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Doege-Potter syndrome presenting with hypoinsulinemic hypoglycemia in a patient with a malignant extrapleural solitary fibrous tumor: a case report
© Schutt et al.; licensee BioMed Central Ltd. 2013
Received: 1 July 2012
Accepted: 20 November 2012
Published: 9 January 2013
Doege-Potter syndrome is a paraneoplastic syndrome characterized by non-islet cell tumor hypoglycemia secondary to a solitary fibrous tumor. This tumor causes hypoglycemia by the secretion of a prohormone form of insulin-like growth factor II. We describe the diagnosis and management of Doege-Potter syndrome and the use of transarterial chemoembolization in a patient with a malignant extrapleural solitary fibrous tumor.
Our patient was a 64-year-old Caucasian woman who initially presented with urinary incontinence and was found to have a 14.5×9.0×9.0cm retroperitoneal solitary fibrous tumor compressing her bladder. Her tumor was surgically resected but recurred with multiple hepatic metastatic lesions. The hepatic metastases progressed despite systemic chemotherapy and treatment with doxorubicin transarterial chemoembolization. Her course was complicated by the development of recurrent fasting hypoglycemia, most likely secondary to Doege-Potter syndrome. Her hypoglycemia was managed with corticosteroid therapy and frequent scheduled nutrient intake overnight.
The rarity of hepatic solitary fibrous tumors and consequent lack of controlled trials make this report significant in that it describes the diagnostic approach to Doege-Potter syndrome, describes our experience with the use of doxorubicin transarterial chemoembolization, and presents management options for tumor-associated hypoglycemia in the case of extensive disease not amenable to surgical resection.
Doege-Potter syndrome [1, 2] is a paraneoplastic syndrome characterized by non-islet cell tumor hypoglycemia (NICTH) secondary to a solitary fibrous tumor (SFT) that secretes a prohormone form of insulin-like growth factor II (IGF-II). Doege-Potter syndrome is an uncommon complication of an uncommon tumor. However, it is potentially life-threatening, and thus requires a careful and attentive approach to diagnosis and management. The following describes the diagnosis and management of Doege-Potter syndrome in a patient with an extrapleural solitary fibrous tumor (ESFT) complicated by hepatic metastases.
Our patient was followed-up with serial imaging, first at three months after resection, then at 15 months post-resection. On the latter scan, four new hepatic masses were identified: an 8.3×10.4cm mass within hepatic segment two, a 4.4×4.8cm mass within hepatic segment four, a 6.8×5.5cm lesion within hepatic segment eight, and a 2.2×2.2cm lesion within hepatic segment six. Fine needle aspiration of the largest lesion demonstrated a similar immunohistochemical profile to the primary retroperitoneal ESFT, and the newly identified masses were considered metastatic malignant ESFT. At this time, she was started on the multi-targeted receptor tyrosine kinase inhibitor sunitinib for treatment of the hepatic metastases. However, this was discontinued three months later due to the development of erythema multiforme, hyponatremia and thrombocytopenia. Given this sunitinib intolerance, she was treated with temozolomide and intravenous bevacizumab for four months. This regimen was tolerated well, but subsequent imaging demonstrated progression of the disease. The liver lesions were then treated with transarterial chemoembolization (TACE) using doxorubicin beads on two separate occasions - at 22 months and 24 months after initial diagnosis and resection. Despite chemoembolization, the liver lesions continued to progress in size, and a new lesion developed.
Approximately 22 months after her initial diagnosis (prior to the first TACE procedure) our patient developed symptomatic hypoglycemia. Her initial episode was heralded by a period of disorientation lasting approximately one hour. Her blood glucose was documented to be 41mg/dL at this time. These symptoms progressed to frequent overnight hypoglycemia requiring frequent snacking to maintain a normal blood glucose level. During the second chemoembolization procedure, she had persistent hypoglycemia (less than 40mg/dL), likely related to pre-procedural fasting. Reversal of hypoglycemia during the procedure required administration of six 25g ampules of 50% dextrose. Our patient was subsequently admitted to the hospital for evaluation of her hypoglycemia. During hospitalization, her blood glucose level decreased precipitously multiple times. Our patient’s hypoglycemia occurred primarily with fasting and was ameliorated with continuous dextrose 10% infusion and frequent snacks (for example, liquid nutritional supplements).
Laboratory evaluation for hypoglycemia
74 to 99mg/dL
3 to 20pmol/L
C-peptide of insulin
0.50 to 2.00ng/mL
Insulin-like growth factor I
55 to 225ng/mL
Insulin-like growth factor II
288 to 736ng/mL
9 to 52pg/mL
14.4μg/dL at 6:59 a.m.
at 8:00 a.m.: 4 to 19μg/dL
Glucagon stimulation test
Before glucagon: 26mg/dL
10 minutes: 33mg/dL
20 minutes: 44mg/dL
30 minutes: 54mg/dL
Total Δ: 28mg/dL
Management strategies for Doege-Potter syndrome
Surgically remove underlying tumor
Most solitary fibrous tumors are benign and adequate resection resolves hypoglycemia
Invasive; may not be a viable option (for example, malignant tumors with metastasis)
Systemic or localized chemotherapy
May be used to treat non-resectable tumors
Chemotherapy regimens are not well studied; significant side effects associated with chemotherapy; tumors are typically poorly responsive to systemic chemotherapy
Relies on patient adherence to schedule
Nocturnal or continuous dextrose infusion
Reliably prevents hypoglycemia
Requires long-term venous access with attendant risks (for example, infection)
Nocturnal or continuous enteral tube feeding
Reliably prevents hypoglycemia
Long-term use requires invasive placement of gastrostomy tube
Non-invasive; may normalize insulin-like growth factor levels; increases appetite
Multiple adverse effects of long-term corticosteroid use
Continuous glucagon infusion 
Effective to prevent hypoglycemia in some patients; subcutaneous administration has less infectious risk than direct venous access
May be practically difficult
Unfortunately, our patient had rapid clinical deterioration shortly thereafter. Her appetite decreased significantly, she developed marked ascites, and she was admitted to another hospital with failure to thrive, atrial fibrillation and hypotension. She was discharged home with hospice care and passed away two days later. Due to her rapid clinical course, she was not able to start the raw cornstarch diet, and she continued to have episodic overnight hypoglycemia until her death.
Summary of prior cases of Doege-Potter syndrome
The patient presented with facial flushing and symptoms of irrationality described as ‘maniacal seizures’ noted to improve with treatment by rectal glucose, morphine and scopolamine. Symptoms continue to recur and urine analysis demonstrated traces of acetone. The patient was found to have 26×16cm tumor filling nearly the entire left thoracic cavity, and was treated with surgical excision and noted to be without recurrence at a three-year follow-up.
The patient was found to be delirious at times and was found to have a large tumor filling the entire left side of the thoracic cavity. The patient subsequently underwent two-stage surgical resection five days apart and made an uneventful recovery.
The patient had a history of convulsive seizures and was found to have a left subphrenic mass. Removal resolved the seizures. Seven years later the patient presented with hypoglycemia. This was managed on a high carbohydrate diet and the patient died. A spindle cell sarcoma of the left chest was found postmortem.
A patient with recurrent hypoglycemia was found to have a sarcoma of the right upper abdomen.
Skillern et al.
The patient had two large tumors composed of round and spindled cells and was found to have recurrent hypoglycemia.
Frantz and Porter 
The patient presented with recurrent hypoglycemia and was found to have a large pelvic mass encasing the ovary, thought to be a spindle cell neoplasm.
A patient with a spindle cell tumor causing hypoglycemia.
Scholz et al. 
Two cases of patients who presented with recurrent hypoglycemia. In one patient, surgical resection of the tumor (described as a renal fibrosarcoma) resolved the hypoglycemia.
August and Hiatt 
Patient with frequent episodes of hypoglycemia that ceased with surgical resection of a large intrathoracic fibrosarcoma.
Grilliat et al.
Tumor described as a pleural mesothelioma associated with hypoglycemia.
Ellorhaoui and Graf 
Patient with an intrathoracic tumor found to have hypoglycemia and diagnosed with Doege-Potter syndrome.
Vollmar and Wockel 
Tumor of the mesenchyme in the renal pelvis with malignant spread to lymph nodes and pathologically classified as malignant histiocytoma.
Payne and Davison 
Intrathoracic spindle cell tumor.
Kecskés et al. 
Thoracic mesenchymal tumor treated with surgical resection.
Dao et al. 
Pleural tumor in a patient with hypoglycemia.
Heinrich et al. 
Tumor described as an intrathoracic fibroma.
Lessel and Erbstosser 
Malignant fibrous histocytoma of the right lung that infiltrated the spinal column causing paralysis, no metastatic disease identified.
Roy et al.
Recurrent SFT of the pleura.
Abonyi et al.
Left-sided pleural mesothelioma and electron microscopy demonstrated neurosecretory granules thought to be insulin-like growth factor II-like material.
Gullo et al.
Abdominal hemangiopericytoma treated with resection, developed recurrence that was treated with chemotherapy and radiotherapy, with subcutaneous biosynthetic growth hormone and prednisone to mitigate symptoms.
Chamberlain and Taggart 
Tumor described as a sub-pleural fibroma measuring 23×21×12cm, treated with surgical resection and noted to have complete recovery.
Herrmann et al. 
Malignant fibrous histiocytoma of the lung with tumor size described as 13×8cm.
Zafar et al. 
Pleural SFT measuring 19×15×14cm.
Kafih et al.
Pleural fibrous tumor involving entire left hemithorax.
Balduyck et al. 
Pleural SFT measuring 22×19×7cm.
Lucas and Ledgerwood 
Malignant SFT of small bowel mesentery, measuring 10×12×20cm.
Pleural SFT measuring 10.9×9.8×9.4cm treated with surgical resection, found to have corresponding resolution of hypoglycemia associated with decrease in serum insulin-like growth factor II level postoperatively.
Milenković et al. 
Benign SFT involving almost the entire hemithorax.
Kalebi et al. 
Pleural SFT measuring 20×15×10cm, treated with surgical resection.
Lee et al. 
Thoracic SFT described pathologically as a low malignant potential tumor.
Fung and Crook 
Patient with tumor associated with spontaneous hypoglycemia.
Campos et al.
Pleural SFT measuring 27×25×11.5cm.
Rosseel et al. 
Patient with hypoglycemia and found to have a right thoracic mass.
Herrak et al. 
Doege-Potter syndrome diagnosed in patient with a pleural tumor.
IGF-II assay results are frequently in the normal reference range in NICTH, and assays for big IGF-II are not commercially available. However, the IGF-II:IGF-I molar ratio is considered to be a surrogate marker of big IGF-II concentration . In NICTH, IGF-II provides central negative feedback of growth hormone, with a subsequent reduction of IGF-I production. This contributes to an increase in the IGF-II:IGF-I ratio; a ratio of 3:1 is considered normal, with a ratio greater than 10 reported to be virtually pathognomonic for NICTH . Parenthetically, decreased growth hormone secretion also leads to lower concentrations of IGF-binding proteins, which may increase the bioavailability of IGF-II .
Our case highlights the importance of considering Doege-Potter syndrome in a patient with SFT and hypoglycemia. This is especially important when the tumor is large (larger than 8cm to 10cm), as this is thought to be a risk factor for the development of this paraneoplastic syndrome [14, 36]. In our case, the presence of massive liver metastases with extensive liver replacement complicated the precise determination of the etiology. The possibility of markedly reduced hepatic glucose output (for example, reduced glycogen stores) was considered; for reasons described previously, this was not felt to be the primary cause of our patient’s hypoglycemia, although it likely contributed. Liver replacement may also have been responsible for an IGF-II:IGF-I ratio less than 10, as shown in a case series of patients with NICTH secondary to a combination of liver destruction and excessive secretion of big-IGF-II, in which the patients had a lower than expected IGF-II:IGF-I ratio .
Treatment options for Doege-Potter syndrome can be divided into therapies that directly reduce tumor burden (for example, surgery, chemotherapy) and therapies that mitigate hypoglycemia without treating the underlying tumor. Our patient’s hepatic metastases exhibited no clear response to employed treatments. TACE has been used for treatment of ESFTs that are not surgically resectable, but there are few data regarding TACE for hepatic ESFT . This in part reflects its rarity; a recent review summarizing treatment approaches to hepatic ESFT found only 30 cases of hepatic ESFT . TACE did not appear to be effective in our patient, as follow-up imaging one month after the second TACE procedure demonstrated significant progression of disease. This is in contrast to a prior case report that demonstrated imaging evidence of response and a stable tumor size in a patient with a SFT treated with doxorubicin chemoembolization .
For our patient, we focused significant attention on her hypoglycemia, which was an immediately life-threatening problem. In this case, any period of fasting for more than four hours was associated with marked hypoglycemia. During the day, our patient prevented severe hypoglycemia via frequent food intake, but prevention of overnight hypoglycemia was more problematic. While under close observation in our hospital, it was clear that continuous administration of either enteral or parental nutrition was effective at preventing overnight hypoglycemia. Possible long-term treatment options are outlined in Table 2. Management options can be significantly different with regard to efficacy, reliability, invasiveness and risk of side effects; with the exception of surgical resection, there are few data to strongly support one modality over another. After thorough discussion of her options, our patient chose frequent overnight food intake in addition to corticosteroid therapy (oral prednisone, 10mg daily). Although this improved our patient’s hypoglycemia, she continued to have periodic hypoglycemia until her death.
Doege-Potter syndrome is an uncommon paraneoplastic phenomenon associated with SFT characterized by hypoinsulinemic hypoglycemia. In our case, our patient had a malignant ESFT that was not amenable to surgical resection and did not respond to doxorubicin TACE. The diagnosis of Doege-Potter syndrome in our patient was based on the large size of the SFT, low insulin level measured while hypoglycemic, and elevated IGF-II:IGF-I ratio. Her hypoglycemia was managed with daily corticosteroid therapy and frequent nutrient intake, with frequent alarm reminders overnight.
Written informed consent was obtained from the patient prior to her death for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
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