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Case Study
Papillary and medullary thyroid carcinomas coexisting in the same lobe, first suspected based on fine-needle aspiration cytology: a case report
Hyun Hee Koh, Young Lyun Oh
J Pathol Transl Med. 2022;56(5):301-308.   Published online September 13, 2022
DOI: https://doi.org/10.4132/jptm.2022.08.03
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AbstractAbstract PDF
Because different types of thyroid malignancies have distinct embryological origins, coexisting tumors are rarely observed. We describe a coexisting papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma (MTC) first suspected by fine-needle aspiration cytology (FNAC). A 57-year-old female presented with an irregular mass in the right thyroid lobe. The cytopathologic findings of fine-needle aspiration showed two components: a papillary-like arrangement consisting of cells with pale enlarged nuclei indicative of PTC and loose clusters comprised of oval cells with granular chromatin indicative of MTC. The diagnosis of a coexisting PTC and MTC was initially confirmed by calcitonin immunocytochemistry and later after total thyroidectomy. Although some surgical case reports of PTC and MTC coexisting in either the same or different lobes have been documented, a case suspected by FNAC before the surgery has rarely been reported. Because appropriate treatment and prognosis of PTC and MTC are different, cytopathologists should be aware of this rare entity.
Original Articles
Evaluation of the characteristics of multiple human papillomavirus (HPV) infections identified using the BD Onclarity HPV assay and comparison with those of single HPV infection
Jinhee Kim, Moonsik Kim, Ji Young Park
J Pathol Transl Med. 2022;56(5):289-293.   Published online September 13, 2022
DOI: https://doi.org/10.4132/jptm.2022.08.02
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AbstractAbstract PDFSupplementary Material
Background
Human papillomavirus (HPV) infection is a major cause of cervical cancer and associated precursor lesions. Multiple HPV genotype infections have been reported. However, their clinicopathological characteristics still remain elusive.
Methods
For this study, 814 consecutive patients who had undergone colposcopy and HPV genotyping test using BD Onclarity HPV assay were retrospectively selected. Clinicopathological parameters of multiple HPV infections were compared with those of single HPV infection.
Results
Multiple HPV infections were found in 110 out of 814 cases (13.5%). Multiple HPV infections were associated with a significantly higher incidence of high-grade intraepithelial lesions (HSILs) compared with single HPV infection. Other high-risk HPV genotypes, in addition to HPV 16, were found more frequently in the multiple HPV infections group; these included HPV 51, 52, 33/58, 56/59/66, and 35/39/68. No specific coinfection pattern was not identified. Additionally, the number of HPV genotypes in multiple HPV infections was not associated with the progression to HSIL or squamous cell carcinoma.
Conclusions
Multiple HPV infections have distinct clinicopathological characteristics (compared with single HPV infection). As their biological behavior is uncertain, close and frequent follow-up is warranted.
Prognostic significance of BLK expression in R-CHOP treated diffuse large B-cell lymphoma
Soyeon Choi, Yoo Jin Lee, Yunsuk Choi, Misung Kim, Hyun-Jung Kim, Ji Eun Kim, Sukjoong Oh, Seoung Wan Chae, Hee Jeong Cha, Jae-Cheol Jo
J Pathol Transl Med. 2022;56(5):281-288.   Published online September 13, 2022
DOI: https://doi.org/10.4132/jptm.2022.07.26
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AbstractAbstract PDF
Background
The aim of the present study was to evaluate the prognostic significance of B-cell lymphocyte kinase (BLK) expression for survival outcomes in diffuse large B-cell lymphoma (DLBCL) patients treated with R-CHOP.
Methods
We retrospectively analyzed the medical records of 89 patients from two tertiary referral hospitals. The expression of BLK, SYK, and CDK1 were evaluated in a semiquantitative method using an H-score, and the proportions of BCL2 and C-MYC were evaluated.
Results
A total of 89 patients received R-CHOP chemotherapy as a first-line chemotherapy. The expression rates of BLK in tumor cells was 39.2% (n = 34). BLK expression status was not significantly associated with clinical variables; however, BLK expression in tumor cells was significantly associated with the expression of both C-MYC and BCL2 (p = .003). With a median follow-up of 60.4 months, patients with BLK expression had significantly lower 5-year progression-free survival (PFS) and overall survival rates (49.8% and 60.9%, respectively) than patients without BLK expression (77.3% and 86.7%, respectively). In multivariate analysis for PFS, BLK positivity was an independent poor prognostic factor (hazard ratio, 2.208; p = .040).
Conclusions
Here, we describe the clinicopathological features and survival outcome according to expression of BLK in DLBCL. Approximately 39% of DLBCL patients showed BLK positivity, which was associated as a predictive marker for poor prognosis in patients who received R-CHOP chemotherapy.
Case Study
Heterotopic mesenteric ossification: a report of two cases
Hisham F. Bahmad, Olga Lopez, Tyson Sutherland, Marisa Vinas, Kfir Ben-David, Lydia Howard, Robert Poppiti, Sarah Alghamdi
J Pathol Transl Med. 2022;56(5):294-300.   Published online September 13, 2022
DOI: https://doi.org/10.4132/jptm.2022.07.23
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AbstractAbstract PDF
Heterotopic mesenteric ossification (HMO) is abnormal bone formation in tissues which usually do not undergo ossification. There are approximately 75 cases reported worldwide. We present two cases of HMO. The first case is that of a 39-year-old man who presented with abdominal pain and a computerized tomography scan of the abdomen and pelvis revealed an apple core lesion resulting in small bowel obstruction. The second case is that of a 36-year-old woman who presented 2 months after undergoing robotic gastric sleeve resection complaining of weakness and emesis. An esophagogram revealed kinking at the distal esophagus. Surgical resection was performed in both, yielding the diagnosis of HMO. There are various theories as to the pathophysiology of HMO, but no clearly defined mechanism has been established. Management should be conservative whenever possible to prevent further ossification with subsequent surgical intervention.
Original Articles
Special AT-rich sequence-binding protein 2 (SATB2) in the differential diagnosis of osteogenic and non-osteogenic bone and soft tissue tumors
Sharon Milton, Anne Jennifer Prabhu, V. T. K. Titus, Rikki John, Selvamani Backianathan, Vrisha Madhuri
J Pathol Transl Med. 2022;56(5):270-280.   Published online September 13, 2022
DOI: https://doi.org/10.4132/jptm.2022.07.11
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AbstractAbstract PDF
Background
The diagnosis of osteosarcoma (OSA) depends on clinicopathological and radiological correlation. A biopsy is considered the gold standard for OSA diagnosis. However, since OSA is a great histological mimicker, diagnostic challenges exist. Immunohistochemistry (IHC) can serve as an adjunct for the histological diagnosis of OSA. Special AT-rich sequence-binding protein 2 (SATB2) was recently described as a reliable adjunct immunohistochemical marker for the diagnosis of OSA.
Methods
We investigated the IHC expression of SATB2 in 95 OSA and 100 non-osteogenic bone and soft tissue tumors using a monoclonal antibody (clone EPNCIR30A). The diagnostic utility of SATB2 and correlation with clinicopathological parameters were analyzed.
Results
SATB2 IHC was positive in 88 out of 95 cases (92.6%) of OSA and 50 out of 100 cases (50.0%) of primary non-osteogenic bone and soft tissue tumors. Of the 59 bone tumors, 37 cases (62.7%) were positive for SATB2, and of the 41 soft tissue tumors, 13 cases (31.7%) were positive for SATB2. The sensitivity of SATB2 as a diagnostic test was 92.6%, specificity 50%, positive predictive value 63.8%, and negative predictive value 87.7%.
Conclusions
Although SATB2 is a useful diagnostic marker for OSA, other clinical, histological and immunohistochemical features should be considered for the interpretation of SATB2.
Cytopathologic features of human papillomavirus–independent, gastric-type endocervical adenocarcinoma
Min-Kyung Yeo, Go Eun Bae, Dong-Hyun Kim, In-Ock Seong, Kwang-Sun Suh
J Pathol Transl Med. 2022;56(5):260-269.   Published online September 13, 2022
DOI: https://doi.org/10.4132/jptm.2022.07.05
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AbstractAbstract PDF
Background
Gastric-type endocervical adenocarcinoma (GEA) is unrelated to human papillomavirus (HPV) infection and is clinically aggressive compared with HPV-associated usual-type endocervical adenocarcinoma (UEA). The cytological diagnosis falls short of a definitive diagnosis of GEA and is often categorized as atypical glandular cells (AGCs). To improve cytologic recognition, cytological findings of HPV-independent GEA were analyzed and the results compared with HPV-associated UEA.
Methods
Cervical Papanicolaou (Pap) smears from eight patients with a histopathologic diagnosis of GEA and 12 control cases of UEA were reviewed. All slides were conventionally prepared and/or liquid-based prepared (ThinPrep) and stained following the Pap method. A mucinous background, architectural, nuclear, and cytoplasmic features were analyzed and compared with UEA.
Results
Preoperative cytologic diagnoses of the eight GEA cases were AGCs, favor neoplastic in three cases, adenocarcinoma in situ in one case, and adenocarcinoma in four cases. Cytologically, monolayered honeycomb-like sheets (p = .002) of atypical endocervical cells with vacuolar granular cytoplasm (p = .001) were extensive in GEA, and three-dimensional clusters (p = .010) were extensive in UEA. Although the differences were not statistically significant, background mucin (p = .058), vesicular nuclei (p = .057), and golden-brown intracytoplasmic mucin (p = .089) were also discriminatory findings for GEA versus UEA.
Conclusions
Although GEA is difficult to diagnose on cytologic screening, GEA can be recognized based on cytologic features of monolayered honeycomb sheets of atypical endocervical cells with abundant vacuolar cytoplasm and some golden-brown intracytoplasmic mucin. UEA cases are characterized by three-dimensional clusters.
Landscape of EGFR mutations in lung adenocarcinoma: a single institute experience with comparison of PANAMutyper testing and targeted next-generation sequencing
Jeonghyo Lee, Yeon Bi Han, Hyun Jung Kwon, Song Kook Lee, Hyojin Kim, Jin-Haeng Chung
J Pathol Transl Med. 2022;56(5):249-259.   Published online September 13, 2022
DOI: https://doi.org/10.4132/jptm.2022.06.11
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AbstractAbstract PDFSupplementary Material
Background
Activating mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) are predictive biomarkers for response to EGFR–tyrosine kinase inhibitor (TKI) therapy in lung adenocarcinoma (LUAD). Here, we characterized the clinicopathologic features associated with EGFR mutations via peptide nucleic acid clamping-assisted fluorescence melting curve analysis (PANAMutyper) and evaluated the feasibility of targeted deep sequencing for detecting the mutations.
Methods
We examined EGFR mutations in exons 18 through 21 for 2,088 LUADs from July 2017 to April 2020 using PANAMutyper. Of these, we performed targeted deep sequencing in 73 patients and evaluated EGFR-mutation status and TKI clinical response.
Results
EGFR mutation was identified in 55.7% of LUADs by PANAMutyper, with mutation rates higher in females (69.3%) and never smokers (67.1%) and highest in the age range of 50 to 59 years (64.9%). For the 73 patients evaluated using both methods, next-generation sequencing (NGS) identified EGFR mutation–positive results in 14 of 61 patients (23.0%) who were EGFR-negative according to PANAMutyper testing. Of the 10 patients reportedly harboring a sensitizing mutation according to NGS, seven received TKI treatment, with all showing partial response or stable disease. In the 12 PANAMutyper-positive cases, NGS identified two additional mutations in exon 18, whereas a discordant negative result was observed in two cases.
Conclusions
Although PANAMutyper identified high frequencies of EGFR mutations, targeted deep sequencing revealed additional uncommon EGFR mutations. These findings suggested that appropriate use of NGS may benefit LUAD patients with otherwise negative screening test results.
Newsletter
What’s new in kidney tumor pathology 2022: WHO 5th edition updates
Maria Tretiakova
Received August 13, 2022  Accepted August 16, 2022  Published online September 8, 2022  
DOI: https://doi.org/10.4132/jptm.2022.08.16    [Epub ahead of print]
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AbstractAbstract PDF
The 5th edition WHO Classification of Urinary and Male Genital Tumours (2022) introduces significant changes relevant to daily practice, especially in the completely restructured renal cell tumor chapters. Herein we highlight the most important diagnostic updates of known kidney tumor types, new and molecularly defined entities and emerging/provisional entities.
Case Study
Primary pulmonary epithelioid inflammatory myofibroblastic sarcoma: a rare entity and a literature review
Priyanka Singh, Aruna Nambirajan, Manish Kumar Gaur, Rahul Raj, Sunil Kumar, Prabhat Singh Malik, Deepali Jain
J Pathol Transl Med. 2022;56(4):231-237.   Published online July 7, 2022
DOI: https://doi.org/10.4132/jptm.2022.05.08
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AbstractAbstract PDF
Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is an aggressive subtype of inflammatory myofibroblastic tumor (IMT) harboring anaplastic lymphoma kinase (ALK) gene fusions and is associated with high risk of local recurrence and poor prognosis. Herein, we present a young, non-smoking male who presented with complaints of cough and dyspnoea and was found to harbor a large right lower lobe lung mass. Biopsy showed a high-grade epithelioid to rhabdoid tumor with ALK and desmin protein expression. The patient initially received 5 cycles of crizotinib and remained stable for 1 year; however, he then developed multiple bony metastases, for which complete surgical resection was performed. Histopathology confirmed the diagnosis of EIMS, with ALK gene rearrangement demonstrated by fluorescence in situ hybridization. Postoperatively, the patient is asymptomatic with stable metastatic disease on crizotinib and has been started on palliative radiotherapy. EIMS is a very rare subtype of IMT that needs to be included in the differential diagnosis of ALKexpressing lung malignancies in young adults.
Original Article
Inflammation and tissue remodeling contribute to fibrogenesis in stricturing Crohn’s disease: image processing and analysis study
Mustafa Erdem Arslan, Rupinder Brar, Lianna Goetz, Dipti Karamchandani, Michael W. Mikula, Kyle Hodge, Hua Li, Sangtae Ahn, Hwajeong Lee
J Pathol Transl Med. 2022;56(5):239-248.   Published online July 4, 2022
DOI: https://doi.org/10.4132/jptm.2022.05.18
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AbstractAbstract PDFSupplementary Material
Background
Inflammation and structural remodeling may contribute to fibrogenesis in Crohn’s disease (CD). We quantified the immunoexpression of calretinin, CD34, and calprotectin as a surrogate for mucosal innervation, telocytes (interstitial cells playing a role in networking), and inflammation, respectively, and correlated them with bowel alterations in stricturing CD.
Methods
Primary resection specimens for ileal CD (n = 44, 31 stricturing CD, 13 inflammatory CD) were identified. Left-sided ulcerative colitis and trauma cases were used as controls. Proximal and distal margin and middle (diseased) sections were stained for calretinin, CD34, and calprotectin. Microscopic images were captured from the mucosa (calretinin), submucosa (calprotectin), and myenteric plexus (CD34), and the immunostaining was quantified using image processing and analysis. Bowel thickness at the corresponding sections were measured and correlated with the amount of immunoexpression.
Results
A total of 2,037 images were analyzed. In stricturing CD, submucosal alteration/thickening at the stricture site correlated with calprotectin staining and inversely correlated with calretinin staining at the proximal margin. Muscularis propria alteration/thickening at the stricture site correlated with mucosal calretinin staining at the proximal margin. Submucosal alteration/thickening at the proximal margin correlated with calretinin and CD34 staining at the proximal margin and inversely correlated with CD34 staining at the stricture site. Calretinin immunostaining at the distal margin was significantly higher in stricturing CD than the controls.
Conclusions
Inflammation and tissue remodeling appear to contribute to fibrogenesis in stricturing CD. Increased mucosal calretinin immunostaining distal to the diseased segment could be helpful in diagnosing CD in the right clinical context.
Review
Lymphoproliferative disorder involving body fluid: diagnostic approaches and roles of ancillary studies
Jiwon Koh, Sun Ah Shin, Ji Ae Lee, Yoon Kyung Jeon
J Pathol Transl Med. 2022;56(4):173-186.   Published online July 4, 2022
DOI: https://doi.org/10.4132/jptm.2022.05.16
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AbstractAbstract PDF
Lymphocyte-rich effusions represent benign reactive process or neoplastic condition. Involvement of lymphoproliferative disease in body cavity is not uncommon, and it often causes diagnostic challenge. In this review, we suggest a practical diagnostic approach toward lymphocyte-rich effusions, share representative cases, and discuss the utility of ancillary tests. Cytomorphologic features favoring neoplastic condition include high cellularity, cellular atypia/pleomorphism, monomorphic cell population, and frequent apoptosis, whereas lack of atypia, polymorphic cell population, and predominance of small T cells usually represent benign reactive process. Involvement of non-hematolymphoid malignant cells in body fluid should be ruled out first, followed by categorization of the samples into either small/medium-sized cell dominant or large-sized cell dominant fluid. Small/medium-sized cell dominant effusions require ancillary tests when either cellular atypia or history/clinical suspicion of lymphoproliferative disease is present. Large-sized cell dominant effusions usually suggest neoplastic condition, however, in the settings of initial presentation or low overall cellularity, ancillary studies are helpful for more clarification. Ancillary tests including immunocytochemistry, in situ hybridization, clonality test, and next-generation sequencing can be performed using cytologic preparations. Throughout the diagnostic process, proper review of clinical history, cytomorphologic examination, and application of adequate ancillary tests are key elements for successful diagnosis.
Original Articles
Founder BRCA1 mutations in Nepalese population
Anurag Mehta, Himanshi Diwan, Garima Gupta, Shrinidhi Nathany, Shalini Agnihotri, Surender Dhanda
J Pathol Transl Med. 2022;56(4):212-216.   Published online June 15, 2022
DOI: https://doi.org/10.4132/jptm.2022.05.02
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AbstractAbstract PDF
Background
Founder mutation is a heritable genetic alteration observed with high frequency in a geographically and culturally isolated population where one or more ancestors becomes the forebearer of the altered gene. The current study reports two founder mutations in the BRCA1 gene in the Nepalese people.
Methods
Germline BRCA testing in all surface epithelial ovarian cancers and the selected case of breast, prostate, and pancreatic cancers has been the standard practice from 2016 to 2021. One thousand one hundred thirtythree probands were screened for germline BRCA variants by next generation sequencing. The variants were classified as per the American Society of Medical Genetics and Genomics recommendations. Pathogenic (class V) and likely pathogenic (class IV) were considered clinically relevant and utilized for cascade screening.
Results
Nepalese population made up a subcohort of 5.12% (58/1,133) of probands tested for germline BRCA1/2 variants. Twenty-seven of these 58 tested harbored pathogenic genetic alterations in BRCA1/2 genes, with 23 being BRCA1 mutant. Sixteen of 23 BRCA1 mutant cases shared one common pathogenic mutation c.2214_2215insT (p.Lys739Ter) (NM_007294.4). Additionally, a second highly recurrent mutation in BRCA1 gene c.5068A>T (p.Lys1690Ter) (NM_007294.4) was noted in six patients from this population.
Conclusions
The overwhelming abundance of the above two variants in a geographically confined population confers these two genetic alterations a status of founder mutations amongst the people of Nepal. A more extensive population-based study to reaffirm these findings will help establish a dual site-specific germline testing similar to the “Multisite-3-assay” in Ashkenazi Jews as the primary screening tool, especially in a resource-constrained environment.
EGFL7 expression profile in IDH-wildtype glioblastomas is associated with poor patient outcome
Bruno Henrique Bressan da Costa, Aline Paixão Becker, Luciano Neder, Paola Gyuliane Gonçalves, Cristiane de Oliveira, Allan Dias Polverini, Carlos Afonso Clara, Gustavo Ramos Teixeira, Rui Manuel Reis, Lucas Tadeu Bidinotto
J Pathol Transl Med. 2022;56(4):205-211.   Published online June 15, 2022
DOI: https://doi.org/10.4132/jptm.2022.04.22
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AbstractAbstract PDFSupplementary Material
Background
Despite the advances in glioblastoma (GBM) treatment, the average life span of patients is 14 months. Therefore, it is urgent to identity biomarkers of prognosis, treatment response, or development of novel treatment strategies. We previously described the association of high epidermal growth factor-like domain multiple 7 (EGFL7) expression and unfavorable outcome of pilocytic astrocytoma patients. The present study aims to analyze the prognostic potential of EGFL7 in GBM isocitrate dehydrogenase (IDH)-wildtype, using immunohistochemistry and in silico approaches.
Methods
Spearman’s correlation analysis of The Cancer Genome Atlas RNA sequencing data was performed. The genes strongly correlated to EGFL7 expression were submitted to enrichment gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Additionally, EGFL7 expression was associated with patient overall survival. The expression of EGFL7 was analyzed through immunohistochemistry in 74 GBM IDH-wildtype patients’ samples, and was associated with clinicopathological data and overall survival.
Results
In silico analysis found 78 genes strongly correlated to EGFL7 expression. These genes were enriched in 40 biological processes and eight KEGG pathways, including angiogenesis/vasculogenesis, cell adhesion, and phosphoinositide 3-kinase–Akt, Notch, and Rap1 signaling pathways. The immunostaining showed high EGFL7 expression in 39 cases (52.7%). High immunolabelling was significantly associated with low Karnofsky Performance Status and poor overall survival. Cox analysis showed that GBMs IDH-wildtype with high EGFL7 expression presented a higher risk of death compared to low expression (hazard ratio, 1.645; 95% confidence interval, 1.021 to 2.650; p = .041).
Conclusions
This study gives insights regarding the genes that are correlated with EGFL7, as well as biological processes and signaling pathways, which should be further investigated in order to elucidate their role in glioblastoma biology.
Case Study
Hepatic carcinoma expressing inhibin: case report of a proposed novel entity and review of the literature
Antonia Syrnioti, Evangelia Athanasiou, Prodromos Hytiroglou
J Pathol Transl Med. 2022;56(4):225-230.   Published online June 15, 2022
DOI: https://doi.org/10.4132/jptm.2022.04.07
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AbstractAbstract PDF
Hepatic carcinoma expressing inhibin is a recently described neoplasm with varied architecture, including trabecular, pseudoglandular, follicular/microcystic, organoid, solid and tubular patterns of growth. We report a case of hepatic carcinoma expressing inhibin that occurred in a 47-year-old woman presenting with epigastric and back pain. The tumor was located in the left hepatic lobe and measured 12 cm in diameter. On immunohistochemical stains, the neoplastic cells were positive for inhibin, as well as cytokeratins 7, 8/18 and 19. There was mild focal expression of synaptophysin, and lack of expression of hepatocytic markers. The histogenesis of hepatic carcinoma expressing inhibin is presently uncertain. From a practical point of view, this neoplasm can potentially cause diagnostic pitfalls by simulating other primary or metastatic tumors, such as hepatocellular carcinoma, cholangiocarcinoma, neuroendocrine tumors, and follicular carcinoma of thyroid gland. Performing inhibin immunostain could assist in the differential diagnosis of liver tumors with unusual histologic features.
Newsletter
What’s new in breast pathology 2022: WHO 5th edition and biomarker updates
Kristen Muller, Julie M. Jorns, Gary Tozbikian
J Pathol Transl Med. 2022;56(3):170-171.   Published online May 15, 2022
DOI: https://doi.org/10.4132/jptm.2022.04.25
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AbstractAbstract PDF
The 5th edition WHO Classification of Breast Tumours (2019) has introduced changes to our practices. Highlights are presented below, with a focus on modifications to morphological subtype categorization. In addition, we summarize important updates to ER and PR testing made in the 2020 ASCO/CAP guidelines, and briefly discuss PD-L1 and Ki-67 testing in breast cancer.

JPTM : Journal of Pathology and Translational Medicine