Pathology of Nonmesothelial Cancers of the Pleura

Nonmesotheliomatous cancers of the pleura include an assortment of malignant neoplasms that primarily or secondarily involve pleura. ^{[1, 2]} They enter into the clinical and histological differential diagnoses of pleural malignant mesothelioma. Using an approach that includes consideration of the morphologic features, appropriate immunohistochemistry, and correct clinical context aids in making the proper diagnosis. ^[2]

The distinction among these various tumors is important both clinically and epidemiologically. Whereas pleural mesothelioma is highly associated with asbestos exposure, nonmesotheliomatous cancers have generally not been proven to result from exposure to airborne asbestos. This article discusses the following neoplasms: ^[3]

• Pseudomesotheliomatous carcinoma

• Synovial sarcoma

• Vascular sarcomas

• Malignant solitary fibrous tumor (SFT)

• Primitive neuroectodermal tumor (PNET) (Askin tumor)

• Desmoplastic small round cell tumor (DSRCT)

Pseudomesotheliomatous carcinoma

The most common category of nonmesotheliomatous cancer to involve the pleura is represented by extrapleural primary malignancies that secondarily involve the pleura via metastatic spread. ^[3]

Three most frequent tumors to involve the pleura secondarily include lung cancer (35%-45% of malignant pleural effusions), metastatic breast cancer (approximately 25%), and malignant lymphoma (about 10%). ^[3]

By definition, pseudomesotheliomatous carcinoma refers to an epithelial neoplasm that secondarily involves the pleura and encases the lung, thereby simulating the radiologic and macroscopic appearance of malignant mesothelioma. ^{[3, 4]} The term "pseudomesotheliomatous carcinoma" was first applied by Harwood and colleagues in 1976 to 6 cases of peripheral lung adenocarcinoma that closely mimicked mesothelioma. ^[5] An earlier report, in 1956, by Babolini and Blasi, described the same clinicopathological entity using the nomenclature, "The pleural form of primary cancer of the lung." ^[6]

Malignant solitary fibrous tumor

SFTs of the pleura are localized mesenchymal neoplasms composed of fibroblastlike cells believed to arise from the subpleural connective tissue. ^[7] Most SFTs are benign or low grade. Low-grade tumors may recur and infiltrate adjacent structures. However, malignant SFTs, which comprise 10%-15% of SFTs, not only aggressively infiltrate adjacent structures but are also capable of metastatic spread. ^{[3, 8, 9, 10]}

The pathological features of SFT were first described in the English literature in 1931 by Klemperer and Rabin. ^[11] SFTs were initially incorrectly considered to be a localized form of fibrous mesothelioma. Moreover, the fibrous nature of the tumor has given rise to various other names, such as pleural fibroma, submesothelial fibroma, and localized fibrous tumor. The term fibroma is inappropriate because the neoplasm exhibits defined histologic features that differ from those of fibromas and may express malignant behavior. The currently accepted nomenclature is solitary fibrous tumor. ^[8]

Pleural synovial sarcoma

Synovial sarcoma is a malignant soft-tissue neoplasm that most commonly affects the extremities near to, but not in continuity with, large joints. The histogenesis of synovial sarcoma is unknown. It has not been proven to arise from synovium.

Synovial sarcomas have been described in many anatomic sites. Within the thorax, synovial sarcoma has been reported in the mediastinum, heart and pericardium, lung, and pleura. Overlapping lung and pleural involvement in individual cases has given rise to the more inclusive term “pleuropulmonary” synovial sarcoma. Synovial sarcomas encompass both biphasic (epithelial and spindle cell components) and monophasic (purely spindle cell) variants. ^{[3, 8]}

Pleural desmoplastic small round cell tumor

DSRCT was first described by Gerald and Rosai in 1989 as a primitive neoplasm of children and young adults that most frequently occurs in the serosa of the pelvic cavity. ^[12] Rare cases of primary pulmonary or pleural DSRCT have subsequently been identified. ^{[13, 14]}

DSRCT is composed of small cells with round hyperchromatic nuclei and a dense fibrous or spindle cell stroma. ^{[3, 8]} The histogenesis of DSRCT is speculated to be “mesothelioblastic,” arising from the submesothelial progenitor cell; however, this concept is controversial and not accepted by all investigators. ^[15]

Primitive neuroectodermal tumor of the thoracopulmonary region (Askin tumor)

The PNET is a member of the Ewing sarcoma (EWS) family of tumors and bears a close resemblance to, if not identity with, EWS. ^{[16, 17, 18]} PNET typically occurs in children and young adults. The frequent occurrence of extraosseous PNETs in the thoracopulmonary region was first described by Askin and colleagues in 1979. ^[19] The Askin tumor, like other PNETs, is composed of small round cells with a high nuclear-to-cytoplasmic ratio. It is primarily a pleural-based tumor that may extend into the soft tissue of the chest wall or the ipsilateral lung.

The distinction between PNET and EWS is at times difficult, if not impossible, to discern. Therefore, tumors in this spectrum are often referred to as the combined designation PNET/EWS.

Vascular sarcomas of the pleura: Epithelioid hemangioendothelioma and angiosarcoma

The two major subtypes of primary vascular sarcomas of the pleura are epithelioid hemangioendothelioma (EHE) and angiosarcoma.

EHE, first described in the soft tissue by Weiss and Enzinger in 1982, is an angio-formative tumor of intermediate malignant potential composed of large neoplastic endothelial cells that have an epithelioid appearance and may be deceptively bland. ^[20] In addition to soft-tissue sites, EHE has been described in multiple other organs, including the lung, where EHE had originally been called "intravascular sclerosing bronchioloalveolar tumor (IVSBAT)." ^{[3, 21]}

Angiosarcoma, conversely, is considered an aggressive and highly malignant neoplasm that recapitulates the morphology of endothelial cells. Angiosarcomas may also arise in diverse locations, including the serosal membranes. Primary angiosarcoma of the serosal surfaces was described in detail by McCaughey et al in 1984. ^[22]

The morphological appearance of angiosarcoma is quite diverse and varies from well-differentiated slitlike vascular spaces to high-grade pleomorphic tumors that little resemblance to blood vessels. The morphological patterns of angiosarcoma also tend to vary with the site of origin. Epithelioid angiosarcoma, a frequent subtype among pleural angiosarcomas, is composed of nests of cohesive pleomorphic large cells that resemble carcinoma. ^[23]

The histological distinction between EHE and epithelioid angiosarcoma is not always well defined. Because of the rarity of these neoplasms, EHE and epithelioid angiosarcoma of the pleura are frequently grouped together in reported series of patients.

Pseudomesotheliomatous carcinoma

The etiology of pseudomesotheliomatous lung cancer is probably similar to that of primary lung adenocarcinoma in general, with tobacco smoke exposure the most important factor.

Previous investigators, including Hammar and Dodson, Koss et al, and Attanoos and Gibbs, have also noted that a high proportion of patients with pseudomesotheliomatous adenocarcinoma have a background of occupational exposure to asbestos. ^{[4, 24, 25, 26]} However, it is not currently certain if there is a truly increased incidence of pseudomesotheliomatous adenocarcinoma in asbestos-exposed individuals. ^[3] Possible explanations for this putative association between pseudomesotheliomatous lung cancer and asbestos exposure may be referral bias in reported series or more intense interrogation regarding asbestos exposure owing to the clinical presentation suggesting mesothelioma. ^[3]

Rare isolated reports also describe pseudomesotheliomatous adenocarcinoma in patients with human immunodeficiency virus (HIV) infection; however, a causal relationship is uncertain. ^[27]

A single case of pulmonary pseudomesotheliomatous adenocarcinoma has also been described in a patient with scleroderma. ^[28]

Malignant solitary fibrous tumor

No specific etiology has been found for SFTs. Occasional SFTs have been noted in persons occupationally exposed to asbestos, ^[9] but, at the present time, SFT is not considered to be an asbestos-related neoplasm. ^{[3, 8, 9]}

Pleural synovial sarcoma

There are no known etiologic factors for pleural synovial sarcomas. Synovial sarcoma is not considered to be an asbestos-related tumor. ^[3]

Pleural desmoplastic small round cell tumor

There is no known etiologic factor. DSRCT is not considered to be an asbestos-related pleural neoplasm.

Primitive neuroectodermal tumor of the thoracopulmonary region (Askin tumor)

PNETs are thought to arise from primitive mesenchymal tissue. There is no evidence of neural crest origin. ^[29] There are no known etiologic factors.

Vascular sarcomas of the pleura: Epithelioid hemangioendothelioma and angiosarcoma

Epithelioid angiosarcomas of the pleura have been causally linked to chronic pyothorax due to tuberculosis, mainly in Japan. ^{[30, 31]} There may also be an association between angiosarcoma of the serosal membranes and prior radiation exposure. ^[32] Although a few cases of pleural angiosarcoma have been reported in persons exposed to asbestos, there are insufficient data to conclude that epithelioid angiosarcomas are causally linked to asbestos. ^{[3, 33, 34]}

Pseudomesotheliomatous carcinoma

Most pseudomesotheliomatous carcinomas of the pleura are thought to arise from occult peripheral adenocarcinomas of the lung. However, metastases from various sites, such as kidney, thyroid, larynx, stomach, and cutaneous melanoma or Merkel cell carcinoma have been described as simulating malignant mesothelioma. ^{[3, 35]} Metastatic soft-tissue sarcomas may also spread to the pleura and mimic mesothelioma. The distinction between metastatic sarcomatoid renal cell carcinoma and sarcomatoid mesothelioma is particularly problematic.

Besides adenocarcinoma, which accounts for 70% of pseudomesotheliomatous pulmonary carcinomas, other primary lung cancers, including squamous cell carcinoma, small cell carcinoma, large cell carcinoma, and carcinosarcoma may also present as a pseudomesotheliomatous tumor. ^{[3, 36]}

Malignant solitary fibrous tumor

SFT is the most common mesenchymal neoplasm of the pleura. It most frequently occurs in the sixth to seventh decade but has a wide age distribution, from 5-87 years. SFTs are rare in children younger than 10 years. Among 223 pleural SFTs reported by England et al, 82 (37%) were considered to be malignant. There is an approximately equal sex distribution for both benign and malignant SFTs. ^{[8, 9]}

Pleural synovial sarcoma

Pleuropulmonary synovial sarcoma is rare, comprising only 0.1%-0.5% of primary lung malignancies. ^[37] [ref93} Pleural synovial sarcomas tend to occur at a younger age (mean, 25-39 years; range, 9-50 years) than do pleural malignant mesotheliomas (mean, 65 years). There is no sex predilection. ^{[3, 37]}

Pleural desmoplastic small round cell tumor

Among the few cases that have been documented, pleural DSRCT mainly occurs in young males (median age, 23 years). ^{[13, 38]}

Primitive neuroectodermal tumor of the thoracopulmonary region (Askin tumor)

Askin tumors, like other PNETs, most commonly occur in children and young adults. They rarely occur in older adults. Some series have shown a female predilection. ^{[19, 39]}

Vascular sarcomas of the pleura: Epithelioid hemangioendothelioma and angiosarcoma

EHE tends to occur in middle-aged adults. In an early series of 14 patients by Lin and colleagues and in a subsequent review by Zhang et al, the vast majority of patients with epithelioid vascular tumors of the pleura are male, with a mean age of 57 years. ^{[40, 41]} This contrasts with epithelioid vascular tumors of soft tissue, which have no sex predilection, and EHE of lung or liver, in which women are predominantly affected.

Pseudomesotheliomatous carcinoma

Lung and pleural involvement are unilateral, without a predilection for side. ^[4] Simultaneous pleural and peritoneal involvement represents an unusual manifestation of pseudomesotheliomatous carcinoma of the lung. ^[42]

Malignant solitary fibrous tumor

Although the pleura is the most common site of origin, SFTs arise in many other body organs and locations. Sixty to 80% of intrathoracic SFTs arise in the visceral pleura. The second most common location within the thorax is the parietal pleura. There is no predilection for laterality. Occasional tumors may arise in the mediastinum, from the diaphragm, or within the lung parenchyma. ^[3] In a large series of extrathoracic SFTs, 11% were found to have atypical (malignant) features. ^[43]

Pleural synovial sarcoma

As the name implies, pleural synovial sarcomas arise in the visceral or parietal pleura and infiltrate underlying lung or chest wall. Within the pleural space, there is no known regional distribution or predilection for laterality. ^[37]

Pleural desmoplastic small round cell tumor

The tumor is present along the parietal and visceral pleura with frequent extension into the mediastinum. Bilateral pleural involvement and metastases to the lung parenchyma have also been reported. There is no predilection for laterality.

Primitive neuroectodermal tumor of the thoracopulmonary region (Askin tumor)

Askin tumors are usually pleural-based lesions that extend into the chest wall or lung. Rarely, a PNET may occur primarily in the lung without pleural involvement. ^[44] Conversely, occasional Askin tumors my present in the chest wall without pleural involvement. ^[39]

Vascular sarcomas of the pleura: Epithelioid hemangioendothelioma and angiosarcoma

By definition, pleural EHE and angiosarcoma unilaterally affect the thoracic cavity and pleural surfaces. There is no predilection for laterality. Occasional bilateral pleural involvement or simultaneous pleural and peritoneal involvement has been described. Some cases of pleural EHE represent pleural extension from a primary lung lesion. ^[45]

Pseudomesotheliomatous carcinoma

As represented in the series of Koss et al, 90% of patients with pseudomesotheliomatous lung adenocarcinoma are male, with a mean age of 63 years. Nearly all patients have symptomatic pleural effusion and/or chest wall invasion. The most frequent symptoms are chest pain, dyspnea, cough, and weight loss.

Physical examination reveals ipsilateral diminished breath sounds and dullness to percussion. Chest radiography and/or chest CT scanning typically shows unilateral pleural effusion, multiple pleural nodularity, and a rind of pleural thickening. The process is accentuated at the lung base, with frequent mediastinal and fissural pleural involvement. ^{[4, 46]}

Malignant solitary fibrous tumor

SFTs are usually asymptomatic and present as mass lesions on thoracic imaging. Systemic symptoms may include fever, fatigue, night sweats, and weight loss. Owing to their intrathoracic location, SFTs may be associated with symptoms of cough, chest pain, and dyspnea. Large tumors may produce digital clubbing, hypertrophic osteoarthropathy (Pierre-Marie-Bamberg syndrome), or hypoglycemia (Doege-Potter syndrome) due to the secretion of insulinlike growth factor II. Hypoglycemia is more frequently seen in females. ^{[3, 9, 10]}

The features of SFT seen on chest radiographs are most commonly those of a sharply circumscribed pleural-based soft-tissue mass. An obtuse angle is present at the intersection with the chest wall, suggesting an extrapulmonary location. The presence of pleural effusion may obscure the associated mass. Calcification is seen in less than 10% of cases. Large tumors may nearly fill the thoracic cavity and require CT scanning to define the site of origin.

On CT scans, most SFTs are heterogeneous, without invasion into adjacent structures. A pedicle at the point of attachment is sometimes seen. ^[8] Compared to benign SFTs, malignant SFTs tend to be larger, have a higher incidence of intratumoral low-attenuation areas, and exhibit pleural metastases on CT imaging, ^[47]  as well as having a casting mould-like growth, a rich blood supply, pleural effusions, and "geographic"-patterned enhancement. ^[48]

Pleural synovial sarcoma

Chest pain is the most common presenting symptom of pleural synovial sarcoma. Pleural effusion, dyspnea, dysphagia, and/or pneumothorax can also occur. In a large series, 40% of patients were asymptomatic, and pleuropulmonary synovial sarcoma was an incidental finding on chest radiography. ^[49] Pleural synovial sarcoma is an aggressive neoplasm with a mean survival of 18 months.

On standard chest radiographs, synovial sarcoma appears as a homogeneous pleural-based mass with sharply marginated borders and round, ovoid, or lobulated contours. ^[37] In some cases, greater than 50% of the hemithorax is opacified. On CT scans, most pleuropulmonary tumors appeared to be pleural based. However, localization to either lung or pleura is sometimes difficult radiographically.

In most cases, the mass shows heterogeneous enhancement with nodular soft-tissue components mixed with areas of low attenuation and occasional septa. An enhanced peripheral rim is present in many cases. Often, an ipsilateral pleural effusion is an associated finding. MRI provides an excellent demonstration of the nodular soft-tissue component and multilocular fluid-filled internal compartments, as well as peripheral rim enhancement after the intravenous administration of gadolinium-based contrast material. ^[37]

Pleural desmoplastic small round cell tumor

Typical symptoms are those of dyspnea and chest pain. DSRCT is frequently associated with an ipsilateral pleural effusion.

Standard chest radiographs and CT scans reveal pleural thickening. ^[13]

Primitive neuroectodermal tumor of the thoracopulmonary region (Askin tumor)

The major presenting clinical manifestations of Askin tumors are a soft-tissue palpable mass of the chest wall that may be painless or painful and dyspnea due to pleural effusion or lung compression.

The most frequent finding on standard chest radiography is a unilateral chest wall mass. Pleural disease is characterized by fluid accumulation and/or pleural thickening by tumor. Associated pulmonary parenchymal disease is noted in some patients. ^[39] Chest CT scanning depicts a heterogeneous soft-tissue mass. ^[50]

On MRI, T2-weighted images tend to be bright and heterogeneous in signal intensity. Tumor heterogeneity due to hemorrhage and necrosis is also seen in the T1-weighted MRI, which usually has a signal intensity greater than skeletal muscle.

Both MRI and CT imaging may reveal chest wall and/or lung invasion. However, neither modality can reliably separate lung invasion from lung compression by the adjacent primary tumor. ^[50] Tumor calcification is rare. Metastatic disease has been reported in approximately 10% of patients at the time of presentation.

In one series, CT scanning was superior to MRI in detecting small pulmonary metastases. ^[50]

Vascular sarcomas of the pleura: Epithelioid hemangioendothelioma and angiosarcoma

Most patients with pleural EHE present clinically with chest pain and dyspnea. Chest radiography reveals unilateral, often hemorrhagic, pleural effusion with or without pleural thickening or ipsilateral loss of lung volume. ^[51] Chest CT scanning typically shows diffuse or localized smooth or nodular pleural thickening. Loculated pleural effusion is a frequent accompaniment. ^{[51, 52]}

Pseudomesotheliomatous carcinoma

Grossly, pseudomesotheliomatous carcinoma presents as a rind of thick, white to tan, firm tissue encasing the lung in a pattern resembling mesothelioma or fibrothorax. Both parietal and visceral pleura are often involved, and the pleural surfaces are frequently described as being studded with tumor nodules or plaquelike thickening.

In advanced cases, the parietal and visceral pleura are densely adhesed, and sharp extrapleural dissection is required for the removal of the lung at thoracotomy or autopsy. Often, the lung parenchymal primary lesion thought to give rise to the extensive pleural involvement is inconspicuous or is unable to be identified grossly. ^{[4, 5, 53]}

Pathology of nonmesothelial cancers of the pleura. Pseudomesotheliomatous adenocarcinoma. The rind of the tumor encases the lower lobe in the region of the costophrenic angle.

View Media Gallery

Malignant solitary fibrous tumor

SFTs are large round to lobulated well-circumscribed tumors that range in size from 1-40 cm and may weigh in excess of 3 kg. ^[9] Tumors arising from the visceral pleura are often pedunculated and attached to the lung by a vascularized pedicle. Other tumors have a broad-based sessile attachment or may appear to be inverted into the lung. The cut surface of the tumor is fleshy, white to gray, often with a whorled pattern. Variably sized cysts are noted in about 13% of cases and tend to be concentrated near the point of pleural attachment. ^[9] Rarely, SFTs may be multiple. ^[8]

Malignant SFTs tend to be of large size (>10 cm in diameter) and exhibit areas of hemorrhage and necrosis. Tumors that undergo malignant transformation may be less well circumscribed with infiltration of lung and chest wall and exhibit more diffuse spread within the thoracic cavity. Other gross features that may suggest malignancy include occurrence in the parietal pleura, sessile attachment, associated pleural effusion, and local tumor recurrence following surgical resection. ^{[3, 9]}

Pathology of nonmesothelial cancers of the pleura. Left image: Large solitary fibrous tumor fills the thoracic cavity as seen at thoracotomy. Right image: Cut surface of the tumor is tan-gray, with a whorled appearance. Large tumor size is often associated with malignant behavior.

View Media Gallery

Pleural synovial sarcoma

Synovial sarcoma usually presents macroscopically as a circumscribed large tumor, sometimes with a fibrous pseudocapsule, having a mean diameter of 13 cm (range, 4-21 cm). The cut surface is gray-tan, often with necrotic friable components, hemorrhage, and focal cystic degeneration. Some tumors are attached to the pleura by a pedicle. ^{[3, 8, 37]} Rarely, synovial sarcoma can diffusely involve the pleura in a pattern that mimics diffuse malignant mesothelioma. ^[54]

Pleural desmoplastic small round cell tumor

The tumor produces multiple firm tan-white rubbery nodules within the pleura, often encasing the lung in the pattern of diffuse malignant mesothelioma.

Primitive neuroectodermal tumor of the thoracopulmonary region (Askin tumor)

Gross examination reveals a large, relatively circumscribed (but nonencapsulated), round, ovoid, and multinodular or multilobular mass (mean, 6 cm in diameter) in the soft tissues of the chest wall or bulging through the parietal pleura. ^[19] The cut surface is grayish-white with foci of hemorrhage and necrosis. The primary soft-tissue mass may directly extend into lung or adjacent ribs. ^[19]

Vascular sarcomas of the pleura: Epithelioid hemangioendothelioma and angiosarcoma

Macroscopically, pleural EHE and angiosarcomas greatly resemble diffuse malignant mesothelioma with multiple tumor nodules emanating from the pleura or with encasement of the lung by a thick rind of gray-tan leathery tumor that adheres to both parietal and visceral pleural surfaces. ^{[34, 55]} Tumor frequently extends along the interlobar fissures. Loculated hemorrhagic effusions are often associated with the pleural growth.

Pseudomesotheliomatous carcinoma

The histological features of pseudomesotheliomatous lung adenocarcinoma are usually described as simple tubular or acinar structures surrounded by a dense collagenous stroma, an appearance termed "tubulo-desmoplastic" by Hammar and Dodson. ^[24] Papillary or tubupapillary epithelial configurations, signet ring cells, and poorly differentiated carcinoma have also been described. ^{[56, 53, 57, 58]} Mucin is frequently detectable on mucicarmine, periodic acid Schiff (PAS) or Alcian blue (resistant to hyaluronidase digestion) stains.

Pathology of nonmesothelial cancers of the pleura. Pseudomesotheliomatous lung adenocarcinoma. Invasive adenocarcinoma with fibrocollagenous desmoplastic reaction infiltrates the diaphragm (upper layer) and atelectatic lung (lower).

View Media Gallery

Pathology of nonmesothelial cancers of the pleura. This micrograph reveals an acinar and papillary focus of adenocarcinoma surrounded by desmoplastic stroma.

View Media Gallery

Pathology of nonmesothelial cancers of the pleura. Tubulodesmoplastic pattern of infiltrating adenocarcinoma. Red-staining intracytoplasmic mucin in tumor cells is a feature that distinguishes adenocarcinoma from epithelioid mesothelioma (periodic acid Schiff stain with diastase predigestion).

View Media Gallery

Malignant solitary fibrous tumor

The histological features of SFTs are quite variable. ^{[3, 8, 9, 59]}

Benign tumors are composed of bland, short, fibroblastlike spindle cells with ovoid nuclei, interspersed amidst a fibrocollagenous stroma. The most common histological pattern has been termed the “patternless pattern” of Stout, in which spindle cells and collagen bundles are randomly dispersed throughout the tumor. In the diffuse sclerosing pattern, dense collagen bundles are the dominant feature. Collagen may assume an eosinophilic wirelike appearance similar to that seen in desmoplastic mesothelioma. A storiform or hyalinized arrangement may also be seen.

Cellularity varies from minimal to diffuse sheets of round to ovoid cells. Cellularity varies inversely with the degree of collagen matrix. Some SFTs have a hypocellular myxoid appearance. ^{[9, 59]} Prominent thin-walled vessels with staghorn configuration resemble hemangiopericytoma. Multiple histological patterns may occur within a single SFT. ^{[9, 59]}

Pathology of nonmesothelial cancers of the pleura. "Patternless pattern" of benign solitary fibrous tumor showing short spindle cells insinuated between coarse bundles of collagen.

View Media Gallery

Histological features associated with malignancy include the following: ^{[3, 9]}

• Increased numbers of mitotic figures (>4 per 10 HPF)

• Nuclear pleomorphism and atypia, including frankly sarcomatous areas within an SFT

• Areas of tumor necrosis (as opposed to ischemic necrosis due to torsion)

An interesting variant of malignant SFT showing lipomatous differentiation has recently been described. ^[60]

Pathology of nonmesothelial cancers of the pleura. Malignant solitary fibrous tumor. Note the hypercellular appearance and area of necrosis on the left side of the image.

View Media Gallery

Pathology of nonmesothelial cancers of the pleura. Pleomorphic sarcomatous appearance with bizarre tumor giant cells. On immunohistochemical staining, the neoplastic cells were positive for CD34 and negative for pankeratin.

View Media Gallery

There is no apparent difference in the histology of intrathoracic versus extrathoracic SFTs. The atypical histological features associated with aggressive behavior in thoracic SFTs are also associated with aggressive behavior in extrathoracic tumors. ^{[43, 61]} Histologic features tend to be more atypical in recurrent or metastatic SFT than in the primary tumor. ^[43] SFTs can be accurately diagnosed presurgically with transthoracic needle biopsy. ^[62] Assessment of malignant potential, however, usually requires sampling of the resected tumor. Diagnosis with fine-needle aspiration is difficult owing to nonspecific cytologic features. ^[62]

Pathology of nonmesothelial cancers of the pleura. (A) Malignant solitary fibrous tumor. A 2 kilogram pleural solitary fibrous tumor in a 36-year-old female. The collagenous area is typical of that seen in low-grade tumors.

View Media Gallery

Pathology of nonmesothelial cancers of the pleura. (B) Another field from the primary pleural solitary fibrous tumor shown in the previous image (A) from the same patient. This image reveals a hypercellular area with minimal pleomorphism. Note the mitotic figure near the center of the field.

View Media Gallery

Pathology of nonmesothelial cancers of the pleura. (C) Metastatic solitary fibrous tumor involving the lung in the same patient as in the previous two images (A) and (B), 3 years after resection of the primary pleural tumor. The tumor has dedifferentiated and has a pleomorphic high-grade sarcomatous appearance with numerous mitotic figures.

View Media Gallery

Pleural synovial sarcoma

Histologically, synovial sarcoma of the pleura resembles its soft-tissue counterpart. Indeed, it may be difficult if not impossible to clearly differentiate between pleural sarcomatoid mesothelioma and pleural synovial sarcoma by hematoxylin-eosin staining, conventional immunohistochemistry markers, and transducin-like enhancer of split 1 (TLE-1) labeling. ^[63]

Monophasic synovial sarcoma is more common than biphasic synovial sarcoma in the pleura. The monophasic variant is composed of densely packed short spindle cells, with a high nuclear-to-cytoplasmic ratio, arranged in interweaving fascicles. A hemangiopericytomatous pattern and/or hyaline fibrosis (with or without calcification) are common features. Frequent stromal mast cells are characteristic of synovial sarcoma.

The mitotic rate varies but is frequently brisk. Biphasic synovial sarcoma includes a spindle cell component as in the monophasic variant in addition to larger epithelial cells that are round to oval with pale cytoplasm and vesicular nuclei. Epithelial cells may be arranged in cords, nests, sheets, or acinar structures that may contain neutral intraluminal mucin. ^{[64, 65]}

Pathology of nonmesothelial cancers of the pleura. Monophasic synovial sarcoma showing interlacing fascicles of spindle cells.

View Media Gallery

Pathology of nonmesothelial cancers of the pleura. Higher magnification of neoplastic spindle cells. Note also round mast cells with granular cytoplasm (center of image).

View Media Gallery

A poorly differentiated variant of synovial sarcoma has also been described in which pleomorphic cells having a high mitotic rate and areas of necrosis may appear as spindle cells in a herringbone pattern, small cells, or large epithelioid cells. Whether biphasic or monophasic, poor cytological differentiation has been said to be associated with poor prognosis. ^[66]

Pleural desmoplastic small round cell tumor

DSRCTs of the pleura have the same histology as tumors occurring in the abdominal/pelvic cavity. They typically consist of demarcated nests of small round cells surrounded by a dense fibrous or cellular spindle cell stroma. Nuclei are hyperchromatic with inconspicuous nucleoli and multiple mitoses (>3 per 10 high power microscopic fields). The cytoplasm contains punctate structures that correspond ultrastructurally to whorls of intermediate filaments. A minority of cases of DSRCT lack dense fibrous stroma or express unusual histological patterns such as papillary, adenoid cystic–like, signet ring cell, or spindle cell. ^{[67, 68, 69]}

Pathology of nonmesothelial cancers of the pleura. Desmoplastic small round cell tumor. Islands of small blue cells are separated by bands of fibrous tissue.

View Media Gallery

Pathology of nonmesothelial cancers of the pleura. Malignant small cells with a high nuclear-to-cytoplasmic ratio.

View Media Gallery

Primitive neuroectodermal tumor of the thoracopulmonary region (Askin tumor)

Askin tumors exhibit 3 patterns of cell organization: diffuse sheets of cells, tumor cells with a nesting arrangement separated by fibrovascular stroma, or serpiginous bands of cells with necrosis. ^[19] The neoplastic cells are round to oval with scant cytoplasm and a dense nucleus with evenly distributed coarse chromatin without prominent nucleoli. A moderate number of mitotic figures may be present. Homer-Wright–like neural rosettes may occasionally be seen. ^[19] PAS-diastase stain is usually negative for glycogen, although some tumors may stain positively, further blurring the histological distinction from classical EWS. ^[18]

Pathology of nonmesothelial cancers of the pleura. A small round blue cell tumor is consistent with a primitive neuroectodermal tumor involving the chest wall of a 28-year-old woman. Small neoplastic cells are present in a diffuse pattern.

View Media Gallery

Vascular sarcomas of the pleura: Epithelioid hemangioendothelioma and angiosarcoma

Histologically, EHE closely resembles either epithelioid or biphasic malignant mesothelioma. The tumor is composed of sheets, cords, and nests of large epithelioid cells with abundant amphophilic cytoplasm and round to oval nuclei with inconspicuous nucleoli. Nuclear pleomorphism is mild, and mitotic figures are inconspicuous. Tumor cells frequently contain bubbly cytoplasmic vacuoles in which erythrocytes are occasionally observed. Pseudoacini, microcysts, and spindle cells heighten the resemblance to malignant mesothelioma. Tumor cells are frequently embedded in a fibrohyaline or myxoid stroma. Histochemical stains are negative for mucin. ^{[40, 41]}

The histological features of angiosarcoma vary from well-differentiated slitlike vascular spaces to high-grade pleomorphic tumors bearing little resemblance to blood vessels. Epithelioid angiosarcomas are composed of moderately to extremely pleomorphic round to polygonal epithelioid cells with nuclei that contain large macronucleoli. Occasional intracytoplasmic lumina that contain erythrocytes may be observed.

Cells are typically arranged in sheets, islands, or cords. Focal areas of anastomosing vessels are usually present but may be lacking in small biopsy samples, which show only sheets of epithelioid cells. Within the sheetlike arrangement of epithelioid cells external laminal arrangement of cells into tubules recapitulates early vasculogenesis. Variable degrees of necrosis, hemorrhage, and numerous mitotic figures are present. ^[23]

Pathology of nonmesothelial cancers of the pleura. Serosal angiosarcoma showing a pleomorphic spindle cell pattern with hemorrhage.

View Media Gallery

Pathology of nonmesothelial cancers of the pleura. Serosal angiosarcoma showing primitive slit-like vascular channels.

View Media Gallery

Pathology of nonmesothelial cancers of the pleura. Low magnification image of a pleural epithelioid hemangioendothelioma. Note the diffuse pleural thickening by a variably cellular and fibrous neoplasm. There is focal acute hemorrhage.

View Media Gallery

Pathology of nonmesothelial cancers of the pleura. This histologic image reveals epithelioid hemangioendothelioma. Large epithelioid cells demonstrate prominent cytoplasmic vacuolization. Occasional vacuoles contain erythrocytes.

View Media Gallery

Pseudomesotheliomatous carcinoma

Pseudomesotheliomatous adenocarcinoma can be distinguished immunohistochemically from pleural epithelioid mesothelioma by the expression of adenocarcinoma markers such as m-CEA, TTF-1, BerEP4, CD15, and B72.3 and the absence of mesothelioma markers such as calretinin, D2-40, and thrombomodulin. ^{[46, 70]} Metastatic adenocarcinoma from an extrapulmonary site can be evaluated with site-sensitive markers such as ER, PR and E-cadherin for breast primary tumors; thyroglobulin for thyroid carcinoma; and CD10 and RCC for renal cell carcinoma.

Pathology of nonmesothelial cancers of the pleura. Nuclear staining for thyroid transcription factor 1 (TTF-1) is consistent with primary adenocarcinoma of the lung and helps to exclude the diagnosis of epithelioid mesothelioma.

View Media Gallery

Malignant solitary fibrous tumor

SFTs nearly always express the immunohistochemical markers vimentin and CD34, with slightly less frequent expression of Bcl-2 and CD99. ^{[71, 72]} Rare tumors may coexpress desmin or actin. Mesothelial markers such as calretinin are negative, as are epithelial markers such as pankeratin and EMA. ^{[3, 8, 9]} However, the mesothelial marker D2-40 is occasionally positive in the spindle cells of SFT. ^[73] CD117 is usually negative. ^[74] Endothelial markers such as CD31 and Factor VIII are negative in tumor spindle cells but highlight intra-tumoral vascular endothelial cells.

CD34, while not specific, is perhaps the most useful marker for supporting the diagnosis of SFT. Staining for CD34 and Bcl-2, however, may be weak or absent in malignant SFTs. ^[8] Rare malignant SFTs with expression of cytokeratin have also been described. ^[10]

The nuclear proliferation marker Ki67 (MIB-1) may be useful in discriminating benign from malignant SFTs, with benign lesions having a low proliferative index (0%-2%), while frankly malignant lesions show 20%-40% nuclear positivity. In one large series, the mean proliferative index for benign tumors was 7.27 versus 13.48 for malignant SFTs. ^[61] P53 has also been advocated as a useful marker seen in a higher proportion of malignant than benign SFTs. ^{[10, 61, 72]}

Pleural synovial sarcoma

Pleural synovial sarcomas stain positive for both cytokeratin (especially CK7) and EMA, which is usually more intense and prominent in the epithelial component. Staining for epithelial markers may be focal, especially in the spindle cell component. Vimentin is strongly and diffusely positive in spindle cells, and Bcl-2 and CD99 are frequently also positive. CEA and Ber-EP4 are variably positive in the epithelial component. Nuclear and cytoplasmic staining for S100 has been reported in up to 30% of synovial sarcomas.

Focal staining for calretinin is often present in either the spindle or epithelial areas of synovial sarcoma and may cause diagnostic confusion with malignant mesothelioma. WT-1 is usually negative in synovial sarcomas, as is CD34. ^{[3, 8, 75]}

A pitfall in the diagnosis of synovial sarcoma is the interpretation of entrapped alveolar pneumocytes as an epithelial component of the tumor. Immunostaining for TTF1 can resolve the presence or absence of alveolar pneumocytes. ^[37]

Pathology of nonmesothelial cancers of the pleura. Focal immunoexpression of keratin in malignant spindle cells.

View Media Gallery

Pathology of nonmesothelial cancers of the pleura. Nuclear expression of calretinin in tumor cell nuclei.

View Media Gallery

Pleural desmoplastic small round cell tumor

DSRCT typically expresses divergent staining for epithelial, mesenchymal, and neuroendocrine markers. ^{[15, 67]} The most frequently positive immunostains include diffuse staining for cytokeratins, EMA, and vimentin; dotlike cytoplasmic staining for desmin; and nuclear staining for the carboxy-terminal end of WT-1. ^{[15, 76]}

DSRCTs also frequently stain for neuron specific enolase (NSE), BerEp4, and CD15. ^[15] Rarely, DSRCT may lack epithelial immunohistochemical markers. ^[77]

Pathology of nonmesothelial cancers of the pleura. Tumor cells positive for cytokeratin are indicative of epithelial differentiation.

View Media Gallery

Pathology of nonmesothelial cancers of the pleura. Discrete, "dot-like" positivity for desmin is a manifestation of mesenchymal differentiation.

View Media Gallery

Pathology of nonmesothelial cancers of the pleura. Immunostaining for neuron specific enolase (NSE) indicates neuroendocrine differentiation.

View Media Gallery

Primitive neuroectodermal tumor of the thoracopulmonary region (Askin tumor)

PNETs consistently stain immunohistochemically for vimentin and CD99. PNETs usually stain for neuron specific enolase and stain variably for other neuronal markers such as S100, synaptophysin, chromogranin, and glial fibrillary acidic protein. Although usually negative for keratin, PNETs may stain focally for keratin, EMA, and desmin. CD99 is regarded as the most useful immunohistochemical marker, staining in a cell membrane pattern. However, CD99 is not specific for PNET and must be interpreted in conjunction with other immunohistochemical markers and with the clinical and histological features of the case. ^{[29, 44]}

Pathology of nonmesothelial cancers of the pleura. This image demonstrates immunostaining for vimentin.

View Media Gallery

Pathology of nonmesothelial cancers of the pleura. This image demonstrates immunostaining for CD99.

View Media Gallery

Pathology of nonmesothelial cancers of the pleura. This image demonstrates immunostaining for glial fibrillary acidic protein (GFAP).

View Media Gallery

Vascular sarcomas of the pleura: Epithelioid hemangioendothelioma and angiosarcoma

Both EHE and angiosarcoma stain strongly for vimentin and are either negative or variably positive for cytokeratin. ^{[40, 45, 78]} Keratin expression is usually weak or spotty. ^[40] The tumor cells also express one or more vascular marker such as CD31, CD34, or factor VIII–related antigen. Mesothelial markers such as calretinin are negative, as are standard epithelial markers such as EMA, CEA, and CD15. CD10, a marker often associated with renal cell carcinoma, has been shown to be positive in most EHEs. ^[79] Accompanying spindle cells may stain positively for keratin consistent with submesothelial reactive mesenchymal cells. ^[40]

Pathology of nonmesothelial cancers of the pleura. Serosal angiosarcoma demonstrating strong immunostaining for vimentin.

View Media Gallery

Pathology of nonmesothelial cancers of the pleura. Serosal angiosarcoma demonstrating weak equivocal immunostaining for pankeratin.

View Media Gallery

Pathology of nonmesothelial cancers of the pleura. Serosal angiosarcoma. The tumor stains strongly for the endothelial marker CD34.

View Media Gallery

Pathology of nonmesothelial cancers of the pleura. Serosal angiosarcoma. Focal expression of the endothelial marker factor VIII. Factor VIII immuno-staining is frequently less intense and more focally distributed than that for CD31 or CD34.

View Media Gallery

Pseudomesotheliomatous carcinoma

There are few studies of molecular or genetic alterations in pseudomesotheliomatous lung adenocarcinoma. In 4 cases, Pardo et al reported a median of 15 chromosomal imbalances per case using a comparative genomic hybridization technique. ^[57] In this study, the most frequent aberrations were gains on chromosome regions 1q, 3q, 5p, 8q, 16p, and 18q and losses in 17p11-13 and 17q22-q25. All cases showed a characteristic association between the gains on 16p and those on 18q. ^[57]

Further molecular and genetic studies are required to discern if there are consistent molecular markers of pseudomesotheliomatous adenocarcinoma that distinguish it from usual non–small cell lung carcinoma or malignant mesothelioma.

Malignant solitary fibrous tumor

There has been a single report of SFT occurring in a mother and daughter. ^[80] A wide variety of karyotypic abnormalities, including both numerical and structural abnormalities, have been identified in SFTs.

Cytogenetic abnormalities are more common in malignant than in benign SFTs. A few numerical imbalances such as extra copies of chromosome 8, gain of chromosome 21, and loss or partial deletions of chromosomes 1, 6, 9, 13, 15, 17, 18, and X and structural rearrangements of 4q1, 9p22-23, 9q22, 9q31-32, and 12q24 have been shown to be recurrent. However, at this time, no consistent chromosomal abnormality has been reported for SFT. ^[81]

Further genetic studies of SFT are necessary to define the presence or absence of useful diagnostic cytogenetic markers.

In regard to other molecular markers, Schirosi et al noted a lack of immunohistochemical expression of SFTs for EGFR and expression of CD117/KIT in 3.4% of cases. PDGFR-alpha and PDGFR-beta were detected in 97.7% and 86.5% of cases, respectively. High p53 staining was noted in 20.4%. Fluorescence in situ hybridization (FISH) analysis for SYT rearrangement was uniformly negative in SFTs. ^[10]

More recently, NAB2-STAT6 gene fusion has been identified, in which there is intrachromosomal inversion involving 12q13.3. ^[7]  "The derived immunohistochemical detection of nuclear STAT6 expression has high diagnostic value in distinguishing SFTs from histologic mimics," although pitfalls exist. "NAB2-STAT6 fusions yield numerous transcript subtypes associated with the clinicopathological variations." ^[7]

Pleural synovial sarcoma

The molecular hallmark of synovial sarcoma is the t(X; 18)(p11.2; q11.2) translocation, which is found in more than 90% of synovial sarcomas, regardless of site of origin.

Pathology of nonmesothelial cancers of the pleura. This image shows a positive finding with the SYT breakapart probe. In an intact (normal) situation, the green and red colors would be juxtaposed, thereby forming yellow. A few intact loci are present, but many loci demonstrate the loss of yellow and the spatial separation of the green and red fluorophores.

View Media Gallery

This translocation results in the fusion of the SYT gene on chromosome 18 to either the SSX1 or SSX2 gene on chromosome X. The presence of the translocation and/or the fusion transcript is considered to be specific for synovial sarcoma, regardless of the histologic variant. ^[82]

Pleural synovial sarcoma results in positive fluorescence in situ hybridization (FISH) or reverse transcriptase polymerase chain reaction (RT-PCR), in contrast to mesotheliomas which have a negative SYT-SSX status. ^[63]

Pleural desmoplastic small round cell tumor

DSRCT is associated with the translocation t(11;22)(p13;q12), which gives rise to the WT1-EWS gene fusion product. This translocation is considered to be specific for DSRCT, regardless of its site of origin. ^{[67, 76, 83, 84]}

Primitive neuroectodermal tumor of the thoracopulmonary region (Askin tumor)

A signature gene fusion product EWS/FLI1 results from a chromosomal translocation t(11;22)(q24;q12) and is found in about 95% of PNET/EWS cases, including Askin tumor. The second most common EWS/ETS translocation, which occurs in about 5% of tumors, is t(12;22)(q22;q12), which leads to the fusion product EWS/ERG. Other translocations that lead to fusion of EWS with other genes in the ETS family of transcription factors occur in fewer than 1% of cases.

Fusion genes involving EWS/ETS are considered to be specific markers for tumors in the PNET/EWS family and are an important tool in the diagnosis of these tumors. ^{[17, 29]} The EWS/ETS fusion proteins appear to act on the expression of target genes in a sequence-specific manner that is determined by the ETS component coming under the control of the EWS component. Considered to be an oncogene, EWS/FLI1 has been shown not only to inhibit tissue specific differentiation but also to promote the Ewing-specific neuroectodermal differentiation seen in these tumors. ^[29]

Pathology of nonmesothelial cancers of the pleura. A: Partial karyotype of the t(11;22)(q24;q12) translocation seen in Ewing sarcoma. Arrowheads identify the translocation breakpoints in the derivative chromosomes 11 and 22. B: Two interphase nuclei from a fluorescent in situ hybridization (FISH) assay, using an Ewing sarcoma breakpoint region 1 (EWSR1) break-apart probe set. The lower left nucleus has a normal signal pattern with two intact EWSR1 signals (yellow). The upper right nucleus has one intact EWSR1 signal identifying the normal chromosome 11 and individual green and red signals (arrows) which identify the derivative chromosomes 11 and 22, respectively.

View Media Gallery

Vascular sarcomas of the pleura: Epithelioid hemangioendothelioma and angiosarcoma

Little is known of the genetics of EHE or angiosarcoma. In two cases of EHE, an identical chromosomal translocation involving chromosomes 1 and 3 t(1:3) was noted. ^[81]

Pseudomesotheliomatous carcinoma

Pseudomesotheliomatous adenocarcinoma spreads within the pleural space. Owing to frequent invasion of chest wall, diaphragm, or mediastinal pleura, patients present at a primary tumor classification of T3. Those with malignant pleural effusion are classed as T4. Patients usually present with advanced disease of stage IIIB or IV. ^[46] Metastases from pseudomesotheliomatous adenocarcinoma have a distribution that is similar to those of metastatic lung carcinoma in general, with frequent metastatic sites being adrenal glands, lymph nodes, liver, and brain. ^[4]

Malignant solitary fibrous tumor

A staging system of pleuropulmonary SFTs, based on common clinicopathologic criteria, proposed by de Perrot et al includes the following stages: ^[85]

• Stage 0: Tumor with peduncle without features of malignancy at histology

• Stage 1: Tumor with sessile or "inverted" appearance without features of malignancy at histology

• Stage 2: Tumor with peduncle with features of malignancy at histology

• Stage 3: Tumor with sessile or inverted appearance with features of malignancy at histology

• Stage 4: Multiple metastatic tumor

The de Perrot staging system was assessed independently by Schirosi et al and shown to correlate statistically, on univariate analysis, with the most important clinicopathologic prognostic parameters in SFTs. Tumor stage also correlated with overall survival and disease-free survival (P< 0.001). ^[10]

Pleural synovial sarcoma

Among all patients with primary intrathoracic synovial sarcoma, 30%-40% develop local recurrence, and approximately 40% develop at least one distant metastasis. Sites of metastases include contralateral lung, liver, peritoneum, brain, pancreas, breast, skin, and bone. In a study by Bégueret and colleagues, 2-year and 5-year disease-specific survival was 64.3% and 31.6%, respectively. ^[86]

Pleural desmoplastic small round cell tumor

Pleural DSRCTs tend to encase the lung with invasion into the contiguous mediastinum. Bilateral pleural involvement has also been reported. ^[13]

Primitive neuroectodermal tumor of the thoracopulmonary region (Askin tumor)

The primary tumor invades locally into the chest wall and lung. Recurrent intrathoracic disease is the most common manifestation of treatment failure. ^[39] Metastases frequently occur in the lung or skeleton. Metastases along the sympathetic chain have also been described. ^[39]

Vascular sarcomas of the pleura: Epithelioid hemangioendothelioma and angiosarcoma

The clinical behavior of EHE varies based on its site of origin. It is generally regarded as a low grade or indolent malignancy in the soft tissue, with a mortality rate of about 20%, whereas hepatic or osseous EHE proves lethal in 30%-40% of cases. In the pleura, however, EHE behaves in a highly aggressive manner and is invariably fatal, causing death within several years. In this respect, EHE resembles the aggressive behavior of malignant mesothelioma or pseudomesotheliomatous carcinoma, with extensive spread within the pleural space.

Metastatic spread to lung and mediastinal lymph nodes is often seen at autopsy. Extrathoracic spread to abdominal viscera or retroperitoneum has also been documented. ^[51] Angiosarcomas, including epithelioid angiosarcomas, of the pleura are highly malignant neoplasms and behave in fashion similar to that of malignant mesothelioma. ^[40]

Curative surgery is the treatment of choice for vascular sarcomas, but this modality is often prohibited in primary tumors of the pleura owing to the diffuse and advanced nature of the disease at the time of clinical presentation. Various chemotherapeutic agents and radiation therapy regimens have been used, without demonstrable therapeutic benefit. ^[51]

Pseudomesotheliomatous carcinoma

Pseudomesotheliomatous adenocarcinoma has a poor prognosis, with a mean survival of approximately 7 months. In the study of Koss et al, the one-year survival was 39%, and the 18-month survival was 13%. ^[4] The prognosis of pseudomesotheliomatous lung adenocarcinoma is similar to that of diffuse epithelioid malignant mesothelioma. ^[46] Extrapleural pneumonectomy or therapeutic regimens of chemotherapy and/or radiation therapy have been used but are generally ineffective for this advanced form of lung adenocarcinoma. ^{[4, 46]}

Malignant solitary fibrous tumor

In a series by Schirosi et al, the median overall survival and disease-free survival in patients with SFT were 70 and 60 months, respectively. ^[10] In a population-based study of patients with malignant SFT, Milano et al found the 1-year, 5-year, and overall survival were 87%, 49%, and 4.6 years, respectively. ^[87]

Complete surgical excision via thoracoscopy or thoracotomy is the mainstay of therapy, which is curative in most SFTs. Complete excision with tumor-free margins is, moreover, the most important prognostic marker. ^[10] Prognosis does not always correlate with the histological appearance of the tumor.

In a series by England et al, 45% of 82 patients with histologically malignant tumors were cured of disease. Malignant tumors with prolonged survival tended to be pedunculated or well circumscribed and were completely excised surgically. Recurrence following surgery is more frequent in malignant than in benign SFTs. ^[9]

In a multivariate analysis of numerous pathologic features, Schirosi et al found that only immunohistochemical high p53 expression and tumor necrosis correlated significantly with overall survival and disease-free survival, respectively. ^[10]

Huang and Huang noted that factors associated with SFT aggressiveness include mitotic figures of more than 4/10 high-power fields (HPFs), TERT promoter, and/or TP53 mutations. ^[7]

Pleural synovial sarcoma

In intrathoracic synovial sarcomas, including pleural synovial sarcomas, bivariate analysis has shown that patient sex, age, fusion type, tumor site, tumor size, histologic grade, and histologic subtype did not significantly affect survival. ^[86] The therapy for synovial sarcoma is usually a multimodal approach consisting of surgical excision, chemotherapy, and radiation therapy.

Pleural desmoplastic small round cell tumor

DSRCT is a highly aggressive neoplasm. Death usually occurs within 2 years of diagnosis. ^[13] There have been no specific predictive factors described. Treatment consists of combination chemotherapy.

Primitive neuroectodermal tumor of the thoracopulmonary region (Askin tumor)

The prognosis of Askin tumor is generally poor. Current treatment usually includes, when possible, neoadjuvant chemotherapy followed by complete excision of the primary tumor to achieve clear surgical margins. ^[88] Postoperative doxorubicin-based chemotherapy is also a current standard approach. ^[89] Postoperative radiotherapy is deployed when surgical margins are positive. ^{[88, 90]}

In the original report by Askin et al, the mean survival was 8 months following diagnosis. ^[19] In another series, the 2-year survival rate was 38% and the 6-year survival rate was 14%. ^[18] Rare instances of extended survival have been reported. ^[91] Early detection of a relatively small primary lesion was thought to have been a factor in prolonged survival in one patient. ^[91]

Complete tumor resection with negative margins followed by chemotherapy may also achieve a longer disease-free survival. ^[89] Laskar et al, reporting on a large series of 104 consecutive patients with Askin tumor, identified pleural effusion, age (≥18 years), and poor response to induction chemotherapy as indicators of inferior survival. ^[92] After a median follow-up of 28 months, these authors found disease-free and overall survivals of 36% and 45%, respectively. Median time to relapse was 25 months, and the median survival was 76 months. ^[92] Fifty-six percent of patients who presented with metastatic disease died within 1 month of diagnosis, with a 2-year survival rate of 14%.

Vascular sarcomas of the pleura: Epithelioid hemangioendothelioma and angiosarcoma

Both EHE and angiosarcomas of the pleural are lethal tumors with a very poor prognosis. ^[93] Presently, there are no reliable prognostic factors. Anecdotal accounts of extended survival in patients with pleural EHE may suggest a better prognosis for well-differentiated tumors in this category; however, further studies of this issue are required. ^[52]

Pseudomesotheliomatous carcinoma

The major differential diagnoses to be considered in the histologic assessment of pseudomesotheliomatous lung adenocarcinoma include epithelioid pleural mesothelioma and pleural involvement by metastatic adenocarcinoma from an extrapulmonary primary site.

Diagnosis based on small pleural biopsy specimens may be difficult and subject to misinterpretation owing to nonrepresentative sampling of the fibrocollagenous stroma without demonstration of infiltrating tumoral glands. Immunohistochemical markers are usually required for diagnosis (See Immunohistochemistry).

Malignant solitary fibrous tumor

The major differential diagnostic considerations for malignant SFT include localized sarcomatoid mesothelioma, desmoplastic mesothelioma, and various benign and malignant mesenchymal tumors, such as hemangiopericytoma, extraintestinal gastrointestinal stromal tumors (GIST), desmoid tumor, monophasic synovial sarcoma, and other spindle cell sarcomas involving the pleura.

The features used to diagnose malignant SFT are those of England et al. ^[9] A high labeling index for Ki-67 and positive staining for p53 have been reported more frequently in malignant than in benign SFTs. ^[61] No difference has been shown in various histopathologic features or in Ki-67 or p53 staining in extrapleural versus pleural SFTs. ^[61]

Negative staining for pankeratin and positive staining for CD34 are useful in differentiating SFT from sarcomatoid mesothelioma. Focal keratin positivity in a histologically typical SFT likely represents entrapped mesothelial cells or lung epithelial cells. ^[3] However, rare CK-positive, CD34-negative malignant SFTs have been described. ^[10] Distinction from extraintestinal GIST can be readily determined by lack of staining of SFT for CD117 (in most cases). ^[74] CD34 is nondiscriminatory in this regard, since 47%-100% of GISTs showed positive staining for CD34. ^[3]

Panels of markers, including CD34 and keratin, are also helpful in distinguishing SFT from other spindle cell mesenchymal neoplasms. Distinction of malignant SFT from monophasic synovial sarcoma may prove challenging, especially in SFTs that lack CD34 expression or exhibit cytokeratin staining. FISH analysis for SYT rearrangement has been shown to be uniformly negative in SFTs and can be diagnostically helpful in this situation. ^[10]

Pleural synovial sarcoma

Major differential diagnostic considerations of biphasic pleural synovial sarcoma include biphasic mesothelioma, pulmonary carcinosarcoma secondarily involving the pleura, and pleuropulmonary blastoma. ^[94] Mesothelioma occurs in an older population and is usually diffuse or multifocal within the pleura compared to the localized mass of synovial sarcoma. The spindle cell component of synovial sarcoma is less pleomorphic and more densely compact than mesothelioma.

Histochemical stains may document mucin, which is resistant to hyaluronidase digestion in biphasic synovial sarcoma. Immunostains for cytokeratin are usually less intense and more focal than seen in mesothelioma. Calretinin may be present in both mesothelioma and synovial sarcoma. Compared to mesothelioma, synovial sarcoma often expresses Bcl-2 and BerEP-4, with absence of the mesothelial marker WT-1. ^{[64, 95]}

The differential diagnoses of monophasic synovial sarcoma include malignant SFT, sarcomatoid mesothelioma, spindle cell carcinoma of the lung with pleural involvement, and various primary spindle cell sarcomas, such as leiomyosarcoma, fibrosarcoma, and malignant peripheral nerve sheath tumors. ^[94] SFT more frequently exhibits the “patternless pattern” of short spindle cells interspersed with dense ropy collagen.

SFTs, like synovial sarcoma, are vimentin- and frequently Bcl-2–positive. CD34 is a useful discriminant since it is positive in SFT and negative in synovial sarcoma. Keratin is also helpful, being present in synovial sarcoma but absent in SFT. ^[65] Consideration of other entities in the differential diagnoses of synovial sarcoma may be accomplished with careful histological assessment and immunohistochemical staining features.

When in doubt regarding the histological and immunohistochemical diagnosis of synovial sarcoma, documentation of the t(X; 18) translocation should confirm the diagnosis.

Metastatic synovial sarcoma from an extrathoracic soft-tissue primary tumor is a more common than primary pleural synovial sarcoma. Histologically, primary pleural synovial sarcoma is similar to metastatic synovial sarcoma. In any case of synovial sarcoma involving the pleura, the possibility of metastatic spread should be considered and excluded clinically. ^{[8, 37]}

Pleural desmoplastic small round cell tumor

The major histologic differential diagnosis of DSRCT is EWS/PNET. The differential diagnoses also include other “small round blue cell tumors” such as small cell carcinoma, small cell variant of malignant mesothelioma, lymphoma, rhabdomyosarcoma, and small cell melanoma. ^[67]

EWS/PNET is characteristically positive for CD99 and vimentin but negative for cytokeratin, desmin, and WT1. The prototypic chromosomal translocation in EWS/PNET is t(11;22)(q24;q12), which involves the long arm of chromosome 11, in contrast to the translocation observed in DSRCT, which involves the short arm of chromosome 11. ^[67]

Small cell neuroendocrine carcinoma demonstrates similar histologic features as DSRCT, but without a prominent fibrous stroma. Small cell carcinoma is, however, a tumor of older individuals and is highly associated with tobacco smoke exposure. Small cell carcinoma is positive for cytokeratin and a wide range of neuroendocrine markers, but, unlike DSRCT, small cell carcinoma is positive for TTF1 and lacks staining for desmin.

Lymphoma generally occurs in a sheetlike infiltrating pattern and lacks the nesting pattern, cell cohesion, and fibrous stroma of DSRCT. Furthermore, lymphomas express characteristic lymphoid markers immunohistochemically and are negative for keratin and muscle and neuroendocrine markers. Primary pleural lymphomas are rare but have a poor prognosis. ^[2]

Rhabdomyosarcomas typically express a broader range of myogenic markers and lack staining for cytokeratin.

The small cell variant of mesothelioma is a very rare and somewhat controversial entity in which the neoplastic cells resemble those of small cell carcinoma but lack neuroendocrine markers and express mesothelial markers. Small cell mesothelioma occurs in older individuals with a history of asbestos exposure. ^{[3, 68]}

When in doubt regarding the differential diagnosis or for DSRCTs with atypical histological or immunohistochemical features, demonstration of the characteristic cytogenetic translocation or gene fusion product EWS-WT1 supports the diagnosis of DSRCT.

Primitive neuroectodermal tumor of the thoracopulmonary region (Askin tumor)

The histological distinction between PNET and extraskeletal EWS is not well defined. Previous studies have emphasized the presence of Homer-Wright rosettes and immunohistochemical neural markers as evidence of PNET. ^[96] Recent studies, however, have failed to reveal significant clinical differences between these two entities. A current recommendation is to classify these tumors as members of the EWS/PNET family, with a comment regarding the presence or absence of neural differentiation. ^[96]

Other entities in the differential diagnoses of Askin tumor include small cell carcinoma, neuroblastoma, alveolar rhabdomyosarcoma, poorly differentiated synovial sarcoma, and DSRCT. Metastatic pulmonary small cell carcinoma usually affects older adult smokers and presents as a primary lung mass. Histologically, the neoplastic cells of small cell carcinoma are more pleomorphic than those of PNET, and immunohistochemical markers show typically staining for cytokeratin and neuroendocrine markers such as synaptophysin and CD56.

Alveolar rhabdomyosarcoma may have a focally diffuse histological pattern that resembles PNET; however, an alveolar pattern is usually seen. Although rhabdomyosarcoma may sometimes stain for CD99, myogenic markers such as desmin, myogenin, or MyoD will be positive. ^[96] Alveolar rhabdosarcoma also exhibits a characteristic cytogenetic marker t(2;13)(q35;q14).

In young patients, neuroblastoma enters the differential diagnoses of PNET. However, compared to PNET, neuroblastoma includes the histological features of neuropil and ganglionic differentiation. Neuroblastoma rarely expresses the immunomarker CD99. Patients with neuroblastoma also have elevated levels of urinary catecholamine metabolites. Finally, neuroblastoma lacks the t(11;22) translocation found in the EWS/PNET family of tumors. ^[96]

Poorly differentiated synovial sarcoma may be difficult to distinguish from PNET owing to the presence of small round cells in poorly differentiated synovial sarcoma, lack of cytokeratin expression, and presence of membranous CD99 staining on immunohistochemistry. ^[96] In difficult cases, detection of the signature t(X;18) translocation or the SSX1/SYT or SSX2/SYT fusion products is diagnostic of synovial sarcoma.

Pleural DSRCT differs histologically from PNET by the presence of islands of small round tumor cells separated by fibrous bands. Immunohistochemically, DSRCT expresses the polyphenotypic expression of cytokeratin, vimentin, desmin, and neural markers. Staining for desmin is present as a perinuclear dot configuration. Up to 20% of DSRCTs may express CD99. DSRCT also usually shows nuclear expression of WT1, unlike PNET. In difficult cases, detection of the unique cytogenetic abnormality t(11;22)(p13;q12) with the detection of the EWS/WT1 fusion product supports the diagnosis of DSRCT. ^[96]

Vascular sarcomas of the pleura: Epithelioid hemangioendothelioma and angiosarcoma

The distinction between EHE and epithelioid angiosarcoma is sometimes difficult because of overlapping histological features and a similar immunohistochemical profile. The differential diagnoses of each of these tumors are similar and include sarcomatoid or biphasic mesothelioma, pseudomesotheliomatous carcinoma, and various metastatic tumors to the pleura, including malignant melanoma and epithelioid sarcoma.

In general, EHE can be differentiated from epithelioid angiosarcoma based on the presence of myxohyaline matrix and large epithelioid cells with little pleomorphism and low mitotic activity in EHE, compared to the marked pleomorphism and atypia with numerous mitotic figures in epithelioid angiosarcoma. ^[32] Immunostains are not helpful since both tumors express endothelial markers. There is not a consistent classification for tumors with a predominantly low-grade pattern of EHE which also have focal high-grade areas resembling epithelioid angiosarcoma. Some authors consider EHE and epithelioid angiosarcoma to represent a continuous spectrum of epithelioid vascular sarcomas involving the pleura. ^{[40, 97]}

Histologically, on routine hematoxylin and eosin stains, EHE and epithelioid angiosarcoma are sometimes indistinguishable from sarcomatoid or biphasic mesothelioma. ^{[55, 97]} Subtle features such as amphophilic cytoplasm, inconspicuous nucleoli, and intracytoplasmic lumina containing erythrocytes may suggest EHE. An initial clue to the presence of an epithelioid vascular sarcoma is strong staining for vimentin with absent or weak staining for pankeratin. ^[45] The reverse is true for mesotheliomas, which nearly always stain strongly for cytokeratin and less strongly for vimentin.

Expression of cytokeratin in some cases of EHE or angiosarcoma may cause confusion. Likewise confusing are the presence of cytokeratin-positive reactive submesothelial fibroblasts, which give a biphasic appearance, simulating mesothelioma. Immunostains for endothelial markers such as CD34, CD31, and factor VIII–related antigen are key to the diagnosis, since mesotheliomas rarely express these antigens.

Another diagnostic challenge is the distinction between epithelioid angiosarcoma and malignant fibrous tumor (see above). Malignant SFT usually presents as a localized mass but rarely spreads within the pleura in a diffuse fashion. Malignant fibrous tumors histologically have a spindle cell appearance compared to the epithelioid appearance of EHE or angiosarcoma. While both malignant fibrous tumor and EHE/epithelioid angiosarcoma are negative for cytokeratin and positive for CD34, malignant fibrous tumors lack staining for the more specific endothelial markers CD31 and factor VIII.

One must always consider the possibility of metastatic pleural disease before concluding that a vascular sarcoma is primary in the pleura. Both EHE and epithelioid angiosarcoma can be mistaken for metastatic carcinoma involving the pleura. ^[97] In general, carcinomas exhibit necrosis, prominent desmoplastic stroma, greater cellular pleomorphism, and evidence of epithelial differentiation compared to EHE.

Intracytoplasmic lumina of EHE may resemble the appearance of signet ring cells; however, mucicarmine stain is negative. Strong immunostaining for cytokeratin and the absence of endothelial markers in carcinoma help differentiate these 2 entities. Pseudoangiomatous squamous carcinoma is notable for simulating angiosarcoma owing to a lack of keratin formation and acantholysis of squamous nests which simulate anastomotic vascular channels. ^[55] CD10 positivity in EHE may simulate metastatic renal cell carcinoma or other tumors which express CD10. ^[79]

Metastatic melanoma involving the pleura can be excluded based on its distinctive immunohistochemical profile.

Finally, epithelioid sarcoma, a low-grade sarcoma usually arising in the extremities of young adults, may metastasize to the pleura and resemble EHE. Compared to EHE, epithelioid sarcoma tends to be histologically more pleomorphic and may have focal necrosis. In contrast to EHE, epithelioid sarcoma lacks significant myxohyaline stroma, and the cells have more eosinophilic nonvacuolated cytoplasm. Epithelioid sarcomas consistently express cytokeratin and EMA in addition to vimentin and may also be positive for CD34. Epithelioid sarcoma, however, lacks the more specific endothelial markers CD31 and factor VIII–related antigen.