Authors
Anand Sachithanandan1, Nicholas Chua2, Aruna Samy3, Siti Harnida1, Lim Boon Khaw1, Usha Rani George1, Balaji Badmanaban4, Pathmanathan Rajadurai4 (order to be decided!)
Institution
1Sunway Medical Centre, Bandar Sunway, Selangor.
2Jeffery Cheah School of Medicine & Health Sciences, Monash University (Sunway campus)
3Subang Jaya Medical Centre, Subang Jaya, Selangor.
4Manipal Hospital Klang, Selangor.
Abstract
Solitary fibrous tumours of the pleura (SFTP) are relatively rare neoplasms, which account for 5% of all pleural tumours. Rarely, a SFTP may be associated with hypoglycaemia; the paraneoplastic Doege-Potter syndrome (DPS). This association carries a higher risk of malignancy. We report successful en bloc resection of a giant SFTP in an elderly Asian male with complete resolution of his life-threatening hypoglycemia. The pathology and clinical management of this rare tumour and even rarer syndrome is reviewed.
Introduction
Solitary fibrous tumours of the pleura (SFTP) are thought to arise from the sub-mesothelial mesenchymal tissue of the visceral pleura although tumours of an intrapulmonary or parietal pleural origin have been described. These rare tumours with an incidence of 2.8 per 10,000 account for only 5% of all pleural tumours (1). The majority are clinically benign however 12-23% may be malignant with a worse outcome (1). Tumours > 15 cm or occupying more than 40% of the hemi thorax are classed as giant SFTP. Rarely, a SFTP may be associated with hypoglycaemia ; the paraneoplastic Doege-Potter Syndrome (DPS) which carries a higher risk of malignancy. There are only 45 reported cases worldwide of the DPS from 1979-2011 (2).
Case presentation
A 70-year-old frail non-diabetic Indonesian male with Parkinson’s disease presented with a five-month history of recurrent chest infections, increasing dyspnea and multiple episodes of symptomatic severe hypoglycemia (glucose 2 - 3 mmol/L). This was associated with several episodes of near hypoglycaemic coma. He had no history of chest trauma or occupational exposure to asbestos. Chest radiograph and subsequent computed tomography (CT) imaging revealed a large 18 x 15 x 11 cm mass occupying more than > 2/3rd of the right hemi thorax with compressive atelectasis of almost the entire right lung (Figure 1). Ultrasound guided percutaneous biopsy confirmed a tumour composed of spindle shaped cells with mixed cellularity. The cells exhibited hyperchromatic nuclei but no mitoses. Immunohistochemistry (IHC) revealed positive stains for CD34, bcl-2 and Stat-6, but negative for pancytokeratin, myoD1, desmin and S100; consistent with the diagnosis of a SFTP (Figure 2).
The patient was admitted for elective surgery and his deranged sugars carefully managed by an endocrinologist with a dextrose/insulin infusion and intravenous hydrocortisone. Pre-operative serum C-peptide was significantly low 44 (normal range 294-1324) and his serum insulin was <0.5. He underwent a successful en bloc resection of this giant SFTP via a large posterolateral right thoracotomy (Figure 3). The tumour was found to occupy the entire right chest cavity and was densely adherent to the lower lobe but not infiltrating. The mass was carefully separated from the diaphragm, pericardium and lung with a combination of blunt and sharp dissection and a small wedge resection of the lower lobe was required to facilitate complete excision. His post-operative recovery was slow but uneventful aside for a small parenchymal air leak which soon resolved and he was discharged home well, a fortnight later. On early review six weeks later, his cough and dyspnea had fully resolved and he reported no further hypoglycaemic episodes. Histology confirmed a completely excised well encapsulated X kg benign SFTP with mild necrosis and a low mitotic count (2-3/hpf).
Discussion
The majority of SFTPs have an intrathoracic origin but one third may arise from an extra thoracic site such as abdominal or pelvic organs, peritoneum, retroperitoneum, spinal cord, or the head and neck region. 13-23% of those arising from the pleura are considered malignant, whereas extra pleural tumors are mostly benign, except those arising in the mediastinum (1).
Histologically, they represent fibroblast-like cells with varying unifying patterns (sheets, fascicles, herringbone, storiform or patternless), separated by collagen bundles and with alternating hypercellular and hypocellular areas. IHC will reveal positive stains for both CD34 (which excludes other lung cancers) and Bcl-2 (an anti-apoptotic proto oncogene), which is highly characteristic of a SFTP. Malignant tumours will have features of England’s criteria; hypercellularity, nuclear atypia, high number of mitoses and presence of necrosis (3).
Very rarely there is an associated paraneoplastic syndrome, causing recurrent hypoglycemia in 1.5-4% of cases, known as Doege-Potter syndrome (DPS) (1,4). The syndrome typically occurs in the 6th to 7th decade of life and is associated with a higher malignancy rate. Features suggestive of recurrence and risk of metastasis includes hypercellularity, pleomorphism, atypia, mitotic figures >4/10 high-powered field, bleeding and necrosis. DPS is characterized by normal to increased insulin-like growth factor (IGF)-II levels secreted by the fibrous tumour cells, and suppressed levels of C-peptide, insulin, growth hormone and IGF-I (1). IGF-II has a similar structure to insulin and is responsible for the recurrent episodes of hypoglycemia, promotes mitogenesis and tumor growth.
Patients usually present with symptoms of hypoglycemia (palpitations, diaphoresis, tremor, dizziness, fainting) in addition to the tumour mass effect (dyspnea, chest pain and infection) depending on the size and location. Our patient had features attributable to both. For cost reasons, we did not check his baseline IGF-II levels however his C-peptide level was very low. Imaging (CT, MRI and PET) can help to guide the diagnosis and assess resectability. IGF-II however may cause an increased FDG uptake in muscle, heart and liver with less tumour uptake thus giving a false positive or false negative result. Hence the role of PET imaging remains undefined. We felt a PET scan would not alter our management as given the size, location and histology, surgical excision was the only feasible treatment to prevent impending death from both his compressive and severe hypoglycaemic symptoms. Poor prognosticators include huge tumour size (> 12-15cm) and an elderly age (> 55 years).
Definitive treatment constitutes complete tumour excision. In a contemporary review of 84 fully resected cases from the Mayo Clinic, the overall 5-year survival rate; 89% (benign) versus 45.5% (malignant) and median survival 55 months (malignant) versus 284 months (benign) was significantly worse with malignant tumours. (4). Similarly the reported 5-year freedom from recurrence was 100% and 58% for benign and malignant tumours respectively (4). Overall, 75% of malignant and 25% of benign SFTP recurred with a median time to recurrence of 34 and 83 months respectively (4). Recurrence may be due to incomplete or conservative surgery.
Data to support neoadjuvant pre-operative therapy (chemoradiation and selective embolization) remains scarce and there is no standard regimen for chemotherapeutic agents. Embolization may increase post-operative morbidity and mortality rate without significant tumor atrophy or resolution of hypoglycemia. Adjuvant radiotherapy however should be given for incompletely resected tumours even those of benign histology.
Conclusion
This is a rare case of DPS; a benign SFTP associated with severe symptomatic hypoglycaemia most likely due to tumour IGF-II over-expression. Based on the tumour size, his age and co-morbidities our patient was a high-risk surgical candidate. Despite the benign histology he had a malignant clinical course treatable only with complete tumour excision. Our case reaffirms that surgery not only alleviates the compressive ‘mass effect’ symptoms but results in complete resolution of IGF-II tumour mediated hypoglycaemia. IHC should be routinely performed to accurately classify these tumours as overall prognosis is largely histology dependant in addition to completeness of resection. Long-term surveillance is advisable to monitor for recurrence even with benign tumours.
1179 words
References
1. Briselli M, Mark EJ, Dickersin GR. Solitary fibrous tumours of the pleura: eight new cases and review of 360 cases in the literature. Cancer 1981; 47(11): 2678-89.
2. Meng W, Zhu HH, Li H, Wang G, Wei D, Feng X. Solitary fibrous tumours of the pleura with Doege-potter syndrome: a case report and three-decade review of the literature. BMC Res Notes 2014;7:515.
3. England DM, Hochholzer L, McCarthy MJ. Localized benign and malignant fibrous tumours of the pleura. Am J Surg Pathol 1989;13: 640-658.
4. Harrison-Phipps KM, Nichols FC, Schleck CD, Deschamps C, Cassivi SD, Schipper PH, Allen MS, Wigle DA, Pairolero PC. Solitary fibrous tumour of the pleura: Results of surgical treatment and long-term prognosis. J Thorac Cardiovasc Surg 2009; 138(1): 19-25. Doi: 10.1016/j.jtcvs.2009.01.026