General Thoracic Surgery (General Thoracic Surgery (Shields)) [2 VOLUME SET]

Editors: Shields, Thomas W.; LoCicero, Joseph; Ponn, Ronald B.; Rusch, Valerie W.

Title: General Thoracic Surgery, 6th Edition

Copyright 2005 Lippincott Williams & Wilkins

> Table of Contents > Volume I - The Lung, Pleura, Diaphragm, and Chest Wall > Section XI - The Pleura > Chapter 64 - Localized Fibrous Tumors of the Pleura

Chapter 64

Localized Fibrous Tumors of the Pleura

Thomas W. Shields

Anjana V. Yeldandi

Localized fibrous tumors of the pleura have previously been most often classified as localized mesotheliomas of the pleura, either benign or malignant. The malignant variety also has been classified by some investigators, including Martini and associates (1987), as fibrosarcomas. Conceptually Moran and Suster (2000) agree that the malignant tumor is best regarded as a fibrosarcoma of the pleura. Scharifker and Kaneko (1979), among others, have suggested that the cell origin of both the benign and malignant tumors is a noncommitted mesenchymal cell present in the subserosal tissue subjacent to the mesothelial lining of the pleura and is not from the mesothelial cells of the pleura, as the earlier name implies. Despite Moran and Suster's (2000) support of the term fibrosarcoma of the pleura, presently the most common term for the malignant variety is a localized malignant fibrous tumor of the pleura.

The studies of Dalton (1979), Said (1984), Dervan (1986), Keating (1987), and England (1989) and their associates, as well as the studies of Witkin and Rosai (1989) and el-Naggar (1989), Steinetz (1990), and Ordonez (2000) and their colleagues, have supported this concept of the mesenchymal origin of both the benign and malignant localized fibrous tumors of the pleura. Additional, but oblique, support of this concept is the observation that a history of asbestos exposure is lacking in the patients with these tumors, although a single case reported by Metintas and colleagues (1997) shows an association of malignant fibrous tumor in a person exposed to tremolite asbestos. Because no immunohistochemical studies were conducted in this case, one could speculate whether this case represented a localized malignant mesothelioma, which is in marked contrast to those patients with diffuse malignant mesothelioma in whom asbestos exposure is recorded in more than 60%.

BENIGN LOCALIZED FIBROUS TUMORS OF THE PLEURA

Pathologic Characteristics

Gross Features

Most benign localized fibrous tumors arise from the visceral pleura on a stalk and project into the pleural space in a pedunculated manner. Sessile attachment to the pleura occurs, and inward growth into the lung parenchyma may be seen infrequently (the so-called inverted fibroma). Yousem and Flynn (1988) reported three intraparenchymal localized fibrous tumors, only one of which was attached to the visceral pleura. They theorized that the other two may have arisen from mesenchymal cells in the interlobular septa or even de novo in the lung tissue. Localized fibrous tumors may also occasionally develop within a fissure. The benign tumors also may arise from the mediastinal, diaphragmatic, or costal portions of the parietal pleura. Tumors in these locations, however, including those arising within a fissure or growing into the lung, often prove to be malignant. In the report of Cardillo and colleagues (2000) of 55 localized fibrous tumors of the pleura, 7 tumors arose from one of these aforementioned nonvisceral pleural locations. Three of these tumors were of the malignant variety (43%), whereas only 4 of the 48 tumors arising from the visceral pleura were malignant (8%). Although many of these localized fibrous tumors that arise from the parietal pleura have a broad base, it was noted by Briselli and associates (1981) that some of these very large tumors may have a vascular pedicle. This may be associated with increased vascularity of the lesion. Weiss and Horton (2002) described such a case, and to facilitate a safer resection these investigators embolized the supplying vessel arising from the left costocervical

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Histologic Features

Microscopically, one or more histologic patterns can be seen. The most common pattern seen is the patternless pattern described by Stout (1971). Fibroblastlike cells and connective tissue are observed in varying proportions and are arranged in a disorderly or random pattern (Fig. 64-1). The tumor cells are spindle or plump ovoid cells with round to oval nuclei and small nucleoli. Collagen and elastin bundles are readily identified. Pleomorphism and mitosis are seen infrequently. The second most common pattern is described as hemangiopericytomalike and is often combined with the patternless pattern. In this variety, closely packed tumor cells are arranged around open or collapsed, irregular branching capillaries. Other uncommon patterns, always mixed with one of the aforementioned patterns, are described as storiform, herringbone, leiomyomalike, or neurofibromalike. Moran and associates (1992) have discussed the histologic growth patterns in both the benign and the malignant solitary fibrous pleural tumors.

Ultrastructural Features

Ultrastructurally, single to clusters of fusiform to round cells are found interspaced between focal or abundant collagen. The cells, according to Said and colleagues (1984), most closely resemble mesenchymal cells of fibroblastic type. Keating and co-workers (1987) noted that no basal lamina, intracellular junctions, or microvilli are seen. The observations of Briselli (1981), el-Naggar (1989), Steinetz (1990), and Ordonez (2000) and their associates support the fibroblastic and myofibroblastic nature of these cells.

Immunohistologic Features

Immunohistochemically, the spindle cells that make up these tumors do not express low- or high-molecular-weight keratin reactivity, nor do they express epithelial membrane antigen, carcinoembryonic antigen, factor VIII related antigen, neurofilament, or S-100 protein. The cells, however, have positive results with vimentin and weakly to variably positive results for muscle-specific actin. Westra (1994) and van de Rijn (1994) and their co-workers, as well as Flint and Weiss (1995) and Hanau and Miettinen (1995), reported consistent positivity of these tumors to CD34 monoclonal antibodies. CD34 reactivity is characteristically described as present in hematopoietic stem cells, endothelium, vascular tumors, and smooth muscle tumors. Bcl-2 oncoprotein (a regulator of cell death) has been identified in both the benign and malignant spindle (fibrous) cell of these pleural tumors as well as in tumors of this cell type in other locations by Chilosi (1997), Suster (1998), and Hasegawa (1998) and their colleagues. The lack of keratin reactivity and positive CD34 antigen and bcl-2 oncoprotein differentiates these fibrous tumors of the pleura from a

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Flow-Cytometric DNA and Cytogenetic Studies

El-Naggar and colleagues (1989) described a diploid DNA pattern in all 12 nonrecurrent benign fibrous tumors in their study. The S phase was low in all 12 as well. Miettinen and associates (1997) demonstrated loss or gain of chromosomes in large solitary fibrous tumors by comparative genomic hybridization, and they suggest that this might be useful in the evaluation of malignant transformation of solitary fibrous tumors.

Clinical Features

Benign localized fibrous tumors of the pleura occur with equal frequency in both men and women, although Milano (1990) reported a greater incidence in women. The tumor may occur in any age group but is more common in the fifth to eighth decades of life. More than half of the tumors are asymptomatic. Previously, Briselli and associates (1981), in a review of 368 patients with these tumors recorded in the literature, including eight of their own cases, noted that 64% were reported to have had symptomatic lesions. However, this included many patients diagnosed late. In addition, 12% of these patients had malignant lesions. Okike (1978) and England (1989) and their colleagues reported that chronic cough, chest pain, and dyspnea were the most common complaints (Table 64-2). Chest pain is most often manifested when the lesion arises from the parietal pleura. Pleural effusion rarely may be observed. Occasionally, in a patient with a large tumor, symptoms of bronchial compression and atelectasis may occur. Okike and colleagues (1978) recorded the occurrence of hypertrophic pulmonary osteoarthropathy in 20% of their patients. Briselli and associates (1981), in their collective review, reported an incidence of 22%. Frequently, the tumor is large (>7 cm) when this is observed. De Perrot (2002) and colleagues reviewed the literature and present clinical and histologic features with an algorithm for the management and follow-up of these patients.

Hypertrophic Pulmonary Osteoarthropathy

This symptom complex occurs in association with many intrathoracic disease processes. Clagett and colleagues (1952) at the Mayo Clinic reported that hypertrophic pulmonary osteoarthropathy occurred in 66% of cases of localized fibrous tumor of the pleura, although their later data presented by Okike and associates (1978) noted this association in only 20% of instances. Nonetheless, this pattern contrasts markedly with the overall 5% incidence of hypertrophic pulmonary osteoarthropathy in bronchial carcinoma, as reported in one of the lead articles in the Lancet (Lead Article, 1959). We have observed the incidence to be only 2% to 3% in this latter disease.

Osteoarthropathy describes a rheumatoidlike disease of the bones and joints. It is frequently associated with clubbing of the fingers, but it may be present without clubbing. Gynecomastia is similarly seen in association with hypertrophic pulmonary osteoarthropathy, but it also may occur as a solitary extrathoracic manifestation of an intrathoracic neoplasm.

The classic findings in hypertrophic pulmonary osteoarthropathy include stiffness of the joints, edema over the ankles and occasionally of the hands, arthralgia, and pain along the surfaces of the long bones, especially the tibia. At times, the joint and bone pain is severe.

The joint and bone involvement is usually bilateral. The distal ends of the ulna and radius are most frequently involved, and radiographic evidence of the periosteal thickening is most commonly seen here. The bones of the hands, ankles, knees, elbows, and shoulders are involved in that approximate order. Finger pressure on the anterior surface

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Clinical symptoms vary from minimally detectable stiffness of the wrists to systemic toxicity. Some of the systemic manifestations seem to be related to one or more endocrine, collagen, or immunologic mechanisms of the body that are not directly related to the osteoarthropathy. Chills and spiking temperature, markedly elevated sedimentation rate, and malaise with obvious systemic toxicity may be present.

Hypertrophic pulmonary osteoarthropathy may be associated with clubbing of the fingers and toes, although many investigators believe the latter is not actually part of the syndrome. Martinez-Lavin (1987) and Shneerson (1981), however, have suggested that the two processes are related and arise from the same underlying cause, most likely the overproduction or lack of metabolism by the lung of a growthlike hormone. Cardillo and associates (2000) assert that abnormal production of hyaluronic acid by the tumor cell is the cause, but no data were presented to support this statement, and there appears to be nothing in the literature concerning its role.

Clubbing

Clubbing is the enlargement of the distal phalanges, usually of both the hands and feet. Diner (1962) described periosteal new growth with lymphocytic and plasma cell infiltration of connective tissue around the nail beds, resulting in increased fibrous tissue between the nail bed and phalanx. Van Hazel (1940) reported the digital arteries to be enlarged and elongated 10 to 15 times normal. Also, Cudkowicz and Armstrong (1953) noted the presence of arteriovenous anastomosis in the distal finger segments near the junction of the dermis and the subcutaneous tissue.

Clinically, the distal phalanx is enlarged, especially widened, with a loss of the obtuse angle that the nail bed normally forms with the plane of the proximal skin surface. A spongy sensation on depression of the proximal nail bed is characteristic.

According to Martinez-Lavin (1987), a common denominator appears to be present in the various processes associated with clubbing. These processes can be broadly classified into pulmonary, cardiac, and extrathoracic. Only the first category is discussed.

Neoplastic lesions of the lung causing clubbing are generally associated with hypertrophic pulmonary osteoarthropathy, whereas the congenital structural and inflammatory pulmonary lesions associated with clubbing rarely show signs of arthropathy. Nonneoplastic pulmonary disorders seen with clubbing include pulmonary arteriovenous fistula, lung abscess, bronchiectasis, empyema, pulmonary infarction, emphysema, chronic bronchitis, chronic inflammation of the lung, sarcoidosis, idiopathic pulmonary fibrosis, diffuse interstitial fibrosis, primary pulmonary hypertension, pneumoconiosis, and atelectasis.

Etiology of Pulmonary Hypertrophic Osteoarthropathy and Clubbing

The etiology of hypertrophic pulmonary osteoarthropathy and clubbing remains an enigma. A single cause for these two frequently associated yet distinct phenomena is possible but seems unlikely. Flavell (1956) reported relief from the pain of hypertrophic osteoarthropathy after division of the vagus nerve at the hilus of the lung in patients with inoperable pulmonary neoplasms. Diner (1962) described dramatic relief of symptoms after cervical or thoracic vagotomy. Ginsburg (1958) found that blood flows in the hand and foot were similar in a control group and in patients with hypertrophic pulmonary osteoarthropathy. Lovell (1950), however, demonstrated increased blood flow in patients with clubbing secondary to congenital cyanotic heart disease. These patients had dilatated venous plexuses in the skin of the nail bed area, accompanied by increased caliber in the digital arteries and abnormal arteriovenous communications.

Although the cause of these conditions remains unknown, several observations may be made. First, clubbing of the fingers has some connection with arteriovenous shunting. Whether these abnormal arteriovenous communications permit a substance that is normally altered or detoxified in the lung to appear in the systemic circulation or whether small emboli that are usually filtered out by the lung are allowed to appear there is unanswered, but certainly the latter is highly debatable. Cudkowicz and Armstrong (1953) demonstrated precapillary bronchopulmonary anastomosis in patients with clubbing. Desaturation of the blood per se seems an unlikely explanation because the incidence of clubbing in severely emphysematous patients is so low. Second, circumstantial evidence exists in the relationship of hypertrophic pulmonary osteoarthropathy and involvement of the pleura. This aspect is borne out by the occurrence of the syndrome in some patients with localized fibrous tumors of the pleura, as well as in patients with peripheral bronchial carcinomas. A neoplastic process involving the pleura, the embryologic origin of which is pluripotential, may elaborate a substance that elicits osseous articular responses. This same neoplastic process also might create an arteriovenous fistula, producing clubbing. It has been suggested by Steiner (1968), Gosney (1990), and Silveira (2000) and their colleagues that ectopic production of a growth hormonelike substance such as vascular endothelial growth factor by a tumor or be it platelet-derived, as suggested by the studies of Mohle (1997) and Fonseca (1992) and their associates, may result in the development of clubbing, as well as in the occurrence of pulmonary osteoarthropathy. The role of platelet particles that interact with endothelial cell platelet-derived growth factor (PDGF), as well as von Willebrand factor antigen, which may indicate endothelial activation and damage, is unsettled, although PDGF plus transforming growth factor- is known to result in cell growth and collagen synthesis.

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The clinical significance of hypertrophic pulmonary osteoarthropathy is greater in its diagnostic than its therapeutic implications. Removal of the pulmonary lesion for the most part gives dramatic remission of the arthralgia and peripheral edema. In the series reported by Okike and associates (1978), 8 of 10 patients with localized fibrous tumors experienced complete relief of the symptom complex after operative removal of the tumor. Osseous radiographic changes regress much more slowly. Recurrence of a localized fibrous tumor is usually heralded by a return of the symptoms present with the original osteoarthropathy.

Hypoglycemia

Doege (1930) reported a large fibrosarcoma of the mediastinum associated with hypoglycemia, and Potter (1930) also recorded the occurrence of hypoglycemia with a large intrathoracic tumor. The association of hypoglycemia with mesenchymal tumors has been referred to as the Doege-Potter syndrome since both of these physicians separately reported the first cases of the presence of hypoglycemia associated with a fibrous intrathoracic tumor. This terminology is infrequently used, although Chamberlain and Taggart (2000) recently used it in a case so that one would be aware of this eponym. In addition, hypoglycemia has been observed infrequently with a number of diverse mesenchymal tumors. In 1968, Devroede and Tirol reported that 58 examples of hypoglycemia secondary to a mesenchymal tumor had been recorded in the literature up to that time. According to Silverstein and colleagues (1964), most of those were fibrosarcomas, although examples of neurofibroma, rhabdomyosarcoma, liposarcoma, leiomyosarcoma, hemangiopericytoma, and mesothelioma were also noted. In Briselli and associates' (1981) review of 360 cases of fibrous tumors of the pleura, the incidence of hypoglycemia was 4%.

As in the instances of hypoglycemia from other causes, the patient can present with varying symptoms of central nervous system deprivation of glucose. Convulsions, syncope, and even coma may occur. Death may result if the severe hypoglycemia is not corrected promptly.

Nelson and co-workers (1975) reviewed the numerous theories to explain the mechanism of hypoglycemia. Among these were (a) increased glucose consumption by the tumor; (b) a defect in glucose regulators (i.e., adrenocorticotropic hormone, growth hormone, or glucagon); (c) ectopic secretion of insulin by the tumor (i.e., the presence of a stimulator of insulin release or a potentiator of circulating insulin); (d) the inhibition of glycogenolysis; (e) the inhibition of lipolysis and hepatic gluconeogenesis; and (f) the presence of nonsuppressible insulinlike activity and insulinlike growth factors 1 and 2 (IGF-1 and -2).

The most acceptable theory of the mechanism of spontaneous hypoglycemia was advanced by Gorden and associates (1981) and supported by studies of Teale and Marks (1990) and Ron and colleagues (1989). According to Gorden and co-workers (1981), some nonpancreatic islet cell tumors (i.e., pleural fibroma, other mesenchymal tumors, and some epithelial and hematologic lesions) may secrete peptides with insulinlike activity: IGF-1 and IGF-2. These are polypeptides and are bound to specific binding proteins in the blood. The main binding protein is usually controlled by the growth hormone. By a negative feedback mechanism, IGF-1 and IGF-2 suppress the growth hormone. There are low levels of serum IGF-1 concentrations and a low insulin level as well as poor growth hormone response to hypoglycemia but a relatively high serum concentration of IGF-2. IGF-2 inhibits glycogenolysis and gluconeogenesis in the liver and suppresses lipolysis, all of which increase the peripheral glucose utilization, resulting in hypoglycemia. It was subsequently shown by Lowe and associates (1989) that messenger RNA for IGF-2 was present in the tumor tissues associated with the hypoglycemia. Kishi (2001) and Fukasawa (1998) and colleagues demonstrated IGF-2 in the tumor by immunohistochemistry and by Northern blot analysis, respectively. Chang and associates (2001) demonstrated IGF-1 receptor in the tumor by immunohistochemistry. Thus, it was postulated that the high levels of IGF-2 were the cause of the hypoglycemia as well as the abnormal ratio between the levels of IGF-1 and IGF-2 in favor of the latter. In support of this concept were the reports of Masson (1991) and Moat (1991) and their colleagues. In their studies, the blood levels of insulin, growth hormone, and IGF-1 and IGF-2 returned to normal values, as did the IGF-1/IGF-2 ratio after successful resection of typical localized fibrous tumors that had been associated with spontaneous nonislet cell tumor hypoglycemia.

Galactorrhea

Galactorrhea is a rare finding in patients with fibrous tumors of the pleura. It has been reported, however, by Briselli (1981) and McCaughey (1980) and their associates. The clinical abnormalities that result in its occurrence remain obscure.

Radiographic Features

The appearance of a localized fibrous tumor of the pleura is for the most part indistinguishable from that of other masses of the lung (Fig. 64-2). A circumscribed mass of varying size is usually located in the lung periphery or in the projection of an interlobar fissure. The larger neoplasms may have irregular shapes, although the margins are usually sharply defined. These tumors arise most often from a pedicle from the visceral pleura, but this latter feature is rarely recognized on the chest radiograph. Desser and Stark (1998) have reviewed the essential radiologic findings. Occasionally, movement of the mass may be demonstrated with changes in position when the tumor is on a stalk, as

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Diagnosis

Fine-needle aspiration (FNA) biopsy appears to be a valuable tool in suggesting a diagnosis in these peripherally located tumors. Milano (1990) has noted that it may occasionally be diagnostic. Dusenbery (1992), Apple (1997), Weynand (1998), and Clayton (2001) and their colleagues reported cytologic features of solitary fibrous tumors of the pleura. Their studies are based on FNA of these peripherally located tumors, preparation of cell blocks from the aspirations, and immunohistochemistry performed on the cell block. Immunohistochemically, the spindle cells of the tumor have negative results to keratin and positive results to CD34 antibodies. In association with cytologic features, immunohistochemistry, and characteristic radiologic findings, a precise diagnosis can be made preoperatively.

Treatment

Localized fibrous tumors of the pleura are usually amenable to surgical resection (Fig. 64-3). Tumors that are considered benign on the basis of being localized, however, may be malignant both histologically and clinically, so adequate removal of the original lesion must be ensured. Nothing in our experience suggests that lobectomy is preferable to local resection of a pedunculated lesion arising from the visceral pleura. If the lesion is within the lung parenchyma, however, resection of the lobe is advisable. A segmentectomy is occasionally sufficient, but even a bilobectomy may be necessary when the lesion is located within a fissure. Localized fibrous tumors of the mediastinal, diaphragmatic, and parietal pleura should be excised as widely as can be accomplished satisfactorily because these locations are more often associated with a malignant lesion. Removal can be accomplished via a standard open thoracotomy; however, Cardillo and associates (2000) recommend a video-assisted thoracic surgery (VATS) approach whenever possible. They reported the use of VATS in 39 of their 55 patients (70.9%). The standard open approach was reserved for patients with very large tumors, with multiple synchronous lesions, with inverted fibromas, and with obvious malignant lesions. It would appear that either approach is satisfactory as long as appropriate judgment is used in the final selection of the procedure.

Prognosis

Almost all patients with benign localized fibrous tumors of the pleura are cured by adequate excision of the lesion. Nomori and associates (1997) described a benign fibrous tumor arising from the diaphragm with subsequent recurrence

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MALIGNANT LOCALIZED FIBROUS TUMORS OF THE PLEURA

Incidence

The relative incidence of malignant localized fibrous tumors as compared with that of the benign lesions is unknown. Thirty-six percent of the fibrous pleural tumors reviewed by England and associates (1989) were malignant, but all of the 223 cases had been referred to the Armed Forces Institute of Pathology for study and represent a biased database. In the review of 360 cases by Briselli and colleagues (1981), the incidence of malignant tumors was 12%. In the report from the Mayo Clinic by Okike and co-workers (1978), the incidence was 13%, and in Cardillo and associates' (2000) series, the incidence was 12.7%. These latter figures may represent a more appropriate incidence of malignancy.

Pathologic Characteristics

Gross Features

The malignant variety of fibrous tumor, as compared with benign tumors, tends to be large, to be more often located atypically (from the parietal pleura, intralobar in location, or to exhibit inverted growth into the pulmonary parenchyma), and to show areas of necrosis and hemorrhage (Table 64-3 and Fig. 64-4).

Microscopic Features

Malignant fibrous tumors of the pleura, in contrast to benign tumors, show an increased cellularity, cellular pleomorphism, and an increased number of mitotic figures (Fig. 64-5; see Table 64-3). El-Naggar and associates (1989) observed higher mitotic counts than in the benign tumors. Extensive areas of myxomatous change, hemorrhage, and necrosis also are commonly seen.

Other Features

Immunohistochemically, no differences exist between benign and malignant tumors. The immunohistochemical features are positive staining for CD34 and vimentin but negative for keratins. The ultrastructural findings are not truly distinguishable from those tumors of the benign variety. Flow cytometric DNA studies showed an elevated S phase in contrast to a low S phase in benign lesions according to the study of el-Naggar and associates (1989). Uzoaru and colleagues (1994) described a single case of malignant fibrous tumor occurring in a 15-year-old girl. Flow cytometric analysis revealed an aneuploid population of tumor cells. Miettinen and associates (1997) demonstrated gain or loss of chromosomes in tumors larger than 10 cm and suggest that this might be useful in the evaluation of malignant transformation.

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Clinical Features

Most of these patients, approximately three fourths, in contrast to those with localized benign mesotheliomas, have symptoms. Chest pain, cough, dyspnea, and fever are the most common symptoms. Osteoarthropathy rarely, if ever, occurs with localized malignant lesions. Hypoglycemia, however, is more commonly seen in patients with malignant than with benign fibrous tumors of the pleura. An incidence of 11% as compared with 3%, respectively, is found according to the data of England and associates (1989).

Radiographic Features

The radiographic findings in patients with malignant fibrous tumors of the pleura are similar to those seen in patients with the benign variety, except that lesions tend to be larger and pleural effusion is seen more often. An incidence of associated pleural effusion of 32% was recorded by England and associates (1989). Occasionally, rib erosion may occur as the result of invasion of the chest wall. The CT scan often shows inhomogeneity of the lesion.

Diagnosis

In most instances, the diagnosis is not apparent until histologic examination of the resected specimen. Invasion of the chest wall or other adjacent structures within the chest grossly establishes the malignant nature of the lesion. Recurrence of a lesion originally thought to be benign must be regarded as suggesting the true malignant nature of the lesion (Fig. 64-6).

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Treatment

Wide local excision, including pulmonary and pleural resections, is performed as indicated. Resection of a lesion arising from the parietal pleura should include the tissue down to the endothoracic fascia when possible. Resection of the adjacent chest wall is done only if involvement is apparent. When complete resection is possible, postoperative adjuvant therapy (irradiation or chemotherapy) is not indicated. When the resection is incomplete, Martini and associates (1987) suggest that radiation therapy, both internal (brachytherapy) and external, should be used. Localized recurrence of a solitary malignant fibrous tumor should be evaluated for possible resection.

Prognosis

Okike and colleagues (1978) reported only a 12% long-term rate of survival in patients with localized malignant tumors. England and associates (1989), however, reported a survival rate of 45% among 71 patients they considered to have had malignant lesions; most of the survivors had either pedunculated or well-circumscribed tumors. Chest wall or pericardial invasion does not preclude long-term survival if a complete excision can be performed. Pleural effusion is a poor prognostic feature in the patients with a malignant fibrous tumor of the pleura.

Martini and colleagues (1987) reported 10 patients with long-term survival after complete resection of the tumor. England and associates (1989) concur that the most important indicator of clinical outcome is whether the tumor can be totally excised initially. Patients with incomplete excision all die from their disease.

Recurrences of even completely excised lesions do occur. Initially, these are almost always local at the site of excision. However, spread to other sites within the thorax or into the abdomen occurs (Fig. 64-7). Miller (2000) has recorded two recurrences at a thoracoscopic site. Operative spillage is to be avoided during VATS removal of any solitary localized fibrous tumor (benign or malignant), and each tumor should be protected by a bag as it is extracted through the chest wall port to prevent this unfortunate occurrence. Lymph node metastases are seen, as are blood-borne metastases, in patients with persistent or recurrent disease. The sites of metastases recorded, in order of decreasing frequency, are the liver, central nervous system, spleen, peritoneum, adrenal gland, gastrointestinal tract, kidney, intraabdominal lymph nodes, and bone. Most patients with recurrent disease survive less than 5 years.

REFERENCES

Apple SK, Nieberg RK, Hirschowitz SL: Fine needle aspiration biopsy of solitary fibrous tumor of the pleura. A report of two cases with discussion of diagnostic pitfalls. Acta Cytol 42:1528, 1997.

Briselli M, Mark EJ, Dickersin R: Solitary fibrous tumors of the pleura: eight new cases and review of 360 cases in the literature. Cancer 47: 2678, 1981.

Cardillo G, et al: Localized (solitary) fibrous tumors of the pleura: an analysis of 55 patients. Ann Thorac Surg 70:1808, 2000.

Chamberlain MH, Taggart DP: Solitary fibrous tumor associated with hypoglycemia: an example of the Doege-Potter syndrome. J Thorac Cardiovasc Surg 119:185, 2000.

Chang ED, et al: Malignant solitary fibrous tumor of the pleura causing recurrent hypoglycemia; immunohistochemical stain of insulin-like growth factor I receptor in three cases. J Korean Med Sci 16:220, 2001.

Chilosi M, et al: bcl-2 expression in pleural and extrapleural solitary fibrous tumors. J Pathol 181:362, 1997.

Clagett OT, McDonald JR, Schmidt HW: Localized fibrous mesothelioma of the pleura. J Thorac Surg 24:213, 1952.

Clayton AC, et al: Solitary fibrous tumor: a study of cytologic features of six cases diagnosed by fine-needle aspiration. Diagn Cytopathol 25:172, 2001.

Cudkowicz L, Armstrong JB: Finger clubbing and changes in the bronchial circulation. Br J Tuberc Dis Chest 47:277, 1953.

Dalton WR, et al: Localized primary tumors of the pleura: an analysis of 40 cases. Cancer 44:1465, 1979.

de Perrot M, et al: Clinical behavior of solitary fibrous tumors of the pleura. Ann Thorac Surg 67:1456,1999.

de Perrot M, et al: Solitary fibrous tumors of the pleura. Ann Thorac Surg 74:285, 2002.

Dervan PA, Tobin B, O'Connor M: Solitary localized fibrous mesothelioma: evidence against mesothelial cell origin. Histopathology 10:867, 1986.

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Desser TS, Stark P: Pictorial essay: solitary tumor of the pleura. J Thorac Imaging 13:27, 1998.

Devroede J, Tirol AF: Grant pleural mesothelioma associated with hypoglycemia and hyperthyroidism. Am J Surg 116:130, 1968.

Diner WC: Hypertrophic osteoarthropathy. JAMA 181:555, 1962.

Doege KW: Fibrosarcoma of the mediastinum. Ann Surg 92:955, 1930.

Dusenbery D, Grimes MM, Frable WJ: Fine needle aspiration cytology of localized fibrous tumor of pleura. Diagn Cytopathol 8:444, 1992.

el-Naggar AK, et al: Localized fibrous tumor of the serosal cavities: immunohistochemical, electron-microscopic and flow-cytometric DNA study. Am J Clin Pathol 92:561, 1989.

England DM, Hochholzer L, McCarthy MJ: Localized benign and malignant fibrous tumors of the pleura: a clinicopathologic review of 223 cases. Am J Surg Pathol 13:640, 1989.

Flavell G: Reversal of pulmonary hypertrophic osteoarthropathy by vagotomy. Lancet 1:260, 1956.

Flint A, Weiss SW: CD-34 and keratin expression distinguishes solitary fibrous tumor (fibrous mesothelioma) of pleura from desmoplastic mesothelioma. Hum Pathol 26:428, 1995.

Fonseca C, et al: Circulating plasma levels of platelet-derived growth factor in patients with hypertrophic osteoarthropathy [Abstract]. Clin Exp Rheumatol 10(suppl 7):73, 1992.

Fukasawa Y, et al: Solitary fibrous tumor of the pleura causing recurrent hypoglycemia by secretion of insulin-like growth factor II. Pathol Int 48:47, 1998.

Ginsburg J: Observations on the peripheral circulation in hypertrophic pulmonary osteoarthropathy. Q J Med 27:335, 1958.

Gorden P, et al: Hypoglycemia associated with non-islet cell tumors and insulin-like growth factors. N Engl J Med 305:1452, 1981.

Gosney MA, Gosney JR, Lye M: Plasma growth hormone and digital clubbing in carcinoma of the bronchus. Thorax 45:545, 1990.

Hanau CA, Miettinen M: Solitary fibrous tumor: histological and immunohistochemical spectrum of benign and malignant variants presenting at different sites. Hum Pathol 26:440, 1995.

Hasegawa T, et al: Frequent expression of bcl-2 protein in solitary fibrous tumors. Jap J Clin Oncol 28:86, 1998.

Keating S, et al: Solitary fibrous tumor of the pleura: an ultrastructural and immunohistochemical study. Thorax 42:976, 1987.

Khan JH, et al: Giant solitary fibrous tumor of the pleura. Ann Thorac Surg 65:1461, 1998.

Kishi K, et al: Hypoglycemia induced by secretion of high molecular weight insulin-like growth factor-II from a malignant solitary fibrous tumor of the pleura. Intern Med 40: 341, 2001.

Lead article. Lancet 2:389, 1959.

Lewis MI, et al: The case of the moving intrathoracic mass. Pedunculated benign localized pleural mesothelioma. Chest 88:897, 1985.

Li X, et al: Expression and localization of basic fibroblastic growth factor and its mRNA in solitary fibrous tumor. J Nippon Med Sch 68:384, 2001.

Lovell RRH: Observations on the structure of clubbed fingers. Clin Sci 9:299, 1950.

Lowe WL Jr, et al. Insulin-like growth factor-II in nonislet cell tumors associated with hypoglycemia: increased levels of messenger ribonucleic acid. J Clin Endocrinol Metab 69:1153, 1989.

Martinez-Lavin M: Digital clubbing and hypertrophic osteoarthropathy: a unifying hypothesis. J Rheumatol 14:6, 1987.

Martini N, et al: Pleural mesothelioma: current review. Ann Thorac Surg 43:113, 1987.

Masson EA, et al. Spontaneous hypoglycaemia due to a pleural fibroma: role of insulin like growth factors. Thorax 46:930, 1991.

McCaughey WTE, Kannerstein M, Churg J (eds): Tumors of submesothelial origin. In: Tumors and Pseudotumors of the Serous Membranes. Bethesda, MD: Armed Forces Institute of Pathology, 1980, p. 81.

Mendelson DS, et al: Localized fibrous pleural mesothelioma: CT findings. Clin Imaging 15:105, 1991.

Metintas M, et al: Malignant localized fibrous tumor of the pleura occurring in a person environmentally exposed to tremolite asbestos. Respiration 64:236, 1997.

Miettinen MM, et al: Tumor size-related DNA copy number changes occur in solitary fibrous tumors but not in hemangiopericytomas. Mod Pathol 10:1194, 1997.

Milano MJ: Benign mesothelioma. In Deslauriers J, Lacquet LK (eds): Thoracic Surgery: Surgical Management of Pleural Disease. St. Louis: CV Mosby, 1990.

Miller DL: Discussion of Cardillo G, et al. Localized (solitary) fibrous tumors of the pleura: an analysis of 55 patients. Ann Thorac Surg 70:1808, 2000.

Moat NE, et al: Spontaneous hypoglycaemia and pleural fibroma: role of insulin like growth factors. Thorax 46:932, 1991.

Mohle R, et al: Constitutive production and thrombin-induced release of vascular growth factor by human megalokaryocytes and platelets. Proc Natl Acad Sci USA 94:663, 1997.

Moran CA, Suster S: Tumors of the lung and pleura. In Fletcher CDM (ed): Diagnostic histopathology of tumors. 2nd Ed. New York: Churchill Livingston, 2000, p. 171.

Moran CA, Suster S, Koss MN: The spectrum of histologic growth patterns in benign and malignant fibrous tumors of the pleura. Semin Diagn Pathol 9:169, 1992.

Nelson R, et al: Hypoglycemic coma associated with benign pleural mesothelioma. J Thorac Cardiovasc Surg 69:306, 1975.

Nomori H, et al: Contacting metastasis of a fibrous tumor of the pleura. Eur J Cardiothorac Surg 12:928, 1997.

Okike N, Bernatz PE, Woolner LB: Localized mesothelioma of the pleura. Benign and malignant variants. J Thorac Cardiovasc Surg 75:363, 1978.

Ordonez NG: Localized (solitary) fibrous tumor of the pleura. Adv Anat Pathol 7:327, 2000.

Potter RP: Intrathoracic tumors. Radiology 14:60, 1930.

Ron D, et al: Increased insulin-like growth factor II production and consequent suppression of growth hormone secretion: a dual mechanism for tumor-induced hypoglycemia. J Clin Endocrinol Metab 68:701, 1989.

Said JW, et al: Localized fibrous mesothelioma: an immunohistochemical and electron microscopic study. Hum Pathol 15:440, 1984.

Scharifker D, Kaneko M: Localized fibrous mesothelioma of pleura (submesothelial) fibroma: a clinicopathologic study of 18 cases. Cancer 43:627, 1979.

Shneerson JM: Digital clubbing and hypertrophic osteoarthropathy: the underlying mechanisms. Br J Dis Chest 75:113, 1981.

Silveira LH, et al: Vascular endothelial growth factor and hypertrophic osteoarthropathy. Clin Exp Rheumatol 18:57, 2000.

Silverstein MN, Wakin KE, Bahn RC: Hypoglycemia associated with neoplasia. Am J Med 36:415, 1964.

Steiner H, Dahlback O, Waldenstrom J: Ectopic growth hormone production and osteoarthropathy in carcinoma of the bronchus. Lancet 1:783, 1968.

Steinetz C, et al: Localized fibrous tumors of the pleura: correlation of histopathological, immunohistochemical and ultrastructural features. Pathol Res Pract 186:344, 1990.

Stout AP: Tumors of the pleura. Harlem Hosp Bull 5:54, 1971.

Suster S, Fisher C, Moran CA: Expression of bcl-2 oncoprotein in benign and malignant spindle cell tumors of soft tissue, skin, serosal surfaces, and gastrointestinal tract. Am J Surg Pathol 22:863, 1998.

Tateishi U, et al: Solitary fibrous tumor of the pleura: MR appearance and enhancement pattern. J Comput Assist Tomogr 26:174, 2002.

Teale JD, Marks V: Inappropriately elevated plasma-like growth factor II in relation to suppressed insulin-like growth factor I in the diagnosis of non islet cell tumour hypoglycemia. Clin Endocrinol (Oxf) 33:87, 1990.

Uzoaru I, Chou P, Reyes-Mugica M: Malignant solitary fibrous tumor of the pleura. Pediatr Pathol 14:11, 1994.

van de Rijn M, Lombard CM, Rouse RV: Expression of CD34 by solitary fibrous tumors of the pleura, mediastinum, and lung. Am J Surg Pathol 18:814, 1994.

Van Hazel W: Joint manifestations associated with intrathoracic tumors. J Thorac Surg 9:495, 1940.

Weiss B, Horton DA: Preoperative embolization of a massive solitary fibrous tumor of the pleura. Ann Thorac Surg 73(3):983 985, 2002.

Westra WH, Gerald WL, Rosai J: Solitary fibrous tumor. Consistent CD34 immunoreactivity and occurrence in the orbit. Am J Surg Pathol 18:992, 1994.

Weynand B, Collard P, Galant C: Cytopathological features of solitary fibrous tumor of the pleura: a study of 5 cases. Diagn Cytopathol 18:118, 1998.

Witkin FG, Rosai J: Solitary fibrous tumor of the mediastinum. A report of 14 cases. Am J Surg Pathol 13:547, 1989.

Yousem SA, Flynn SD: Intrapulmonary localized fibrous tumor: intraparenchymal so-called localized fibrous mesothelioma. Am J Clin Pathol 89:365, 1988.

P.900

Zirinsky K, Hsu JT: Flopping mass in an asymptomatic woman. Chest 81: 733, 1982.

Reading References

Arkless D, Goranow I, Krastinow G: Hypoglycemia in an intrathoracic fibroma. Med Bull Vet Admin 19:225, 1942.

Arrigoni MC, et al: Benign tumors of the lung: a ten-year surgical experience. J Thorac Cardiovasc Surg 60:589, 1970.

Aufiero TX, et al: Intrapulmonary benign fibrous tumor of the pleura. J Thorac Cardiovasc Surg 110:549, 1995.

Barclay N, Ogbeide M, Grillo A: Gross hypertrophic pulmonary osteoarthropathy in a 7-year-old child. Thorax 25:484, 1970.

Barrett NR: The pleura. Thorax 25:515, 1970.

Berne AS, Heitzman ER: The roentgenologic signs of pedunculated pleural tumors. AJR 87:892, 1962.

Bouchi J, et al: Tumer fibrose solitaire de la pleura avec coma et hypoglycemi . Rev Pneumol Clin 49:243, 1993.

Cudkowicz L, Wraith DC: A method of study of the pulmonary circulation in finger clubbing. Thorax 12:313, 1957.

Hernandez FJ, Fernandez BB: Localized fibrous tumors of pleura: a light and electron microscopic study. Cancer 34:1667, 1974.

Maier HC, Barr D: Intrathoracic tumors associated with hypoglycemia. J Thorac Cardiovasc Surg 44:321, 1962.

Marie P: De l'ost oarthropathie hypertrophiante pneumonique. Rev Med Paris 10:1, 1890.

Oliaro A, et al: Il-mesothelom fibroso benigno della pleura. Minerva Chir 49:1311, 1994.

Sanguinetti CM, et al: Localized fibrous pleural tumour of the interlobular pleura. Eur Respir J 9:1094, 1996.

Spry CI, Williamson DH, James ML: Pleuromesothelioma and hypoglycemia. Proc R Soc Med 61:1105, 1968.

Sternon I, Paramentier G, Rutsaert J: Comas hypoglycemiques et mesotheliome pleural benin. Acta Clin Belg 26:44, 1971.

Von Bamberger E: Ueber Knochenveranderungen bei chronischen Lungen- und Herzkrankheiten. Z Klin Med 18:193, 1890.

Wierman H, Clagett OT, McDonald JR: Articular manifestations in pulmonary diseases. JAMA 155:1459, 1954.