Rapidly progressive squamous cell lung cancer with MET exon 14 skipping mutation metastasized to atypical bone sites – a case report

Overview

Background: The mesenchymal-epithelial transition factor (MET) exon 14 skipping mutation has recently emerged as a driver gene in non-small cell lung cancer (NSCLC) in clinical practice. Clinical trials of several MET inhibitors have shown the effectiveness of MET inhibitors in NSCLC patients with MET exon 14 skipping mutation. To the best of our knowledge, however, there was no patient with sole MET exon 14 skipping mutation who progressed rapidly and had a poor prognosis. Case: A 61-year-old man presented with pain in the dorsum of the left foot and in the left elbow. Chest CT revealed a mass in the right lower lobe of the lung, and FDG-PET showed metastases in the ribs, thoracic vertebra, left elbow, and left metacarpal bone. Corrected calcium level was elevated up to 14.1 mg/dL. The histopathology of the transbronchial bio­psy specimen was morphologically consistent with squamous cell carcinoma. MET exon 14 skipping mutation was positive in Oncomine Dx Target Test Multi-CDx system. Within a few weeks of admission, the patient‘s respiratory condition rapidly deteriorated carcinomatous lymphangiosis and died of acute respiratory failure one month after admission. In this patient, bone metastases to atypical sites and hypercalcemia were also observed. Conclusion: Chest physicians should be noted that there might be rapidly progressive fatal patients among those with MET exon 14 skipping mutations.

Keywords:

hypercalcemia – rapid progression – squamous cell lung cancer – MET exon 14 skipping mutation – bone metastasis

Introduction

Treatment of advanced non-small cell lung cancer (NSCLC) has dramatically improved due to development of driver gene targeted tyrosine kinase inhibitors (TKIs) [1]. As one of the treat­able driver mutations in NSCLC patients, the mesenchymal-epithelial transition factor (MET) exon 14 skipping mutation has recently emerged in clinical practice [2,3]. Clinical trials of several MET inhibitors have shown the effectiveness of MET inhibitors in NSCLC patients with MET exon 14 skipping mutation [4,5]. NSCLC patients with MET exon 14 skip gene are known to have a higher median age and a higher proportion of patients with a history of smoking than those in NSCLC patients with other driver genes [4,5]. Very recently, rapid progressed case in a NSCLC patient with both MET exon 14 skipping mutation and epidermal growth factor receptor (EGFR) exon 20 insertion was reported [6]. It was unclear which driver gene was more involved in the rapid progression of this patient. To the best of our knowledge, however, there was no patient with sole MET exon 14 skipping mutation who progressed rapidly and had a poor prognosis. In this patient, we found metastasis to atypical bone sites and hypercalcemia. We show herein a case with a MET exon 14 skipping mutation-positive NSCLC patient with pain due to bone metastases in elbow and dorsum of the foot as the first symptom. He had rapid deterioration in a month and had unfortunate outcome. In this driver gene positive patients, there might be patients who progress rapidly. Physicians should be aware of these rare  patients.

Case report

A 61-year-old man presented with pain in the dorsum of the left foot and in the left elbow. The patient had smoking history with 39 pack-year, but he had no asbestos exposure. Physical examination was unremarkable and his performance status (PS; Eastern Cooperative Oncology Group) at admission was 1. Chest CT revealed a mass and atelectasis in the right upper lobe of the lung (Fig. 1), and FDG-PET showed metastases in the ribs, thoracic vertebra, left elbow, and left metacarpal bone (Fig. 2). Albumin-corrected calcium level was elevated up to 14.1mg/dL. The histopathology of the transbronchial bio­psy specimen obtained from the right lower lobe was morphologically consistent with squamous cell carcinoma. The EGFR gene mutation, ALK fusion gene, ROS1 fusion gene, and BRAF gene mutation were all negative. But MET exon 14 skipping mutation was positive in Oncomine Dx Target Test Multi-CDx system. His clinical stage was T4N2M1c stage IVB. Since the pain in the left foot and elbow was strong, oxycodon was administered. In addition, treatment of hypercalcemia was started with zoledronic acid, saline infusion, and diuretics. Within a few weeks of admission, the patient‘s general condition rapidly deteriorated to PS of 3. In addition, decreased permeability of both lung fields in chest radiograph, which was due to deterioration of carcinomatous lymphangiosis, and rapid exacerbation of respiratory condition appeared. The patient was unable to receive MET inhibitor treatment due to the rapid deterioration of his general condition but also negative result of Archer MET, a test used for companion dia­gnostics. He died of acute respiratory failure one month after admission. Autopsy was not permitted.

Discussion

In some driver genes of NSCLC, there are drugs that act specifically on their respective molecular target sites [7]. Patients treated with such drugs often have a long term of response. However, not all the patients who received TKI responded, and some patients did not [8,9]. In EGFR mutation and ALK fusion gene, patients with rapid progression despite administration of specific drugs have been reported [10,11]. On the other hand, there have been reports of lung cancer patients who rapidly worsened and died even though their condition were not poor at the first reference [12,13]. However, most of them were patients with negative driver genes or those with uncommon histopathological malignancies [12,13]. In our patient, MET exon 14 skipping mutation was positive in Oncomine Dx Target Test Multi-CDx system. But Archer MET, a test used for companion dia­gnostics, was negative. Therefore, specific TKI could not be administered. Due to the progression of respiratory failure, which is thought to be due to the progression of cancerous lymphangiopathy of the lung, only supportive therapies had to be performed.

In our patient, hypercalcemia was observed, and it was possible to be a functioning tumor. It is well known that lung cancer patients with paraneoplastic syndrome including hypercalcemia have poor prognosis [14–18]. Most of the histological types of lung cancer presenting with hypercalcemia have been squamous cell lung cancer [15], which was the same histopathological type as confirmed in our patient. Hypercalcemia in lung cancer patients has also been reported in those with bone metastases in various sites, and this hypercalcemia has been often observed in patients with lung adenocarcinoma [19,20]. In our patient, metastases were present in two ribs, forearms, and metatarsals, and it was possible that hypercalcemia was related to bone metastases [21]. Mea­surement of parathyroid hormone-related peptide was not performed, but if it was, it was highly possible that a meaningful value might be obtained. Bone metastasis frequently develops in bones near the primary lesion in relation to blood flow. Therefore, NSCLC patients metastasize to the vertebrae and rib, but rarely metastasize to the metacarpal bone and elbow [23–25]. Patients with systemic dissemination might develop bone metastases away from the primary site throughout the body [26]. Our patient developed bone metastases to atypical sites, but as he had no meta­stases to other organs, therefore, he was evaluated not to be in a dissemination state. In patient with MET exon 14 skipping mutation, bone metastasis in such uncommon bone sites might occur in patients without dissemination.

Very recently, Jiao et al reported a case of a 33-year-old NSCLC patient with MET exon 14 skipping mutation, who also harbored a somatic EGFR exon 20 insertion. They reported that the overall survival of this patient was 9 months [6]. This patient had bone metastases, but the metastatic sites were T8 and T12 vertebral bones. The patient had no paraneoplastic syndrome including hypercalcemia. At present, exon 20 insertion is one of the types of EGFR mutated NSCLC that is difficult to treat and is associated with a poor prognosis [27]. Therefore, it was quite possible that EGFR exon 20 insertion was involved in the poor prognosis of this patient. Our patient was negative for EGFR mutation and other driver genes. There was such a difference between the patient reported by Jiao et al and ours. However, the presence of their patient and ours might suggest the possibility of rapid progression in some patients with MET exon 14 skipping mutation.

Conclusion

NSCLC patients with MET exon 14 skipping mutations might include patients with rapid progression as observed in our patient. Such aggressive progression might associate with bone metastases to atypical sites and hypercalcemia. Chest physicians should be noted that there might be rapid progressive fatal patients among those with MET exon 14 skipping mutations. It is desired that effective treatments would be established for these patients with poor prognosis.

Funding

The authors received no financial support for the research and/or authorship of this article.

Authors’ contributions

NK and SH designed the study, NK, HS, KY, SY, and SH collected the data. NK, KY and SH prepared the manuscript. All authors approved the final version of the article.

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.
Autoři deklarují, že v souvislosti s předmětem studie nemají žádné komerční zájmy.
The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.
Redakční rada potvrzuje, že rukopis práce splnil ICMJE kritéria pro publikace zasílané do biomedicínských časopisů.

Hiroaki Satoh, MD, PhD
Division of Respiratory Medicine,
Mito Medical Center
University of Tsukuba-Mito Kyodo
General Hospital
Miya-machi 3-2-7
Mito-city, Ibaraki
310-0015, Japan
e-mail: hirosato@md.tsukuba.ac.jp
Submitted/Obdrženo: 22. 6. 2021
Accepted/Přijato: 11. 8. 2021