Solitary Fibrous Tumors of the Pleura
Although most solitary tumors of the pleura (SFTP) are composed of benign-appearing cells, they can nonetheless undergo malignant transformation and cannot simply be classified as “benign” lesions.8 SFTP are most commonly discovered as incidental radiographic findings. They can grow very large and cause chest pain, cough, and dyspnea from mass effect. Although unusual, malignant transformation is evidenced by rapid growth or even distant metastasis. Occasionally, SFTP are secretory and the liberation of factors such as insulin-like growth factor 2 (IGF2) can create hypoglycemia.9 SFTP are also associated with pulmonary osteoarthropathy.
Chest CT scan is typically adequate for diagnosis of SFTP although occasionally MRI or PET scanning can provide useful diagnostic and anatomic information. SFTP has pathologic correlates in the kidney, cervix, meninges, thigh, pelvic fossa, retroperitoneal, and serosal surfaces. In earlier literature, this entity was referred to as “localized mesothelioma” or “fibrous mesothelioma.” However, it has now become clear that these tumors arise from pleural mesenchymal cells most closely resembling pericytes (a dendritic-like smooth muscle cell) rather than mesothelium. The majority of SFTP arise from the visceral pleural layer, presenting as pedunculated lesions (Fig. 21-3A).
Solitary fibrous tumor of the pleura: Gross image (A), H&E stained section (B).
The histologic features include bipolar spindle cells with varying areas of cellularity, often with small vessels and perivascular hyalinization (Fig. 21-3B). These tumors stain for CD34 (a vascular marker) and are distinguished from sarcomatoid mesotheliomas by absence of staining for cytokeratin and calretinin.10,11 There are no definitive histologic features that discriminate benign from malignant SFTP. However, tumors with a mitotic rate greater than 4 mitoses per 10 high-power fields and greater than 10 cm in size are more likely to recur locally. The treatment of SFTP is surgical resection (Fig. 21-3A). Adjuvant therapy is not typically warranted, particularly if the lesion is completely resected.
Malignant pleural mesothelioma (MPM) is a rare thoracic malignancy, directly linked to asbestos exposure. The incidence of MPM remains low at about 2000 to 3000 new cases12 per year compared with lung cancer that has over 160,000 new cases per year, but has gradually increased over the past 5 decades. Although the use of asbestos dates back to thousands of years, it became widespread with increased industrialization as it was used as a form of insulation in many industries. These include construction, shipbuilding, pipefitting, and car brake assembly, due to its properties of light weight, low cost, and high heat resistance. Asbestos is a natural silicate mineral that can be categorized as serpentine and amphibole. Serpentine asbestos is composed of spiral fibers compared with amphibole asbestos whose fibers are linear and needle-like. This shape of amphibole is believed to cause chronic irritation that may lead to malignant transformation of the pleura.
The link between asbestos and MPM was first noted in asbestos mine workers dating back to the 1940s.13,14 The vast majority of patients diagnosed with MPM have a documented link to asbestos exposure. Other less common etiologies include high-dose radiation exposure as well as simian virus infection.12 However, asbestos remains the most clearly established causative agent. The development of mesothelioma typically trails exposure by 2 to 3 decades.
MPM arises from the mesothelial lining of the pleura and is often radiographically characterized by diffuse pleural thickening (Figs. 21-4 and 21-5). They are typically found as two major histologic variants: epithelioid type and sarcomatoid types (Figs. 21-6A and 21-6B). Some tumors have characteristics of both and are considered biphasic or mixed. In the workup, MPM must be differentiated from pleural dissemination of non–small cell lung cancer (especially adenocarcinoma). Although it is difficult to distinguish between the two with routine histologic examination, antibodies specific to mesothelioma have greatly increased diagnostic accuracy. Specially, antibodies to calretinin, Wilms tumor-1 (WT-1), and cytokeratin 5/615 are strongly positive in malignant epithelioid mesothelioma but are negative in adenocarcinoma.
Sagittal plane image of malignant pleural mesothelioma from an extrapleural pneumonectomy specimen.
Malignant pleural effusion is seen posteriorly. Arrow shows pleural thickening.
Malignant pleural mesothelioma. A. Epithelioid type. B. Sarcomatoid type.
Recent advances in cancer genetics have identified several pathways that appear to be in MPM. Numerous tumor suppressor genes including p16, p14, and p53 are affected, and aberrant expression of growth factors/receptors such as transforming growth factor-α (TGF-α), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF), and hepatocyte growth factor (HGF) are identified.16 However, the molecular mechanism by which asbestos induces MPM has not been determined.
The most common presenting symptom of MPM is dyspnea, and it is typically caused by pleural effusion. On physical examination, dullness to percussion is found on the affected hemithorax. Chest pain is also common due to tumor involvement of the parietal pleura or chest wall. Weight loss is an ominous and late sign of disease along with generalized malaise and failure to thrive. No specific laboratory studies are diagnostic of MPM although thrombocytosis can be present.17
Radiographic Evaluation and Clinical Staging
Chest CT is the most commonly used modality for the evaluation of MPM. Early-stage tumors present with focal areas of pleural thickening and may be accompanied by pleural effusions. (Fig. 21-5). In later stages, MPM presents as large masses or circumferential tumors that completely encase the lung and invade mediastinal structures. PET scanning is used to screen for metastatic disease that is common,18 although it is not as helpful for detecting locoregional and lymph node involvement.19 MRI can be used to evaluate transdiaphragmatic invasion if radical surgery is being considered.
Clinical staging occurs after definitive tissue diagnosis. This can be obtained by cytology obtained from a pleural effusion or via a single-port thoracoscopy. Again, this port should be placed in line of a potential future thoracotomy if the patient appears to be a multimodality therapy candidate. The staging system for MPM has been defined in the 7th edition of the American Joint Commission on Cancer (AJCC) staging manual using standardized T, N, and M designations. PET scanning is useful in clinical staging although its sensitivity for T and N staging has been questioned. As mediastinal lymph node disease portends poor prognosis, cervical mediastinoscopy is recommended for patients who are candidates for aggressive multimodality therapy. Brain imaging should be performed to rule out metastatic disease. Although some centers recommend peritoneal lavage to rule out transdiaphragmatic spread, this is not routine for most centers. Due to the inherent inaccuracy of T and N staging based on CT and PET imaging, clinical staging of mesothelioma is imperfect. Definitive staging can only be obtained after radical surgical resection and evaluation of the entire pathologic specimen. Transdiaphragmatic and extensive chest wall invasion are usually contraindications to radical surgery.
Treatment modalities depend on the patient’s age, performance status, and disease stage at presentation. As most patients present with advanced disease, the mainstay of therapy for most is chemotherapy. Life expectancy in advanced disease is short and prolongation of life with chemotherapy is limited. The 5-year overall survival for this group of patients is about 15 percent. Traditional chemotherapy had included monotherapy with a wide variety of agents. Recently, a phase III trial testing a doublet using pemetrexed and cisplatin has shown efficacy. There was an overall 23 percent risk reduction for this cocktail compared with cisplatin monotherapy and the median survival was increased from 9.3 to 12.1 months.20 Thus, the current recommendations for chemotherapy for mesothelioma include cisplatin and an antifolate agent such as pemetrexed or raltitrexed.
Radiation therapy is not indicated as primary therapy given the large treatment field required and associated toxicities. Instead, radiotherapy is used as an adjunct after radical surgery (extrapleural pneumonectomy, EPP) in multimodality therapy treatment protocols, or for palliation of pain.
Intraoperative photodynamic therapy (PDT) is a less common therapy. PDT uses laser light to activate a photosensitizer loaded into tumor cells to cause cytotoxicity and apoptosis. This treatment also stimulates a vigorous antitumor immune response.21 It has been argued that because the cytotoxic effect penetrates several millimeters in depth on surfaces such as the visceral pleura and the diaphragm, radical resection is unnecessary.22 Although there have been no studies that have clearly shown a benefit, future studies in early-stage patients may yet validate this treatment modality.
Although still debated, surgical therapy appears to offer improved survival in highly selected patients with MPM. Unfortunately, only a small fraction of patients who present with MPM are candidates for surgical resection. Due to the nature of MPM, “complete” resection is improbable and the goal of surgery is as a cytoreductant. Adjuvant therapies are aimed at eradicating residual microscopic disease postoperatively.
The main surgical options include EPP or pleurectomy/decortication (P/D). P/D is preferred for patients with disease primarily limited to the parietal pleura, where the removal of the parietal pleura provides significant tumor cytoreduction. When more extensive disease is present, EPP may yield maximal cytoreduction. The outcomes from both surgeries are comparable when adjusted for stage.23 The results of that study also suggested that P/D might be preferred for stage I disease and EPP for stage II disease.
Most studies have focused on surgery with adjuvant therapy rather than surgery as monotherapy. A report of 183 patients who underwent EPP followed by chemotherapy (carboplatin and paclitaxel) and radiation (30 Gy) demonstrated a 2- and 5-year survival of 38 and 15 percent, respectively, as well as a 3.8-percent per-operative mortality.24 Nodal metastasis, sarcomatoid subtype, and positive resection margins were risks for poor survival. In the absence of these risk factors, a 5-year survival of 45 percent and a median survival of 51 months were observed. Another recent study examining induction chemotherapy followed by EPP and hemithoracic radiation (>50 Gy) also showed similar survival.25,26 Specifically, a 75-percent survival in ypT1-2NO patients and an overall 5-year survival for node negative patients of 53 percent were demonstrated. Intracavitary hyperthermic chemotherapy (ICHC) has been tested but has not shown a clear benefit.