Hypoglycemia caused by co-secretion of insulin from lung tumor and cardia cancer: first case report

ABSTRACT CONTEXT: Non-islet-cell-tumor-induced hypoglycemia (NICTH) is caused on rare occasions by secretion of insulin from tumor cells that are reported to have a single tissue origin. CASE REPORT: A 67-year-old male patient had cardia adenocarcinoma and concomitant lung adenocarcinoma with extensive metastases and repeated episodes of intractable hypoglycemia. Immunohistochemical staining for insulin showed that lung adenocarcinoma stained positive and gastric cardia adenocarcinoma stained weakly positive. These results indicate that tumor cells of different tissue origins co-secreted insulin. CONCLUSIONS: This is the first report on intractable hypoglycemia due to co-secretion of insulin from two kinds of primary tumor cells in a single patient.


INTRODUCTION
Non-islet-cell-tumor-induced hypoglycemia (NICTH) is a rare paraneoplastic syndrome characterized by repeated episodes of hypoglycemia. NICTH is commonly associated with excessive secretion of immature insulin-like growth factor (IGF)-2 precursor or IGF-1, by mesenchymal or epithelial tumor cells. Several studies have also reported that NICTH is related to excessive secretion of insulin from some tumors originating from a single tissue. Here, we report the first case of intractable hypoglycemia due to co-secretion of insulin from gastric cardia adenocarcinoma (GCA) and lung adenocarcinoma (LA), as confirmed by immunohistochemical staining for insulin. We obtained approval from our institution's ethics committee to report this case and the patient's family consented to the publication.

CASE REPORT
A cardia mass was found in a 67-year-old male patient in May 2012, and surgical resection was performed. Postoperative pathological examination showed moderately to poorly differentiated ulcerative gastroesophageal junction (GEJ) adenocarcinoma. In March 2015, the patient complained of frequent dizziness in the mornings, which improved after eating. On the morning of May 4, 2015, he presented limb convulsion unconsciously and could not be awakened. The patient's blood glucose level was 0.9 mmol/L. Five minutes after 50% glucose treatment, he recovered consciousness. Positron emission tomography-computed tomography (PET-CT) showed pulmonary, adrenal, intracranial, intrahepatic, retroperitoneal and thoracic vertebral lesions.
On May 11, the patient underwent CT-guided biopsy of a lesion in the left lung (Figure 1).
Pathological examination showed lung adenocarcinoma (LA), and he received stereotactic radiotherapy in the whole brain, lungs and abdominal cavity. He and his family refused chemotherapy and further surgery. During the treatment, hypoglycemia occurred many times.
At first, extra meals could maintain normal blood glucose. Later, continuous intravenous infusion of glucose injection was required, while the glucose concentration and infusion rate progressively increased. To prevent hypoglycemia, the maximum infusion rate for 50% glucose injection was 100 ml per hour. Dynamic enhanced MRI did not show any clear lesion in the pancreas. Adrenocorticotropic hormone, cortisol, growth hormone, glucagon and five thyroid function parameters were within normal ranges. An insulin autoantibody test was negative.
IGF-1 was 222 (96-212 ng/ml) and IGF-2 was significantly lower than normal according to western blotting. The patient was unresponsive to diazoxide (125 mg, three times a day for 10 days), and at that time, his blood diazoxide concentration was 13.4 µg/ml.
The treatment was subsequently changed to tacrolimus capsules (10 mg, once a day), but the patient died five days later. The patient's family refused to allow an autopsy.

DISCUSSION
In NICTH, there are mainly three mechanisms leading to hypoglycemia: tumor cells secrete excessive high-molecular-weight IGF-2 precursor, IGF-1, and insulin. 1 Previous studies have reported that insulin-secreting non-islet-cell tumors can originate in any germ layer, and that all of them have a single tissue origin. In the present study, the patient had two kinds of tumors that originated from the endoderm, i.e. GCA and LA, and both of them secreted insulin.

A B
index of 10%. TTF-1 and napsin-A-positive results showed that the pulmonary lesion was not metastatic GCA, but was a primary LA. Thus, our patient was diagnosed as having tumors from two kinds of tissue cells of endodermal origin.
Hence, our patient's high insulin levels came from tumors of two different tissue origins. This is the first reported case of NICTH caused by co-secretion of insulin from multiple primary carcinomas.  We reviewed the literature in MEDLINE and EMBASE using the English keywords "Hyperinsulinism", "Hypoglycemia", "Cardia neoplasms" and "Lung neoplasms" ( Table 1). No other similar case was found.

CONCLUSION
In summary, this is the first reported case of hypoglycemia associated with co-secretion of insulin by LA and GCA.
Regardless of the type of tumor tissues, NICTH should be taken into consideration for some nonspecific symptoms of hypoglycemia in tumor patients, such as dizziness, convulsions, hallucinations and coma. Early diagnosis and timely treatment are recommended for these patients, to improve their quality of life.