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Volume 51(3); May 2017
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Reviews
Good Laboratory Standards for Clinical Next-Generation Sequencing Cancer Panel Tests
Jihun Kim, Woong-Yang Park, Nayoung K. D. Kim, Se Jin Jang, Sung-Min Chun, Chang-Ohk Sung, Jene Choi, Young-Hyeh Ko, Yoon-La Choi, Hyo Sup Shim, Jae-Kyung Won
J Pathol Transl Med. 2017;51(3):191-204.   Published online May 10, 2017
DOI: https://doi.org/10.4132/jptm.2017.03.14
  • 21,568 View
  • 1,026 Download
  • 28 Citations
AbstractAbstract PDF
Next-generation sequencing (NGS) has recently emerged as an essential component of personalized cancer medicine due to its high throughput and low per-base cost. However, no sufficient guidelines for implementing NGS as a clinical molecular pathology test are established in Korea. To ensure clinical grade quality without inhibiting adoption of NGS, a taskforce team assembled by the Korean Society of Pathologists developed laboratory guidelines for NGS cancer panel testing procedures and requirements for clinical implementation of NGS. This consensus standard proposal consists of two parts: laboratory guidelines and requirements for clinical NGS laboratories. The laboratory guidelines part addressed several important issues across multistep NGS cancer panel tests including choice of gene panel and platform, sample handling, nucleic acid management, sample identity tracking, library preparation, sequencing, analysis and reporting. Requirements for clinical NGS tests were summarized in terms of documentation, validation, quality management, and other required written policies. Together with appropriate pathologist training and international laboratory standards, these laboratory standards would help molecular pathology laboratories to successfully implement NGS cancer panel tests in clinic. In this way, the oncology community would be able to help patients to benefit more from personalized cancer medicine.

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Molecular Testing of Brain Tumor
Sung-Hye Park, Jaekyung Won, Seong-Ik Kim, Yujin Lee, Chul-Kee Park, Seung-Ki Kim, Seung-Hong Choi
J Pathol Transl Med. 2017;51(3):205-223.   Published online May 12, 2017
DOI: https://doi.org/10.4132/jptm.2017.03.08
  • 26,390 View
  • 1,082 Download
  • 36 Citations
AbstractAbstract PDF
The World Health Organization (WHO) classification of central nervous system (CNS) tumors was revised in 2016 with a basis on the integrated diagnosis of molecular genetics. We herein provide the guidelines for using molecular genetic tests in routine pathological practice for an accurate diagnosis and appropriate management. While astrocytomas and IDH-mutant (secondary) glioblastomas are characterized by the mutational status of IDH, TP53, and ATRX, oligodendrogliomas have a 1p/19q codeletion and mutations in IDH, CIC, FUBP1, and the promoter region of telomerase reverse transcriptase (TERTp). IDH-wildtype (primary) glioblastomas typically lack mutations in IDH, but are characterized by copy number variations of EGFR, PTEN, CDKN2A/B, PDGFRA, and NF1 as well as mutations of TERTp. High-grade pediatric gliomas differ from those of adult gliomas, consisting of mutations in H3F3A, ATRX, and DAXX, but not in IDH genes. In contrast, well-circumscribed low-grade neuroepithelial tumors in children, such as pilocytic astrocytoma, pleomorphic xanthoastrocytoma, and ganglioglioma, often have mutations or activating rearrangements in the BRAF, FGFR1, and MYB genes. Other CNS tumors, such as ependymomas, neuronal and glioneuronal tumors, embryonal tumors, meningothelial, and other mesenchymal tumors have important genetic alterations, many of which are diagnostic, prognostic, and predictive markers and therapeutic targets. Therefore, the neuropathological evaluation of brain tumors is increasingly dependent on molecular genetic tests for proper classification, prediction of biological behavior and patient management. Identifying these gene abnormalities requires cost-effective and high-throughput testing, such as next-generation sequencing. Overall, this paper reviews the global guidelines and diagnostic algorithms for molecular genetic testing of brain tumors.

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Molecular Testing of Lymphoproliferative Disorders: Current Status and Perspectives
Yoon Kyung Jeon, Sun Och Yoon, Jin Ho Paik, Young A Kim, Bong Kyung Shin, Hyun-Jung Kim, Hee Jeong Cha, Ji Eun Kim, Jooryung Huh, Young-Hyeh Ko
J Pathol Transl Med. 2017;51(3):224-241.   Published online May 10, 2017
DOI: https://doi.org/10.4132/jptm.2017.04.09
  • 14,307 View
  • 604 Download
  • 9 Citations
AbstractAbstract PDF
Molecular pathologic testing plays an important role for the diagnosis, prognostication and decision of treatment strategy in lymphoproliferative disease. Here, we briefly review the molecular tests currently used for lymphoproliferative disease and those which will be implicated in clinical practice in the near future. Specifically, this guideline addresses the clonality test for B- and T-cell proliferative lesions, molecular cytogenetic tests for malignant lymphoma, determination of cell-of-origin in diffuse large B-cell lymphoma, and molecular genetic alterations incorporated in the 2016 revision of the World Health Organization classification of lymphoid neoplasms. Finally, a new perspective on the next-generation sequencing for diagnostic, prognostic, and therapeutic purpose in malignant lymphoma will be summarized.

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Molecular Testing of Lung Cancers
Hyo Sup Shim, Yoon-La Choi, Lucia Kim, Sunhee Chang, Wan-Seop Kim, Mee Sook Roh, Tae-Jung Kim, Seung Yeon Ha, Jin-Haeng Chung, Se Jin Jang, Geon Kook Lee
J Pathol Transl Med. 2017;51(3):242-254.   Published online April 21, 2017
DOI: https://doi.org/10.4132/jptm.2017.04.10
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  • 21 Citations
AbstractAbstract PDF
Targeted therapies guided by molecular diagnostics have become a standard treatment of lung cancer. Epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements are currently used as the best predictive biomarkers for EGFR tyrosine kinase inhibitors and ALK inhibitors, respectively. Besides EGFR and ALK, the list of druggable genetic alterations has been growing, including ROS1 rearrangements, RET rearrangements, and MET alterations. In this situation, pathologists should carefully manage clinical samples for molecular testing and should do their best to quickly and accurately identify patients who will benefit from precision therapeutics. Here, we grouped molecular biomarkers of lung cancers into three categories—mutations, gene rearrangements, and amplifications—and propose expanded guidelines on molecular testing of lung cancers.

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Original Articles
Clinicopathological Study of 18 Cases of Inflammatory Myofibroblastic Tumors with Reference to ALK-1 Expression: 5-Year Experience in a Tertiary Care Center
Ramesh Babu Telugu, Anne Jennifer Prabhu, Nobin Babu Kalappurayil, John Mathai, Birla Roy Gnanamuthu, Marie Therese Manipadam
J Pathol Transl Med. 2017;51(3):255-263.   Published online April 17, 2017
DOI: https://doi.org/10.4132/jptm.2017.01.12
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  • 22 Citations
AbstractAbstract PDF
Background
Inflammatory myofibroblastic tumor is a histopathologically distinctive neoplasm of children and young adults. According to World Health Organization (WHO) classification, inflammatory myofibroblastic tumor is an intermediate-grade tumor, with potential for recurrence and rare metastasis. There are no definite histopathologic, molecular, or cytogenetic features to predict malignant transformation, recurrence, or metastasis.
Methods
A 5-year retrospective study of histopathologically diagnosed inflammatory myofibroblastic tumors of various anatomic sites was conducted to correlate anaplastic lymphoma kinase-1 (ALK-1) expression with histological atypia, multicentric origin of tumor, recurrence, and metastasis. Clinical details of all the cases were noted from the clinical work station. Immunohistochemical stains for ALK-1 and other antibodies were performed. Statistical analysis was done using Fisher exact test.
Results
A total of 18 cases of inflammatory myofibroblastic tumors were found during the study period, of which 14 were classical. The female-male ratio was 1:1 and the mean age was 23.8 years. Histologically atypical (four cases) and multifocal tumors (three cases, multicentric in origin) were noted. Recurrence was noted in 30% of ALK-1 positive and 37.5% of ALK-1 negative cases, whereas metastasis to the lung, liver, and pelvic bone was noted in the ALK-1 positive group only.
Conclusions
Overall, ALK-1 protein was expressed in 55.6% of inflammatory myofibroblastic tumors. There was no statistically significant correlation between ALK-1 expression, tumor type, recurrence and metastasis. However, ALK-1 immunohistochemistry is a useful diagnostic aid in the appropriate clinical and histomorphologic context.

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Characteristic Changes in Decidual Gene Expression Signature in Spontaneous Term Parturition
Haidy El-Azzamy, Andrea Balogh, Roberto Romero, Yi Xu, Christopher LaJeunesse, Olesya Plazyo, Zhonghui Xu, Theodore G. Price, Zhong Dong, Adi L. Tarca, Zoltan Papp, Sonia S. Hassan, Tinnakorn Chaiworapongsa, Chong Jai Kim, Nardhy Gomez-Lopez, Nandor Gabor Than
J Pathol Transl Med. 2017;51(3):264-283.   Published online February 22, 2017
DOI: https://doi.org/10.4132/jptm.2016.12.20
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  • 18 Citations
AbstractAbstract PDFSupplementary Material
Background
The decidua has been implicated in the “terminal pathway” of human term parturition, which is characterized by the activation of pro-inflammatory pathways in gestational tissues. However, the transcriptomic changes in the decidua leading to terminal pathway activation have not been systematically explored. This study aimed to compare the decidual expression of developmental signaling and inflammation-related genes before and after spontaneous term labor in order to reveal their involvement in this process.
Methods
Chorioamniotic membranes were obtained from normal pregnant women who delivered at term with spontaneous labor (TIL, n = 14) or without labor (TNL, n = 15). Decidual cells were isolated from snap-frozen chorioamniotic membranes with laser microdissection. The expression of 46 genes involved in decidual development, sex steroid and prostaglandin signaling, as well as pro- and anti-inflammatory pathways, was analyzed using high-throughput quantitative real-time polymerase chain reaction (qRT-PCR). Chorioamniotic membrane sections were immunostained and then semi-quantified for five proteins, and immunoassays for three chemokines were performed on maternal plasma samples.
Results
The genes with the highest expression in the decidua at term gestation included insulin-like growth factor-binding protein 1 (IGFBP1), galectin-1 (LGALS1), and progestogen-associated endometrial protein (PAEP); the expression of estrogen receptor 1 (ESR1), homeobox A11 (HOXA11), interleukin 1β (IL1B), IL8, progesterone receptor membrane component 2 (PGRMC2), and prostaglandin E synthase (PTGES) was higher in TIL than in TNL cases; the expression of chemokine C-C motif ligand 2 (CCL2), CCL5, LGALS1, LGALS3, and PAEP was lower in TIL than in TNL cases; immunostaining confirmed qRT-PCR data for IL-8, CCL2, galectin-1, galectin-3, and PAEP; and no correlations between the decidual gene expression and the maternal plasma protein concentrations of CCL2, CCL5, and IL-8 were found.
Conclusions
Our data suggests that with the initiation of parturition, the decidual expression of anti-inflammatory mediators decreases, while the expression of pro-inflammatory mediators and steroid receptors increases. This shift may affect downstream signaling pathways that can lead to parturition.

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A Small Case Series of Intravascular Large B-Cell Lymphoma with Unexpected Findings: Subset of Cases with Concomitant Extravascular Central Nervous System (CNS) Involvement Mimicking Primary CNS Lymphoma
Kate Poropatich, Dave Dittmann, Yi-Hua Chen, Kirtee Raparia, Kristy Wolniak, Juehua Gao
J Pathol Transl Med. 2017;51(3):284-291.   Published online April 17, 2017
DOI: https://doi.org/10.4132/jptm.2017.02.16
  • 8,461 View
  • 194 Download
  • 5 Citations
AbstractAbstract PDF
Background
Intravascular large B-cell lymphoma (IVLBCL) is a rare type of extranodal lymphoma with growth mainly in the lumina of vessels. We studied a small series of IVLBCL and focused on its central nervous system (CNS) involvement.
Methods
Searching the medical records of Northwestern Memorial Hospital, we identified five cases of IVLBCL from January 2007 to January 2015. Clinical information, hematoxylin and eosin stained histologic slides and immunohistochemistry studies were reviewed for all cases. Polymerase chain reaction (PCR) analysis for the immunoglobulin (Ig) heavy and light chain gene rearrangement was performed on all five cases.
Results
Three of the five cases of IVLBCL were autopsies. Patients’ age ranged from 56 to 84. CNS involvement was present in two cases—in both patients, the CNS involvement showed an extravascular pattern with confluent sheet-like formation. PCR analysis confirmed that in one case the systemic intravascular and CNS extravascular components were clonally identical.
Conclusions
In a small case series of IVLBCL, we observed that CNS involvement by IVLBCL often has an extravascular morphology, but is clonally identical to the intravascular counterpart by PCR analysis. As IVLBCL can have a rapidly progressing poor outcome, it should be kept in the differential diagnoses for patients presenting with lymphoma of the CNS. The presence of extravascular growth patterns in the CNS should not exclude IVLBCL as a diagnosis.

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An Experimental Infarct Targeting the Internal Capsule: Histopathological and Ultrastructural Changes
Chang-Woo Han, Kyung-Hwa Lee, Myung Giun Noh, Jin-Myung Kim, Hyung-Seok Kim, Hyung-Sun Kim, Ra Gyung Kim, Jongwook Cho, Hyoung-Ihl Kim, Min-Cheol Lee
J Pathol Transl Med. 2017;51(3):292-305.   Published online May 10, 2017
DOI: https://doi.org/10.4132/jptm.2017.02.17
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  • 5 Citations
AbstractAbstract PDF
Background
Stroke involving the cerebral white matter (WM) has increased in prevalence, but most experimental studies have focused on ischemic injury of the gray matter. This study was performed to investigate the WM in a unique rat model of photothrombotic infarct targeting the posterior limb of internal capsule (PLIC), focusing on the identification of the most vulnerable structure in WM by ischemic injury, subsequent glial reaction to the injury, and the fundamental histopathologic feature causing different neurologic outcomes.
Methods
Light microscopy with immunohistochemical stains and electron microscopic examinations of the lesion were performed between 3 hours and 21 days post-ischemic injury.
Results
Initial pathological change develops in myelinated axon, concomitantly with reactive change of astrocytes. The first pathology to present is nodular loosening to separate the myelin sheath with axonal wrinkling. Subsequent pathologies include rupture of the myelin sheath with extrusion of axonal organelles, progressive necrosis, oligodendrocyte degeneration and death, and reactive gliosis. Increase of glial fibrillary acidic protein (GFAP) immunoreactivity is an early event in the ischemic lesion. WM pathologies result in motor dysfunction. Motor function recovery after the infarct was correlated to the extent of PLIC injury proper rather than the infarct volume.
Conclusions
Pathologic changes indicate that the cerebral WM, independent of cortical neurons, is highly vulnerable to the effects of focal ischemia, among which myelin sheath is first damaged. Early increase of GFAP immunoreactivity indicates that astrocyte response initially begins with myelinated axonal injury, and supports the biologic role related to WM injury or plasticity. The reaction of astrocytes in the experimental model might be important for the study of pathogenesis and treatment of the WM stroke.

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Overexpression of POSTN in Tumor Stroma Is a Poor Prognostic Indicator of Colorectal Cancer
Hyeon Jeong Oh, Jeong Mo Bae, Xian-Yu Wen, Nam-Yun Cho, Jung Ho Kim, Gyeong Hoon Kang
J Pathol Transl Med. 2017;51(3):306-313.   Published online April 12, 2017
DOI: https://doi.org/10.4132/jptm.2017.01.19
  • 11,810 View
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  • 35 Citations
AbstractAbstract PDF
Background
Tumor microenvironment has recently drawn attention in that it is related with tumor prognosis. Cancer-associated fibroblast also plays a critical role in cancer invasiveness and progression in colorectal cancers. Periostin (POSTN), originally identified to be expressed in osteoblasts and osteoblast-derived cells, is expressed in cancer-associated fibroblasts in several tissue types of cancer. Recent studies suggest an association between stromal overexpression of POSTN and poor prognosis of cancer patients.
Methods
We analyzed colorectal cancer cases for their expression status of POSTN in tumor stroma using immunohistochemistry and correlated the expression status with clinicopathological and molecular features.
Results
High level of POSTN expression in tumor stroma was closely associated with tumor location in proximal colon, infiltrative growth pattern, undifferentiated histology, tumor budding, luminal necrosis, and higher TNM stage. High expression status of POSTN in tumor stroma was found to be an independent prognostic parameter implicating poor 5-year cancer-specific survival and 5-year progression-free survival.
Conclusions
Our findings suggest that POSTN overexpression in tumor stroma of colorectal cancers could be a possible candidate marker for predicting poor prognosis in patients with colorectal cancers.

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Comparison of Unsatisfactory Samples from Conventional Smear versus Liquid-Based Cytology in Uterine Cervical Cancer Screening Test
Hoiseon Jeong, Sung Ran Hong, Seoung-Wan Chae, So-Young Jin, Hye Kyoung Yoon, Juhie Lee, Eun Kyung Kim, Sook Tai Ha, Sung Nam Kim, Eun-Jung Park, Jong Jae Jung, Sun Hee Sung, Sung-chul Lim
J Pathol Transl Med. 2017;51(3):314-319.   Published online April 17, 2017
DOI: https://doi.org/10.4132/jptm.2017.03.17
  • 9,068 View
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  • 14 Citations
AbstractAbstract PDF
Background
Cervical cytology for uterine cervical cancer screening has transitioned from conventional smear (CS) to liquid-based cytology (LBC), which has many advantages. The aim of this study was to compare the proportion of unsatisfactory specimens from CS versus LBC at multiple institutions including general hospitals and commercial laboratories.
Methods
Each participating institution provided a minimum of 500 Papanicolaou (Pap) test results for analysis. Pap tests were classified according to the participating institution (commercial laboratory or general hospital) and the processing method (CS, ThinPrep, SurePath, or CellPrep). The causes of unsatisfactory results were classified as technical problems, scant cellularity, or complete obscuring factors.
Results
A total of 38,956 Pap test results from eight general hospitals and three commercial laboratories were analyzed. The mean unsatisfactory rate of LBC was significantly lower than that of CS (1.26% and 3.31%, p = .018). In the LBC method, samples from general hospitals had lower unsatisfactory rates than those from commercial laboratories (0.65% vs 2.89%, p = .006). The reasons for unsatisfactory results were heterogeneous in CS. On the other hand, 66.2% of unsatisfactory results in LBC were due to the scant cellularity.
Conclusions
Unsatisfactory rate of cervical cancer screening test results varies according to the institution and the processing method. LBC has a significantly lower unsatisfactory rate than CS.

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Case Studies
Unusual Histology of Eosinophilic Myenteric Ganglionitis: A Case Report
Hyekyung Lee, Dongwook Kang, Heejin Kim, Byungsun Cho, Jeho Jang
J Pathol Transl Med. 2017;51(3):320-324.   Published online April 4, 2017
DOI: https://doi.org/10.4132/jptm.2016.09.07
  • 6,756 View
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  • 2 Citations
AbstractAbstract PDF
Eosinophilic myenteric ganglionitis is a disorder characterized by infiltration of the Auerbach myenteric plexus by eosinophils. As a cause of chronic intestinal pseudo-obstruction (CIPO), eosinophilic myenteric ganglionitis has been rarely reported and the majority of the reported cases in the literature were children. We experienced a case of eosinophilic myenteric ganglionitis associated with CIPO in a 53-year-old female patient. Histologic examination of the resected descending colon showed moderate eosinophilic infiltrates with hypogangliosis in the myenteric plexus. Immunohistochemical study revealed increased number of CD4-positive lymphocytes and stronger but scantier glial fibillary acid protein expression in the inflamed myenteric plexus.

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  • Histological characteristics of eosinophilic myenteric ganglionitis: an under-recognised cause of chronic intestinal pseudo-obstruction
    Yoichi Akazawa, Takuo Hayashi, Tsuyoshi Saito, Koichiro Niwa, Hirohiko Kamiyama, Noriko Sasahara, Kazuhiro Sakamoto, Akihito Nagahara, Takashi Yao
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  • Colonic Pseudo-obstruction With Transition Zone: A Peculiar Eastern Severe Dysmotility
    Eun Mi Song, Jong Wook Kim, Sun-Ho Lee, Kiju Chang, Sung Wook Hwang, Sang Hyoung Park, Dong-Hoon Yang, Kee Wook Jung, Byong Duk Ye, Jeong-Sik Byeon, Suk-Kyun Yang, Hyo Jeong Lee, Chang Sik Yu, Chan Wook Kim, Seong Ho Park, Jihun Kim, Seung-Jae Myung
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Clear Cell Renal Cell Carcinoma with Intratumoral Granulomatous Reaction: A Case Report and Review of the Literature
Hayeon Kim, Jong Wook Kim, Aeree Kim, Hyeyoon Chang
J Pathol Transl Med. 2017;51(3):325-328.   Published online March 14, 2017
DOI: https://doi.org/10.4132/jptm.2016.09.08
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AbstractAbstract PDF
Granulomatous reaction associated with clear cell renal cell carcinoma (CCRCC) is a rare finding, and only a few cases have been described in the literature. It is postulated to occur due to cancer- related antigenic factors such as cancer cells themselves or soluble tumor antigens shed into the blood. Herein, we describe a case of a 56-year-old male patient diagnosed with CCRCC with intratumoral granulomatous inflammation.
Brief Case Reports
Human Papillomavirus Infection–Associated Adenoid Cystic Carcinoma of the Hard Palate
Arthur Minwoo Chung, Dong Il Sun, Eun Sun Jung, Youn Soo Lee
J Pathol Transl Med. 2017;51(3):329-331.   Published online December 5, 2016
DOI: https://doi.org/10.4132/jptm.2016.07.07
  • 6,775 View
  • 102 Download
  • 1 Citations
PDF

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    Shekhar K. Gadkaree, Anuraag S. Parikh, Alejandro I. Rodarte, Ashton Lehmann, Stacey T. Gray, Derrick T. Lin
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A Rare Case of Nodular Mucinosis of the Breast
Hyun Min Koh, Young Hee Maeng, Bo Geun Jang, Jae Hyuk Choi, Chang lim Hyun
J Pathol Transl Med. 2017;51(3):332-334.   Published online December 5, 2016
DOI: https://doi.org/10.4132/jptm.2016.07.26
  • 6,338 View
  • 119 Download
  • 6 Citations
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DOI: https://doi.org/10.4132/jptm.2016.07.24
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JPTM : Journal of Pathology and Translational Medicine