- Case report
- Open Access
- Open Peer Review
An autopsy case of anaplastic lymphoma kinase-positive lung cancer exacerbated in a short period of time: a case report
© The Author(s). 2019
- Received: 22 January 2019
- Accepted: 15 March 2019
- Published: 29 April 2019
Anaplastic lymphoma kinase-positive lung cancer is a form of lung cancer that accounts for approximately 5% of non-small cell lung cancers. Recently, anaplastic lymphoma kinase inhibitors have been used for treatment of anaplastic lymphoma kinase-positive lung cancer, and their high clinical effect has also been demonstrated in cases of advanced stage lung cancer. Alectinib is an anaplastic lymphoma kinase inhibitor that it is recognized as a standard drug for primary therapy because of its superiority to crizotinib.
A 37-year-old Japanese man was admitted to our hospital due to multiple brain metastases. An autopsy report revealed that the cause of death was anaplastic lymphoma kinase-positive lung cancer, exacerbated in a short period despite treatment with alectinib. Necropsy revealed anaplastic lymphoma kinase-positive adenosquamous carcinoma of the lung, suggesting that it was involved in the prognosis of this patient. Based on the autopsy results, we reviewed the pathological tissue from transbronchial lung biopsy at the time of clinical diagnosis. The tissue specimen for clinical diagnosis in this case was a papillary adenocarcinoma. However, when this tissue was immunostained, thyroid transcription factor 1-negative and cytokeratin 5/6-positive parts were recognized. This result indicates that we could diagnose this patient as having had adenosquamous carcinoma of the lung.
In cases of anaplastic lymphoma kinase-positive lung cancer poorly responsive to anaplastic lymphoma kinase inhibitors, re-examination of the tissue should be considered because there is a possibility of anaplastic lymphoma kinase-positive adenosquamous carcinoma.
- ALK-positive lung cancer
- ALK-positive adenosquamous carcinoma
In recent years, it has been reported that epidermal growth factor receptor (EGFR) mutations and the echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene are involved in the diagnosis of lung cancer, and it is known that the presence or absence of these also affect treatment [1, 2]. ALK-positive lung cancer is a form of lung cancer that accounts for approximately 5% of non-small cell lung cancers [3, 4]. Recently, ALK inhibitors have been used for the treatment of ALK-positive lung cancer, and their high clinical effect has also been demonstrated in cases of advanced stage lung cancer. Alectinib is an ALK inhibitor that is recognized as a standard drug for primary therapy because of its superiority to crizotinib . We encountered a case in which alectinib was administered as a primary treatment for ALK-positive lung cancer with brain metastases, but our patient died in a short period of approximately 4 months. Here, we report on the cause of death revealed at autopsy with a review of the literature.
Approximately 96 days after start of treatment, he was aware of headaches and nausea, and he visited our emergency department on day 103 of administration. Contrast MRI confirmed the findings of meningeal carcinomatosis. He was re-hospitalized for systemic management, including pain care. Dexamethasone infusion was started for increased intracranial pressure due to meningeal carcinomatosis. His Eastern Cooperative Oncology Group (ECOG) performance status at the time of his second admission was three, which was markedly lower than that at the onset of alectinib administration. He also experienced severe headache pain, so orally administered oxycodone was started. A few days after start of oxycodone administration, it became difficult for him to take orally administered medications, and palliative treatment was started using morphine hydrochloride infusion. Administration of alectinib was discontinued 108 days after start of treatment. Subsequently, it became difficult for him to sit up, his state of consciousness worsened, and his general condition worsened. He died 124 days after the first administration of alectinib.
Alectinib is an ALK inhibitor with high selectivity for EML4-ALK, and in recent years a direct comparison trial with crizotinib demonstrated that its therapeutic effect was superior to that of crizotinib . Also, the transitivity of alectinib to the brain is generally considered to be better, making it a drug that can be the first choice for cases of lung cancer with brain metastasis . Based on pathological autopsy, the present case was ultimately diagnosed as ALK-positive lung adenosquamous carcinoma because carcinoma cells were immunohistologically positive for ALK. ALK-positive lung adenosquamous carcinoma is a rare cancer, with only a few cases being reported to date [7, 8]. There are no reports on the effect of ALK inhibitors on ALK-positive lung adenosquamous carcinoma; therefore, its clinical course is unknown. In general, lung adenosquamous carcinoma is known to have a poor prognosis as compared with adenocarcinoma and squamous cell carcinoma . Although its sensitivity to ALK inhibitors is unknown, the fact that this was a case of adenosquamous carcinoma but not pure adenocarcinoma may be one reason for its aggressive nature.
In this case, the primary tumor and metastatic brain tumor were temporarily reduced by an ALK inhibitor, but leptomeningeal carcinomatosis developed only 3 months after initiation of treatment. At necropsy of the site exhibiting leptomeningeal carcinomatosis, the ratio of the squamous cell carcinoma component to the adenocarcinoma component was higher than that in the primary tumor of the left lung.
Regarding the prognosis of adenosquamous carcinoma, there is a report that the prognosis is worse for the tissue type with a greater squamous cell carcinoma component . In this case, the existence of tumors with different cell ratios may have in part led to exacerbation in a short period of time. Based on the autopsy results, we reviewed the pathological tissue from the transbronchial lung biopsy at the time of clinical diagnosis. The tissue specimen for clinical diagnosis in this case was a papillary adenocarcinoma. However, when this tissue was immunostained, thyroid transcription factor 1 (TTF-1)-negative and CK5/6-positive parts were recognized. This result indicates that we could diagnose this patient as having adenosquamous carcinoma of the lung. Although the prognosis of lung cancer has improved owing to the development of current treatments, there are cases where the prognosis is poor, such as adenosquamous carcinoma. Pathological diagnosis of adenosquamous carcinoma is actually difficult; therefore, it is necessary to review the tumor composition when encountering cases of ALK-positive lung adenocarcinoma that respond poorly to ALK inhibitors.
In summary, we reported an autopsy case of ALK-positive lung cancer that worsened in a short time. An autopsy revealed adenosquamous carcinoma of the lung, suggesting that it was involved in the prognosis of our patient. In cases of ALK-positive lung adenocarcinoma poorly responsive to treatment, re-examination of the tissue should be considered because there is a possibility of adenosquamous carcinoma.
Availability of data and materials
MT, KS, SS, YI, NK, KS, YOk, MA, MSa, and KN examined the patient clinically, analyzed laboratory data and histopathology, and decided the treatment for this patient by group conference. MT, MSu, and YOm revealed the patient’s pathogenesis by pathologic dissection. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Consent for publication
Written informed consent was obtained from the patient and patient’s family for publication of this case report and any accompanying images.
A copy of the written consent is available for review by the Editor-in-Chief of this journal.
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Hsu WH, Yang JC, Mok TS, Loong HH. Overview of current systemic management of EGFR-mutant NSCLC. Ann Oncol. 2018;29(suppl_1):i3–9.View ArticleGoogle Scholar
- Toschi L, Rossi S, Finocchiaro G, Santoro A. Non-small cell lung cancer treatment (r)evolution: ten years of advances and more to come. Ecancermedicalscience. 2017;11:787.View ArticleGoogle Scholar
- Boland JM, Erdogan S, Vasmatzis G, Yang P, Tillmans LS, Johnson MR, Wang X, et al. Anaplastic lymphoma kinase immunoreactivity correlates with ALK gene rearrangement and transcriptional up-regulation in non-small cell lung carcinomas. Hum Pathol. 2009;40:1152–8.View ArticleGoogle Scholar
- Li Y, Li Y, Yang T, Wei S, Wang J, Wang M. Clinical significance of EML4-ALK fusion gene and association with EGFR and KRAS gene mutations in 208 Chinese patients with non-small cell lung cancer. PLoS One. 2013;8:e52093.View ArticleGoogle Scholar
- Hida T, Nokihara H, Kondo M, Kim YH, Azuma K, Seto T, et al. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet. 2017;390:29–39.View ArticleGoogle Scholar
- Tamura T, Kiura K, Seto T, Nakagawa K, Maemondo M, Inoue A, et al. Three-Year Follow-Up of an Alectinib Phase I/II Study in ALK-Positive Non-Small-Cell Lung Cancer: AF-001JP. J Clin Oncol. 2017;35:1515–21.View ArticleGoogle Scholar
- Chaft JE, Rekhtman N, Ladanyi M, Riely GJ. ALK-rearranged lung cancer: adenosquamous lung cancer masquerading as pure squamous carcinoma. J Thorac Oncol. 2012;7:768–9.View ArticleGoogle Scholar
- Dragnev KH, Gehr G, Memoli VA, Tafe LJ. ALK-rearranged adenosquamous lung cancer presenting as squamous cell carcinoma: a potential challenge to histologic type triaging of NSCLC biopsies for molecular studies. Clin Lung Cancer. 2014;15:37–40.View ArticleGoogle Scholar
- Wang R, Pan Y, Li C, Zhang H, Garfield D, Li Y, et al. Analysis of Major Known Driver Mutations and Prognosis in Resected Adenosquamous Lung Carcinomas. J Thorac Oncol. 2014;9:760–8.View ArticleGoogle Scholar
- Gawrychowski J, Brulinski K, Malinowski E, Papla B. Prognosis and survival after radical resection of primary adenosquamous lung carcinoma. Eur J Cardiothorac Surg. 2005;27:686–92.View ArticleGoogle Scholar