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Volume 52(5); September 2018
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Original Articles
C-reactive Protein Overexpression in the Background Liver of Hepatitis B Virus–Associated Hepatocellular Carcinoma Is a Prognostic Biomarker
Jin Ho Shin, Eunsil Yu, Eun Na Kim, Chong Jai Kim
J Pathol Transl Med. 2018;52(5):267-274.   Published online July 27, 2018
DOI: https://doi.org/10.4132/jptm.2018.07.14
  • 5,112 View
  • 161 Download
  • 4 Citations
AbstractAbstract PDF
Background
Chronic hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma (HCC). Peripheral blood C-reactive protein (CRP) concentration and CRP overexpression in HCC cells are proven to be prognostic markers for HCC, but the significance of CRP expression in non-neoplastic hepatocytes, which are the primary origin of CRP, has not been studied. This study was conducted to determine the clinicopathologic significance of CRP immunoreactivity in the background liver of HBV-associated HCC.
Methods
CRP immunostaining was done on tissue microarrays of non-neoplastic liver tissues obtained from surgically resected, treatment-naïve HBV-associated HCCs (n = 156). The relationship between CRP immunoreactivity and other clinicopathologic parameters including cancer-specific survival was analyzed. CRP immunoreactivity was determined using a 4-tier grading system: grades 0, 1, 2, and 3.
Results
CRP was positive in 139 of 156 cases (89.1%) of non-neoplastic liver in patients with HCCs: grade 1 in 83 cases (53.2%); grade 2 in 50 cases (32.1%); and grade 3 in six cases (3.8%). The patients with diffuse CRP immunoreactivity (grade 3) had decreased cancer-specific survival (p = .031) and a tendency for shorter interval before early recurrence (p = .050). The degree of CRP immunoreactivity correlated with serum CRP concentration (p < .001).
Conclusions
CRP immunoreactivity in non-neoplastic liver is a novel biomarker for poor cancer-specific survival of HBV-associated HCC and correlates with serum CRP concentration.
Differential MicroRNA Expression between EGFR T790M and L858R Mutated Lung Cancer
Ji Yeon Kim, Woo Jeong Lee, Ha Young Park, Ahrong Kim, Dong Hoon Shin, Chang Hun Lee
J Pathol Transl Med. 2018;52(5):275-282.   Published online August 16, 2018
DOI: https://doi.org/10.4132/jptm.2018.07.29
  • 4,611 View
  • 113 Download
  • 4 Citations
AbstractAbstract PDFSupplementary Material
Background
MicroRNAs (miRNAs) are short, non-coding RNAs that mediate post-transcriptional gene regulation. They are commonly deregulated in human malignancies, including non-small cell lung cancer (NSCLC). The aim of this study is to investigate miRNA expression in T790M-mutated NSCLC resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors.
Methods
Six cases of resected NSCLC harboring the T790M mutation were examined. We performed miRNA time polymerase chain reaction (PCR) array profiling using EGFR T790M-mutated NSCLC and L858R-mutated NSCLC. Once identified, miRNAs that were differentially expressed between the two groups were validated by quantitative real-time polymerase chain reaction (qRT-PCR).
Results
miRNA PCR array profiling revealed three up-regulated miRNAs whose expression levels were altered 4.0-fold or more in the EGFR T790M mutation group than in the L858R group: miR-1 (fold change, 4.384), miR-196a (fold change, 4.138), and miR-124 (fold change, 4.132). The three differentially expressed miRNAs were validated by qRT-PCR, and they were found to be overexpressed in the T790M group relative to L858R group. In particular, expression levels of miR-1 and miR-124 were significantly higher in the T790M group (p-value of miR-1 = .004, miR-124 = .007, miR-196a = .096).
Conclusions
MiR-1, miR-124, and miR-196a are overexpressed in EGFR T790M mutated NSCLC.
p40 Immunohistochemistry Is an Excellent Marker in Primary Lung Squamous Cell Carcinoma
Khairunisa Ahmad Affandi, Nur Maya Sabrina Tizen, Muaatamarulain Mustangin, Reena Rahayu MdReena Rahayu Md Zin
J Pathol Transl Med. 2018;52(5):283-289.   Published online August 31, 2018
DOI: https://doi.org/10.4132/jptm.2018.08.14
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  • 13 Citations
AbstractAbstract PDF
Background
Lung cancer is the third most common cancer worldwide. With major advances in the molecular testing of lung cancers and the introduction of targeted therapies, the distinction between adenocarcinoma and squamous cell carcinoma as well as pathologic subtyping has become important. Recent studies showed that p40 is highly specific for squamous and basal cells and is superior to p63 for diagnosing lung squamous cell carcinoma. The aim of this study was to evaluate the use of p40 immunohistochemical stain in the diagnosis of non-small cell lung carcinoma and its potential to replace current p63 antibody as the best immunohistochemical squamous marker.
Methods
Seventy formalin-fixed paraffin-embedded cases previously diagnosed as primary lung squamous cell carcinoma (n = 35) and lung adenocarcinoma (n = 35) from January 2008 to December 2016 were retrieved. The results of tumour cell immunoreactivity for p40 and p63 antibodies in lung squamous cell carcinoma and lung adenocarcinoma were compared.
Results
p40 was expressed in 27 cases of lung squamous cell carcinoma (77.1%). All cases of lung adenocarcinoma (35/35, 100%) were negative for p40. p63 expression was positive in 30 cases of lung squamous cell carcinoma (85.7%) and 13 cases of lung adenocarcinoma (37.1%). Reactivity for both p40 and p63 in lung squamous cell carcinoma was strong and diffuse, whereas variable reactivity was observed in lung adenocarcinoma.
Conclusions
p40 is an excellent marker for distinguishing lung squamous cell carcinoma from adenocarcinoma, and p40 expression is equivalent to p63 expression in lung squamous cell carcinoma.
Chronic Placental Inflammation as a Risk Factor of Severe Retinopathy of Prematurity
Chae Young Kim, Euiseok Jung, Eun Na Kim, Chong Jai Kim, Joo Yong Lee, Ji Hye Hwang, Woo Sun Song, Byong Sop Lee, Ellen Ai-Rhan Kim, Ki-Soo Kim
J Pathol Transl Med. 2018;52(5):290-297.   Published online July 16, 2018
DOI: https://doi.org/10.4132/jptm.2018.07.09
  • 8,667 View
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  • 9 Citations
AbstractAbstract PDF
Background
Chronic placental inflammation (CPI) has been implicated in the pathogenesis of diseases in premature infants, whereas retinopathy of prematurity (ROP) is a major complication primarily affecting preterm and very low-birth-weight (VLBW) infants. This study aims to investigate the association between CPI and ROP in VLBW infants.
Methods
We performed a retrospective review of clinical records of VLBW infants born between 2013 and 2016. Placental pathology findings including CPI cases were analyzed using logistic regression to study infants’ morbidities and other clinical characteristics.
Results
A total of 402 infants with a mean (standard deviation) gestational age of 28.5 (2.8) weeks and birth weight of 1,027.2 (304.4) g were included. The incidence of ROP was 24.1%. CPI was found in 90 infants (22.4%), among which 28.9% (26 of 90) developed ROP, and 21.1% (19 of 90) underwent laser photocoagulation. Lower gestational age, lower birth weight, longer duration of oxygen supply, and presence of CPI were associated with the development of ROP. After adjustment for gestational age, birth weight, sex, duration of oxygen supply, and other overlapping placental pathology, CPI was associated with the odds for type 1 ROP that required laser photocoagulation (adjusted odds ratio, 2.739; 95% confidence interval, 1.112 to 6.749; p = .029).
Conclusions
CPI was associated with severe ROP requiring treatment with laser photocoagulation in VLBW infants.
Prognostic Significance of EPHB2 Expression in Colorectal Cancer Progression
Bo Gun Jang, Hye Sung Kim, Weon Young Chang, Jeong Mo Bae, Gyeong Hoon Kang
J Pathol Transl Med. 2018;52(5):298-306.   Published online July 18, 2018
DOI: https://doi.org/10.4132/jptm.2018.06.29
  • 4,917 View
  • 131 Download
  • 10 Citations
AbstractAbstract PDF
Background
A receptor tyrosine kinase for ephrin ligands, EPHB2, is expressed in normal colorectal tissues and colorectal cancers (CRCs). The aim of this study was to investigate EPHB2 expression over CRC progression and determine its prognostic significance in CRC.
Methods
To measure EPHB2 mRNA and protein expression, real-time polymerase chain reaction and immunohistochemistry were performed in 32 fresh-frozen and 567 formalin-fixed paraffin-embedded CRC samples, respectively. We further investigated clinicopathological features and overall and recurrence-free survival according to EPHB2 protein expression.
Results
The EPHB2 level was upregulated in CRC samples compared to non-cancerous tissue in most samples and showed a strong positive correlation with AXIN2. Notably, CD44 had a positive association with both mRNA and protein levels of EPHB2. Immunohistochemical analysis revealed no difference in EPHB2 expression between adenoma and carcinoma areas. Although EPHB2 expression was slightly lower in invasive fronts compared to surface area (p < .05), there was no difference between superficial and metastatic areas. EPHB2 positivity was associated with lymphatic (p < .001) and venous (p = .001) invasion, TNM stage (p < .001), and microsatellite instability (p = .036). Kaplan–Meier analysis demonstrated that CRC patients with EPHB2 positivity showed better clinical outcomes in both overall (p = .049) and recurrence-free survival (p = .015). However, multivariate analysis failed to show that EPHB2 is an independent prognostic marker in CRCs (hazard ratio, 0.692; p = .692).
Conclusions
Our results suggest that EPHB2 is overexpressed in a subset of CRCs and is a significant prognostic marker.
Interleukin-31, Interleukin-31RA, and OSMR Expression Levels in Post-burn Hypertrophic Scars
Mi Young Lee, Eun Shin, Hyunchul Kim, In Suk Kwak, Younghee Choi
J Pathol Transl Med. 2018;52(5):307-313.   Published online August 16, 2018
DOI: https://doi.org/10.4132/jptm.2018.08.03
  • 4,489 View
  • 169 Download
  • 4 Citations
AbstractAbstract PDF
Background
Although several studies have shown the role of interleukin-31 (IL-31) and its receptors in inducing pruritus in certain skin disorders, knowledge of its role in post-burn hypertrophic scars is insufficient. Therefore, the histopathological expression levels of IL-31, IL-31 receptor alpha (IL-31RA), and oncostatin M receptor (OSMR) in post-burn hypertrophic scar tissues were investigated and compared with normal tissue expression levels.
Methods
Samples of hypertrophic scar tissue were obtained from 20 burn patients through punch biopsy. Normal samples were obtained from areas adjacent to the burn injury site of the same patients. Samples were placed in 10% neutral buffered formalin, embedded in paraplast, and processed into serial 5-μm sections. Immunohistochemistry results were semi-quantitatively evaluated for IL-31, IL-31RA, and OSMR. By hematoxylin and eosin staining, epidermal and dermal thickness were assessed with a microscope and digital camera. Intensities were rated on a scale of 1 to 4.
Results
Percentages for IL-31, IL-31RA, and OSMR in the epidermal basal layer cell cytoplasm were significantly greater in the burn scar tissue compared to normal skin, as well as the dermal and epidermal thickness (p < .05). There was a significant difference in IL-31 epidermal basal layer intensity in burn scar tissue compared to normal skin (p < .05). Besides the OSMR basal layer intensity, IL-31 and IL-31RA intensities between the burn scar and normal tissues were not significant. However, correlations were significant, indicating that the greater the infiltration percentage, the higher the intensity (p < .05).
Conclusions
IL-31, IL-31RA, and OSMR expression levels are increased in hypertrophic scars compared with normal tissue.
An Immunohistochemical and Polarizing Microscopic Study of the Tumor Microenvironment in Varying Grades of Oral Squamous Cell Carcinoma
Aeman Khalid, Safia Siddiqui, Bharadwaj Bordoloi, Nafis Faizi, Fahad Samadi, Noora Saeed
J Pathol Transl Med. 2018;52(5):314-322.   Published online July 27, 2018
DOI: https://doi.org/10.4132/jptm.2018.07.17
  • 5,166 View
  • 126 Download
  • 1 Citations
AbstractAbstract PDF
Background
Invasion of epithelial cells into the connective tissue brings about massive morphological and architectural changes in the underlying stroma. Myofibroblasts reorganize the stroma to facilitate the movement of tumor cells leading to metastasis. The aim of this study was to determine the number and pattern of distribution of myofibroblasts and the qualitative and quantitative change that they cause in the collagen present in the stroma in various grades of oral squamous cell carcinoma (OSCC).
Methods
The study was divided into two groups with group I (test group, 65 cases) consisting of 29 cases of well-differentiated squamous cell carcinoma, 25 moderately differentiated SCC, and 11 poorly differentiated SCC, and group II (control group) consisting of 11 cases of normal mucosa. Sections from each sample were stained with anti–α-smooth muscle actin (α-SMA) antibodies, hematoxylin and eosin, and Picrosirius red. Several additional sections from each grade of OSCC were stained with Masson’s trichrome to observe the changes in collagen. For the statistical analysis, Fisher’s exact test, Tukey’s post hoc honest significant difference test, ANOVA, and the chi-square test were used, and p < .05 was considered statistically significant.
Results
As the tumor stage progressed, an increase in the intensity α-SMA expression was seen, and the network pattern dominated in more dedifferentiated carcinomas. The collagen fibers became thin, loosely packed, and haphazardly aligned with progressing cancer. Additionally, the mean area fraction decreased, and the fibers attained a greenish yellow hue and a weak birefringence when observed using polarizing light microscopy.
Conclusions
Myofibroblasts bring about numerous changes in collagen. As cancer progresses, there isincrease in pathological collagen,which enhances the movement of cells within the stroma.
Significance of Intratumoral Fibrosis in Clear Cell Renal Cell Carcinoma
Jae Won Joung, Hoon Kyu Oh, Sun Jae Lee, Young Ah Kim, Hyun Jin Jung
J Pathol Transl Med. 2018;52(5):323-330.   Published online August 19, 2018
DOI: https://doi.org/10.4132/jptm.2018.07.21
  • 4,992 View
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  • 11 Citations
AbstractAbstract PDF
Background
Intratumoral fibrosis (ITF) is a frequent histologic finding in solid organ tumors. Renal cell carcinoma (RCC) is a highly vascularized tumor with different shapes and degrees of ITF and inflammation. ITF is a poor prognostic factor, especially in breast cancer, and is related to intratumoral necrosis (ITN) and intratumoral inflammation (ITI). However, the significance of ITF in RCC has not been fully studied. In this study, we evaluate the relationships between ITF and other clinicopathologic parameters associated with RCC prognosis.
Methods
ITF was evaluated in 204 clear cell renal cell carcinoma (CCRCC) specimens according to presence and grade of fibrosis, degree of ITI, and presence of ITN. Lysyl oxidase (LOX) expression in tumor cells was also evaluated with clinicopathologic parameters.
Results
Among 204 CCRCC cases, 167 (81.7%) showed ITF, 71 (34.8%) showed ITI, 35 (17.2%) showed ITN, and 111 (54.4%) showed LOX expression. ITF correlated with Fuhrman nuclear grade (p = .046), lymphovascular invasion (LVI) (p = .027), and ITN (p = .036). Patients with ITF had a poor five-year overall survival rate (p = .104).
Conclusions
ITF is related to other poor prognostic factors in CCRCC, such as Fuhrman nuclear grade, ITN, and LVI, but ITF itself had no significant correlation with prognosis of CCRCC.
Prognostic Role of Metastatic Lymph Node Ratio in Papillary Thyroid Carcinoma
Jung-Soo Pyo, Jin Hee Sohn, Kyungseek Chang
J Pathol Transl Med. 2018;52(5):331-338.   Published online August 30, 2018
DOI: https://doi.org/10.4132/jptm.2018.08.07
  • 5,125 View
  • 112 Download
  • 4 Citations
AbstractAbstract PDF
Background
The aim of this study is to elucidate the clinicopathological significances, including the prognostic role, of metastatic lymph node ratio (mLNR) and tumor deposit diameter in papillary thyroid carcinoma (PTC) through a retrospective review and meta-analysis.
Methods
We categorized the cases into high (≥ 0.44) and low mLNR (< 0.44) and investigated the correlations with clinicopathological parameters in 64 PTCs with neck level VI lymph node (LN) metastasis. In addition, meta-analysis of seven eligible studies was used to investigate the correlation between mLNR and survival.
Results
Among 64 PTCs with neck level VI LN metastasis, high mLNR was found in 34 PTCs (53.1%). High mLNR was significantly correlated with macrometastasis (tumor deposit diameter ≥ 0.2 cm), extracapsular spread, and number of metastatic LNs. Based on linear regression test, mLNR was significantly increased by the largest LN size but not the largest metastatic LN (mLN) size. High mLNR was not correlated with nuclear factor κB or cyclin D1 immunohistochemical expression, Ki-67 labeling index, or other pathological parameters of primary tumor. Based on meta-analysis, high mLNR significantly correlated with worse disease-free survival at the 5-year and 10-year follow-up (hazard ratio [HR], 4.866; 95% confidence interval [CI], 3.527 to 6.714 and HR, 5.769; 95% CI, 2.951 to 11.275, respectively).
Conclusions
Our data showed that high mLNR significantly correlated with worse survival, macrometastasis, and extracapsular spread of mLNs. Further cumulative studies for more detailed criteria of mLNR are needed before application in daily practice.
Case Studies
Bile Granuloma Mimicking Peritoneal Seeding: A Case Report
Hasong Jeong, Hye Won Lee, Hye Ra Jung, Ilseon Hwang, Sun Young Kwon, Yu Na Kang, Sang Pyo Kim, Misun Choe
J Pathol Transl Med. 2018;52(5):339-343.   Published online July 16, 2018
DOI: https://doi.org/10.4132/jptm.2018.06.02
  • 4,210 View
  • 91 Download
  • 3 Citations
AbstractAbstract PDF
Laparoscopic cholecystectomy is a widely used treatment method for most cholelithiasis and is a relatively safe procedure. Foreign body granulomatous reaction to bile or gallstone spillage during laparoscopic cholecystectomy has rarely been reported. We report a case of bile granuloma after laparoscopic cholecystectomy, which mimicked peritoneal seeding. A 59-year-old Korean man presented with right upper quadrant pain. He underwent laparoscopic cholecystectomy for acute cholecystitis with cholelithiasis. Pathologic examination revealed an incidental adenocarcinoma invading the lamina propria with acute cholecystitis and cholelithiasis. After 3 months, follow-up abdominal computed tomography revealed a subhepatic nodule, which showed hypermetabolism on positron emission tomography–computed tomography. Suspecting localized peritoneal seeding, wedge resection of the liver, wedge resection of the transverse colon, and omentectomy were performed. Pathologic examination of the resected specimens revealed multiple bile granulomas. Awareness of bile granuloma mimicking malignancy is noteworthy for patient management to reduce unnecessary procedure during postoperative surveillance.
Ovarian Gynandroblastoma with a Juvenile Granulosa Cell Tumor Component in a Postmenopausal Woman: A Case Report and Literature Review
Nu Ri Jang, Dae Hyung Lee, Eun Jung Jang, Young Kyung Bae, Jina Baek, Min Hye Jang
J Pathol Transl Med. 2018;52(5):344-348.   Published online July 17, 2018
DOI: https://doi.org/10.4132/jptm.2018.06.28
  • 4,718 View
  • 121 Download
  • 2 Citations
AbstractAbstract PDF
Gynandroblastoma is an extremely rare sex cord-stromal tumor with both female (granulosa cell tumor) and male (Sertoli-Leydig cell tumor) elements. Juvenile granulosa cell tumors are also very rare and are so named because they usually occur in children and adolescents. A 71-year-old woman with right upper quadrant abdominal pain visited our hospital. Pelvic computed tomography showed a large multilocular cystic mass, suspected to be of ovarian origin. We performed a total abdominal hysterectomy (total abdominal hysterectomy was performed) with bilateral salpingooophorectomy. A 13-cm multilocular cystic mass with serous fluid was observed in her right ovary. Upon microscopic examination, the solid component of the mass showed both Sertoli-Leydig cell and juvenile granulosa cell differentiation, which we diagnosed as gynandroblastoma. Gynandroblastoma with a juvenile granulosa cell tumor component is extremely rare and, until now, only six cases have been reported in the English literature. We report the first gynandroblastoma with a juvenile granulosa cell tumor component diagnosed in an elderly patient, along with a literature review.
Abrupt Dyskeratotic and Squamoid Cells in Poorly Differentiated Carcinoma: Case Study of Two Thoracic NUT Midline Carcinomas with Cytohistologic Correlation
Taebum Lee, Sangjoon Choi, Joungho Han, Yoon-La Choi, Kyungjong Lee
J Pathol Transl Med. 2018;52(5):349-353.   Published online July 27, 2018
DOI: https://doi.org/10.4132/jptm.2018.07.16
  • 4,983 View
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  • 9 Citations
AbstractAbstract PDF
Cytologic diagnosis of nuclear protein in testis (NUT) midline carcinoma (NMC) is important due to its aggressive behavior and miserable prognosis. Early diagnosis of NMC can facilitate proper management, and here we report two rare cases of thoracic NMC with cytohistologic correlation. In aspiration cytology, the tumor presented with mixed cohesive clusters and dispersed single cells, diffuse background necrosis and many neutrophils. Most of the tumor cells had scanty cytoplasm and medium-sized irregular nuclei, which had fine to granular nuclear chromatin. Interestingly, a few dyskeratotic cells or squamoid cell clusters were present in each case. Biopsy specimen histology revealed more frequent squamous differentiation, and additional immunohistochemistry tests showed nuclear expression of NUT. Because this tumor has a notorious progression and has been previously underestimated in terms of its prevalence, awareness of characteristic findings and proper ancillary tests should be considered in all suspicious cases.

JPTM : Journal of Pathology and Translational Medicine