Non-islet cell tumor hypoglycemia that required immediate surgery after a long-term asymptomatic state: recommendation for early intervention

Background

Non-islet cell tumor hypoglycemia (NICTH) is a rare disease characterized by hypoglycemia. NICTH is caused by non-islet cell tumors, including those that produce big insulin-like growth factor 2 (IGF-2). Big IGF-2 dimers have very high capillary permeability and strong hypoglycemic effects, as they easily penetrate into tissues from the circulation (1). Tumor resection is the only curative therapy and the first choice of treatment for resectable cases.

This report presents a patient with NICTH caused by a solitary fibrous tumor (SFT) of pleural origin that appeared asymptomatic for approximately 60 years but then progressed rapidly and provoked a fracture triggered by a hypoglycemic attack. Few reports regarding long-term asymptomatic NICTH have been documented. This report highlights the significance of early intervention when NICTH is suspected, regardless of the presence of an asymptomatic state.

Case presentation

A mass in the lung was noted in a 20-year-old woman, though no treatment or follow-up was conducted. No symptoms were reported for 60 years. At 82 years of age, the patient experienced decreased vitality for several days and presented to our hospital. She was 151.3 cm tall and weighed 35.6 kg. The patient reported losing 10 kg over the past 2 years. Decreased respiratory sounds were noted in the left dorsal area, with no other abnormal physical signs. The patient had no relevant family history.

Investigation

Laboratory findings revealed low fasting blood glucose, insulin, and C-peptide levels (Table 1). Computed tomography (CT) revealed a well-circumscribed and relatively enhanced mass at the apex of the left lung (Fig. 1). There were no signs of adrenal insufficiency, liver failure, sepsis, or alcohol consumption. The lung mass was diagnosed as an SFT via ultrasound-guided biopsy.

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Computed tomography. A CT image reveals a well-circumscribed and relatively enhanced mass in the apex of the left lung.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2024, 3; 10.1530/EDM-23-0148

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Table 1

Laboratory findings.

Parameters	Values
Hematology
White blood cells, /μL	7600
Red blood cells, ×104/μL	327
Hemoglobin, g/dL	9.8
Platelet, ×104/μL	31.9
Chemistry
Albumin, g/dL	3.0
AST, IU/L	23
ALT, IU/L	10
Blood urea nitrogen, mg/dL	6.1
Creatinine, mg/dL	0.24
eGFR, mL/min / 1.73 m2	193
Sodium, mEq/L	142
Potassium, mEq/L	3.4
Calcium, mg/dL	8.4
CRP, mg/dL	0.44
Fasting blood glucose, mg/dL	35
HbA1c, %	4.8
Hormone
ACTH (early morning), pg/mL	24.0
Cortisol (early morning), μg/dL	18.3
TSH, μIU/mL	1.64
fT4, ng/dL	1.21
Insulin, μU/mL	< 0.5
C-peptide, ng/mL	0.08
IGF-1, ng/mL	17
IGF-2, ng/mL	686
Urinalysis
Glucose	–
Ketone	–
C-peptide (24 h), μg/day	6.9

ACTH, adrenocorticotropic hormone; ALT, alanine aminotransaminase; AST, aspartate aminotransaminase; CRP, C-reactive protein; eGFR, estimated glomerular filtration ratio; fT4, free thyroxine, HbA1c, glycated hemoglobin; IGF-1, insulin-like growth factor 1; IGF-2, insulin-like growth factor-2 (measured by radioimmunoassay, reference value: 333–-967 ng/mL); TSH, thyroid-stimulating hormone.

Treatment

The patient was discharged on hospital day 7 as her blood glucose level remained > 70 mg/dL with supplemental food. At the 1-month follow-up visit, she reported no hypoglycemic symptoms. However, approximately 6 weeks after hospital discharge, she experienced repeated hypoglycemic attacks. She had a fracture of her left humerus caused by a fall triggered by a hypoglycemic attack. The hypoglycemia did not resolve with supplemental food; instead, the patient required continuous intravenous administration of glucose. Although an SFT-provoking NICTH was suspected, the patient was transferred to a rehabilitation hospital after 2 weeks of hospitalization based on her desire to prioritize rehabilitation, with the plan to resect the tumor after rehabilitation. However, rehabilitation was interrupted approximately 3 weeks later due to frequent hypoglycemia that was not resolved via the intravenous administration of dextrose 10% in water. One week after her transfer back to the hospital, prednisolone (5 mg prior to sleep) was used to achieve a blood glucose level > 90 mg/dL.

Three months after the patient’s initial presentation, she underwent a thoracoscopic-assisted median sternotomy to resect the tumor. The resected tumor and histological findings were consistent with those of a benign SFT (Fig. 2). The patient’s hypoglycemia resolved postoperatively, and she was transferred to the rehabilitation hospital 2 weeks postoperatively.

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Histological findings of the resected tumor. (A, B) Hematoxylin and eosin staining reveals a dense proliferation of spindle-shaped cells (×4 and ×10 respectively). Immunohistochemical stains (×40) reveal bcl-2 (C), CD34 (D), STAT6 (E), and Ki67 (1%) (F) positivity.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2024, 3; 10.1530/EDM-23-0148

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Outcome and follow-up

The blood glucose levels remained stable without medication (Fig. 3). A 75 g oral glucose tolerance test (OGTT) showed insulin secretion in response to glucose loading, and a glucagon stimulation test showed that the patient’s C-peptide levels normalized and increased after glucagon loading (Table 2). Western immunoblot analysis revealed big IGF-2 in the patient’s preoperative blood that disappeared in the postoperative blood. Big IGF-2 was also observed in the tumor tissue, but not in the adjacent tissues (Fig. 4). Based on these findings, the patient was diagnosed with NICTH and confirmed to be in remission. The patient was discharged home after approximately 8 weeks of rehabilitation.

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Patient’s fasting blood glucose levels. Preoperatively, the hypoglycemia required supplemental food, intravenous glucose solution, and prednisolone. Postoperatively, the patient’s fasting glucose levels remained stable without medication.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2024, 3; 10.1530/EDM-23-0148

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Western immunoblot analysis. Western immunoblot analysis reveals big insulin-like growth factor 2 (IGF-2) in the patient’s preoperative blood that disappeared in the postoperative blood. Big IGF-2 is observed in the tumor tissue, but not in the adjacent tissues.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2024, 3; 10.1530/EDM-23-0148

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Table 2

Results of 75 g OGTT and glucagon stimulation test (GST).

	75-g OGTT (min)							GST (min)
	0	30	60	90	120	180	240	0	6
Pre-operation
Glucose (mg/dL)	32	79	114	121	108	80	80	89	103
Insulin (μU/mL)	< 0.4	< 0.4	5.0	5.8	5.4	< 0.4	< 0.4
C-peptide (ng/mL)								0.2	0.3
Post operation
Glucose (mg/dL)	98	155	226	205	132	98	98	104	126
Insulin (μU/mL)	4.1	6.6	95.1	124	40	17.1	14.9
C-peptide (ng/mL)								1.28	2.85

Discussion

The patient in this report appeared asymptomatic for 60 years. However, her hypoglycemia worsened rapidly at the age of 82, resulting in a fracture, suggesting the importance of early intervention in patients with NICTH.

Approximately 50% of patients with NICTH have known tumors at the onset of hypoglycemia. The mean time from the detection of tumors to the onset of hypoglycemia is 8.5 ± 1.9 months (2); however, delayed onsets of hypoglycemia 19 and 30 years after diagnosis have been reported (3, 4). The effect of tumor size on the onset and severity of hypoglycemia has not been completely proven, and the correlation between tumor size and big IGF-2 levels is unknown. It was difficult to clarify the etiology of the rapid progression of symptoms in this patient. However, her weight loss and low serum albumin level implied that latent hypoglycemia may have developed due to the gradual worsening of her nutritional status. Malnutrition (weight loss and low serum albumin levels) was observed in previously reported cases of late-onset NICTH (3, 4). Therefore, patients with NICTH must be carefully monitored, especially when they are at risk of malnutrition.

Tumor resection is the only curative treatment and the first choice of treatment for patients with NICTH; however, there is no clear consensus regarding the timing of surgery. In the present case, the patient remained asymptomatic for a long time, and her hypoglycemia was controlled with supplemental food for a period after its onset. However, her symptoms rapidly progressed, leading to a fracture. Considering the possibility of rapid symptom progression, as observed in this patient, individuals suspected of having NICTH should be examined and treated in a timely manner, regardless of severity, especially when they are at risk of malnutrition. In addition, unless it is inoperable due to metastasis or the patient’s general condition, prompt surgery is recommended. Although a complete cure may not be expected in some patients in whom extensive surgery cannot be conducted, debulking surgery may result in remission for limited cases (5).

As a prompt diagnosis is essential for surgery, NICTH should be considered early in patients with low insulin or C-peptide levels in the setting of hypoglycemia (6). If NICTH is suspected, a systematic search should be performed to detect tumors. The type of tumor should be determined; mesenchymal-derived tumors (especially SFTs) are common in patients with NICTH (1). Since most patients with NICTH have serum IGF-2 levels within the normal range, a definitive diagnosis requires Western immunoblot analysis, which is typically time-consuming. In urgent cases, an elevated blood IGF-2/IGF-1 ratio (especially > 20) may be a major supportive finding for diagnosing NICTH (7). The glucagon stimulation test is another effective method for differentiating hyperinsulinemia (8), and neuroendocrine tumor scintigraphy may also be used for diagnosis (5).

This case report has a limitation. The patient had been asymptomatic for approximately 60 years, although this was self-reported; the possibility of hypoglycemia during this period cannot be ruled out. However, supplemental food lost its effectiveness for the treatment of hypoglycemia in a short period, accounting for the patient’s rapid progression of hypoglycemia.

NICTH can cause rapidly progressive symptoms after a long-term asymptomatic state, and an asymptomatic state does not preclude the necessity for early intervention, especially when the patient is at risk for malnutrition. If NICTH is suspected, prompt examination and treatment are recommended regardless of symptom severity.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the study reported.

Funding

This study did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Patient consent

Written informed consent for the publication of their clinical details and clinical images was obtained from the patient.

Author contribution statement

TK was involved in patient care, evaluated the published data, and wrote the manuscript. KF was involved in editing the manuscript. TI was involved in patient care and edited the manuscript. YH was involved in editing the manuscript. DY was involved in preparing and reporting the pathology images. NM was involved in editing the manuscript.