Journal of Pathology and Translational Medicine

Volume 54(5); September 2020

Reviews

Immune landscape and biomarkers for immuno-oncology in colorectal cancers: Jeong Mo Bae, Seung-Yeon Yoo, Jung Ho Kim, Gyeong Hoon Kang; J Pathol Transl Med. 2020;54(5):351-360. Published online June 26, 2020; DOI: https://doi.org/10.4132/jptm.2020.05.15

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Abstract PDF: Recent advances in immuno-oncology have increased understanding of the tumor immune microenvironment (TIME), and clinical trials for immune checkpoint inhibitor treatment have shown remission and/or durable response in certain proportions of patients stratified by predictive biomarkers. The TIME in colorectal cancer (CRC) was initially evaluated several decades ago. The prognostic value of the immune response to tumors, including tumor-infiltrating lymphocytes, peritumoral lymphoid reaction, and Crohn’s-like lymphoid reaction, has been well demonstrated. In this review, we describe the chronology of TIME research and review the up-to-date high-dimensional TIME landscape of CRC. We also summarize the clinical relevance of several biomarkers associated with immunotherapy in CRC, such as microsatellite instability, tumor mutational burden, POLE/POLD mutation, consensus molecular subtype, and programmed death-ligand 1 expression.

Thyroid fine-needle aspiration cytology in Taiwan: a nationwide survey and literature update: Chien-Chin Chen, Jen-Fan Hang, Chih-Yi Liu, Yeh-Han Wang, Chiung-Ru Lai; J Pathol Transl Med. 2020;54(5):361-366. Published online August 31, 2020; DOI: https://doi.org/10.4132/jptm.2020.07.17

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Abstract PDF: In Taiwan, thyroid fine-needle aspiration cytology is easily accessible and reliable for evaluating thyroid nodules. The sonographic pattern plays a major role and is the deciding factor for aspiration. We conducted a nationwide survey in 2017 and it revealed that 31% of laboratories had adopted The Bethesda System for Reporting Thyroid Cytopathology. There was a relatively high unsatisfactory rate (24.04%) and low rates of indeterminate diagnoses, including atypia of undetermined significance/follicular lesions of undetermined significance: 4.87%, and follicular neoplasm/suspicious for a follicular neoplasm: 0.35%. Moreover, the risks of malignancy in benign, atypia of undetermined significance, and suspicious for a follicular neoplasm were relatively high. These may reflect strict diagnostic criteria for indeterminate categories and better patient selection for surgery. Improvements in specimen sampling and continuing education programs are crucial. Newly-developed thyroid cytology technologies, such as immunocytochemistry, molecular testing, and computerized cytomorphometry, may further facilitate cytology diagnoses.

Pathologic interpretation of endoscopic ultrasound–guided fine needle aspiration cytology/biopsy for pancreatic lesions: Haeryoung Kim, Kee-Taek Jang; J Pathol Transl Med. 2020;54(5):367-377. Published online August 31, 2020; DOI: https://doi.org/10.4132/jptm.2020.07.21

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Abstract PDF: Pathologic interpretation of endoscopic ultrasound–guided fine needle aspiration (EUS-FNA) cytology/biopsy specimens is one of the most challenging tasks in cytology and surgical pathology practice, as the procedure often yields minimal amounts of diagnostic material and contains contaminants, such as blood cells and normal intestinal mucosa. EUS-FNA cytology/biopsy will nevertheless become a more popular procedure for evaluation of various pancreatic lesions because they are difficult to approach with conventional endoscopic procedures. Pathologists should understand the structural differences and limitations of EUS-FNA that make pathologic diagnosis difficult. Ancillary tests are available for differential diagnosis of EUS-FNA for various pancreatic lesions. Immunostains are the most commonly used ancillary tests, and pathologists should able to choose the necessary panel for differential diagnosis. Pathologists should review clinical history and radiologic and/or EUS findings before selecting an immunostain panel and making a pathologic diagnosis. In addition, one’s threshold of malignancy should be adjusted according to the appropriate clinical setting to avoid under-evaluation of pathologic diagnoses. Clinico-pathologic correlation is essential in pathologic evaluation of EUS-FNA for pancreatic lesions. Pathologists can reduce errors by correlating clinical and radiologic findings when evaluating EUS-FNA. Some molecular tests can be applied in differential diagnosis of pancreatic neoplastic and cystic lesions. Molecular data should be used as supportive evidence of a specific disease entity, rather than direct evidence, and should be correlated with clinico-pathologic findings to avoid errors in pathologic diagnosis.

Original Articles

Prediction of TP53 mutations by p53 immunohistochemistry and their prognostic significance in gastric cancer: Hye Jung Hwang, Soo Kyung Nam, Hyunjin Park, Yujun Park, Jiwon Koh, Hee Young Na, Yoonjin Kwak, Woo Ho Kim, Hye Seung Lee; J Pathol Transl Med. 2020;54(5):378-386. Published online July 1, 2020; DOI: https://doi.org/10.4132/jptm.2020.06.01

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Abstract PDF Supplementary Material: Background
Recently, molecular classifications of gastric cancer (GC) have been proposed that include TP53 mutations and their functional activity. We aimed to demonstrate the correlation between p53 immunohistochemistry (IHC) and TP53 mutations as well as their clinicopathological significance in GC.
Methods
Deep targeted sequencing was performed using surgical or biopsy specimens from 120 patients with GC. IHC for p53 was performed and interpreted as strong, weak, or negative expression. In 18 cases (15.0%) with discrepant TP53 mutation and p53 IHC results, p53 IHC was repeated.
Results
Strong expression of p53 was associated with TP53 missense mutations, negative expression with other types of mutations, and weak expression with wild-type TP53 (p<.001). The sensitivity for each category was 90.9%, 79.0%, and 80.9%, and the specificity was 95.4%, 88.1%, and 92.3%, respectively. The TNM stage at initial diagnosis exhibited a significant correlation with both TP53 mutation type (p=.004) and p53 expression status (p=.029). The Kaplan-Meier survival analysis for 109 stage II and III GC cases showed that patients with TP53 missense mutations had worse overall survival than those in the wild-type and other mutation groups (p=.028). Strong expression of p53 was also associated with worse overall survival in comparison to negative and weak expression (p=.035).
Conclusions
Results of IHC of the p53 protein may be used as a simple surrogate marker of TP53 mutations. However, negative expression of p53 and other types of mutations of TP53 should be carefully interpreted because of its lower sensitivity and different prognostic implications.

Lymph node size and its association with nodal metastasis in ductal adenocarcinoma of the pancreas: Jaehoon Shin, Seungbeom Shin, Jae Hoon Lee, Ki Byung Song, Dae Wook Hwang, Hyoung Jung Kim, Jae Ho Byun, HyungJun Cho, Song Cheol Kim, Seung-Mo Hong; J Pathol Transl Med. 2020;54(5):387-395. Published online July 21, 2020; DOI: https://doi.org/10.4132/jptm.2020.06.23

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Abstract PDF: Background
Although lymph node metastasis is a poor prognostic factor in patients with pancreatic ductal adenocarcinoma (PDAC), our understanding of lymph node size in association with PDAC is limited. Increased nodal size in preoperative imaging has been used to detect node metastasis. We evaluated whether lymph node size can be used as a surrogate preoperative marker of lymph node metastasis.
Methods
We assessed nodal size and compared it to the nodal metastatic status of 200 patients with surgically resected PDAC. The size of all lymph nodes and metastatic nodal foci were measured along the long and short axis, and the relationships between nodal size and metastatic status were compared at six cutoff points.
Results
A total of 4,525 lymph nodes were examined, 9.1% of which were metastatic. The mean size of the metastatic nodes (long axis, 6.9±5.0 mm; short axis, 4.3±3.1 mm) was significantly larger than that of the non-metastatic nodes (long axis, 5.0±4.0 mm; short axis, 3.0±2.0 mm; all p<.001). Using a 10 mm cutoff, the sensitivity, specificity, positive predictive value, overall accuracy, and area under curve was 24.8%, 88.0%, 17.1%, 82.3%, and 0.60 for the long axis and 7.0%, 99.0%, 40.3%, 90.6%, and 0.61 for the short axis, respectively.
Conclusions
The metastatic nodes are larger than the non-metastatic nodes in PDAC patients. However, the difference in nodal size was too small to be identified with preoperative imaging. The performance of preoperative radiologic imaging to predict lymph nodal metastasis was not good. Therefore, nodal size cannot be used a surrogate preoperative marker of lymph node metastasis.

Indirect pathological indicators for cardiac sarcoidosis on endomyocardial biopsy: Myung-Jin Cha, Jeong-Wook Seo, Seil Oh, Eun-Ah Park, Sang-Han Lee, Moon Young Kim, Jae-Young Park; J Pathol Transl Med. 2020;54(5):396-410. Published online July 29, 2020; DOI: https://doi.org/10.4132/jptm.2020.06.10

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Abstract PDF Supplementary Material: Background
The definitive pathologic diagnosis of cardiac sarcoidosis requires observation of a granuloma in the myocardial tissue. It is common, however, to receive a “negative” report for a clinically probable case. We would like to advise pathologists and clinicians on how to interpret “negative” biopsies.
Methods
Our study samples were 27 endomyocardial biopsies from 25 patients, three cardiac transplantation and an autopsied heart with suspected cardiac sarcoidosis. Pathologic, radiologic, and clinical features were compared.
Results
The presence of micro-granulomas or increased histiocytic infiltration was always (6/6 or 100%) associated with fatty infiltration and confluent fibrosis, and they showed radiological features of sarcoidosis. Three of five cases (60%) with fatty change and confluent fibrosis were probable for cardiac sarcoidosis on radiology. When either confluent fibrosis or fatty change was present, one-third (3/9) were radiologically probable for cardiac sarcoidosis. We interpreted cases with micro-granuloma as positive for cardiac sarcoidosis (five of 25, 20%). Cases with both confluent fibrosis and fatty change were interpreted as probable for cardiac sarcoidosis (seven of 25, 28%). Another 13 cases, including eight cases with either confluent fibrosis or fatty change, were interpreted as low probability based on endomyocardial biopsy.
Conclusions
The presence of micro-granuloma could be an evidence for positive diagnosis of cardiac sarcoidosis. Presence of both confluent fibrosis and fatty change is necessary for probable cardiac sarcoidosis in the absence of granuloma. Either of confluent fibrosis or fatty change may be an indirect pathological evidence but they are interpreted as nonspecific findings.

Prevalence of high-risk human papillomavirus and its genotype distribution in head and neck squamous cell carcinomas: Yuil Kim, Young-Hoon Joo, Min-Sik Kim, Youn Soo Lee; J Pathol Transl Med. 2020;54(5):411-418. Published online July 21, 2020; DOI: https://doi.org/10.4132/jptm.2020.06.22

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Abstract PDF: Background
High-risk (HR) human papillomavirus (HPV) is found in a subset of head and neck (HN) squamous cell carcinomas (SCCs). For oropharyngeal SCCs, HR HPV positivity is known to be associated with good prognosis, and a separate staging system for HPV-associated carcinomas using p16 immunohistochemistry (IHC) as a surrogate test has been adopted in the 8th American Joint Committee on Cancer staging system. We examined the HR HPV status and the genotype distribution in five HN subsites.
Methods
Formalin-fixed paraffin-embedded tissue sections were used for p16 IHC and DNA extraction. HPV DNA detection and genotyping were done employing either a DNA chip-based or real-time polymerase chain reaction–based method.
Results
During 2011–2019, a total of 466 SCCs were tested for HPV DNA with 34.1% positivity for HR HPV. Among HN subsites, the oropharynx showed the highest HR HPV prevalence (149/205, 75.1%), followed by the sinonasal tract (3/14, 21.4%), larynx (5/43, 11.6%), hypopharynx (1/38, 2.6%), and oral cavity (1/166, 0.6%). The most common HPV genotype was HPV16 (84.3%) followed by HPV35 (6.9%) and HPV33 (4.4%). Compared with HR HPV status, the sensitivity and specificity of p16 IHC were 98.6% and 94.3% for the oropharynx, and 99.2% and 93.8% for the tonsil, respectively.
Conclusions
Using a Korean dataset, we confirmed that HR HPV is most frequently detected in oropharyngeal SCCs. p16 positivity showed a good concordance with HR HPV DNA for oropharyngeal and especially tonsillar carcinomas. The use of p16 IHC may further be extended to predict HR HPV positivity in sinonasal tract SCCs.

A retrospective cytohistological correlation of fine-needle aspiration cytology with classification by the Milan System for Reporting Salivary Gland Cytopathology: Ji Hyun Park, Yoon Jin Cha, Ja Yeong Seo, Jae Yol Lim, Soon Won Hong; J Pathol Transl Med. 2020;54(5):419-425. Published online July 8, 2020; DOI: https://doi.org/10.4132/jptm.2020.06.09

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Abstract PDF: Background
Before publication of the new classification system named the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) in 2018, there was no standard classification for salivary gland lesions obtained by fine-needle aspiration (FNA). We therefore aimed to evaluate the diagnostic utility of this system by retrospectively reviewing FNA samples using the MSRSGC and to determine their risk of developing into neoplasms and becoming malignant.
Methods
Retrospective slide review and classification of salivary gland FNAs obtained over a 6-year period (2013–2018) at a single center were performed by two pathologists. The risks of neoplasm and malignancy for each category also were calculated.
Results
This study surveyed 374 FNAs (371 patients) performed over a six-year period and selected 148 cases that included documented surgical follow-up (39.6%). Among the surgically treated cases, the distributions of FNA categories were as follows: non-diagnostic (ND; 16.9%), non-neoplastic (NN; 2.7%), atypia of undetermined significance (AUS; 3.4%), benign (BN; 54.7%), salivary gland neoplasm of uncertain malignant potential (SUMP; 10.1%), suspicious for malignancy (SM; 6.8%), and malignant (M; 5.4%). The risk of malignancy (ROM) was 24.0% for ND, 0% for NN, 40.0% for AUS, 2.5% for BN, 46.7% for SUMP, 100% for SM, and 87.5% for M. The overall diagnostic accuracy was 95.9% (142/148 cases).
Conclusions
The newly proposed MSRSGC appears to be a reliable system for classification of salivary gland lesions according to the associated ROM.

Case Study

Renal intravascular large B cell lymphoma: the first case report in Korea and a review of the literature: Moonsik Kim, Haerim Chung, Woo Ick Yang, Hyeon Joo Jeong; J Pathol Transl Med. 2020;54(5):426-431. Published online August 13, 2020; DOI: https://doi.org/10.4132/jptm.2020.06.18

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Abstract PDF Supplementary Material: Herein, we describe the first case of renal intravascular large B cell lymphoma in Korea occurring in a 66-year-old female. She presented with mild fever and dyspnea. On physical and laboratory evaluations, hemophagocytic lymphohistiocytosis was suspected, but the bone marrow biopsy results were unremarkable. During the work-up, massive proteinuria developed, which led to a renal biopsy. The renal architecture was relatively well-preserved, but the glomeruli were hypercellular with the infiltration of atypical, large lymphoid cells with increased nucleus-cytoplasm ratio and clumped chromatin. Similar cells were also present in the peritubular capillaries. The tumor cells exhibited membranous staining for CD20 and CD79a. After the diagnosis of intravascular large B cell lymphoma, the patient received rituximab-based chemotherapy under close follow-up.

Brief Case Report

Breast implant–associated anaplastic large cell lymphoma: the first South Korean case: Jongwon Lee, Hyungwoo Cho, Dok Hyun Yoon, Eun Key Kim, Gyungyub Gong, Cheolwon Suh, Joo-ryung Huh; J Pathol Transl Med. 2020;54(5):432-434. Published online August 18, 2020; DOI: https://doi.org/10.4132/jptm.2020.07.01

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Corrigendum

Correction of author’s name: Atypical femoral neck fracture after prolonged bisphosphonate therapy: Kwang-kyoun Kim, Yong Wook Park, Tae-hyeong Kim, Kyung-deok Seo; J Pathol Transl Med. 2020;54(5):435-435. Published online September 10, 2020; DOI: https://doi.org/10.4132/jptm.2020.09.07; Corrects: J Pathol Transl Med 2020;54(4):346

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