Ann Thorac Surg 2007;84:292-294
© 2007 The Society of Thoracic Surgeons
Case Reports
Solitary Fibrous Tumor Associated With Non-Islet Cell Tumor Hypoglycemia
Kotaro Kameyama, MD*,
Norihito Okumura, MD,
Yujiro Kokado, MD,
Kentaroh Miyoshi, MD,
Tomoaki Matsuoka, MD,
Tatsuo Nakagawa, MD
Department of Thoracic Surgery, Kurashiki Central Hospital, Okayama, Japan
Accepted for publication February 12, 2007.
* Address correspondence to Dr Kameyama, Department of Thoracic Surgery, Kurashiki Central Hospital, 1-1-1 Miwa, Kurashiki, Okayama, 710-8602, Japan (Email: kk8724{at}kchnet.or.jp).
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Abstract
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A 79-year-old man presented with abnormal fluttering movements of his extremities early in the morning. Fasting hypoglycemia was believed to be the cause of the movements. A computed tomographic scan showed a large mass in the left inferior hemithorax. Non-islet cell tumor hypoglycemia was suspected, and the mass was resected while the patient was under glucose supplementation therapy. The plasma glucose level became stable shortly after tumor excision. The resected tumor was diagnosed as a solitary fibrous tumor producing insulin-like growth factor II. In the follow-up examination approximately 2 years after the surgery, no recurrence of the tumor was observed, and the plasma glucose level was stable.
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Introduction
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Solitary fibrous tumors (SFT) are rare, the incidence being only 2.8 cases per 100,000 and less than 5% of all pleural tumors [1]. Its mesenchymal cell origin in the submesothelial tissue has been suggested [2, 3]. On admission, 64% of SFT patients have symptoms such as cough, chest pain, and dyspnea. Most of these symptoms are caused by oppression by the tumors [2]. We experienced a rare case of SFT associated with non-islet cell tumor hypoglycemia.
A 79-year-old man displayed abnormal fluttering movements of his extremities early in the morning. Thereafter he repeatedly displayed the same symptoms several times and was referred to our hospital’s neurology department. He was found to have fasting hypoglycemia, which was believed to be the cause of the abnormal movements. A computed tomographic scan showed a mass in the left inferior hemithorax, and subsequently the patient was referred to our department.
Abnormalities were not observed in the routine blood biochemistry examination or tumor markers. The insulin and C-peptide levels and insulin antibody binding ratio were not high. Iatrogenic cause, insulinoma, and insulin autoimmune syndrome were excluded as causes of the hypoglycemia, and non-islet cell tumor hypoglycemia (NICTH) was suspected. Furthermore, because the insulin-like growth factor I (IGF-I) level was low, a high level of insulin-like growth factor II (IGF-II) was expected, and a tumor producing IGF-II was suspected.
On admission a chest roentgenogram showed a mass in the left inferior field (Fig 1A). At a later date, we found that this abnormal shadow was diagnosed as a benign tumor of the chest wall at another hospital and was being monitored by follow-up examinations. The chest roentgenograms showed that 14 years ago the diameter of the tumor was 4 cm, 7 years ago, the diameter was 5.5 cm. The computed tomographic scan upon admission showed a 13 x 10 cm diameter mass with heterogeneous density in the left inferior hemithorax. Coronal magnetic resonance imaging showed a multinodular mass. There was a relatively well-defined boundary between the mass and its surroundings. Such conditions as SFT and fibrosarcoma were suspected (Fig 1B).
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Fig 1. (A) Chest roentgenogram on admission showing a large mass in the left inferior lung field. (B) Coronal magnetic resonance imaging showing a well-defined multinodular mass.
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Complete resection of the tumor was performed by posterolateral thoracotomy. The tumor was adhered to the left lower lobe S8 and the diaphragm, and their combined resection was performed. The tumor weight was 850 g, and it was believed to have originated from the visceral pleura of the left lower lobe S8 (Fig 2A).
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Fig 2. (A) The cut section of the resected tumor, which was believed to have originated from the visceral pleura of the left lower lobe. (B) Immunohistochemical staining of insulin-like growth factor II (IGF-II). Many tumor cells were positive for IGF-II antibody (original magnification, x400). (C) Western immunoblot of serum IGF-II. Lane 1: recombinant IGF-II. Lane 2: our patient (preoperative). Lane 3: our patient (postoperative). Lane 4: another non-islet cell tumor hypoglycemia (NICTH) patient. Lane 5: normal subjects. Lane 6: another NICTH patient. Western immunoblot analysis shows that a large amount of high molecular weight IGF-II (20-kDa) was detected in the preoperative serum, whereas the amount of normal IGF-II (7.5-kDa) was increased in the postoperative serum.
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The postoperative pathologic findings of hematoxylin and eosin staining indicated proliferation of spindle-shaped tumor cells with little atypia and with accompanying collagen hyperplasia. Four mitotic figures were observed per 10 high-power fields. The resected tumor tissue was immunohistochemically positive for CD34; the tumor was diagnosed as SFT. In addition, immunohistochemical staining was positive for IGF-II (Fig 2B). Preoperatively, a large amount of high molecular weight IGF-II (approximately 20 kDa) was observed in the Western immunoblot of the serum IGF-II. Postoperatively, the amount of normal 7.5-kDa IGF-II was increased (Fig 2C). The tumor was diagnosed as SFT producing IGF-II.
At preoperative fasting, glucose supplementation of 10 g/hr was necessary to maintain the plasma glucose level, but the glucose level became stable shortly after tumor excision (Fig 3). Postoperative progress was good, and abnormal movements did not recur. The patient was discharged on postoperative day 10. No tumor recurrence was observed and the plasma glucose level was stable at a follow-up examination at an outpatient clinic 2 years after surgery.
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Fig 3. Clinical course of plasma glucose level before and after surgery. Glucose supplementation of 10 g/hr was necessary for maintenance of the plasma glucose level during the preoperative fasting period. Shortly after tumor excision, the plasma glucose level was stable with glucose supplementation of 3.4 g/hr. (BS = blood sugar.)
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Comment
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There are malignant cases of SFT [3]. England and colleagues [4] defined a case as malignant if high cellularity and mitotic activity (more than four mitotic figures per 10 high-power fields), pleomorphism, hemorrhage, and necrosis are observed. Using this definition, they found that 36.8% of the subjects they studied were malignant cases. In the case that we studied, we observed four mitotic figures per 10 high-power fields, suggesting the possibility of malignancy.
Hypoglycemia is said to be associated in 4% of SFT patients [2]. Hypoglycemia caused by a tumor not producing insulin is called non-islet cell tumor hypoglycemia (NICTH). In 1930, Doege reported a case of fibrosarcoma with hypoglycemia, and the condition is now called Doege-Potter syndrome [5]. Many diseases with NICTH have massive mesenchymal tumors. Epithelial tumors such as hepatocellular carcinoma and adrenal gland tumors are also seen, although they are rare. As a cause of NICTH, overexpression of IGF-II mRNA and IGF-II were verified in leiomyosarcoma [6]. In SFT associated with NICTH, the overexpression of IGF-II has also been verified, and IGF-II is believed to be involved in most cases of SFT associated with NICTH [7].
The IGF-II, a 7.5-kDa cytokine produced by various tissues, has many biological activities other than its insulin-like effects, such as growth promotion, cell proliferation, promotion of cell differentiation, and anti-apoptosis. The IGF-II in NICTH has high molecular weights of 15 to 20 kDa. This substance is believed to be pro-IGF-II before processing, also seen in healthy individuals, with a carbohydrate chain attachment [8]. The biological activities of IGF-II with high molecular weights are the same as normal IGF-II. However, high molecular weight IGF-II can not form its normal complex with an acid labile protein, a macromolecule 84-kDa in size. It easily passes through the capillary walls, and therefore its biological activities are speculated to be overexpressed [9]. The secretion of IGF-II, along with that of IGF-I, is promoted by growth hormone. However, when IGF-II is overproduced, serum IGF-I is lowered by negative feedback [9]. Because a decline in serum IGF-I was observed in our patient, we suspected a tumor producing IGF-II. Presently there are only a limited number of institutions that measure serum IGF-II. Therefore we believe that the level of IGF-I is a significant marker.
In our patient, the tumor had a diameter of 4 cm at the time of its initial discovery, which was asymptomatic and monitored by follow-up examinations. Its diameter increased to 5.5 cm in 7 years after its discovery and to 13 cm in 14 years after its discovery. Tumor doubling time per 7-year period had decreased from 5.51 years to 1.87 years. The diameter of most SFT with NICTH is said to be 10 cm or more [4]. It has been reported that overexpression of IGF-II mRNA is not observed for tumors with diameters less than 5 cm [10]. Furthermore, there are significantly more cases of malignant SFT for tumors with diameters of 10 cm or more [4]. The shortening of the tumor doubling time was suspected to be from the overproduction of tumor growth factors, including IGF-II, during the follow-up period. Recent evidence suggests that SFT derive from long-lived fibroblastic stem cells and that successive mutations may lead to the malignant form [10]. This overproduction of tumor growth factors could be involved in the malignant transformation of SFT. We believe that aggressive resection at an early stage should be performed in a case like that of our patient, whose pleural tumor originally had a diameter less than 5 cm and was suspected of being benign.
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Acknowledgments
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We would like to thank the physicians at the Tokyo Women’s Medical University, Department of Internal Medicine II, who cooperated in the study of IGF-II in our patient.
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References
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- England DM, Hochholzer L, McCarthy MJ. Localized benign and malignant fibrous tumors of the pleura: a clinicopathologic review of 223 cases Am J Surg Pathol 1989;13:640-658.[Medline]
- Doege KW. Fibro-sarcoma of the mediastinum Ann Surg 1930;92:955-960.[Medline]
- Daughaday WH, Emanuele MA, Brooks MH, Barbato AL, Kapadia M, Rotwein P. Synthesis and secretion of insulin-like growth factor II by a leiomyosarcoma with associated hypoglycemia N Engl J Med 1988;319:1434-1440.[Abstract]
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Abstract
Introduction
