Abstract
A 60-year-old man with a history of smoking was transferred to our hospital for consciousness disorder. A diagnosis of ALK-rearranged lung adenocarcinoma associated with a paraneoplastic electrolytic disorder was made following a cutaneous needle biopsy. Both the primary lung lesion and multiple metastases shrunk and his electrolytic disorder resolved after the introduction of a first-line molecular-targeted drug chemotherapy with crizotinib. We herein report a case of ALK-rearranged lung adenocarcinoma accompanied by SIADH, successfully treated with crizotinib.
Keywords: ALK, SIADH, Hyponatremia, Crizotinib, Lung adenocarcinoma
1. Introduction
ALK gene rearrangements are found in approximately 3.4%–6.2% of resected non-small cell lung cancer (NSCLC) cases [1,2]. Since ALK rearrangement has been identified as a driver oncogene in NSCLC [3], molecular-targeted therapy for NSCLC harboring the ALK rearrangement has progressed.
Paraneoplastic syndromes occur in at least 10% of patients with bronchogenic carcinoma [4]. A larger series of patients has revealed that SIADH occurs in 0.7% of patients with NSCLC (three cases out of 427 patients) [5]. SIADH in ALK-rearranged NSCLC has not been previously reported. We herein report a case of ALK-rearranged lung adenocarcinoma accompanied by SIADH, successfully treated with crizotinib.
2. Case report
A 60-year-old man was transferred to our hospital in August 2014 due to a consciousness disorder. He had no remarkable medical history but for a 20 pack-year smoking history. Physical examination indicated a grossly distended sternum and several palpable lymph nodes at the left axial fossa. Laboratory data revealed severe hyponatremia combined with hypertonic sodium diuresis. His renal and adrenal functions were normal, and the serum levels of ADH, NT-proBNP, and several tumor markers were slightly elevated (Table 1). Contrast-enhanced chest computed tomography (CT) revealed a giant mass lesion in the left lower lung field and multiple bone metastases (Fig. 1A and B). Abdominal CT revealed bilateral adrenal gland metastases and peritoneal tumor disseminations (Fig. 1C and D).
Table 1.
The patient's Laboratory Findings on Admission.
| 【Hematology】 | 【Tumor markers】 | ||
|---|---|---|---|
| White blood cells | 18700/μL | CEA | 39.5 ng/mL |
| Red blood cells | 556 104/μL | CA19-9 | 70.5 U/mL |
| Hemoglobin | 14.6/dL | SCC | 81.7 ng/mL |
| Hematocrit | 44.90% | SLX | 130 U/mL |
| Platelets | 504 104μL | NSE | 59.3 ng/mL |
| 【Blood chemistry】 | pro-GRP | 59.4 ng/mL | |
| Total protein | 7.0g/dL | ||
| Albumin | 3.6g/dL | 【Urinalysis】 | |
| Blood urea nitrogen | 11.8mg/dL | Specific gravity | 1.041 |
| Creatinine | 0.71mg/dL | Proteinuria | + |
| Sodium | 98.7mEq/L | Hematuria | 2+ |
| Potassium | 5.7mEq/L | Red blood cells | 5-9/HPF |
| Chloride | 67.2mEq/L | White blood cells | 1-4/HPF |
| C-reactive protein | 22.9mg/dL | Urinary-Na | 50.7 mEq/L |
| NT-proBNP | 3089pg/mL | Urinary-K | 40.9 mEq/L |
| Serum osmotic pressure | 217.0mOsm/L | Urinary-Cl | 51.0 mEq/L |
| Antidiuretic hormon | 3.6pg/mL | Urine osmotic pressure | 550.0mOsm/L |
| Cortisol | 21.2μg/dL | ||
CEA:carcinoembryonic antigen.
CA19-9:carbohydrate antgen 19-9.
SCC:squamous cell carcinoma antigen.
SLX:sialy lex-I antigen.
NSE:neuron-spacific enolase.
pro-GRP:pro-gastrin releasing polypeptide.
Fig. 1.
Chest CT showed a tumor mass measuring 90 × 80 mm in the left lower lung with metastasis to the sternum, right rib, and both supraclavicular lymph nodes (A, B; arrows). Abdominal CT showed metastatic bilateral adrenal glands and peritoneal lesions (C, D; arrows).
Transcutaneous needle biopsy was performed at the sternum. A diagnosis of poorly differentiated adenocarcinoma was made according to the pathological findings (Fig. 2), and immunohistochemical analysis showed positive staining for ALK (Fig. 3). An additional fluorescence in-situ hybridization (FISH) test confirmed the diagnosis of ALK gene rearrangement in lung adenocarcinoma (data not shown). The patient's electrolytic disorder was compatible with SIADH according to a systemic screening examination.
Fig. 2.
A cytological specimen obtained by a transcutaneous needle biopsy at the sternum showed atypical epithelial cells with eccentric nuclei and intracytoplasmic (ICL) cells (arrow), which led to the diagnosis of adenocarcinoma (A: Papanicolaou staining, original magnification × 200, B: Giemsa staining, original magnification × 200.).
Fig. 3.
A pathological specimen obtained by a transcutaneous needle biopsy at the sternum showed atypical cell clusters in the desmoplastic stroma (A: hematoxylin and eosin staining, original magnification × 400). These atypical cell clusters showed trabecular and solid structures with small glands (arrows). Immunohistochemical staining for ALK was positive (B, original magnification × 400).
Post-diagnosis, an electrolytic replacement therapy with administration of the first-line molecular-targeted drug crizotinib was significantly effective, and the serum Na concentration recovered from 98.7mEq/L to 130mEq/l. A shrinkage in both the primary lung lesion and multiple metastases was observed upon resolution of the electrolytic disorder (Fig. 4). Other than an ileus induced by abdominal tumor shrinkage, no adverse reactions to chemotherapy were observed. The complete response was maintained with crizotinib for one year without recurrence of the tumor and SIADH. His tumor relapsed at the right upper arm bone and cervical lymph nodes, and alectinib was introduced as second line treatment after radiation therapy for pain control of the right upper arm bone. A partial response was observed, and SIADH did not relapse until the end of his life, on July 2017.
Fig. 4.
The primary lung tumor markedly shrunk after the introduction of chemotherapy as demonstrated on serial CT images; on admission (A), 10 days after the introduction of chemotherapy (B), 70 days (C), and 140 days (D).
3. Discussion
ALK gene rearrangements are found in approximately 3.4%–6.2% of resected NSCLC cases [1,2]. Crizotinib is one of the most widely available drugs, and is an oral small-molecule tyrosine kinase inhibitor that targets ALK, MET, and ROS1 tyrosine kinases [6]. Crizotinib has been approved in Japan (since March, 2012) and the USA (since August 2011) in any line of treatment, and alectinib was also approved in the first-line setting since 2017 [7].
Paraneoplastic syndromes occur in at least 10% of patients with bronchogenic carcinoma [4]. A larger series of patients has revealed that SIADH occurs in 15% of small cell lung cancers (SCLC) (214 of 1,473 patients), and in 0.7% of patients with NSCLC (three of 427 patients) [5]. A review of clinical data from 350 patients with SCLC revealed that hyponatremia (sodium concentration < 130 mEq/L) was attributed to SIADH in 11% of the patients, and there was no correlation between the development of SIADH and factors such as sex, histologic subtype, clinical stage, and distribution of metastatic sites [4]. All patients with hyponatremia related to SIADH in lung cancer have elevated serum levels of ADH; however, atrial natriuretic peptide is another hormone produced ectopically by lung cancer cells, which affects renal salt and water handling [5]. Hyponatremia in SCLC was significantly associated with a shorter survival duration of the study cohorts in seven of the 13 studies on univariate analysis (54%), and in six studies on multivariate analysis (46%) [9]. However, another study reported that hyponatremia in SCLC was prognostic for a shorter survival time in patients with extensive disease but not in patients with limited disease in a Japanese cohort [10]. The potential life-threatening hyponatremia (sodium concentration less than 100 mEq/L) in the present case might have occurred due to a large tumor burden accompanied by multiple metastatic sites and a large primary pulmonary tumor, in conjunction with elevated serum ADH and NT-proBNP concentrations. We successfully treated life-threatening hyponatremia by electrolytic replacement therapy for the acute symptomatic phase followed by crizotinib, a drug against the molecular target. Despite initial control of SIADH, dilutional hyponatremia recurred in 70% of patients, with tumor regression in SCLC patients [8]. In the present case, hyponatremia did not recur during the administration of crizotinib or at the time of disease progression. However, careful attention should be paid to the recurrence of SIADH in the treatment duration.
4. Conclusion
To the best of our knowledge, SIADH in ALK-rearranged NSCLC has not been reported. Clinicians should be aware that hyponatremia complicated with lung cancer may be caused by ALK-rearranged NSCLC as well as small cell lung cancer.
Funding
None.
Declaration of competing interest
The authors state that they have no conflict of interest.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2020.101136.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
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