53 - Tumors of the Diaphragm
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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trunk. Even with some smaller benign tumors, vascular adhesion between the tumor and the adjacent visceral or parietal pleura is not uncommon and may be troublesome at the time of operation. The benign fibrous tumors are almost always solitary and are ovoid or round. The external surface may be smooth or bosselated. According to England and associates (1989), a thin, membranous capsule is present in approximately half of the cases. The size may vary greatly from a small nodule to a huge mass that may completely fill the hemithorax. Recent reports of massive (giant) localized solitary tumors of the pleura have been published by Khan and colleagues (1998) and Chamberlain and Taggart (2000). One case of a massive tumor was noted in Cardillo and associates' (2000) series, and an additional case report has been published by Weiss and Horton (2002). Regardless of the size, on cut section, the tumor is nodular and is composed of dense, whorled fibrous tissue that may contain cystlike structures filled with a clear viscid fluid in 10% to 15% of cases. Calcifications may be present within the tumor.
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Fig. 64-1. Localized benign fibrous tumor of pleura with dense, wirelike strands of collagen sprinkled with plump fibroblastlike cells forming a patternless pattern. B. Photomicrograph of a hemangiopericytic pattern from a benign localized fibrous tumor of the pleura. |
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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desmoplastic mesothelioma (Table 64-1). Li and associates (2001) demonstrated the expression of basic fibroblastic growth factor in the tumor cells by immunohistochemistry and by in situ hybridization.
Table 64-1. Differentiation of Localized Fibrous Tumor and Diffuse Mesothelioma of the Pleura: Immunoreactivity | |||||||||||||||||||||||||||
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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.
Table 64-2. Symptoms of Benign Localized Fibrous Tumors of the Pleura | |||||||||||||||||||||||||||||||||
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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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of the distal tibia often elicits pain in advance of any radiologic changes.
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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Such interaction may have a role in the development of hypertrophic osteoarthropathy.
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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recorded by Lewis and associates (1985). Zirinsky and Hsu (1982) also demonstrated this change in location by computed tomography (CT). However, CT examination, per se, has little to add to the standard radiographic examination of these lesions. Mendelson and colleagues (1991) have reviewed the CT findings relative to this tumor. The report of de Perrot and associates (1999) confirms the CT findings of the heterogeneity of the density of these tumors. The Hounsfield units (HU) vary between 25 and 40 as a general rule. Tateishi and colleagues (2002) have reviewed the magnetic resonance (MR) imaging findings, which showed variable appearance and enhancing patterns based on the morphologic heterogeneity of the tumor. Infrequently, a pleural effusion may be present. In the collective review of England and associates (1989), 8% of 138 patients had a pleural effusion as the initial clinical finding.
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.
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Fig. 64-2. Posteroanterior (A) and lateral (B) radiographs of the chest of a 68-year-old woman revealing a small peripheral mass in the anterior aspect of right upper lobe. At thoracotomy, the mass was found to be a pedunculated fibrous tumor attached to the visceral pleura of the right upper lobe. |
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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of the tumor to the parietal pleura within an area of contact from the primary tumor. England and associates (1989) noted only two recurrences in 98 patients (2%), and in both patients a second curative resection was possible. Any recurrences, however, must be viewed with suspicion.
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Fig. 64-3. Radiograph of the chest revealing a 3-cm solitary nodule at the level of the fifth interspace anteriorly in the right lung. B. Radiograph of the same patient 10 years later, revealing marked enlargement of the mass. At thoracotomy a benign fibrous tumor was readily removed. |
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.
Table 64-3. Pathologic Features that Distinguish Benign and Malignant Localized Fibrous Tumor of Pleura | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Fig. 64-4. Gross morphology of a malignant fibrous tumor in a 77-year-old man. A. The lobulated mass weighed 624 g and measured 15 11 5 cm. B. Cut section of the tumor shows a firm tumor with areas of necrosis and hemorrhage. The tumor recurred in 8 months, and the patient died after 17 months. |
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Fig. 64-5. Microscopic section of a malignant fibrous tumor of the pleura. A. Histology demonstrates increased cellularity and increased number of mitotic figures. B. High-power view shows cellular pleomorphism. |
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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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Fig. 64-6. A, B. Posteroanterior and lateral radiographs of the chest revealing a large solitary mass, which was diagnosed as a benign fibrous tumor on its removal by a right upper lobectomy. C, D. Posteroanterior and lateral radiographs of the chest 6 months after removal of the tumor, revealing rapid recurrence of the tumor, which required a pneumonectomy for its complete removal. The mass was frankly malignant on histologic examination. The patient died from recurrent malignant fibrous tumor of the pleura. |
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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.
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Fig. 64-7. Gross morphology of a recurrent malignant fibrous tumor from a 60-year-old woman. A, B. Multiple nodules of various sizes are seen. |
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.
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