11387, p=0.2800). The above results suggest that an overexpression of p53 protein and a downregulation of nm23 protein are associated with tumor progression and metastasis in non-small-cell lung cancer.

Case Reports

Mucinous Tubular and Spindle Cell Carcinoma of Kidney Occurring in a Patient with Pulmonary Adenocarcinoma.: Seog Yun Park, Gyeong Hoon Kang, Jae Y Ro, Jennifer Black, Jinsoo Chung, Kang Hyun Lee, Eun Kyung Hong, Weon Seo Park; Korean J Pathol. 2008;42(1):54-59.

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Abstract PDF: Mucinous tubular and spindle cell carcinoma (MTSCC) is a rare type of kidney tumor that has only been recently described. Furthermore, a case of MTSCC associated with a simultaneous lung cancer in the same patient has never been reported in the literature. In this paper, we describe a kidney tumor that was detected during staging work-up in a 72-year-old lung cancer patient. The kidney tumor was removed and shown to exhibit histological and immunophenotypic features of MTSCC, completely distinct from the pulmonary adenocarcinoma. In addition, this case was unique because it was characterized by neuroendocrine differentiation as well as p53 and Ki-67 overexpression in tumor cells. Therefore, we report a case of MTSCC diagnosed in a patient with pulmonary adenocarcinoma and describe the detailed histologic and immunohistochemical features of MTSCC.

Choroidal Metastasis of Adenocarcinoma of the Lung: A case report.: Seong Hwan Park, Ju Han Lee, Jeong Seok Moon, Jong Sang Choi; Korean J Pathol. 1999;33(6):471-473.

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Abstract PDF: Choroidal metastatic carcinoma is very rare. We recently experienced a case of lung adenocarcinoma which presented to the clinic with ocular symptoms. This 57-year-old Korean male patient visited the department of ophthalmology due to decreased visual acuity and pain of the left eye. On MRI scan, a nodule was attached to the retina of the left eyeball. On simple chest radiograph, a large amount of pleural effusion was noted in the left pleural cavity. Emergency enucleation of the left eyeball was done with an impression of malignant melanoma causing an intractable ocular pain. Grossly, the lesion in the eyeball was rising from the choroid. On histologic examination, tumor cells formed many irregular, small gland-like structures. The tumor cells showed alcian blue-positive mucin in the cytoplasm and glandular lumens and were positive for CEA. Chest CT scan was performed postoperatively and showed a huge mass in the left lower lobe and multiple nodular opacities in both lung fields. Bronchoscopic biopsy revealed moderately differentiated adenocarcinoma similar to that of the eyeball.

Original Articles

Establishment and Characterization of a Small Cell Lung Cancer Cell Line(JePa-1).: Mi Ja Lee, Ho Jong Jeon, Jong Hoon Chung; Korean J Pathol. 1997;31(8):695-710.

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Abstract PDF: Lung cancer is the most common malignant tumor worldwide and its incidence continues to rise each year. Recent development of molecular biologic method has led to advances in determining the etiologic factors of lung cancer and the establishment of cell lines has provided a lot of information on the through chemosensitivity, radiation biology studies, cytogenetics, and molecular biologic studies, which permits improved treatment for lung cancer. We established a small cell lung cancer cell line, designated JePa-1, obtained from malignant pericardial effusion of small cell lung cancer patient and characterized its morphologic and molecular biologic features. the JePa-1 cell line grew relatively slowly (doubling time 45hrs) as very loosely adherent floating aggregates growing in small clumps with distinct cell outlines and intertwined cords. Also JePa-1 cell line secreted antidiuretic hormones. Electronmicroscopic examination revealed that JePa-1 cell line and xenografts contained electron dense core granules, characteristic of being of neuroendocrine origin. To investigate the tumorigenic capacity, the JePa-1 cell line was injected into SCID and nude mice. Tumors taken from xenografts were observed in 3 out of 4 of the SCID mice and 2 out of 4 of the nude mice. The histologic characteristics of the xenografts were similar to those of the cell line and the original cytologic finding of the pericardial fluid, suggesting small cell carcinoma. The results of immunohistochemical markers showed reactivity for Rb protein, c-myc, TGF-alpha, TGF-beta , EGFR, keratin, NSE, chromogranin, and EMA. The DNA ploidy and the index of the JePa-1 cells was tetraploid and 2.13, respectively. The positive rate for the Rb, c-myc and K-ras proteins of the JePa-1 cell line were 98.9%, 99.3%, and 99.7% respectively as determined by flow cytometry. Cytogenetic analysis using the G-banding technique showed 65 chromosomes with various numerical and structural abnormalities. On examination of the expression of TGF-alpha, TGF-beta , and EGFR by PCR, only the EGFR was positive Through the establishment of JePa-1 cell line, we report in this paper the characterization of a small cell lung cancer such as morphologic and immunocytochemical features, growth characteristics in culture, hormone production, expression of oncoprotein and several growth factors, tumorigenicity, chromosomal abnormalities, and DNA ploidy and index. The JePa-1 cell line will be valuable in vitro studies for the etiology, treatment and the prognostic factors in small cell lung cancer.

A Cytopathologic Study of Fine Needle Aspiration Biopsy of Lung Cancer.: Soon Won Hong, Kwang Gil Lee; Korean J Pathol. 1990;24(4):465-475.

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Abstract PDF: Available conventional pathologic diagnostic tools for lung cancer include sputum cytology, lung biopsy using bronchoscopy, and washing and brushing cytology. In addition, fine needle aspiration (FNA) cytology is now available and has become popular. In this study, an attempt was made to compare the relative sensitivity between conventional cytopathologic methods and FNA cytology, to study the clinical characteristics of lung cancer in which the diagnosis was established by FNA cytology, and to study the cellular findings and diagnostic criteria of lung cencers. Cases included in this study were selected from 105 patients who had been diagnosed an lung cancer at Yonsei University Medical Center during the 5-year period from January 1984 to December 1988. These 105 cases were reviewed with respect to medical records and pathologic slides and then the following conclusions were made. The mean age of cases was 58.5 years, and the sex ratio of males to females was 3.5:1. Tumors were mostly solitary in number and were mainly located at the periphery of the lung. The sensitivity of FNA cytology, sputum, and bronchial washing was as follows: FNA cytology was 0.93, sputum, 0.2, and bronchial washing, 0.14. The coincidence rate of cytopathologic diagnosis with histologic diagnosis was as follows: epidermoid carcinoma was 92%, adenocarcinoma 83%, undifferentiated large cell carcinoma 66%, and undifferentiated small cell carcinoma 100%. The false negativity of FNA cytology was 7%, which was mainly due to material insufficiency. For the differential diagnosis of histologic type, some brief criteria could be summarized. Differential diagnostic points of each histologic type were as follows: epidermoid carcinoma showed a large cellular group with keratinized cytoplasms and hyperchromatic and pyknotic nuclei, adenocarcinoma showed a glandular or ball-like arrangement by monotonous round cells, undifferentiated large cell carcinoma was mainly composed of irregular large cells and showed emperipolesis, and undifferentiated small cell carcinoma showed an Indian file appearance with molding by small, round hyperchromatic cells. In conclusion, FNA cytology is a more efficient, definite, and sensitive method for diagnosing lung cancer than other cytopathologic studies, so that careful selection of patients and experienced technique will improve the diagnostic accuracy of FNA cytology in diagnosing lung cancer.

Immunohistochemical Study of the Expression of the p53 Protein in Primary Lung Cancer.: Sang Yong Lee, Jin Sook Jeong, Sook Hee Hong; Korean J Pathol. 1996;30(3):218-227.

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Abstract PDF: An immunohistochemical stain for p53 tumor suppressor gene product was performed in 59 primary lung cancers to study the relation between its expression and type of the tumor, degree of tumor differentiation,clinical stage and smoking. The results were as follows: 1. The expression of mutant p53 protein was noted in 28 of 59 cases(47.5%) of primary lung cancers. The p53 protein was expressed in 21 of 35(60%) squamous cell carcinomas, in 6 of 21(28.6%) adenocarcinomas, and 1 of 1(100%) small cell carcinoma. There was a significant difference in expression of p53 among the different histologic types of lung cancer(p<0.05). 2. The incidence of p53 protein expression did not correlate with the degree of tumor cell differentiation or the clinical stage of lung carcinoma(p>0.05). 3. The incidence of p53 protein expression was higher in smokers(current: 75%, former: 46.2%) than in non-smokers(5.6%) and was increased in direct proportion to the pack years. There was a statistically significant correlation between p53 expression and smoking(p<0.05). The mutation of p53 gene may often be an early event in the development of lung cancer and it is suggested that the smoking known as a risk factor for the development of the lung cancer may be associated with the transformation of p53 tumor suppressor gene into mutant p53 gene or oncogene.

Results of Sputum Cytology in Diagnosis of Lung Cancer: Based on the Results Obtained for 16 months in Presbyterian Medical Center.: Hye Kyung Lee, Kwang Min Lee, Dong Kyu Chung, Dae Song Kang, Kwi Wan Kim; J Pathol Transl Med. 1994;5(2):148-153.

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Abstract PDF: A prospective survey of sputum cytologic specimen was performed for 16 months from Jan. 1993 to Apr. 1994 in Presbyterian Medical Center. The purpose of this study is to find the positive rate of sputum cytology in the diagnosis of lung cancer and to correlate these results with tumor location and stage. Sputum cytologic specimen were received from 104 patients among 168 patients diagnosed as lung malignancy by histologic examination. Cytologic diagnosis of "suggestive of malignancy" was made in 61 patient(59%) and dysplasia in 9 patients(9%), atypia in 14 patients(13%), benign in 15 patients(14%) and inadequate specimen in 5 patients(5%), respectively. Among 84 patients beyond the cytologic diagnosis of atypia, 51 patients(61%) disclosed a central location, while 33patients(39%) showed peripheral lesions. All 54 patients diagnosed as suggestive of non-small cell carcinoma were stage III or over, and all 7 patients diagnosed as suggestive of small cell carcinoma were in advanced stage.

Cytologic Findings of Giant Cell Carcinoma of the Lung.: Cheol Hee Yun, Ji Yeon Bae, Sang Pyo Kim, Kun Young Kwon, Chung Sook Kim, Eun Sook Chang; J Pathol Transl Med. 1994;5(2):154-159.

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Abstract PDF: Pulmonary giant cell carcinoma is one of the most highly malignant neoplasms of the lung. Although mixed malignant glandular or squamous components may be associated with a giant cell carcinoma, it is a distinct clinical and morphologic entity. We reviewed cytologic presentations of 6 cases of pulmonary giant cell carcinoma. Cytologically, the single most characteristic feature of giant cell carcinoma was an extremely large, bizarre cancer cell engulfing numerous leukocytes. The nuclei of these cells showed occasional prominent nucleoli, and the cytoplasm was abundant. Giant cells were also seen in other types of pulmonary carcinoma, but the giant cells of this neoplasm could be differentiated from those encountered in undifferentiated large cell carcinoma and squamous cell carcinoma by the abundant cytoplasm, the presence of markedly enlarged nuclei, prominent nucleoli, and an significant degree of phagocytosis, In conclusion, precise diagnosis and classification of lung cancer is imperative because of proved correlation between cell type and prognosis.

Immunohistochemical Study of Primary Large Cell Undifferentiated Carcinoma of the Lung.: Hye Seung Han, Jeong Wook Seo, Eui Keun Ham; Korean J Pathol. 1996;30(5):417-426.

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Abstract PDF: We performed a histopathologic and immunohistochemical study of 23 cases of surgically resected large cell undifferentiated carcinoma(LCUC) of the lung. The relative incidence of LCUC was 7.6% among the total resected cases of primary lung cancer over 7 years(1987-1993). The mean age of the patients was 56 years and 21 cases were male. The mean size of the mass was 5 cm and 11 cases were located peripherally. According to the histologic features, LCUC could be divided into three groups: squamous cell carcinoma-like(6 cases), adenocarcinoma-like(13 cases), and small cell carcinoma-like(4 cases) groups. The histologic differences were related to the variations of the immunohistochemical properties, but there were no differences in prognosis among these groups. Immunoreactivity to cytokeratin(CAM 5.2) was demonstrated in 22/23(96%). Carcinoembryonic antigen was positive in 13/23(57%). Neuron specific enolase and chromogranin were positive in 11/23(48%) and 5/23(22%), respectively. Vimentin was seen in 11/23(48%). From these observations, we could subclassify them by their immunologic phenotypes; exocrine features in 6/23(26%), neuroendocrine(NE) features in 4/23(17%), both exocrine and NE phenotypes in 7/23(30%), and 6 cases(26%) showed neither phenotype. The group with NE features showed a worse prognosis(P<0.05) and immunoreactivity for vimentin was also related to a worse prognosis(P<0.05). These findings imply that the immunohistochemical properties of LCUC are closely related to the histopathologic features. The groups, subdivided by histology and immunoreactivity, showed no prognostic difference except for the NE differentiation and reaction for vimentin.

Expression of Anaphase Promoting Complex in Surgically Resected Squamous Cell Carcinoma and Adenocarcinoma of the Lung.: Ji Sun Song, Soon Hee Jung, Minseob Eom, Sang Yeop Yi, Kwang Hwa Park, Yup Kang, Ho Young Kim; Korean J Pathol. 2006;40(1):52-59.

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Abstract PDF: BACKGROUND
The anaphase promoting complex (APC) promotes the degradation of mitotic cyclins as well as other substrates involved in sister chromatid adhesion. This study was carried out to examine the relationship between the APC expression and the clinicopathological variables, in an attempt to determine the role of the APC in the proliferation of lung cancer and to evaluate the possibility of an aberrant APC function in surgically resected squamous cell carcinomas and adenocarcinomas of the lung.
METHODS
Immunohistochemical staining was performed for APC, Ki-67, cyclin B1, Cdc2, MMP-2 and VEGF in 55 cases of squamous cell carcinoma and 34 cases of adenocarcinoma of the lung, using the avidin-biotin-peroxidase method.
RESULTS
The immunohistochemical stains for APC revealed a positive reaction in 49 cases (55.1%). The APC expression level was higher in the cyclin B1-positive group (p= 0.01), the Cdc2-positive group (p=0.001), the MMP-2-positive group (p=0.03), the group with lymph node metastasis (61.4% vs 48.9%), and the group with stage II/III cancer (60.7%) compared with those with stage I (42.9%).
CONCLUSIONS
The APC may have an aberrant function, such as a change in its role in controlling the cell cycle, and might be associated with the invasiveness and proliferation of tumor cells.

Immunohistochemical Expression of the Sodium/Iodide Symporter in Patients with Primary Lung Cancer.: Hyoun Wook Lee, Do Young Kang, Phil Jo Choi, Doo Kyung Yang, Ki Nam Kim, Kyung Eun Lee, Mee Sook Roh; Korean J Pathol. 2006;40(2):81-85.

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Abstract PDF: BACKGROUND
The sodium/iodide symporter (NIS) is a membrane glycoprotein that facilitates the uptake of iodine by thyroid follicular cells. Although the use of radioiodide is essential for the diagnosis and treatment of thyroid diseases, few studies have been conducted to investigate the use of NIS-mediated radioiodide accumulation in lung cancer. We evaluated the expression of NIS by immunohistochemistry in order to examine the diagnostic or therapeutic feasibility of using radioiodide in the treatment of primary lung cancer.
METHODS
Immunohistochemistry for NIS was performed in 139 lung cancers. The expression pattern of NIS was compared with the clinicopathological characteristics of the tumors.
RESULTS
NIS immunoreactivity was detected in 75 (54.0%) of the 139 cases. Twenty-three (37.7%) of the 61 squamous cell carcinomas, 49 (76.6%) of the 64 adenocarcinomas, 2 (40.0%) of the 5 small cell carcinomas, and 3 (33.3%) of the 9 other carcinomas showed positive NIS immunoreactivity. The expression of NIS was significantly associated with the histologic type (p<0.001), but it did not correlate with tumor size, lymphovascular invasion or lymph node metastasis.
CONCLUSIONS
The presence of NIS was detected in lung cancer tissue using immunohistochemistry. Lung cancer potentially could be targeted with radioiodide for both diagnosis and treatment, especially in cases of adenocarcinoma.

Diagnostic Application of p53 IMMUNOSTAINING in Bronchial Brush Specimens.: Sang Sook Lee, Ji Yeon Bae, Yu Na Kang, Young Rok Cho, Si Nam Kim, Nam Jo Park, Seun Young Kim, Jung Hi Kim; J Pathol Transl Med. 1996;7(2):163-168.

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Abstract PDF: Abnormalities of p53 gene are common in lung cancers and are associated with immunologically detectable p53 protein. p53 immunoreactivity is uncommon in normal cells but is frequently seen in neoplasia. Therefore, assessment of p53 expression may assist in the cytological diagnosis of malignancy. The usefulness of p53 immunostaining as a marker of malignancy in the cytological analysis of bronchial brush specimens from the patients with lung cancers was investigated in this study. A total of 71 bronchial brush samples submitted for cytologic diagnosis were immunostained with D07, a monoclonal antibody to recombinant p53 protein.
Result
ant p53 data were correlated with cytologic diagnosis and clinical information. Of the 17 smears with a benign cytodiagnosis, all were p53 negative. Of the 40 cases with a malignant cytodiagnosis(histologically confirmed), 35 were p53 positive and 5 were negative. Of the 14 cases that were cytologically suspicious but nondiagnostic for malignancy, 11 were p53 positive, 9 of which were subsequently proved to be malignant by histologic examination, and the remaining 2 cases were tuberculosis clinically. Forty four of 51 histologically confirmed lung carcinomas were p53 positive, including 25 of 28 squamous cell carcinomas, 13 of 17 small cell carcinomas, 3 of 3 adeno- carcinomas, and 3 of 3 large cell undifferentiated carcinomas. These results suggest that p53 immunostaining could be of value as a marker of malignancy in the cytologic examination of bronchial brush specimens. Furthermore, we have shown the possible clinical utility of p53 immunostaining in cytopathological diagnosis, that is, as a valuable adjunct to morphological assessment in the analysis of cytopathologically suspicious cases.

Histopathologic Findings, and p53 and K-ras Mutational Analysis in Biopsy Specimens Using Fluorescence Bronchoscopy.: Young Sik Kim, Seol Hee Park, Myung Hee Jung, Eun Chang Choi, I Yong Park, Han Kyeom Kim, Insun Kim; Korean J Pathol. 2000;34(8):550-558.

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Abstract PDF: A fluorescence bronchoscope system has been developed for detecting early lung cancer including dysplasia and carcinoma in situ. To determine the histologic findings and genetic alterations of the lung tissues, which were biopsied by the fluorescence bronchoscope, we analyzed 104 specimens from 62 heavy smokers for their histopathology, cell proliferation index, and genetic mutations of p53 and K-ras. We used immunohistochemistry for MIB-1 and p53, and PCR-SSCP and direct DNA sequencing for p53 and K-ras. The histology was variable from reactive conditions to invasive cancers, and consisted of basal cell hyperplasia (26.9%), dysplasia (4.8%), carcinoma in situ (1.9%), squamous cell carcinoma (7.7%), adenocarcinoma (4.8%), and small cell carcinoma (10.6%). The cellular proliferation index of the lesions increased as their aggressiveness increased. p53 and K-ras mutations were detected in 33.7% and 14.4% of all tissues, respectively. In dysplasia, p53 and K-ras mutations were observed in 3 of 5 and in 2 of 5 tissues, respectively. However, these genetic alterations were not found in carcinoma in situ. Interestingly, 28.6% of basal cell hyperplasia showed p53 mutations. In conclusion, these data suggest that the biopsy specimens using fluorescence bronchoscopy show variable histologic findings, ranging from reactive conditions to invasive cancers. In addition, some of the dysplastic lesions are related to p53 and K-ras mutations, although these genetic alterations are also seen in basal cell hyperplasia.

Effectiveness of Transbronchial Fine Needle Aspiration in Diagnosing Lung Cancers.: Tae Yub Kim, Gyung Yub Gong, Won Dong Kim, On Ja Kim; J Pathol Transl Med. 1997;8(2):109-114.

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Abstract PDF: Transbronchial fine needle aspiration(TBNA) is one of the cytologic methods in diagnosing lung cancers. TBNA can be used in cases of hilar, mediastinal or lung masses adjacent to the bronchi. We analyzed and compaired the findings of 27 cases of TBNA and bronchial washing and brushing(BW/BB) in lung cancers confirmed by either biopsy or surgical resection between Jun, 1996 and May, 1997 in Asan Medical Center. They were 18 cases of non-small cell carcinomas(eight squamous cell carcinomas, nine adenocarcinomas, and one large cell undifferentiated carcinoma), eight cases of small cell carcinomas, and one case of metastatic hepatocellular carcinoma. The sensitivity of TBNA was 37%(10/27) and false negative was 63%(17/27). Although the sensitivity of BW/BB was 56%(15/27), it was not different statistically from that of TBNA(Chi square, p=0.38). Overall sensitivity of TBNA and BW/BB in this series was 70%(19/27). Forty-seven percent of false negative TBNA(8/17) were positive in BW/BB. The findings suggest that the addition of TBNA to the standard BW/BB increases diagnostic yield in cytologic diagnosis of lung cancer.

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