Journal of Pathology and Translational Medicine

Original Article

Immunohistochemical expression of anaplastic lymphoma kinase in neuroblastoma and its relations with some clinical and histopathological features: Thu Dang Anh Phan, Thao Quyen Nguyen, Nhi Thuy To, Thien Ly Thanh, Dat Quoc Ngo; J Pathol Transl Med. 2024;58(1):29-34. Published online January 10, 2024; DOI: https://doi.org/10.4132/jptm.2023.12.07

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Abstract PDF: Background
Anaplastic lymphoma kinase (ALK) mutations have been identified as a prominent cause of some familial and sporadic neuroblastoma (NB). ALK expression in NB and its relationship with clinical and histopathological features remains controversial. This study investigated ALK expression and its potential relations with these features in NB.
Methods
Ninety cases of NB at the Department of Pathology, University of Medicine and Pharmacy at Ho Chi Minh City, Viet Nam from 01/01/2018 to 12/31/2021, were immunohistochemically stained with ALK (D5F3) antibody. The ALK expression and its relations with some clinical and histopathological features were investigated.
Results
The rate of ALK expression in NB was 91.1%. High ALK expression (over 50% of tumor cells were positive with moderate-strong intensity) accounted for 65.6%, and low ALK expression accounted for 34.4%. All the MYCN-amplified NB patients had ALK immunohistochemistry positivity, most cases had high ALK protein expression. The undifferentiated subtype of NB had a lower ALK-positive rate than the poorly differentiated and differentiated subtype. The percentages of ALK positivity were significantly higher in more differentiated histological types of NB (p = .024). There was no relation between ALK expression and: age group, sex, primary tumor location, tumor stage, MYCN status, clinical risk, Mitotic-Karyorrhectic Index, prognostic group, necrosis, and calcification.
Conclusions
ALK was highly expressed in NB. ALK expression was not related to several clinical and histopathological features. More studies are needed to elucidate the association between ALK expression and ALK gene status and to investigate disease progression, especially the oncogenesis of ALK-positive NB.

Case Studies

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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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.

Citations

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Mediastinal epithelioid inflammatory myofibroblastic sarcoma with the EML4‐ALK fusion: A case report and literature review
Tingyu Pan, Xinyu Sun, Xiao Wu, Futing Tang, Xianmei Zhou, Qian Wang, Shi Chen
Respirology Case Reports.2024;[Epub] CrossRef
Case report: Epithelioid inflammatory myofibroblastic sarcoma treated with an ALK TKI ensartinib
Mengmeng Li, Ruyue Xing, Jiuyan Huang, Chao Shi, Chunhua Wei, Huijuan Wang
Frontiers in Oncology.2023;[Epub] CrossRef
Epithelioid Inflammatory Myofibroblastic Sarcoma With Poor Response to Crizotinib: A Case Report
Soheila Aminimoghaddam, Roghayeh Pourali
Clinical Medicine Insights: Case Reports.2023;[Epub] CrossRef
Epithelioid inflammatory myofibroblastic sarcoma: a case report and brief literature review
Weidong Dou, Yu Guan, Tao Liu, Hang Zheng, Shuo Feng, Yingchao Wu, Xin Wang, Zhanbing Liu
Frontiers in Oncology.2023;[Epub] CrossRef

A case of concomitant EGFR/ALK alteration against a mutated EGFR background in early-stage lung adenocarcinoma: Ki-Chang Lee, Jiwon Koh, Doo Hyun Chung, Yoon Kyung Jeon; J Pathol Transl Med. 2021;55(2):139-144. Published online January 22, 2021; DOI: https://doi.org/10.4132/jptm.2020.12.16

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Abstract PDF

Rare cases of lung adenocarcinoma (LUAD) with concomitant epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) translocation have been reported. However, their clonal and evolutional relationship remains unclear. We report a case of early-stage EGFR-mutated LUAD with a focal concomitant EGFR/ALK alteration. A 63-year-old male underwent lobectomy to remove a 1.9-cm-sized lung nodule, which was diagnosed with EGFR-mutated LUAD. ALK immunohistochemistry (IHC) showed focal positivity within the part of the tumor characterized by lepidic pattern, also confirmed by fluorescence in-situ hybridization (FISH). Targeted next-generation sequencing was performed separately on the ALK IHC/FISH-positive and -negative areas. EGFR L833V/L858R mutations were detected in both areas, whereas EML4 (echinoderm microtubule-associated protein-like 4)-ALK translocations was confirmed only in the ALK IHC/FISH-positive area, suggesting the divergence of an EGFR/ALK co-altered subclone from the original EGFR-mutant clone. Our study suggests that concurrent alterations of EGFR and ALK can arise via divergent tumor evolution, even in the relatively early phases of tumorigenesis.

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Original Article

Analysis of Histologic Features Suspecting Anaplastic Lymphoma Kinase (ALK)-Expressing Pulmonary Adenocarcinoma: In Ho Choi, Dong Won Kim, Sang Yun Ha, Yoon-La Choi, Hee Jeong Lee, Joungho Han; J Pathol Transl Med. 2015;49(4):310-317. Published online June 22, 2015; DOI: https://doi.org/10.4132/jptm.2015.05.13

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Abstract PDF

Background
Since 2007 when anaplastic lymphoma kinase (ALK) rearrangements were discovered in non-small cell lung cancer, the ALK gene has received attention due to ALK-targeted therapy, and a notable treatment advantage has been observed in patients harboring the EML4/ALK translocation. However, using ALK-fluorescence in situ hybridization (FISH) as the standard method has demerits such as high cost, a time-consuming process, dependency on interpretation skill, and tissue preparation. We analyzed the histologic findings which could complement the limitation of ALK-FISH test for pulmonary adenocarcinoma. Methods: Two hundred five cases of ALK-positive and 101 of ALK-negative pulmonary adenocarcinoma from January 2007 to May 2013 were enrolled in this study. The histologic findings and ALK immunohistochemistry results were reviewed and compared with the results of ALK-FISH and EGFR/KRAS mutation status. Results: Acinar, cribriform, and solid growth patterns, extracellular and intracellular mucin production, and presence of signet-ring-cell element, and psammoma body were significantly more often present in ALK-positive cancer. In addition, the presence of goblet cell-like cells and presence of nuclear inclusion and groove resembling papillary thyroid carcinoma were common in the ALK-positive group. Conclusions: The above histologic parameters can be helpful in predicting ALK rearranged pulmonary adenocarcinoma, leading to rapid FISH analysis and timely treatment.

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Review

Guideline Recommendations for Testing of ALK Gene Rearrangement in Lung Cancer: A Proposal of the Korean Cardiopulmonary Pathology Study Group: Hyojin Kim, Hyo Sup Shim, Lucia Kim, Tae-Jung Kim, Kun Young Kwon, Geon Kook Lee, Jin-Haeng Chung; Korean J Pathol. 2014;48(1):1-9. Published online February 25, 2014; DOI: https://doi.org/10.4132/KoreanJPathol.2014.48.1.1

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Abstract PDF

Rearrangement of anaplastic lymphoma kinase (ALK) gene is the best predictor of response to crizotinib, an ALK tyrosine kinase inhibitor. However, the prevalence of the ALK fusion is low, so accurate patient identification is crucial for successful treatment using ALK inhibitors. Furthermore, most patients with lung cancer present with advanced-stage disease at the time of diagnosis, so it is important for pathologists to detect ALK-rearranged patients while effectively maximizing small biopsy or cytology specimens. In this review, we propose a guideline recommendation for ALK testing approved by the Cardiopulmonary Pathology Study Group of the Korean Society of Pathologists.

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Original Articles

Cytologic Features of ALK-Positive Pulmonary Adenocarcinoma: Seung Yeon Ha, Jungsuk Ahn, Mee Sook Roh, Joungho Han, Jae Jun Lee, Boin Lee, Jun Yim; Korean J Pathol. 2013;47(3):252-257. Published online June 25, 2013; DOI: https://doi.org/10.4132/KoreanJPathol.2013.47.3.252

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Abstract PDF

Background

The aim of this study was to determine the cytologic features of anaplastic lymphoma kinase (ALK) expressing pulmonary adenocarcinoma.

Methods

We analyzed the cytopathological findings of 15 cases of endobronchial ultrasound guided aspiration and a case of bronchial washing. These cases were selected based on the histomorphology of ALK-rearranged lung adenocarcinoma.

Results

Cytology showed mucinous (81.3%) and hemorrhagic (50%) backgrounds. The cells were arranged in tubulopapillary or tubulocribriform patterns (93.8%), and clusters (56.3%) admixed with signet ring cell features (87.5%). The tumor cells were monotonous and uniform with vesicular nuclei and a small nucleolus.

Conclusions

The characteristic findings were sheets showing a tubulopapillary or tubulocribriform appearance, with vesicular nuclei and a bland chromatin pattern (p<0.001). Scattered signet ring cells were helpful in suggesting ALK-positive adenocarcinoma (p<0.001).

Citations

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Machine learning‐based gene alteration prediction model for primary lung cancer using cytologic images
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Qualitative and quantitative cytomorphological features of primary anaplastic lymphoma kinase‐positive lung cancer
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ALK-rearranged adenocarcinoma with extensive mucin production can mimic mucinous adenocarcinoma: clinicopathological analysis and comprehensive histological comparison with KRAS-mutated mucinous adenocarcinoma
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Clinicopathological Analysis of Systemic Anaplastic Large Cell Lymphoma.: Soo Young Chung, Han Suk Ryu, Jae Soo Ko, Baek Youl Ryoo, Seung Sook Lee; Korean J Pathol. 2006;40(6):399-405.

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Abstract PDF: BACKGROUND
Several studies from western countries have reported variable prognoses for patients with systemic anaplastic large cell lymphoma (ALCL) depending strongly on the expression of anaplastic lymphoma kinase (ALK). However, no prognostic significance of ALK expression in Koreans was reported in a single report regarding these patients, although the number of cases was limited in that study.
METHODS
We analyzed the clinicopathological features of ALK+ ALCL and ALK- ALCL in 30 Korean patients diagnosed with primary systemic ALCL.
RESULTS
ALK expression was detected in 60% of all ALCL patients (18/30), and there was no statistical significance to ALK expression in overall survival. Patients with ALK+ ALCL were younger in age and had negative bcl-2 expression; these differences were statistically significant. Tumors positive for ALK protein and granzyme B expression, and negative for bcl-2 expression with a null-cell phenotype tended to have better survival outcomes, althought this trend failed to reach statistical significance (p<0.2), probably due to the limited number of cases in this study.
CONCLUSION
ALK protein expression and the absence of bcl-2 in tumor cells tend to result in better survival despite the failure of this trend to achieve statistical significance. Further studies that examine potential pathologic prognostic factors combined with the expression of ALK and apoptotic factors such as bcl-2 are needed. Additional larger-scale studies are also needed to conclude that ALK expression has no prognostic significance among Koreans.

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