Journal of Pathology and Translational Medicine

Review

Molecular Testing for Gastrointestinal Cancer: Hye Seung Lee, Woo Ho Kim, Yoonjin Kwak, Jiwon Koh, Jeong Mo Bae, Kyoung-Mee Kim, Mee Soo Chang, Hye Seung Han, Joon Mee Kim, Hwal Woong Kim, Hee Kyung Chang, Young Hee Choi, Ji Y. Park, Mi Jin Gu, Min Jin Lhee, Jung Yeon Kim, Hee Sung Kim, Mee-Yon Cho; J Pathol Transl Med. 2017;51(2):103-121. Published online February 19, 2017; DOI: https://doi.org/10.4132/jptm.2017.01.24

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With recent advances in molecular diagnostic methods and targeted cancer therapies, several molecular tests have been recommended for gastric cancer (GC) and colorectal cancer (CRC). Microsatellite instability analysis of gastrointestinal cancers is performed to screen for Lynch syndrome, predict favorable prognosis, and screen patients for immunotherapy. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved in metastatic CRCs with wildtype RAS (KRAS and NRAS exon 2–4). A BRAF mutation is required for predicting poor prognosis. Additionally, amplification of human epidermal growth factor receptor 2 (HER2) and MET is also associated with resistance to EGFR inhibitor in metastatic CRC patients. The BRAF V600E mutation is found in sporadic microsatellite unstable CRCs, and thus is helpful for ruling out Lynch syndrome. In addition, the KRAS mutation is a prognostic biomarker and the PIK3CA mutation is a molecular biomarker predicting response to phosphoinositide 3-kinase/AKT/mammalian target of rapamycin inhibitors and response to aspirin therapy in CRC patients. Additionally, HER2 testing should be performed in all recurrent or metastatic GCs. If the results of HER2 immunohistochemistry are equivocal, HER2 silver or fluorescence in situ hybridization testing are essential for confirmative determination of HER2 status. Epstein-Barr virus–positive GCs have distinct characteristics, including heavy lymphoid stroma, hypermethylation phenotype, and high expression of immune modulators. Recent advances in next-generation sequencing technologies enable us to examine various genetic alterations using a single test. Pathologists play a crucial role in ensuring reliable molecular testing and they should also take an integral role between molecular laboratories and clinicians.

Citations

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Original Article

The Expression of TGF-beta1 and TGF-beta Receptor I in Human Lung Cancer.: Hye Kyung Ahn, Young Hee Choi, Jung Weon Shim, Young Euy Park, Han Kyeom Kim, Jong Sang Choi, Joung Ho Han; Korean J Pathol. 1998;32(1):9-20.

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Abstract PDF: A majority of human lung cancer cell lines have developed resistance to growth inhibition via the activation of transforming growth facter-beta (TGF-beta). Previous studies have reported that growth inhibition of TGF-beta is linked to the expression of transforming growth factor-beta receptor type I (TGF-betaRI). Immunohistochemical studies of TGF-beta1 and TGF-betaRI have been carried out in 43 cases of lung neoplasm; including 25 cases of squamous cell carcinoma, 13 cases of adenocarcinoma, 2 cases of adenosquamous cell carcinoma, and 1 case each of undifferentiated carcinoma, small cell carcinoma and neuroendocrine carcinoma. Reverse transcriptase polymerase chain reaction (RT-PCR) for TGF-beta1 mRNA was also performed in 40 cases of tumors and 14 control cases of normal parenchyme. Immunohistochemically, TGF-beta1 and TGF-betaRI expression were noted in the cytoplasm of all type of tumor cells. The staining intensity and areas were examined and scored from 0 to 5. As a whole, TGF-beta1 staining scores in the neoplastic lesions were higher than that of the adjacent normal parenchyme, bronchial epithelium or alveolar epithelium. However, TGF-betaRI staining scores were generally lower than that of the adjacent normal components. The TGF-beta1 mRNA showed a higher percentage of expression in tumors than in normal control. Tumor size, lymph node metastasis, histological differentiation and histological type of tumors did not correlated with the staining score of TGF-beta1 and TGF-betaRI. These results indicate that although various types of human lung carcinoma cells produce TGF-beta1, they show a reduction in TGF-betaRI, resulting in an escape from growth inhibition by TGF-beta1.

Case Reports

Malignant Eccrine Poroma of Abdomen Brief case report.: Jin Ja Park, Young Hee Choi, Kyung Chan Choi, Young Euy Park; Korean J Pathol. 1998;32(4):312-314.

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Abstract PDF: Eccrine porocarcinoma is a rare tumor of the skin. A case report of an eccrine porocarcinoma metastasizing to epidural space of spinal cord and inguinal area with a nine year follow up is described. The patient had a nodular growth of the abdomen with both inguinal lymphadenopathy three years before its first excision. After a follow up of nine years, he complained a weakness of lower extremities and back pain. Extradural mass of 10th thoracic vertebra and left inguinal mass were found. Subsequently, the masses histologically identical to the skin tumor were found.

Polypoid Ganglioneuromatosis of Colon: A case report.: Jin Ja Park, Kyung Chan Choi, Young Hee Choi, Young Euy Park; Korean J Pathol. 1998;32(5):388-390.

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Abstract: Gastrointestinal ganglioneuromatosis is an extremely rare lesion which typically occurs with a significant systemic syndrome. It is known to be a major component of multiple endocrine neoplasia, type 2b. We presented a case of polypoid ganglioneuromatosis of the colon in a 3-year-old female with abdominal pain and diarrhea. She had no clinical evidence of the systemic syndrome or von Recklinghausen's neurofibromatosis, conditions in which intestinal ganglioneuromatosis can occur. Gross examination showed diffuse polypoid masses in ascending and transverse colons with normal-appearing mucosa. Microscopic examination revealed a proliferation of spindle-shaped neuronal cells containing multiple clusters of mature ganglion cells in the mucosa, submucosa and proper muscle. We describe a case of colonic ganglioneuromatosis without any component of multiple endocrine neoplasia or family history.

Original Articles

Expression of Transforming Growth Factor-beta1 and Its Effects on the Extracellular Matrix Formation and Angiogenesis in Gastric Carcinoma.: Young Hee Choi, Young Euy Park; Korean J Pathol. 1998;32(9):647-654.

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Abstract: Malignant cells in culture express elevated levels of transforming growth factor-beta1 (TGF-beta1) mRNA and secrete an abundant amount of the TGF-beta1 protein. An attempt was made to define the role of the TGF-beta1 secreted from tumor cells, as a possible humoral factor which functions in a paracrine manner to stimulate the production of collagen and angiogenesis in gastric carcinoma. The expression of the TGF-beta1 by immunohistochemical stain (n=70) in gastric adenocarcinoma tissues was studied. Angiogenesis was evaluated by immunohistochemical staining of tumor vessels, using polyclonal antibody to factor VIII related antigen and counting the three most active areas of neovascularization. The extracellular matrix was counted as area density by using an image analyzer following Masson-Trichrome staining. The prominent reactivity for TGF-beta1 was associated with invasion depth (r=0.2, p<0.05), increased number of microvessel (r=0.49, p<0.05) and increased area density of extracellular matrix (r=0.36, p<0.05), respectively. In summary, TGF-beta1 may have a role in tumor invasion and metastasis by increased angiogenesis and deposits of extracellular matrix.

The Effects of Transforming Growth Factor beta1 on Apoptosis in Rat Hepatocellular Carcinoma.: Young Euy Park, Young Hee Choi, Won Yo Lee, Jin Ja Park, Kyung Chan Choi, Hyung Shik Shin; Korean J Pathol. 1999;33(2):71-79.

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Abstract: Based upon the concept that carcinogenesis is associated with apoptosis, specific therapies designed to enhance the susceptibility of cancer cells to undergo apoptosis could be developed. Thus, in this paper, it was designed to investigate whether, using rat animal model with chemical-induced hepatocellular carcinoma, TGF-1 in vivo could induce apoptosis in cancer. The chemical hepatocarcinogenic procedure of Solt-Farber method was used on Sprague-Dawley rats. Experimental groups were divided into group A treated with the standard Solt-Farber regimen of diethylnitrosamine (DEN) and 2-Acetaminofluorene (AAF), group B TGF-, group C TGF-1, and group D adriamycin after hepatocellular carcinoma developed. For detection of apoptotic cells, apoptotic indices were examined by the in situ end DNA labelling method. The expression of proliferating cell nuclear antigen was examined by immunohistochemical staining. Apoptosis of rat hepatocellular carcinoma cells increased significantly to 4.92+/-2.32/HPF in the group C compared with the control group (A) (2.54+/-1.13/HPF; P<0.05). Two distinctly different populations of proliferating hepatocellular carcinoma cells were identified. The cells at G1/S boundary (weak granular staining) increased to 15.75+/-6.19/HPF and 6.45+/-2.93/HPF in the groups C and D, respectively, but decreased to 2.42+/-2.06/HPF in the group B compared with the control group (A) (6.38+/-2.18/HPF; p<0.05). The cells at S phase (strong granular staining) increased to 3.37+/-2.69/HPF in the group B but decreased to 0.32+/-0.47/HPF in the group D (p<0.05). In conclusion, these results indicate that the TGF-1 may be used as an effective anticancer agent.

Expression of p21 and p53 Proteins in Gastric Adenocarcinoma.: Yun Jung Kim, Young Hee Choi, Kyoung Chan Choi, Young Euy Park; Korean J Pathol. 1999;33(3):187-192.

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Abstract PDF: Fifty-four adenocarcinomas of stomach were investigated to assess the expression of p21 and p53 using an immunohistochemical method. The relationship between p21 and p53 expression and the clinicopathologic parameters were analysed. The staining pattern of p21/p53 were: p21+/p53+, p21-/p53+, p21+/p53-, and p21-/p53- in 30, 12, 8, and 4 cases, respectively. Loss of p21 expression was observed in 16 of 54 tumor tissues (29%). p21 expression, however, had an inverse correlation with vascular invasion and depth of tumor invasion. The p21 and p53 protein expression showed intratumoral heterogeneity. In 63% of the adenocarcinoma, a proportional relationship was found between p21 and p53 immunostaining. The present results suggest that p53 independent induction of p21 expression may be involved in the molecular mechanism of these tumors, and expression of p21 protein may be related to a favorable prognosis in gastric adenocarcinomas.

Expression of p21, p53 and Ki-67, and Apoptosis in Colorectal Adenocarcinoma.: Young Euy Park, Kyung Chan Choi, Jin Hee Sohn, Young Hee Choi, Hyung Sik Shin; Korean J Pathol. 2002;36(5):296-304.

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Abstract PDF: BACKGROUND
The purpose of this study is to assess the roles of p21 protein, p53 protein, and Ki-67 expressions and apoptosis in colorectal tumorigenesis.
METHODS
Fifty-seven colorectal cancers and 15 villotubular adenomas were investigated by immunohistochemical staining for p21 protein, p53 protein, Ki-67, and in situ labeling of apoptotic cells. Clinicopathologic values (tumor size, histologic grade, Dukes stage, and lymph node metastasis) were compared with the incidence of expressions of p21 protein and p53 protein, index of Ki-67 expression, and apoptosis.
RESULTS
The incidence of p21 protein expression was decreased with lymph node metastasis (p<0.005), and that of p53 expression was increased with lymph node metastasis (p<0.005). There were no statistically significant correlations among the p21 protein or p53 protein expressions, tumor size, histologic grade and stage. The correlation between the Ki-67 labeling index and the clinicopathologic values was not statistically significant. The labeling index of apoptosis was increased with the Astler-Coller stage (p<0.05). Statistical analysis revealed a significant inverse correlation between the p21 protein and p53 protein expressions (p<0.05).
CONCLUSIONS
It is suggested that p21 protein, p53 protein and the apoptotic labeling index are useful variables for the prognostic assessment of colorectal adenocarcinoma. Down-regulation of p21 protein expression may be associated with poor prognosis. Also, the expressions of p21 protein and p53 protein may play an important role in the tumorigenesis and progression of the colorectal adenoma-carcinoma sequence.

Nuclear Morphometry of Fibroadenoma and Carcinoma of Breast: Comparison between fine needle aspiration cytology and biopsy.: Jin Hee Sohn, Young Hee Choi, Young Eui Park; Korean J Cytopathol. 1998;9(2):161-168.

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Abstract PDF: Primary breast lesions diagnosed by fine needle aspiration cytology, confirmed by histologic examination were analyzed by morphometry to evaluate the difference between benign and malignant lesions, and the methods obtaining the sample. Four size factors and 5 form factors were evaluated in 22 fibroadenomas and 20 carcinomas by image analyzer(Zeiss Ibas 2000) using the H-E stained slides. Nuclear size was significantly larger in the carcinoma cells than fibroadenoma cells both in the cytology and biopsy specimens, but the form factors were not significantly different. Both fibroadenoma and carcinoma cells were significantly larger in cytologic smear than histologic section. The cells in the cytology were more regular and round than those in histology, but not statistically significant. Fibroadenomas having cellular proliferation and atypism exhibited larger size and more irregular nuclei than non-proliferative fibroadenoma, but not statistically significant. Therefore nuclear morphometric analysis can be a helpful method to diagnose the questionable breast lesions and is a method appropriate for use as a quality control procedure in the fine needle aspiration cytology.

Differential Diagnosis between Small Cell Carcinoma and Adenocarcinoma of Lung in Fine Needle Aspiration Cytology.: Young Hee Choi, Jae Soo Koh, Sunhoo Park, Min Suk Kim, Soo Youn Cho, Jung Soon Kim, Hwa Jung Ha, Seung Sook Lee; Korean J Cytopathol. 2006;17(2):120-125.

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Abstract PDF: Distinguishing small cell carcinoma from other lung malignancies is of great clinico-therapeutic significance. Small cell carcinoma is an aggressive tumor with a tendency to metastasize early. Survival time if untreated is low but this tumor is highly responsive to chemotherapy. We have occasionally experienced difficulties in differentiation between adenocarcinoma and small cell carcinoma of the lung in fine needle aspiration cytology (FNAC). The aim of this study was to investigate the possibility of distinguishing small cell carcinoma from adenocarcinoma of the lung in FNAC. We evaluated cytomorphological features of FNAC specimens from 62 small cell carcinomas and 57 adenocarcinomas from the lung that were confirmed by biopsy and/or immunohistochemistry on cell block. Cytomorphological details of the two tumors were compared. Nuclear smearing and nearly absent cytoplasm were the most distinct findings in small cell carcinoma compared to adenocarcinoma (p<0.05). Necrotic background, architecture and chromatin pattern, nuclear molding and nucleoli were significantly different (p<0.05). Nuclear size, nuclear membrane nature and nuclear size variation however were not helpful in distinguishing the two tumors. Combining several features described above, small cell carcinoma can be properly differentiated from adenocarcinoma on FNAC. FNAC is proposed as a diagnostic tool of small cell carcinoma of the lung in the case of inaccessibility to biopsy, and so may allow the proper therapeutic strategies to be determined in such cases.

A Multiinstitutional Consensus Study on the Pathologic Diagnosis of Endometrial Hyperplasia and Carcinoma.: Kwang Sun Suh, Insun Kim, Moon Hyang Park, Geung Hwan Ahn, Jin Hee Sohn, In Ae Park, Hye Kyoung Yoon, Kyu Rae Kim, Hee Jung An, Dong Won Kim, Mi Jin Kim, Hee Jae Joo, Eun Kyung Kim, Young Hee Choi, Chong Woo Yoo, Kyung Un Choi, Sang Yeop Yi, Hye Sun Kim, Sung Ran Hong, Hee Jeong Lee, Sun Lee; Korean J Pathol. 2008;42(2):87-93.

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Abstract PDF: BACKGROUND
The purpose of this study was to examine the reproducibility of both the diagnosis of endometrial hyperplasia (EH) or adenocarcinoma, and the histologic grading (HG) of endometrioid adenocarcinoma (EC).
METHODS
Ninety-three cases of EH or adenocarcinomas were reviewed independently by 21 pathologists of the Gynecologic Pathology Study Group. A consensus diagnosis was defined as agreement among more than two thirds of the 21 pathologists.
RESULTS
There was no agreement on the diagnosis in 13 cases (14.0%). According to the consensus review, six of the 11 EH cases (54.5%) were diagnosed as EH, 48 of the 57 EC cases (84.2%) were EC, and 5 of the 6 serous carcinomas (SC) (83.3%) were SC. There was no consensus for the 6 atypical EH (AEH) cases. On the HG of EC, there was no agreement in 2 cases (3.5%). According to the consensus review, 30 of the 33 G1 cases (90.9%) were G1, 11 of the 18 G2 cases (61.1%) were G2, and 4 of the 4 G3 cases (100.0%) were G3.
CONCLUSIONS
The consensus study showed high agreement for both EC and SC, but there was no consensus for AEH. The reproducibility for the HG of G2 was poor. We suggest that simplification of the classification of EH and a two-tiered grading system for EC will be necessary.

Case Report

A Case Report of Strumal Carcinoid of the Ovary.: Young Hee Choi, Seoung Wan Chae, Hye Rim Park, Min Chul Lee, Young Euy Park; Korean J Pathol. 1994;28(3):307-312.

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Abstract: Strumal carcinoid of the ovary is a rare turkor characterized by an intimate mixture of thyroid follicles and carcinoid. Herein is reported an ovarian strumal carcinoid in a serous cystadenoma from a 27-year-old pregnant woman. The thyroid follicular epithelial cells had immunohistochemically thyroglobulin and carcinoid tumor cells contained neuron-specific enolase, chromogranin and carcinoembryonic antigen. In addition, carcinoid cells showed neuroendocrine granules ultrastructurally. Calcitonin and amyloid were not found. This tumor may be originated from pluripotent endodermal germ cells on the basis of morphologic, immunohistochemical and ultrastructural studies.

Original Article

Immunohistochemical Analysis of Transforming Growth Factor-beta Expression in Gastric Adenocarcinoma.: Young Hee Choi, Seoung Wan Chae, Min Chul Lee, Jung Weon Shim, Hye Kyung Ahn, Hye Rim Park, Gu Kang, Hyung Sik Shin, Young Euy Park; Korean J Pathol. 1994;28(3):272-281.

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Abstract: Thirty cases of gastric adenocarcinoma were examined immunohistochemically for expression of transforming growth factor-beta(TGF-beta) in order to analyze significant correlation with clinical stage and pathologic grade of gastric adenocarcinoma. Specific immunostaining was clearly detected in the cytoplasm of the neoplastic cells. The TGF-,6 expression in the gastric adenocarcinoma is closely related to the depth of invasion, the degree of invasiveness and the presence of metastasis. Thus, we observed the stronger immunohistochemical. expression of TGF-beta in the deeper portion of invasion and in the invasive gastric adenocarcinomas with the lymph nodal metastasis than in the superficial portion of invasion and in those without the lymph nodal metastasis. There results suggest that the transforming growth factors expression in carcinoma cells may play an important role in the carcinomatous invasion resulting in metastasis.

Case Reports

Endobronchial Inflammatory Pseudotumor: A case report.: Seoung Wan Chae, Young Hee Choi, Hye KYung Ahn, Young Euy Park; Korean J Pathol. 1994;28(2):213-215.

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Abstract: Inflammatory pseudotumors of the bronchus have been reported infrequently. Histologic diagnosis remains difficult because of their Polymorphic histologic characteristics and confusing terminology, which are also the problems in the diagnosis of intrapulmonary pseudotumors. We report a case of inflammatory pseudotumor in the left main bronchus which occurred in a 37-year-old man. Histologically, the main portion of the tumor was composed of pale eosinophilic spindle shaped cells covered by respiratory epithelium with squamous metaplasia. Mononuclear inflammatory cells, including plasma cells but acute inflammatory cells were also present in the superficial portion.

Giant Cystic Adenomatoid Tumor of the Uterus: A case report.: Young Hee Choi, Seoung Wan Chae, Hye Kyung Ahn, Min Chul Lee, Young Euy Park; Korean J Pathol. 1993;27(1):85-87.

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Abstract PDF: Adenomatoid tumor of the uterus is a rare benign neoplasm which has been known as mesothelial origin. Characteristically, it appears as a small nodular lesion less than 2.0cm in the myometrium of subserosal region. We describe a case of giant adenomatoid tumor of the uterus having multicystic gross appearance. A 49-year-old woman complained of vaginal bleeding. The tumor was an intramural mass with maximum diameter of 10 cm and located at posterior wall of the uterus. Histologically, the tumor was composed of multiple cystic cavities of variable size lined by flattened cells, lying among thin septa of connective tissue. Immunohistochemically, the cells are positive for low molecular weight cytokeratin(CAM 5.2) and are negative for factor VIII.

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