S P E C I A L C l i n i c a l

C a s e

F E A T U R E S e m i n a r

Hypoglycemia Observed on Continuous Glucose Monitoring Associated With IGF-2-Producing Solitary Fibrous Tumor Sonoko Otake, Takuma Kikkawa, Miho Takizawa, Junko Oya, Ko Hanai, Nobue Tanaka, Junnosuke Miura, Izumi Fukuda, Masato Kanzaki, Tatsuo Sawada, Naomi Hizuka, Takamasa Onuki, and Yasuko Uchigata Diabetes Center (S.O., M.T., J.O., K.H., N.T., J.M., Y.U.) and Departments of Surgery I (T.K., M.K., T.O.), Pathology I (T.S.), and Medicine II (I.F., N.H.), Tokyo Women’s Medical University School of Medicine, 162-8666 Tokyo, Japan

Context: Tumors producing IGF-2 (IGF-2oma) are a major cause of spontaneous hypoglycemia. The treatment mainstay is surgical resection. Many case reports note resolution of hypoglycemia after IGF-2oma resection; however, outcomes are variable according to tumor type. We report a case of resolving hypoglycemia, observed on continuous glucose monitoring, after resection of an IGF-2producing solitary fibrous tumor of pleura and review the current literature. Case Report: A 69-year-old woman presented with impaired consciousness because of hypoglycemia. An IGF-2oma was diagnosed as the cause for hypoglycemia because of decreased serum insulin and IGF-1, the presence of a pleural tumor, and a high-molecular-weight form of serum IGF-2 detected by Western immunoblot. Surgical resection was performed; pathological examination demonstrated a solitary fibrous tumor with low-grade malignancy. Continuous glucose monitoring showed reversal of hypoglycemia after tumor resection. Approximately 2 years after resection, the patient has no signs of tumor recurrence or hypoglycemia. Conclusions: An IGF-2-producing solitary fibrous tumor of pleura in this case caused hypoglycemia. From a search of the literature of 2004 –2014, 32 cases of IGF-2oma with hypoglycemia that underwent radical surgery were identified; in 19 (59%) patients, hypoglycemia was reversed, and there was no subsequent recurrence. The remaining 13 (41%) patients experienced tumor recurrence or metastasis an average of 43 months after initial tumor resection. The tumor of the present case was a low-grade malignancy. Regular follow-up with biomarker monitoring of glucose metabolism and assessment of hypoglycemic symptomatology, in conjunction with imaging tests, is important for detecting possible tumor recurrence and metastasis. (J Clin Endocrinol Metab 100: 2519 –2524, 2015)

umors that produce IGF-2 (IGF-2oma) are one of the major causes of spontaneous hypoglycemia (1). IGF-2 is a 7.5-kDa polypeptide that has structural similarities with proinsulin and acts qualitatively like insulin via the insulin receptor (2, 3). Normally, IGF-2 mainly binds to IGF binding protein-3 and the acid-labile subunit, forming a ternary complex of molecular mass 150 kDa (4). Abnormal IGF-2 produced by such tumors is thought to be

T

a hypoglycemic agent (5, 6), which has a high molecular mass of around 10 –20 kDa, designated as big IGF-2 (7, 8). Because this has low affinity for IGF binding proteins (9, 10), it circulates as a 60- to 80-kDa binary complex or in the free form (11, 12), eventually passing through capillaries to cause hypoglycemia. Therapeutic modalities for tumor management are surgical resection or transarterial embolization and chemo-

ISSN Print 0021-972X ISSN Online 1945-7197 Printed in USA Copyright © 2015 by the Endocrine Society Received December 27, 2014. Accepted April 17, 2015. First Published Online April 27, 2015

Abbreviations: CGM, continuous glucose monitoring; CGMS, CGM system; IGF-2oma, tumors that produce IGF-2; OGTT, oral glucose challenge test.

doi: 10.1210/jc.2014-4534

J Clin Endocrinol Metab, July 2015, 100(7):2519 –2524

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Table 1.

Hypoglycemia Associated With IGF-2oma

J Clin Endocrinol Metab, July 2015, 100(7):2519 –2524

Pre- and Postoperative Laboratory Values of the Current Case

Fasting blood glucose, mg/dL HbA1c, % Fasting insulin, ␮U/mL Postprandial insulin (60/120 min), ␮U/mL Fasting C-peptide, ng/mL Postprandial C-peptide (60/120 min), ng/mL Urinary C-peptide, ␮g/d GH, ng/mL IGF-1, ng/mL Free T3, pg/mL Free T4, ng/dL TSH, ␮U/mL Glucagon, pg/mL Cortisol, ␮g/dL ACTH, pg/mL Potassium, mEq/L

Reference Range

4 Years Pre-Op

On Admission Pre-Op

Day 14 Post-Op

70 –109 4.6 – 6.2 1.7–10.4

94 5.7

62 5.5 ⬍0.3 14.2/0.3 ⬍0.2 1.4/0.3 12.8 0.05 27 2.77 0.99 3.76 47 7.0 30.3 3.2

99

0.6 –1.8 20.1–155 0.13–9.88 59 –177 2.1– 4.1 1.0 –1.7 0.39 – 4.01 70 –174 4.0 –19.3 7.2– 63.3 3.5–5.0

10.3 115.1/24.2 1.9 8.8/5.5 64.9 0.22 66

1 Year Post-Op 90 5.8 12.4 120.5/101.4 (75-g OGTT) 2.2 —/12.4 (75-g OGTT)

4.6

Figure 1. CGM results. A, Presurgical. B, Postsurgical (after 14 d). G20, 20-g glucose ingestion (red arrows). Before surgery, a 1600-kcal normal meal was ingested as six equal portions at the six time points indicated (blue arrows). Fourteen days after surgery, the same meal was ingested as three equal portions at the three time points indicated (blue arrows). Blue squares indicate capillary glucose level for sensor signal calibration.

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doi: 10.1210/jc.2014-4534

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mass index, 22.9 kg/m2; and blood pressure, mildly elevated at 146/52 mm Hg. Admission laboratory results are shown in Table 1. Preprandial serum immunoreactive insulin and C-peptide levels were undetectable in this setting of hypoglycemia, which excluded insulinoma and exogenous insulin or insulin secretagogue administration. Serum GH and IGF-1 concentrations were low. Western immunoblot analysis revealed a high molecular weight form of IGF-2 (see Figure 2A, lane 3). Also noted was hypokalemia. The patient tested negative for anti-insulin antibody and anti-insulin receptor antibody. A chest-enhanced computed tomogFigure 2. A, Western blot to detect serum IGF-2. Lane 1, IGF-2; lane 2, IGF-2oma as a control; raphy scan showed the presence of a 12 lane 3, current case, presurgically; lane 4, current case, postsurgically; lane 5, healthy adult cm ⫻ 6 cm tumor in the right pleural control. B, Macroscopic view of resected tumor. This is a 20 cm ⫻ 15 cm, 450 g, yellowish-white cavity with a weak contrast effect. solid lobulated mass, with areas of partial bleeding and necrosis. C and D, Microscopic findings (hematoxylin and eosin stain; magnification,⫻200). C, The tumor was composed of moderately We observed serum glucose fluctuacellular areas of spindle-shaped tumor cells with hyperchromatic and acidophilic cytoplasm. D, tions using a CGM system (CGMS) Immunostaining for IGF-2. The tumor cells are positive for IGF-2. from the first day of admission. CGM revealed recurrent hypoglycemia; glutherapy, with prompt and complete tumor resection being cose was administered orally, and the hypoglycemia imthe ideal (13). There are many case reports of IGF-2oma with tumor proved. On the second hospital day, a 1600-kcal normal resection; however, outcomes are variable according to meal was divided into six equal portions, and the patient tumor type. Here we present a case of resolving hypogly- ingested one portion at the six time points indicated on cemia, observed on continuous glucose monitoring Figure 1A; after each ingestion, hyperglycemia of around (CGM), after resection of an IGF-2-producing solitary fi- 220 mg/dL was observed. Because of suppressed blood immunoreactive insulin brous tumor of pleura and the results of a literature search and C-peptide levels during the hypoglycemic episode, the for outcomes in similar cases. presence of a high molecular weight form of IGF-2 in serum, and the pleural tumor, we diagnosed an IGF-2oma. For prevention of hypoglycemia during the night, a gluCase Report cose infusion (20 g/h) was administered. Surgical resection A 69-year-old female was admitted to our hospital for of the right pleural cavity tumor and areas of disseminainvestigation of recurrent episodes of impaired conscious- tion into the middle and lower lobes and parietal pleura ness because of hypoglycemia. Two years before admis- was performed. sion, she began to feel fatigue before meals; 1 month before The macroscopic view of the surgical specimen is admission, impaired consciousness and urinary inconti- shown in Figure 2B. Microscopic examination revealed nence occurred in the early morning; 18 days before ad- admixed hypercellular and hypocellular foci of spindlemission, impaired consciousness lasted from morning un- shaped cells with acidophilic cytoplasm, moderate nutil the afternoon, and she was rushed to a nearby hospital clear atypia, and abnormal mitosis (Figure 2C). On imwhere hypoglycemia was suspected. She had received an munostaining, CD34 positivity and negativity for annual medical examination from ages 50 to 65 years, and S-100, ␣-smooth muscle actin, and c-kit confirmed the a blood glucose abnormality had never been noted. She diagnosis of a solitary fibrous tumor with low-grade had been diagnosed with Graves’ disease at 35 years of age malignancy. Immunohistochemical analysis revealed and has taken thiamazole 5 mg/d since then. positive immunostaining for IGF-2 in the tumor cells The following data were recorded on admission: body (Figure 2D).

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Hypoglycemia had disappeared on CGM performed 14 days after the resection. After surgery, mild postprandial hyperglycemia of around 175 mg/dL was observed (Figure 1B). Endogenous insulin secretion had recovered (Table 1). GH and IGF-1 concentrations were improved to within the normal range. Postoperatively, the high molecular weight IGF-2 band had disappeared on serum immunoblot analysis (Figure 2A, lane 4). At the time of this writing, approximately 2 years after resection, the patient has no signs of tumor recurrence or hypoglycemia.

Discussion An IGF-2-producing solitary fibrous tumor of pleura was resected, and tumor-induced hypoglycemia resolved in this case. Furthermore, we observed the resolving hypoglycemia by CGMS after tumor resection. There has been Table 2.

J Clin Endocrinol Metab, July 2015, 100(7):2519 –2524

no recurrence of the tumor in approximately 2 years of follow-up. A search of the literature from 2004 to 2014 revealed 57 IGF-2oma case reports. Radical surgery was performed in 32 cases of IGF-2oma with hypoglycemia (14 – 44), 19 (59%) of which had no recurrence and had reversal of hypoglycemia, and 13 (41%) of which experienced tumor recurrence or metastasis an average of 43 months (n ⫽ 10) after initial surgical resection. Details of the outcome and tumor pathology are shown in Table 2. Tumor types were mainly benign, but there were a few malignant tumors among the 19 cases. However, because details of longterm follow-up of cases with malignant tumors, such as malignant solitary fibrous tumor and mesenteric sarcoma, were not rigorously described, their long-term outcomes remain unknown. On the other hand, hypoglycemia occurred with progression of tumor in 12 of the 13 cases that experienced tumor recurrence and metastasis after tumor

Cases of IGF-2oma With Hypoglycemia Treated Surgically and Reported in the Literature of 2004 –2014 Follow-Up Time, mo

Management

Hypoglycemic Outcome

10 2 4 1

3–25 (median 24) (n ⫽ 7) 108 (n ⫽ 1) 8 (n ⫽ 1) 36

Surgical resection Surgical resection Surgical resection Surgical resection

Resolved Resolved Resolved Resolved

1 1

No data No data

Surgical resection Surgical resection

Resolved Resolved

Time to Recurrence or First Metastasis From Surgical Resection, mo

Management for Tumor Recurrence or Metastasis

9 –108 (median, 48) (n ⫽ 3)

5–36

Debulking surgery (n ⫽ 2) No detailed data No treatment Surgical resection of metastatic region Radiation Radiosurgery, dacarbazin, doxorubicin Chemotherapy, radiation Imatinib

n No recurrence or metastasis after first surgical resection Benign SFT Low-grade malignancy SFT Malignant SFT Benign phyllodes tumor of the breast Uterine leiomyoma Mesenteric sarcoma

Recurrence or metastasis after first surgical resection Malignant SFT

Malignant hemangiopericytoma

Malignant gastrointestinal stromal tumor

19 (59%)

13 (41%) 4

4

2

84 –120 (n ⫽ 2)

Phyllodes sarcoma of the breast

1

12

Imatinib, debulking surgery No detailed data

Gastric adenocarcinoma

2

2– 4

No treatment (death)

Resolved Persisted Persisted Resolved Resolved Persisted

Persisted Persisted Persisted No hypoglycemia despite metastasis Persisted

Abbreviation: SFT, solitary fibrous tumor.

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doi: 10.1210/jc.2014-4534

resection. In some of these cases, hypoglycemia was reversed by radiation or further surgical treatment, such as resection of the metastatic region or debulking of the tumor. Tumor reduction was effective for prevention of tumor-induced hypoglycemia. In five of 13 (38%) cases, recurrence and metastasis were identified by an episode of hypoglycemia. Hypoglycemia symptoms after surgical resection can be a signal of tumor recurrence. The tumor of the present case had low-grade malignancy. Therefore, follow-up regarding possible hypoglycemic events, in conjunction with imaging tests, is important for detecting possible tumor recurrence. We observed glucose fluctuation in this case with a CGMS before and after tumor resection. CGM showed persistent hypoglycemia during the night lasting into the early morning, requiring glucose supplementation; this resolved after tumor resection. However, postprandial hyperglycemia was observed both before and after the operation. There have been some previous reports of hyperglycemia by the oral glucose tolerance test (OGTT) and postprandial hyperglycemia coexisting with fasting hypoglycemia in preoperative IGF-2oma cases (20, 45). Elevated IGF-2 secretion suppresses the normal insulin response, which may lead to postprandial hyperglycemia. The mild postprandial hyperglycemia after tumor resection could have been caused by the presence of glucose intolerance both before and after surgery; this case had normal blood glucose levels 4 years before admission, but there were no blood glucose data from the more recent period before admission. Furthermore, when CGM and OGTT were performed 1 year after tumor resection, both postprandial hyperglycemia of over 200 mg/dL by CGM (data not shown) and insulin hypersecretion were observed, and these are characteristic of the early stages of type 2 diabetes. In conclusion, an IGF-2-producing solitary fibrous tumor of pleura was resected, and tumor-induced hypoglycemia resolved. Such patients need careful follow-up with regard to glucose levels and possible hypoglycemic episodes, in addition to imaging tests, for detecting possible tumor recurrence and metastasis.

Acknowledgments Address all correspondence and requests for reprints to: Yasuko Uchigata, MD, Diabetes Center, Tokyo Women’s Medical University School of Medicine, 8-1, Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. E-mail: [email protected]. Disclosure Summary: The authors have no competing financial interests to disclose.

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Hypoglycemia Observed on Continuous Glucose Monitoring Associated With IGF-2-Producing Solitary Fibrous Tumor.

Tumors producing IGF-2 (IGF-2oma) are a major cause of spontaneous hypoglycemia. The treatment mainstay is surgical resection. Many case reports note ...
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