Primary mesenchymal tumors of the lung, whether benign or malignant, are rare. Sarcomas with histopathologic features similar to those seen in soft tissues may arise in the bronchopulmonary region; thus, the histopathologic criteria for the diagnosis of pulmonary sarcomas or benign mesenchymal neoplasms are basically the same as those used when these tumors occur in more common locations, such as soft tissue or bone. Nevertheless, bronchopulmonary sarcomas are unusual tumors, accounting for no more than 1% of all the primary lung neoplasms. In 1954, Iverson documented three cases of primary pulmonary sarcomas and noted that between 1900 and 1950, only 16 cases had been presented in the literature. In 1979, Eskenasy reported 118 cases of primary lung sarcomas; however, close analysis showed that at least 68 of those cases, in today’s nomenclature, would not be designated mesenchymal tumors. Included in this study were pediatric cases, which may account for the high volume of pulmonary sarcomas. Eskenasy estimated a ratio of 1 sarcoma per every 30 to 35 cases, which appears to be fairly high, in view of the unusual occurrence of pulmonary sarcomas.
In a study from the Mayo Clinic encompassing a period of 28 years, Nascimiento and associates encountered only 18 cases of primary pulmonary sarcomas in adult or young adult patients ranging in age from 22 to 77 years. Attanoos and coworkers documented only 14 cases of primary sarcomas of the lung over a period of 30 years. These workers estimated that the incidence of primary sarcomas of the lung is in the range of 1 per every 550 bronchogenic carcinomas. Their study population ranged in age from 20 to 73 years, with a mean of 47 years. More recently, Keel and colleagues documented 26 cases of primary pulmonary sarcoma in a similar population, in which patient age ranged from 18 to 75 years, with a mean of 48 years. In this study, no time frame was reported to permit determination of the frequency of these tumors; however, the evidence indicates that primary pulmonary sarcomas are relatively rare and account for less than 1% of all primary malignant neoplasms.
This chapter considers all mesenchymal neoplasms, whether they are benign or malignant, which are grouped according to their cell differentiation when known.
HAMARTOMA (BENIGN MESENCHYMOMA)
Hamartoma is the most common mesenchymal neoplasm in the lung. Debate continues over whether this tumor represents a hamartomatous lesion or a true neoplasm that should be termed mesenchymoma . Arguments in both camps are interesting and convincing, but both have concluded that the tumor is benign. Two other lesions that are considered by some researchers to fall into the category of hamartoma are presented in this chapter under different designations: chondroma, defined as a mesenchymal neoplasm composed only of cartilage, and lipoma, as a similar lesion composed only of adipose tissue. The tumors that are designated here as hamartomas (or benign mesenchymomas) are composed of several tissue types.
Clinical Features
No predilection for either gender has been clearly documented for hamartomas, although in some series, male patients have predominated. Patient age may range from 17 to 77 years; however, the peak incidence is in the fifth and sixth decades of life. These tumors generally are intraparenchymal lesions and have been demonstrated to account for approximately 7% to 14% of all coin lesions. Central tumors also have been described but are rather uncommon and may account for approximately 10% of all lesions. The anatomic location of the tumor will determine symptomatology: When the tumor is intraparenchymal, patients may be completely asymptomatic, and the lesion usually is discovered during a routine chest radiographic examination. When the tumor is in a central location, patients may present with clinical signs and symptoms of bronchial obstruction including shortness of breath, cough, fever, and even weight loss. Although in the great majority of cases the tumor is a solitary mass, in some unusual cases multiple lesions may be noted on clinical presentation. The presence of intraparenchymal tumor in association with endobronchial tumor is even more unusual; nevertheless, such cases have been reported.
Macroscopic Features
Intraparenchymal lesions appear to be well circumscribed but not encapsulated and may be covered by a thin membranous tissue. On examination of the cut surface, the lesion appears to be slightly lobulated, with different-sized lobules apparent. The tumor is firm and whitish, with a mucoid or cartilaginous appearance. These lesions do not display areas of necrosis and hemorrhage. Tumor size may range from 1 cm to more than 10 cm in greatest dimension ( Fig. 7-1 ).
Lesions that are in an endobronchial location are smaller than intraparenchymal tumors, at 1 to 3 cm in greatest dimension. The tumor is firm and white and may be attached to the bronchial wall.
Histopathologic Features
Hamartomas are characterized by the presence of different types of tissues, including cartilage, adipose tissue, strands of smooth muscle, and invaginations of respiratory epithelium ( Figs. 7-2 to 7-5 ). These tissues may appear in various proportions in different tumors, and to some extent this variability will depend on the size of the lesion. If the tumor is centrally located, the lesions may be composed predominantly of cartilage, with little adipose tissue, and covered by respiratory epithelium; however, the invagination of respiratory epithelium seen in intraparenchymal lesions may be absent. Cellular pleomorphism and nuclear atypia are not common, except in large lesions, in which some nuclear atypia of the cartilaginous component may be seen. In endobronchial lesions, it is possible to observe residual endobronchial glands admixed with cartilage or adipose tissue.
Treatment and Prognosis
The treatment of choice for these lesions is surgical resection, which may be accomplished by different techniques depending on the location and size of the tumor. These lesions usually “shell out” easily, making them amenable to use of a more conservative surgical approach such as wedge resection. For larger or endobronchial tumors, the required surgical resection may be more extensive. These lesions are benign; therefore, complete surgical resection is curative. A few recurrences have been reported; these may be related to multicentricity.
TUMORS OF MUSCLE ORIGIN
Tumors of muscle origin constitute a family of both benign and malignant neoplasms including leiomyoma, leiomyosarcoma, and rhabdomyosarcoma.
Leiomyoma
Primary leiomyomas of the lung are rare; they are far less common than their malignant counterparts. In a majority of cases, leiomyomas are described in conjunction with other tumors of muscle origin, such as leiomyosarcomas, and they are thought to account for approximately 1% of all benign tumors of the lung. In earlier reports, the term leiomyomatous hamartoma has been used for these tumors when they appear to be multicentric. Some researchers, however, have suggested that such neoplasms should not be considered to be primary lesions of the lung but should rather be regarded as metastatic tumors.
Horstmann and colleagues documented a case of multiple pulmonary nodules in a 30-year-old pregnant woman that originally had been interpreted as leiomyomatous hamartomas and that underwent spontaneous regression during pregnancy and the postpartum period. The authors concluded that pulmonary fibroleiomyomatous hamartoma cannot be distinguished from the so-called benign metastasizing leiomyoma by clinical, radiologic, or histopathologic criteria, and that all of these tumors should be regarded as metastatic lesions from uterine tumors. Wolff and associates documented nine cases (six in women and three in men) in which the patients had multiple pulmonary nodules that originated in the soft tissues or the uterus. The investigators concluded that the designation “fibroleiomyomatous hamartoma” should be abandoned.
Although the great majority of multiple pulmonary lesions occur in female patients, similar cases have been reported in male patients. In cases with multicentric tumors, however, no definitive explanation for the multicentricity of the tumor has been properly documented at the time of diagnosis and brief follow-up, raising the possibility that in unusual circumstances, multicentric tumors may recur. In such cases, therefore, an appropriate clinical investigation should be undertaken in order to rule out the possibility of a metastatic tumor, from the uterus if the patient is female or from soft tissues if the patient is male. Primary leiomyomas in the lung do occur, but they are rare, and the vast majority of descriptions in the literature consist of single case reports or short series of cases.
Clinical Features
This tumor appears to be more frequent in female patients, an observation that raises some concern about whether the possibility of uterine leiomyoma was adequately investigated in some of the reported cases. The tumor appears to affect patients of various ages, ranging from children younger than 10 years to adults older than 50 years of age. The highest incidence appears to be in adults, with an average age of 35 years.
Primary leiomyomas of the lung may occur in intraparenchymal or endobronchial locations. With central tumors, patients may present with clinical signs and symptoms of bronchial obstruction that may include cough, chest pain, shortness of breath, or hemoptysis. Other presenting manifestations may include atelectasis and obstructive pneumonia. Patients with intraparenchymal tumors may be completely asymptomatic; in such cases, the tumor usually is discovered on a routine chest radiograph.
Macroscopic Features
Leiomyomas may range in size from 1 cm to more than 10 cm in greatest dimension. However, in our experience these tumors are rarely longer than 5 cm. Intraparenchymal tumors are sharply circumscribed, but not encapsulated. They are of firm consistency and whitish and display a homogeneous-appearing cut surface ( Fig. 7-6 ). Areas of hemorrhage or necrosis are not apparent. Centrally located tumors may appear to be pedunculated or attached to the wall of the bronchus, obliterating the lumen.
Histopathologic Features
These tumors appear as well-circumscribed masses obliterating normal lung parenchyma. Characteristically, they show a spindle cell proliferation arranged in fascicles that, in some areas, appear to intersect at 45-degree angles. The cellular proliferation is composed of fusiform cells with elongated nuclei, a moderate amount of eosinophilic cytoplasm, and inconspicuous nucleoli ( Figs. 7-7 to 7-9 ). Intermixed with this spindle cell proliferation are areas showing entrapped structures resembling clefts that appear to be lined by respiratory epithelium. Centrally located tumors show morphologic features similar to those of tumors in an intraparenchymal location and usually are covered by a rim of respiratory epithelium. In either of these anatomic locations, the tumor may display focal areas of myxoid change. In general, leiomyomas of the lung do not show hemorrhage or necrosis, and within the cellular proliferation, nuclear atypia or mitotic activity are absent.
Immunohistochemical Features
Although the diagnosis of leiomyoma usually is not challenging, in some cases immunohistochemical studies may aid in the diagnosis. Muscle markers, including muscle-specific actin, smooth muscle actin, and desmin, usually show positive staining in tumor cells. In some cases, keratin antibodies also may show positive staining.
Differential Diagnosis
The most important consideration in the differential diagnosis is metastatic disease, either from a uterine leiomyoma (i.e., benign metastasizing leiomyoma) or from a leiomyosarcoma. In both of those instances, a good clinical history or physical examination will lead to the correct interpretation. Primary pulmonary leiomyosarcoma also should be considered, mainly in cases in which limited biopsy material is available for evaluation. Another important diagnostic possibility is primary benign neural tumor (schwannoma). In this setting, the use of other stains, including those for S-100 protein and neurofilament protein, may aid in arriving at a correct interpretation.
Treatment and Prognosis
The treatment of choice is complete surgical resection, which is curative. The surgical approach for these tumors may vary, depending on their location. Intraparenchymal tumors are more amenable to a conservative approach because these tumors “shell out” easily. Endobronchial tumors may be more challenging to resect conservatively, and in some cases, lobectomy or even pneumonectomy has been necessary.
Leiomyosarcoma
Primary leiomyosarcomas of the lung are rare; however, they are more common than their benign counterparts (leiomyomas). Essentially the same principles are applied to the diagnosis of these tumors; a careful clinical history and physical examination are necessary to rule out metastatic disease. The diagnostic criteria are similar to those for soft tissue leiomyosarcomas. Most of the information regarding pulmonary leiomyosarcomas has been presented as single case reports or short series of cases, with only a few larger series. In some reported series, however, pulmonary leiomyosarcomas have been included in the general context of smooth muscle tumors or with other sarcomas, such as fibrosarcomas.
Clinical Features
Primary leiomyosarcomas in the lung are more common in adult patients; however, several cases occurring in children as young as newborns also have been described. These tumors may appear as intraparenchymal masses or may arise in an endobronchial location. Clinical signs and symptoms may be related to the anatomic location of the tumor. Patients with tumors in a central location may present with symptoms of bronchial obstruction, including cough, shortness of breath, chest pain, and hemoptysis. Patients with peripheral tumors may present with more systemic complaints such as weight loss, or they may be completely asymptomatic, with the tumor discovered on a routine chest radiograph. Other presenting manifestations may include clubbing of the fingers, pleural effusion, or Pancoast tumor. A unique case of a renin-producing leiomyosarcoma has been reported. On radiologic evaluation, no specific diagnostic hallmarks for leiomyosarcomas in the lung have been recognized.
Macroscopic Features
Tumor size may range from 1 cm to more than 10 cm in greatest dimension. Intraparenchymal tumors appear to be well-demarcated masses that may be encapsulated or surrounded by a thin covering of fibroconnective tissue. The cut surface may appear a bit “whorly” and whitish, with a firm consistency ( Fig. 7-10 ). Areas of hemorrhage and necrosis may be seen, and it is important to document such findings. Endobronchial tumors may manifest as pedunculated masses or may be firmly adherent to the bronchial wall. They are smaller than intraparenchymal tumors but may have the same gross features in terms of necrosis and hemorrhage.
Histopathologic Features
The morphologic features of primary leiomyosarcomas of the lung are similar to those seen in soft tissue tumors. The microscopic appearance is characterized by a spindle cellular proliferation arranged in broad fascicles of tumor cells that intersect at right angles, replacing normal lung parenchyma or protruding into the bronchial lumen. The cells have light eosinophilic cytoplasm, elongated “cigar-shaped”nuclei, and inconspicuous nucleoli. On the basis of their cytoarchitectural features, pulmonary leiomyosarcomas have been separated into three distinct histologic grades :
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Low-grade leiomyosarcomas: Tumors are composed of a spindle cell proliferation, which on higher magnification shows mild cytologic atypia and a mitotic count of 1 to 3 mitotic figures per 10 high-power fields ( Figs. 7-11 to 7-13 ). Cellular pleomorphism and hemorrhage and necrosis are absent.
Figure 7-11
Low-grade pulmonary leiomyosarcoma. A spindle cell proliferation can be seen replacing lung parenchyma.
Figure 7-12
Low-grade pulmonary leiomyosarcoma with ectatic vessels.
Figure 7-13
High-power view of a low-grade leiomyosarcoma showing mild nuclear atypia and scattered mitotic figures.
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Intermediate-grade leiomyosarcoma: The fascicular pattern of growth is preserved; however, the tumors show more prominent cellularity and increased mitotic activity in the range of 4 to 8 mitotic figures per 10 high-power fields ( Figs. 7-14 to 7-16 ). Cytologic atypia is present but not marked, and occasionally, pleomorphic cells may be present. Necrosis and hemorrhage are absent.
Figure 7-14
Intermediate-grade leiomyosarcoma with more obvious cellular atypia.
Figure 7-15
Intermediate-grade leiomyosarcoma showing a focal infarcted area.
Figure 7-16
Intermediate-grade leiomyosarcoma with readily identifiable mitotic figures.
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High-grade leiomyosarcoma: A more solid spindle cell proliferation is displayed, with areas still preserving the fascicular pattern of growth, which may acquire a storiform or hemangiopericytic pattern. Areas of necrosis or hemorrhage are readily identified. Degenerative changes, such as myxoid change and stromal hyalinization, can be seen. Cellular pleomorphism is marked, with larger cells that have prominent nucleoli; mitotic figures are easily identified and number more than 8 per 10 high-power fields ( Figs. 7-17 to 7-21 ). In some cases, vascular invasion is identified.
Figure 7-17
High-grade leiomyosarcoma with marked cellular atypia.
Figure 7-18
High-grade leiomyosarcoma with a hemangiopericytic pattern.
Figure 7-19
High-grade leiomyosarcoma with extensive areas of necrosis.
Figure 7-20
High-grade leiomyosarcoma showing myxoid changes.
Figure 7-21
High-grade leiomyosarcoma showing mitotic figures and nuclear atypia.
Immunohistochemical Features
The tumor cells show positive staining for smooth muscle actin, desmin, and vimentin. As the tumor loses differentiation, however, variability in the staining pattern for these muscle markers may be noted. In high-grade tumors, the staining may be only focal, whereas in low-grade tumors, the staining may be stronger and diffuse. Leiomyosarcomas also may coexpress positive staining for keratin antibodies, so a wider than usual panel of immunohistochemical studies will be necessary to properly evaluate these neoplasms.
Molecular Studies
Schneider and associates reported a case of a primary pulmonary leiomyosarcoma in a child. Karyotypic studies demonstrated consistent abnormalities of chromosomes 1, 5, 6, and 7; relative gain of chromosomes 2 and 11; and relative loss of chromosomes 9, 19, 20, and 22.
Differential Diagnosis
One of the most important considerations in the differential diagnosis is metastatic disease. The only way to distinguish between primary and metastatic disease is by careful analysis of findings on the clinical history and physical examination. On morphologic grounds, other spindle cell sarcomas may enter into the differential diagnosis, including monophasic synovial sarcoma, intrapulmonary solitary fibrous tumor, and neurogenic sarcoma. In this setting, positive immunostaining for muscle markers (smooth muscle actin and desmin) and negative staining for S-100 protein and CD34 should indicate the correct interpretation. In high-grade tumors, pleomorphic carcinoma may enter into the differential diagnosis. Although pleomorphic carcinoma also may show focal staining for actin, it usually does not show positive staining for desmin and negative staining for keratin. In the same context, malignant melanoma also may be a consideration; the use of S-100 protein, HMB-45, and Melan A may be helpful in these cases.
Treatment and Prognosis
The initial treatment for patients with pulmonary leiomyosarcoma usually is surgical excision of the tumor. Once that is accomplished, the patient may be a candidate for adjuvant treatment (e.g., chemotherapy, immnotherapy, radiotherapy), depending on the clinical details of the case. Tumor size and degree of differentiation are important factors in determining prognosis. Tumors of low-grade malignancy may follow a more protracted course, whereas those of high-grade malignancy may exhibit more aggressive behavior. Widespread metastatic disease with spread to adjacent organs or viscera has been documented. In some cases of high histologic grade, fatal outcome within a 24-month period has been documented.
Rhabdomyosarcoma
Primary pulmonary rhabdomyosarcomas are exceedingly rare in the adult population. Rhabdomyosarcoma may be encountered as a component of another neoplasm, such as carcinosarcoma; the tumor in its pure form is rare. Nevertheless, it has been described in adults as well as in children. Some of the pediatric cases have been reported as cystic, raising the possibility that they may belong in the spectrum of pleuropulmonary blastomas.
Adult patients may present with clinical signs and symptoms of bronchial obstruction, including chest pain, shortness of breath, hemoptysis, and weight loss. These tumors may occur in a central or peripheral anatomic location, and tumor size may be more than 10 cm in greatest dimension.
Histopathologic Features
The tumors described in the adult population have been characterized by a closely packed spindle cell proliferation, arranged in fascicles and alternating with areas of discohesive cellular proliferation ( Fig. 7-22 ). The spindle cell proliferation is arranged in a storiform pattern, and areas of necrosis and hemorrhage are readily identified ( Figs. 7-23 and 7-24 ). At high magnification, the neoplastic cells can be seen to have moderate amounts of eosinophilic cytoplasm, oval nuclei, and, in some cells, prominent nucleoli ( Figs. 7-25 to 7-27 ). Areas showing extensive pleomorphism with atypical mitotic figures are readily identified, as well as numerous rhabdomyoblasts ( Fig. 7-28 ). Cross-striations are present in some cases, although they may be difficult to identify.
Immunohistochemical Features
The use of immunohistochemical studies, including staining for muscle markers, may aid in the diagnosis of rhabdomyosarcoma. Desmin, myoglobin, caldesmon, and myo-D are important markers that may show different staining patterns. The use of a wider panel of stains is important, however, because some tumors may show a stronger reaction with one or more of these markers. Rhabdomyosarcomas also may coexpress keratin positivity—hence the importance of expanding the panel of immunohistochemical studies performed.
Differential Diagnosis
Because of the rarity of primary rhabdomyosarcomas in the lung, considerations in the differential diagnosis should include other primary tumors of different histogenesis that may show the same pleomorphic features. The most important diagnostic consideration is pleomorphic carcinoma, an epithelial tumor that may show extensive areas of cellular pleomorphism, necrosis, hemorrhage, and spindle cell component. Pleomorphic carcinomas will not show positive staining for desmin, myoglobin, caldesmon, or myo-D, although they may show staining for smooth muscle actin. Another important diagnostic entity to consider is primary rhabdoid carcinoma of the lung. Rhabdoid carcinoma, as its name implies, usually shows a cellular proliferation that may closely resemble that of rhabdomyoblastic differentiation. Once again, staining for muscle markers—desmin, myoglobin, caldesmon, or myo-D—generally is negative in these tumors, whereas staining for keratin shows strong positive reaction in tumor cells. Because of the prominent spindle cell proliferation seen in pleomorphic rhabdomyosarcomas, other spindle cell sarcomas also should be considered in the differential diagnosis. In this setting, the use of a wider panel of antibodies should lead to a more accurate interpretation.
Treatment and Prognosis
The treatment for most primary rhabdomyosarcomas of the lung is complete surgical resection, followed by chemotherapy. In most of the published cases, the outcome has been death, despite aggressive treatment, in as little as 24 months. Therefore, every effort should be made to obtain early diagnosis and accurate classification of these neoplasms.
TUMORS WITH PROMINENT FIBROBLASTIC COMPONENT
Tumors that show a prominent fibroblastic component are of varied histology and may include the entire spectrum of differentiation, ranging from benign to high-grade malignancy. Although these tumors are rarely encountered as primary lung neoplasms, it is important to include them as possibilities in the differential diagnosis for spindle cell tumors of the lung. Owing to advances in immunohistochemical studies and molecular techniques, some tumors that used to be classified as common, such as pulmonary fibrosarcoma, are now considered to be tumors of unusual occurrence. These changes have had a positive impact not only on diagnosis and classification of these rare tumors but also on the treatment of affected patients.
Some of the tumors that are discussed in this section also may be classified as biphasic tumors (adenofibromas), because they also may show some epithelial component in addition to the usual fibroblastic component; however, because of the prominence of their spindle cell fibroblastic component, they are included here. Similar claims can be made for hemangiopericytoma, which traditionally has been considered to be a vascular tumor; however, other lung tumors also may show a striking hemangiopericytic pattern, making this particular entity very difficult to diagnose as a primary lung tumor. It also shares immunohistochemical features with other tumors, especially with the intrapulmonary solitary fibrous tumor. Therefore, these tumors are grouped by histopathologic growth patterns, rather than similar histogenesis, which remains a matter of debate. The following tumors are discussed:
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Pulmonary adenofibroma
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Fibrosarcoma
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Intrapulmonary solitary fibrous tumor
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Hemangiopericytoma
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Monophasic synovial sarcoma
Pulmonary Adenofibroma
Pulmonary adenofibroma was described in 1993 as a glandular and spindle cell proliferation closely resembling adenofibromas of the genital tract and ovary. The reporting investigators thought that these tumors might be benign hamartomatous lesions and alluded to at least two different cases in which different terminology might have been used for the same neoplasm. In one of the previously described cases, the tumor was an incidental finding at autopsy and the stated diagnosis was fibroadenoma, owing to its close resemblance to similar tumors in the breast. The other case belonged to a series of pulmonary hamartomas. Therefore, it is possible that adenofibromas represent a variant of pulmonary hamartoma, without the presence of cartilage or adipose tissue.
Clinical Features
Adenofibromas occur in adults, who may be completely asymptomatic, with discovery of the pulmonary nodule made incidentally during a routine radiographic examination. The lesions often are described as intrapulmonary “coin” lesions.
Macroscopic and Histopathologic Findings
Pulmonary adenofibromas usually are rather small tumors that measure approximately 1 or 2 cm in greatest dimension. They are well-circumscribed, intraparenchymal lesions, not related to airways, with a firm to rubbery consistency. On histologic examination, the tumors display a spindle cell proliferation composed of oval cells embedded in a sclerotic background and arranged in a papillary growth pattern, reminiscent of those described in müllerian adenofibromas ( Figs. 7-29 to 7-31 ). The spindle cells show elongated nuclei and scant cytoplasm. Myxoid changes and inflammatory infiltrate may be seen focally; cellular atypia and mitotic activity generally are absent. The tumor also shows complex, branching spaces lined by an epithelium that is surrounded by cuboidal or columnar cells. In some areas, gland-like spaces lined by tall columnar epithelium also may be seen ( Figs. 7-32 and 7-33 ).
Immunohistochemical Features
Adenofibromas usually stain positively for vimentin, with positive staining for keratin and epithelial membrane antigen (EMA) in the epithelial lining. Staining for other antibodies including those for actin, desmin, S-100 protein, and CD34 is negative.
Differential Diagnosis
Although the diagnosis of adenofibroma is straightforward, some malignant tumors that show a biphasic growth pattern may enter into the differential diagnosis, including pulmonary blastoma, carcinosarcoma, and biphasic synovial sarcoma. In these entities the spindle cell proliferation will show cellular atypia and mitotic activity, which generally is absent in pulmonary adenofibroma. In addition, negative staining for antibodies against keratin, EMA, S-100 protein, or Bcl-2 in the spindle cell component may provide valuable information in cases of synovial sarcoma. Finally, the epithelial component of adenofibromas is benign and lacks atypia and mitotic activity, unlike that of blastoma or carcinosarcoma.
Treatment and Prognosis
Surgical resection by either tumor enucleation, wedge resection, or even lobectomy is the treatment of choice for adenofibromas. The clinical course of these tumors appears to be indolent; thus, complete surgical resection appears to be curative.
Fibrosarcoma
Fibrosarcomas represent a distinct tumor of rare occurrence, which in the past was claimed to be one of the most common sarcomas of the lung. With the use of immunohistochemical studies in current daily practice, however, it is possible that a good number of the cases previously reported as bronchopulmonary fibrosarcomas would now be classified as different neoplasms. In 1972, Guccion and Rossen reported a study of 32 cases of primary pulmonary sarcomas in which they described 13 cases of bronchopulmonary fibrosarcoma and alluded to 48 previously reported cases. These tumors were separated by anatomic location into central and peripheral lesions; histologically, they appeared to range from low- to high-grade malignancy. The investigators noted similarities between fibrosarcomas with pleural involvement and what used to be called “localized fibrous mesothelioma” (currently classified as solitary fibrous tumors), citing their comparable behavior and metastatic potential. This analogy may have been the basis for the current term intrapulmonary solitary fibrous tumor .
Pettinato and colleagues described five cases of bronchopulmonary fibrosarcoma, emphasizing the importance of separating this tumor from other sarcomas and linking it to the infantile fibrosarcoma of soft tissue. These workers also documented the indolent behavior displayed by some of these tumors and noted the possible difference in tumor behavior between pediatric and adult cases.
Clinical Features
Fibrosarcomas appear to affect people of all ages—they have been described in newborns, young children, adolescents, and older adults. No gender predilection has been recognized, nor any predilection for either lung or particular lung segment. Associated clinical signs and symptoms will depend largely on the anatomic location of the tumor and patient age at presentation. In young adults and in older persons with centrally located tumors, the clinical presentation may include shortness of breath, cough, chest pain, and hemoptysis, which are common findings in bronchial obstruction. Patients with peripheral tumors may be asymptomatic, and the tumor may be identified during a routine radiographic examination. Partial lung opacification may be seen on the chest film in some cases.
Macroscopic Features
The size of these tumors will depend on the anatomic location; tumors in a central location may be smaller than those in the periphery of the lung. In general, they have been described as ranging in size from 1 cm to more than 10 cm in greatest dimension. In a central location, the tumor may appear to obstruct the bronchial lumen and grow in a polypoid fashion, whereas intraparenchymal tumors may appear to be well circumscribed but not encapsulated. Regardless of their anatomic distribution, the tumors are firm to rubbery in consistency and whitish, and the cut surface may have a homogeneous, smooth appearance. Areas of necrosis or hemorrhage may be seen in high-grade tumors.
Histopathologic Features
The classic histopathologic description for fibrosarcoma is that of a spindle cell proliferation composed of elongated cells arranged in a herringbone-like pattern ( Figs. 7-34 and 7-35 ). The spindle cells have scant cytoplasm, vesicular nuclei, granular chromatin, and inconspicuous nucleoli. The spindle cell proliferation is tightly packed, with little intercellular matrix ( Fig. 7-36 ). Mitotic activity varies, with counts ranging from 2 or 3 ( Fig. 7-37 ) to more than 10 mitotic figures per 10 high-power fields. Areas with extensive hyalinization, calcifications, and a discrete inflammatory infiltrate may be seen in some cases. Areas of necrosis are more common in high-grade tumors. Centrally located tumors are more likely to show features of low-grade histology, in contrast with the larger and more mitotically active peripheral tumors.
Immunohistochemical Features
Because the histopathologic features described for bronchopulmonary fibrosarcoma also may be seen with intrapulmonary solitary fibrous tumor and synovial sarcoma, a battery of immunohistochemical staining procedures must be performed to accomplish proper histologic classification. The use of immunostains for keratin, EMA, CD34, Bcl-2, and vimentin is required. In cases of solitary fibrous tumor, CD34 and Bcl-2 may show positive staining, whereas keratin, EMA, and Bcl-2 may be of help in identifying synovial sarcoma. Vimentin will show positive staining in all of these tumors. When tumors of muscle origin enter into the differential diagnosis, the use of smooth muscle actin, desmin, or caldesmon may be of help. If immunohistochemical stains fail to identify the tumor with certainty, then molecular studies should be conducted, because synovial sarcomas are associated with a specific translocation that may aid in distinguishing them from fibrosarcoma. In essence, the diagnosis of fibrosarcoma in the lung has become one of exclusion.
Differential Diagnosis
As mentioned previously, the diagnosis of fibrosarcoma relies on distinguishing it from other tumors with similar histopathologic features, including monophasic synovial sarcoma, leiomyosarcoma, neurogenic sarcoma, and solitary fibrous tumor. The use of immunohistochemical studies is of great importance for accurate classification of these tumors.
Treatment and Prognosis
The treatment for fibrosarcoma is complete surgical resection, which may be followed by chemotherapy or radiation therapy, depending on the clinical circumstances. In the cases reported by Guccion and Rossen, the tumors displayed aggressive clinical behavior, with development of metastatic disease within a period of 24 months. In the pediatric cases described by Pettinato and associates, however, four of the children survived for periods ranging from 4 to 9 years. Accordingly, the investigators suggested that bronchopulmonary fibrosarcomas in children may carry a more favorable prognosis than that for tumors reported in adults.
Intrapulmonary Solitary Fibrous Tumor
Although solitary fibrous tumors of the pleura occur relatively frequently, their intrapulmonary counterparts are rather rare, and no sizable series of cases have been published thus far. A majority of the cases have been presented as individual case reports, and the histopathologic description has been that of a low-grade tumor with a low mitotic index. This observation raises the possibility that when this entity displays features of high-grade sarcoma, it may be classified as other than a “malignant” intrapulmonary solitary fibrous tumor.
Yousem and Flynn are credited with the original description of these tumors in an intrapulmonary location. Their three cases represent the largest series reported to date, and the histopathologic features of these specimens resembled those of pleural solitary fibrous tumors. Subsequently, only a few additional case reports have been presented in the literature.
Clinical Features
The tumor affects patients in various age groups, and although one pediatric case has been reported, a majority of the cases appear to occur in adults. Patients may be completely asymptomatic, with the tumor identified during a routine radiographic examination, whereas others may present with nonspecific signs and symptoms such as cough, fatigue, and dyspnea. Hypoglycemia, a finding often encountered in pleural tumors, has not been reported in connection with intraparenchymal tumors. No predilection for gender, lung, or lung segment has been noted. On radiographic evaluation, some of these tumors have been described as “coin” lesions.
Macroscopic Features
The tumors appear to be well circumscribed, but not encapsulated, with no pleural involvement. Size may range from 1 to 4 cm in greatest dimension. The tumors have been described as firm and white to gray in color, with a whorled appearance ( Fig. 7-38 ). Areas of calcification may be seen. Focal areas of necrosis or hemorrhage have been observed in a few cases and may indicate a possibly higher-grade tumor.
Histopathologic Features
The basic histologic pattern in intraparenchymal tumors is the same as that described in pleural tumors. They may display hypo- and hypercellular areas with a spindle cell proliferation, which may adopt different histopathologic patterns, including the so-called patternless pattern and hemangiopericytic, neural, and angiofibromatous patterns. Areas of collagenization alternating with a spindle cell proliferation, composed of elongated, medium-sized cells with elongated nuclei and inconspicuous nucleoli in different proportions, are common features in these tumors ( Figs. 7-39 to 7-44 ). The presence of different growth patterns within the same tumor is an indication that intrapulmonary solitary fibrous tumor may be the correct diagnosis. Although the histopathologic characteristics described in published cases have been similar to those of conventional solitary fibrous tumors with low or absent mitotic activity and absent necrosis and hemorrhage, numerous cases encountered in our own experience displayed the histopathologic features of malignant solitary fibrous tumors (unpublished data), including areas of increased mitotic activity ( Figs. 7-45 and 7-46 ), necrosis, or hemorrhage. The spectrum of histopathologic features may be similar to that described for pleural tumors. An important feature of intrapulmonary solitary fibrous tumors is the presence of entrapped alveolar epithelium, which in some cases may mimic a biphasic lung neoplasm.
Immunohistochemical Features
Like their counterparts in the pleura, intrapulmonary solitary fibrous tumors will display positive staining for CD34 ( Fig. 7-47 ), vimentin, and Bcl-2 ( Fig. 7-48 ), whereas staining for keratin, actin, desmin, and S-100 protein is negative in the spindle cell component. In one of the reported cases, the investigators performed genetic studies disclosing that the tumor was negative for HMGA1 and HMGA2 (high mobility group AT-hook 1 and 2) translocations.
Differential Diagnosis
The most important consideration in the differential diagnosis is other spindle cell sarcomas—namely, fibrosarcoma and monophasic synovial sarcoma. Use of a panel of immunohistochemical stains may help with proper classification. It is vital to distinguish these tumors from other, higher-grade neoplasms, because the treatment for intrapulmonary solitary fibrous tumors is different from that for high-grade tumors. The presence of low mitotic activity, coupled with the positive staining pattern with use of CD34 and Bcl-2 and negative staining for epithelial markers including keratin and EMA, should lead to the correct interpretation.
Treatment and Prognosis
No large series with long follow-up have been presented, so the natural course of these tumors is unknown. In a majority of cases, the treatment has been complete surgical resection, with an uneventful postoperative course. The follow-up period has been short, however, and the histologic features described have been characteristic of benign or low-grade tumors with low mitotic activity. In cases in which the histologic pattern is similar to that of a high-grade sarcoma, surgical resection of the tumor may be followed by adjuvant treatment (e.g., chemotherapy, immunotherapy, radiotherapy).
Hemangiopericytoma
Whether hemangiopericytomas truly exist in the lung parenchyma has been a subject of controversy. Some investigators argue that many tumors may show a hemangiopericytic-like pattern of growth, and that in the lung, “hemangiopericytoma” may occur only as a growth pattern, rather than as a specific entity. The overlap of immunophenotype with that of other tumors, including the solitary fibrous tumor, which may show a hemangiopericytic growth pattern, has raised other issues regarding the validity of classifying hemangiopericytomas as a true clinicopathologic entity. Nevertheless, hemangiopericytomas have rarely been described as primary pulmonary neoplasms.
In 1974, Meade and associates reported 4 cases and analyzed the current literature, accumulating 24 additional cases of hemangiopericytoma that presumably had arisen in the lung parenchyma as a primary neoplasm. These investigators divided the hemangiopericytomas into benign and malignant tumors but also noted their lack of uniformity in appearance and growth. In 1987, Yousem and Hochholzer reported the largest series of pulmonary hemangiopericytomas to date, describing 18 cases that were morphologically similar to soft tissue tumors. Although these workers separated the tumors into benign, undetermined, and malignant categories, they did not find any correlation between histologic pattern and clinical behavior except for the size of the tumor (>8 cm). To date, no large series of pulmonary hemangiopericytomas, detailing a longer follow-up period and additional immunohistochemical analysis, has been published to confirm or deny the existence of hemangiopericytoma in the lung. Nevertheless, the hemangiopericytic pattern commonly is seen as a growth pattern with several different tumors.
Clinical Features
Hemangiopericytomas have been described in young and older adults, without predilection for either lung or any lung segment. In the analysis of Meade and colleagues, the tumor was reported more often in female patients, whereas Yousem and Hochholzer did not find any gender predilection. The tumor appears to be more common among patients in the fifth decade of life, and patients may be completely asymptomatic or may present with nonspecific signs and symptoms such as cough, shortness of breath, and hemoptysis. Cases in which patients have presented with hypoglycemia or osteoarthropathy have been described ; these latter clinical manifestations also have been seen in association with solitary fibrous tumors. In contrast with previous studies, Yousem and Hochholzer found that these tumors were more commonly seen in the periphery or midportion of the lung than in a central location. In only a few of their cases was the tumor centrally located.
Macroscopic Features
Hemangiopericytomas appear to occur in an endobronchial location, in the midlung field, or in the periphery of the lung. Tumor size may range from 1 cm to more than 10 cm in greatest dimension. The tumor usually is firm in consistency and appears to be well circumscribed but not encapsulated and light brown or tan, with or without areas of necrosis or hemorrhage. When the tumor is in an endobronchial location, it may show a polypoid growth pattern; cystic tumors also have been described.
Histopathologic Features
The histopathologic hallmark of hemangiopericytomas is a proliferation composed of oval to spindle cells growing around large, prominent, gaping, staghorn-like vessels with an attenuated endothelium, which may or may not contain red cells in their lumens ( Figs. 7-49 and 7-50 ). The cells have scant cytoplasm, oval nuclei, and inconspicuous nucleoli. Mitotic activity may vary, with counts ranging from none to more than 10 mitotic figures per 10 high-power fields ( Fig. 7-51 ). Areas of hemorrhage and necrosis may be seen in some cases. The tumor usually appears to be fairly well circumscribed, but in some cases, tumor cells appear to infiltrate adjacent lung parenchyma.
Immunohistochemical Features
Because a hemangiopericytic pattern may be seen in many different tumors, it is important to perform a wide panel of immunohistochemical studies, which should include epithelial, muscle, neural, and vascular markers. Leiomyosarcomas may show areas of a hemangiopericytic pattern, and these tumors usually will demonstrate positive staining for muscle markers such as smooth muscle actin, desmin, or caldesmon. Synovial sarcoma, which also shows a hemangiopericytic pattern, demonstrates positive staining for keratin or EMA, or both, whereas neuronal tumors may show staining for S-100 protein or neurofilament protein. Some of the immunostains, however, may show reactivity when used with other tumors that also show a hemangiopericytic pattern. For instance, CD34 and Bcl-2 may stain positively in solitary fibrous tumors and synovial sarcomas, respectively. If the main distinction in the differential diagnosis is from synovial sarcoma, for example, an expected finding would be at least focal staining in tumor cells with keratin or EMA; in cases of solitary fibrous tumor, however, the issue is more complex, because both tumors share a similar immunophenotype. In this setting, careful evaluation of the morphology of the tumor may be more important. Solitary fibrous tumors usually show different patterns of growth within the same tumor, thus providing an important diagnostic feature.
Differential Diagnosis
The most important considerations in the differential diagnosis are solitary fibrous tumor, synovial sarcoma, and leiomyosarcoma. As indicated previously, a broad panel of immunohistochemical studies should be used to distinguish these tumors from one another. Also, when the possible diagnostic entities share a similar immunophenotype, a clear interpretation is very difficult. The current tendency is to label those tumors for which a designation of hemangiopericytoma versus solitary fibrous tumor is in question as the latter type.
Treatment and Prognosis
The largest series and reviews of pulmonary hemangiopericytoma have documented recurrences and metastatic disease in many patients. Accordingly, some researchers have suggested that all “hemangiopericytomas” are potentially malignant. Yousem and Hochholzer were not able to identify with certainty any particular histopathologic feature to correlate with clinical behavior and further claimed that mitotic count was not reliable. Meade and colleagues documented mortality rates of 32% to 50%, with higher rates in males than in females. The size of the tumor at the time of diagnosis appears to correlate with prognosis, and an arbitrary size of 8 cm or more has been mentioned as a cutoff size.
The treatment of choice is surgical resection, which may be followed by adjuvant medical therapy, depending on individual clinical circumstances, including the extent of disease at the time of diagnosis.
Monophasic Synovial Sarcoma
Primary intrathoracic sarcomas with features of synovial sarcomas of soft tissues are neoplasms of more recent description. These tumors were first reported in an intrapulmonary location in 1995, in a series of 25 cases. This original description constitutes the largest series to date of intrapulmonary monophasic synovial sarcomas. Following this description, numerous case reports have been presented corroborating the diagnosis by means of immunohistochemistry or molecular biology techniques. Other brief series of cases have expanded the anatomic distribution to include pleuropulmonary synovial sarcomas or have added molecular studies to the assessment protocol. Some studies, although they appear to present a larger number of cases, have emphasized gathering cases that may affect the pleura, lung, and mediastinum. In one of these larger series, which reported 60 cases, it is very likely that some, if not a majority, of the cases reported as tumors of the lung may have been included in the initial description of the tumor, because both of these series came from the same institution. Agreement appears to be unanimous that these tumors occur in the lung as well as in other thoracic locations. Only tumors occurring within the lung parenchyma are considered in the following discussion.
Clinical Features
The tumors affect a wide range of age groups, with reported cases in patients ranging from 16 to 77 years of age. The tumors affect both males and females, without any specific gender predilection. Clinical signs and symptoms typically are related to the anatomic distribution of the tumors. Patients with centrally located tumors may present with manifestations of bronchial obstruction, including shortness of breath, chest pain, cough, and hemoptysis; patients with peripheral tumors may be completely asymptomatic or may experience other nonspecific symptoms. In rare cases, patients may present with pneumothorax or may report a history of radiation therapy.
Macroscopic Features
As previously stated, the tumor may be centrally or peripherally situated in the lung. Size ranges from less than 1 cm to larger than 10 cm in greatest dimension. Monophasic synovial sarcomas usually are well circumscribed but not encapsulated and gray to tan in color. Necrosis, hemorrhage, and cystic changes may be seen in some cases ( Fig. 7-52 ). The cut surface is smooth in appearance, with a rubbery to firm consistency. In some cases, the tumor appears to be infiltrative, with differing degrees of airway involvement.
