Clinical Attributes

SCs arise in the large bronchi and peripheral lung fields much more often than in the trachea, although the authors have indeed seen some lesions that originated above the carina. The majority of individuals with pulmonary SC are men, and most have a history of heavy smoking.^14,23,24 The average patient is 60 years of age.³³ Clinical signs and symptoms produced by these tumors are directly associated with the tumor’s specific location. Endoluminal lesions in large tubular airways characteristically cause refractory or recurrent pneumonia in the corresponding distal parenchyma, or they are associated with progressive dyspnea, cough, hemoptysis, and audible expiratory rhonchi over the affected lung field.^{14–17,23,45–47,50,51} In contrast, SC in the peripheral lung often manifests no symptoms or, alternatively, leads to chest pain caused by invasion of the pleura and extrapulmonary soft tissue.²³ As might be expected, central endobronchial tumors are smaller than peripheral SCs; their average sizes are 6 cm and greater than 10 cm, respectively^46,52 (Fig. 14-1).

Figure 14-1 A, Computed tomogram showing an endobronchial mass in the left mainstem bronchus. B, Resection of the lung demonstrated an endoluminal neoplasm that proved to be a sarcomatoid carcinoma.

Despite their anaplastic nature, SCs of the lung are surgically resectable in roughly 90% of cases,^23,33 and approximately one half of patients with such neoplasms present with stage I disease. Paradoxically, however, the prognosis of pulmonary SC is still dismal. Overall 5-year survival is 20%, with a slightly better figure being associated with small, central endobronchial lesions.^23,33,52 Metastatic SC of the lung involves the same organ sites that are affected by more usual forms of lung cancer: namely, the opposite lung, liver, bones, adrenal glands, and brain.^46,51 The metastases may exhibit either carcinomatous or sarcoma-like histologic configurations, or both.⁴⁶ Adjuvant radiation treatment and chemotherapy have been used in many cases of pulmonary SC, but these measures have provided little benefit in general.^14,33,38

Macroscopic Features

Grossly, the lesions of pulmonary SC that are greater than 5 cm in size tend to exhibit central necrosis and hemorrhage, and they also demonstrate irregular permeation of the surrounding lung parenchyma^33,34 (Fig. 14-2). Tumors that are smaller and located within bronchial confines often exhibit a polypoid appearance and are attached to the subjacent mucosa by a relatively narrow stalk of tissue.⁵² SCs in the peripheral lung parenchyma may have the gross appearance of conventional adenocarcinomas.³⁴

Figure 14-2 Peripheral sarcomatoid carcinoma of the right lung, as seen in a plain chest film (A) and in a lobectomy specimen (B). A reconstructed computed tomography image (C) demonstrates a Pancoast tumor.

Histologic Characteristics

Biphasic SCs of the lung can be divided into two subgroups, based on the nature of the stromal elements in each lesion. These variants may be called homologous and heterologous SCs.

Homologous Biphasic Sarcomatoid Carcinoma

Variants of SC that are also called spindle cell carcinomas are constituted microscopically by a predominance of nondescript spindled and pleomorphic cells, admixed with a minor, obviously carcinomatous, component. The latter portion of such lesions is generally inconspicuous and variably distributed; in roughly 40% of cases, such foci are very rare and require extensive sampling to document their presence. The general appearance of the carcinomatous elements is that of a well- to moderately differentiated squamous malignancy in most instances, whereas adenosquamous, adenocarcinomatous, large cell undifferentiated, or neuroendocrine carcinoma is seen in a minority of cases^14,53–56 (Fig. 14-3). Rare examples of this tumor type show mixtures of several carcinoma morphotypes.⁵⁴ Zones of transition between epithelial and sarcoma-like components are usually evident, at least focally.

Figure 14-3 A to C, Homologous biphasic sarcomatoid carcinoma of the lung, showing overtly epithelial growth apposed to sarcoma-like pleomorphic elements. D, An immunostain for keratin demonstrates reactivity in both neoplastic components. Cytokeratin expression can be highly variable, with some tumors expressing only scant cytokeratin immunoreactivity.

The sarcomatoid elements of this subtype of SC lack specialized differentiation into identifiable myogenic, chondro-osseous, or vasoformative tissues by standard light microscopy, and, as such, are homologous (organ-appropriate) to the lung. They are composed of markedly heterogeneous cells with nuclear atypia and variable growth patterns. The corresponding microscopic images range from those of fibromatosis-like or low-grade fibrosarcoma-like areas, with relatively bland nuclear features, sparse mitoses, moderate-to-rich matrical collagen deposition, and a “herringbone” pattern, to others in which pleomorphic giant cells are mixed with fusiform elements showing dense cellularity, coarse chromatin, prominent nucleoli, and numerous mitoses14–16,^23,33,45 (Fig. 14-4). The last of these descriptions is closely similar to that attending spindle cell–pleomorphic malignant fibrous histiocytoma (MFH) of the soft tissues.⁵⁴ Neoplastic spindle cells often infiltrate the submucosa of small- and medium-sized bronchi, which nonetheless tend to retain their mural cartilage plates and mucosal integrity.^33,34

Figure 14-4 Sarcomatoid carcinoma of the lung simulating malignant fibrous histiocytoma (A) with storiform growth of neoplastic fusiform and pleomorphic cells (B; boxed area in part A). C, Fine needle aspiration biopsy of sarcomatoid carcinoma showing dyshesive and pleomorphic malignant cells, such as those seen in true sarcomas.

Sarcoma-like elements in some biphasic spindle cell carcinomas may include cytologically bland, osteoclast-like giant cells^52,57,58 (Fig. 14-5). The latter are admixed with atypical fusiform cells or more uniform polygonal tumor cells. Another variant histologic pattern is that in which bluntly fusiform tumor cells surround discrete zones of necrosis, producing a necrotizing granuloma-like image. Rare examples of SC may demonstrate extravasated erythrocytes between relatively bland spindled tumor cells, simulating the characteristics of Kaposi sarcoma (KS) or even nodular fasciitis.³³

Figure 14-5 Osteoclast-like giant cells may be identified in sarcomatoid lung carcinoma.

Heterologous Biphasic Sarcomatoid Carcinoma

Other biphasic sarcomatoid neoplasms differ from the descriptions just given, in regard to their content of focal myogenous, vasogenic, chondro-osseous, or lipogenic differentiation.⁵⁹ Thus, they are analogous to the heterologous form of malignant mixed müllerian tumors of the uterus, ovaries, and other female genital sites.^60,61 Those neoplasms may exhibit microscopic foci that simulate embryonal or adult-type pleomorphic rhabdomyosarcoma, which contain proliferations of closely apposed compact round cells with a slightly myxoid background, or large “strap” cells with cytoplasmic eosinophilia and cross-striations, respectively^{14–16,33,34,46,52} (Fig. 14-6). Other heterologous SCs contain components that closely imitate the histologic features of osteosarcoma or chondrosarcoma.^23,34 In light of this information, it is easy to understand why lesions with such microscopic features were believed to be carcinosarcomas in the past and are still so designated by some observers today. The obviously carcinomatous elements in these lesions usually take the form of squamous carcinoma, but lesions with glandular or neuroendocrine differentiation have also been reported.^14,54,55 Transitional zones between obvious epithelial foci, nondescript sarcomatoid areas, and myosarcoma-like components are often evident.

Figure 14-6 A, Heterologous biphasic sarcomatoid carcinoma of the lung, showing obviously epithelial elements juxtaposed to rhabdomyosarcoma (RMS)-like elements with cytoplasmic cross-striations (arrows). B, Cytoplasmic eosinophilia is present in the RMS-like cells. C, Immunoreactivity is seen for myogenin in the RMS-like foci.

With regard to the relationship between biologic behavior and histologic appearance, there is no difference in the clinical evolution of homologous and heterologous biphasic pulmonary SCs. A distinction is made between those lesions only to reflect their synonymity with sarcomatoid epithelial tumors in other body sites.^60,61

Monophasic Sarcomatoid Carcinomas

Some SCs display no conventional light microscopic evidence of epithelial differentiation whatsoever. A carcinomatous nature for these neoplasms is discerned only after immunohistochemical or ultrastructural evaluations have been done, but it is usually suspected beforehand because of the clinical and gross characteristics of the lesions.³³

Most tumors in this category are constituted exclusively of cell populations like those in the sarcoma-like components of biphasic SCs. These potentially include foci that have an unremarkable spindle cell or pleomorphic image (Fig. 14-7) as well as areas imitating rhabdomyosarcoma, osteosarcoma, or other morphologic appearances that do not correspond to native tissues in the non-neoplastic lung. Because of the monomorphic nature of the tumor variants under discussion here, which lack any attributes of conventional lung carcinomas histologically, the corresponding diagnosis suggested by the World Health Organization criteria for pulmonary neoplasms⁶² (based only on hematoxylin and eosin stains and conventional histologic examination) would be that of a primary pulmonary sarcoma. The latter point has made the existence of monophasic SC of the lung somewhat contentious. Nevertheless, we have no doubt of its validity as a reproducible pathologic entity, and other authors appear to concur.³⁵

Figure 14-7 A, Monophasic spindle cell sarcomatoid carcinoma of the lung, simulating fibrosarcoma or monophasic synovial sarcoma. B, Fine needle aspiration specimens from this case demonstrate loosely cohesive aggregates of the spindle cells and may be viewed as generic images for all lesions discussed in this chapter.

Indeed, one might go so far as to state that virtually all malignant pulmonary tumors that are exclusively composed of heterologous (organ-inappropriate) elements—such as osteoblastic tissues^63,64—are, in reality, monophasic SCs. That statement pertains even if no immunohistochemical evidence of epithelial differentiation can be found, because the ultimate biological evolution of such lesions is identical to that of conventional lung cancers.

Pulmonary Blastoma

Since its initial description by Barnett and Barnard⁶⁵ and a later discussion by Spencer,⁶⁶ pulmonary blastoma (PB) has been regarded by some observers as the pulmonary counterpart of primitive childhood tumors of other organs.^67–73 This view has been fostered in part by confusion of PB with pleuropulmonary blastoma (PPB; discussed subsequently), the latter of which is primarily seen in adolescent patients.^74–80 PB is a biphasic neoplasm, containing a mixture of tubular epithelial cell profiles and compact groupings of nondescript bluntly fusiform cells with a blastema-like configuration^39,74,77 (Fig. 14-8). These resemble the elements of renal Wilms tumors.⁸¹ On the other hand, PPB altogether lacks epithelial differentiation and may instead show divergent mesenchymal differentiation into myogenous or chondro-osseous tissues.⁷⁷ Moreover, PB shows no particular disease associations, whereas PPB is linked in a familial fashion to a number of other malignant neoplasms and non-neoplastic disorders.⁷⁹

Figure 14-8 Adult-type pulmonary blastoma (carcinosarcoma), showing an admixture of fetal-type primitive glands and undifferentiated spindle cell elements. This tumor is a special morphologic form of sarcomatoid carcinoma, and it occurs preferentially in adults (not to be confused with pleuropulmonary blastoma, which occurs in childhood).

If one carefully excludes examples of PPB from consideration, it becomes clear that PB is seen overwhelmingly in adults, and its clinical characteristics are superimposable on those of ordinary lung cancers and other pulmonary SCs. This realization allows one to more easily embrace an alternative view of the nature of PB that was advanced in the past by Souza and colleagues,⁸² Stackhouse and associates,¹⁴ and Millard,⁸³ among others. Those authors held the opinion that PB is merely a special, usually peripheral form of pulmonary SC (carcinosarcoma), rather than a blastemal neoplasm that contains truly embryonal tissues. We also espouse the latter premise.

Returning to the particular microscopic attributes of PB, it should be noted that this tumor may demonstrate the same range of epithelial and mesenchymoid differentiation that is seen in other biphasic pulmonary SCs.^39,69,84 The epithelial elements in PB resemble fetal pulmonary pseudoglands (a misnomer), composed of stratified columnar cells with glycogen-rich clear cytoplasm and high nuclear-to-cytoplasmic ratios.^69,84–86 Luminal mucin may be present in those cellular arrays, and squamous morules are sometimes also evident.⁶⁹ Interestingly, “occult” neuroendocrine differentiation is a rather common finding in the epithelial components of PB, with potential histochemical argyrophilia and immunoreactivity for neuroendocrine markers.^87,88 There is a significant sharing of microscopic features between classic PB and the tumor described as “pulmonary endodermal tumor resembling fetal lung” or alternatively as “well-differentiated adenocarcinoma simulating fetal lung” (Fig. 14-9). It differs in its relative lack of a malignant stromal component and more frequent synthesis of a particular oncofetal polypeptide—α-fetoprotein.^{39,85,87–90}

Figure 14-9 Gross (A) and microscopic (B and C) images of fetal-type adenocarcinoma of the lung, representing a monophasic epithelial variant of pulmonary blastoma.

(A, Courtesy of Dr. Samuel A. Yousem, Pittsburgh, PA.)

The elements of PB showing mesenchymoid differentiation are, as stated earlier, usually nondescript morphologically and blastema-like or fibroblast-like. However, examples of this tumor have been documented in which heterologous rhabdomyoblastoid, leiomyosarcomatoid, or apparent chondro-osseous tissues were present.^69,84 This observation serves to further solidify the linkage of PB to other sarcomatoid pulmonary carcinomas, as do reports of some tumors in which “typical” PB was admixed with homologous or heterologous biphasic SC, as described earlier.^82,91–93

The clinical behavior of PB is difficult to determine with certainty, because of the aforementioned contamination of some series with cases of PPB. However, mortality figures of 30% to 70% have been reported, with death usually being due to distant metastases.^67,69,84 Secondary deposits of PB may have a purely epithelial, purely mesenchymal-like, or biphasic appearance, as is true of other SCs.

Pseudoangiosarcomatous (Pseudovascular) Carcinoma

The authors have studied several lung tumors in which obvious squamous cell carcinoma was admixed with areas demonstrating interanastomosing channels mantled by anaplastic, plump, epithelioid cells, focally grouped into pseudopapillae. Because the open spaces in these areas contained erythrocytes and focally formed blood lakes, the histologic appearance was that of biphasic SC in which an angiosarcomatoid component was admixed with overt squamous carcinoma.⁹⁴ (Fig. 14-10). These neoplasms are believed to represent the pulmonary counterparts of pseudovascular adenoid squamous cell carcinoma, as seen in the skin, breast, thyroid gland, and other organs.^34,94–99 This is a tumor type that is known to simulate true angiosarcoma but lacks actual endothelial differentiation. Thus, pseudoangiosarcomatous carcinoma (PASC) would be an apt synonym.⁹⁶

Figure 14-10 A, Pseudoangiosarcomatous sarcomatoid carcinoma of the lung demonstrating dyscohesion of the neoplastic cells in a fashion simulating the image of angiosarcoma. B, A focus of more obviously carcinomatous growth is apparent in the center of this figure. C and D, Immunoreactivity for epithelial membrane antigen and for p63 protein confirm the carcinomatous nature of the tumor.

Primary pulmonary angiosarcoma is, comparatively, a very rare lesion, comprising only 10% of true sarcomas of the lung in one report from the Mayo Clinic.² Mainly anecdotal reports of this tumor exist in the remaining literature, and not all of them satisfy rigorous diagnostic criteria.^100–108 Metastases to the lung from angiosarcomas arising in extrapulmonary sites are much more common, including examples that have originated in the heart, great vessels, or extrathoracic viscera.¹⁰⁰

Similar to reports on previously cited pseudovascular carcinomas in other body sites, two publications have specifically considered squamous cell carcinomas of the lung that imitated angiosarcomas. The first, by Banerjee and coworkers,⁹⁶ showed that such tumors produced clinical symptoms and signs resembling those of ordinary types of lung cancer. They presented in the fifth to seventh decades of life; were associated with cigarette smoking, complaints of cough, weight loss, and dyspnea; and were visible on chest radiographs as well-defined central or peripheral parenchymal masses. In another series by Nappi and colleagues,⁹⁴ the tumors were essentially identical microscopically to pseudovascular squamous carcinomas of the breast and skin. Important differences between PASCs and true pleuropulmonary angiosarcomas include an absence of atypical endothelial cells in stromal blood vessels surrounding the tumor mass in PASCs; less infiltrative growth through the interstitium of the lung; and, perhaps most importantly, the presence of small foci of morphologically obvious squamous cell carcinoma in most PASCs.⁹⁴

The behavioral features of PASCs are similar to those of other sarcomatoid pulmonary carcinomas. The patients studied by Nappi and colleagues developed distant metastases to the bones, liver, adrenal glands, and contralateral lung, and they died after follow-up periods of 5 to 34 months.

Inflammatory Sarcomatoid Carcinoma

Much attention has been given to a group of space-occupying lesions in the lung that carry the popular but inaccurate designation of inflammatory pseudotumors (IPs).^101–114 These proliferations may occur in children or adults and have been divided into fibrohistiocytic, plasma cell granulomatous, and focal organizing pneumonia types, based on their individual clinicopathological features. The nomenclature used for this group of lesions has been well summarized by Koss¹¹⁴ and Matsubara and associates.¹⁰⁶ There is still some controversy over whether all such lesions are neoplastic, or whether some might be reactive in nature.¹¹⁵ However, the bulk of available information indicates that IPs are relatively innocuous clinical imitators of overtly malignant neoplasms.¹¹⁴ Occasional cases have been linked causally to specific infectious organisms,^116,117 but the etiologic factors associated with most pulmonary IPs are uncertain.

In contrast, primary SC is generally regarded as a neoplasm that may simulate pleuropulmonary mesenchymal malignancies, and it is typically not mentioned in discussions on the pathologic differential diagnosis of IPs. This is so because SC usually demonstrates obvious cytologic anaplasia and lacks a significant component of inflammatory cells. Indeed, the morphologic distinction between IPs and all bronchogenic carcinomas (including SC) has been portrayed by some authors as an uncomplicated process.^105,108 However, we have observed several examples of pulmonary SC that exhibited surprisingly bland morphologic appearances, and which, as a result, were separable from IP only by thorough study and adjunctive pathologic techniques. These have been designated as examples of inflammatory sarcomatoid carcinoma (ISC).^118,119

Examples of ISC are composed of variably densely apposed spindle cells with only modest pleomorphism, arranged haphazardly or in fascicular and storiform patterns. The stroma is at least partially myxoid in some cases and may be prominently so. The tumors demonstrate an irregular, spiculated interface with the surrounding lung. The adjacent parenchyma exhibits interstitial fibrosis, and small nodular infiltrates of mature lymphocytes are admixed with dense collagenous tissue at the periphery of ISCs (Fig. 14-11). Focally hyalinized, keloidal-type collagen is admixed with the tumor cells in the central portions of some of these tumors, with or without small foci of central necrosis. Vascular invasion and luminal obliteration by neoplastic cells may be apparent. Similarly, bronchial submucosal infiltration is another potential observation. ISCs do not contain appreciable stromal neutrophils, eosinophils, or xanthoma cells, but a moderate number of lymphocytes and plasma cells can be seen.

Figure 14-11 A, Inflammatory sarcomatoid carcinoma of the lung showing brisk intratumoral and peritumoral chronic inflammation. B, Bland proliferation of fibroblast-like cells at the periphery.

Cytologically, the nuclei of the tumor cells in ISCs are relatively uniform in size and spindle-shaped, with coarse chromatin and occasional small nucleoli (Fig. 14-12). Cytoplasm is moderate in amount and amphophilic. Generally, there are no more than 2 mitoses per 10 high-power fields (×400) on average, and pathologic division figures are absent. Thorough sampling of the tumor tissue in cases of ISC typically demonstrates minute foci of cohesive epithelioid cells, suggesting the diagnosis of squamous carcinoma on conventional histologic grounds. However, some ISCs lack such foci and are recognizable as carcinomas only with special pathologic evaluations (see Fig. 14-12B).¹¹⁸

Figure 14-12 A, Higher magnification of the tumor shown in Figure 14-11 reveals nuclear atypia in the spindle cells. B, The tumor cells are all keratin-reactive immunohistologically.

Pleurotropic (Pseudomesotheliomatous) Sarcomatoid Carcinoma

Occasional examples of SC are distinctive not because of their histologic attributes but because of their macroscopic appearances. In particular, a small subset of these neoplasms arises in the very periphery of the pulmonary parenchyma and grows preferentially into the pleura that encases the lungs.^120,121 This produces clinical symptoms and signs that are indistinguishable from those of malignant mesothelioma; hence, the names pleurotropic or pseudomesotheliomatous carcinoma.^121,122 Moreover, the microscopic features of pleurotropic SC are basically superimposable with those of biphasic or sarcomatoid mesotheliomas.

Even though there is no pragmatic clinical value in making the distinction between pleurotropic SC and mesothelioma, with regard to the efficacy of treatment or prognosis, legal ramifications of these diagnoses are worthy of comment. Because of the potential causal linkage of mesothelioma with occupational-level amphibole asbestos exposure, some patients with that tumor are eligible for monetary compensation. However, there is no convincing evidence to link pleurotropic SC with asbestos, and its etiology appears to be identical to that of “routine” forms of lung cancer.

Clinical Summary

In the context just mentioned, many patients with KS of the lung are homosexual men,^150–156 but they also include other high-risk groups for AIDS such as intravenous drug abusers. Most individuals with KS generally have other symptoms and signs of AIDS, such as weight loss, fever, night sweats, fatigue, lymphadenopathy, and opportunistic infections. However, fever may be directly caused by KS in the lungs. There has been a case report of an AIDS patient with persistent pyrexia for which no source of infection was found but that finally resolved after radiation therapy.¹⁵⁷ Cutaneous KS is usually detected early in its clinical evolution, but identical tumors of the bronchial mucosa and lung parenchyma typically have grown to a volume sufficient to produce symptoms and therefore are relatively advanced at the time of diagnosis.¹⁵⁸ Presenting complaints specific to the neoplasm include dyspnea, stridor (when endobronchial lesions are present), cough, and hemoptysis, which may be massive.¹⁴⁹

On bronchoscopic examination, nodular or flat bluish-red discolorations in the mucosa are seen, some of which may be actively bleeding. This bronchoscopic appearance is usually considered diagnostic, and endobronchial lesions are not generally biopsied. The diagnostic yield of transbronchial biopsies is usually low, and unless they are deep enough, KS of the lung will be missed because the mucosa itself is uninvolved.¹⁵⁹ Open lung biopsies are more productive, but they are not absolutely sensitive.

Radiographic findings on chest x-rays may be nonspecific, showing only ill-defined interstitial infiltrates (Fig. 14-14). An alveolar filling pattern is usually evident only if the patient has suffered hemoptysis and aspirated blood, but pleural effusions or pneumothorax may be seen in cases where the lesion involves the serosal surfaces as well as the lung parenchyma.^160,161 Mediastinal adenopathy is not common, but, if it is present, this can be very helpful in separating KS from Pneumocystis jiroveci infection, because the latter does not cause adenopathy. Computed tomography (CT) scans and magnetic resonance imaging (MRI) generally provide no more information than chest radiography. In summary, the presence of bilateral pleural effusions and bilateral interstitial infiltrates with ill-defined nodularity is suggestive of pulmonary KS, especially in a patient with known tumor elsewhere.^150,151

Figure 14-14 A relatively nondescript reticulonodular interstitial infiltrate is seen on a conventional chest radiograph (A) and computed tomogram (B) in a patient with acquired immunodeficiency syndrome. The clinical differential diagnosis of such a pattern would include infection as well as neoplasia, but pulmonary Kaposi sarcoma was the ultimate interpretation in this case. C, An autopsy example of this condition shows irregularly consolidated and hemorrhagic parenchyma.

Pathologic Findings

As alluded to above, it is distinctly uncommon for the pathologist to be able to make a definitive diagnosis of KS of the lung on a transbronchial biopsy specimen. Usually, a wedge biopsy is necessary, as obtained via video-guided thoracoscopy or a limited thoracotomy.¹⁵⁹ On gross examination, this type of specimen exhibits numerous hemangiomatoid or ecchymosis-like zones of bluish-red discoloration in the parenchyma, with ill-defined borders.

In the lung, KS shows a tendency to grow along pre-existing fibrous intrapulmonary septa, and it also concentrates around small tubular airways and blood vessels (Fig. 14-15). The tumor comprises a mixture of ectatic, thin-walled blood vessels that “dissect” or push through the pulmonary interstitial collagen, together with haphazardly arranged fascicles of spindle cells that show only modest nuclear atypia and may contain cytoplasmic vacuoles.^149,159 Extravasated erythrocytes and hemosiderin pigment are common in and around the tumor masses (Fig. 14-16). Pleural KS “layers” itself over the submesothelial mantle of connective tissue, effacing the mesothelium itself in doing so.

Figure 14-15 A, Low-magnification image of pulmonary Kaposi sarcoma (KS), showing a nodular proliferation of spindle cells and neovascular spaces (left) that permeates the pulmonary interstitium (right). B, A transbronchial biopsy specimen of KS shows a spindle cell proliferation and interanastomosing vascular channels.

Figure 14-16 Kaposi sarcoma of the lung. A, Formation of interanastomosing vascular channels. B, Foci of solid spindle cell growth. C, Areas with extravasation of erythrocytes into the stroma and deposition of hemosiderin pigment.

Mitotic activity is variable in primary KS of the lung, but it is usually detectable. If it is present at all, necrosis is limited in scope and visible only on microscopy.

The differential diagnosis of KS from vascular granulation tissue and other spindle cell proliferations in the lung is greatly enhanced by immunohistochemical analyses. KS is reactive for latent nuclear antigen-1 of human herpesvirus-8 in approximately 85% of cases¹⁶² (Fig. 14-17). It also labels for FLI-1¹⁶³ and podoplanin.¹⁶⁴

Figure 14-17 Diffuse immunoreactivity is seen for herpesvirus-8–latent nuclear antigen-1 in Kaposi sarcoma of the lung.

Therapy and Prognosis

Regardless of its occurrence in AIDS or in non–human immunodeficiency virus (HIV)-related cases, the presence of KS in the lung is prognostically ominous. Virtually all patients with visceral disease die within 2 years, from infection if not from KS itself.^148,154,156 Because of the multiplicity of KS, surgical resection is not a realistic option in the management of patients with this neoplasm. Chemotherapy is considered the treatment of choice, with a relatively good response rate and relatively rapid improvement within 2 to 4 weeks.²⁵ Chemotherapy regimens in the few published therapeutic trials designed specifically for pulmonary KS have primarily included adriamycin, bleomycin, and vincristine.^{149,165–167} Gill and colleagues found an 85% response with combination chemotherapy in a group of 13 patients.¹⁶⁶ Patients who benefited from this treatment included those who achieved at least partial responses. Complete response is defined by the following three criteria:

A partial response is characterized by the same three points, except that the degree of resolution is not total.^165,166

Despite fairly good results with combination chemotherapy, patients with pulmonary KS do not show long survival. In the trial reported by Gill and colleagues, the median survival for responders was slightly but significantly longer than that of nonresponders (10 versus 6 months, respectively). However, considerable overlap between the two groups was present.¹⁶⁶

Other more experimental (and inconclusive) approaches have included the administration of zidovudine, interferon, and other antiviral compounds.^147,153,154 Radiotherapy may provide palliation of symptoms but is noncurative. The most important piece of data in prognosticating cases of KS of the lung is the serologic HIV status of the patient, inasmuch as AIDS is currently a uniformly lethal, albeit chronic, illness.

Clinical Summary

Guccion and Rosen studied 13 cases of FSL, which were divided into endobronchial and intrapulmonary types.¹⁶⁸ This classification scheme was said to have clinical and prognostic importance. In conjunction with a review of 48 reported cases in the literature, the authors just cited found that the majority of endobronchial FSLs occurred in children and young adults, whereas parenchymal tumors predominated in middle-aged and elderly patients. In contrast, Pettinato and associates reported three parenchymal tumors in two newborns and a 6-month old infant.¹⁷² There was roughly an equal distribution by gender among endobronchial lesions; however, most intraparenchymal neoplasms occurred in men. All cases of endobronchial FSL in a series reported from the Armed Forces Institute of Pathology (AFIP) had symptoms of cough, hemoptysis, or chest pain; some of the parenchymal cases did as well.¹⁶⁸ Thoracic imaging studies of FSL usually show discrete, homogenous masses. However, one reported pulmonary fibrosarcoma simulated a bronchogenic cyst clinically and radiographically.¹⁷³ Gladish and coworkers¹³ have observed that fibrosarcoma is much more likely to arise in the soft tissue of the chest wall and secondarily involve the lung than it is to show the converse of that relationship.

Pathologic Findings

Endobronchial fibrosarcomas are smaller than microscopically similar tumors in the parenchyma; the former variants usually measure less than 3 cm, and the latter range from 3.5 to 23 cm in greatest dimension. Parenchymal masses are typically well-delimited and lobulated, with frequent areas of necrosis and hemorrhage.

FSL is histologically identical to its soft tissue counterparts and characteristically shows sheets and intertwining fascicles of spindle-shaped cells with a typical interdigitating growth pattern and discernible stromal collagenogenesis (Fig. 14-18). The tumor cells contain oval to elongated, hyperchromatic nuclei, and scant amphophilic cytoplasm with ill-defined cellular borders. In addition, some areas may have a slightly epithelioid appearance, in which the tumor cells are more ovoid than spindled, and others may show significant pleomorphism that merges with the image of MFH (Fig. 14-19). Mitotic activity is variable.

Figure 14-18 A, Pulmonary fibrosarcoma represented by a cellular proliferation of atypical spindle cells. B, Nuclear anaplasia is apparent on high magnification.

Figure 14-19 This image from another case of high-grade intrapulmonary fibrosarcoma shows more nuclear pleomorphism in the tumor cells, overlapping the appearance of malignant fibrous histiocytoma.

Electron microscopic and immunohistochemical studies are required to confirm the fibroblastic nature of these neoplasms. The tumor cells in FSL are characterized by abundant rough endoplasmic reticulum and free ribosomes, as well as the production of extracellular collagen fibers that may be aligned at right angles to the tumor cell membranes. There should be no detectable myofilaments, pericellular basal lamina, or intercellular junctions in lesions thought to represent FSL. Because there are no specific immunologic markers for fibroblasts, the diagnosis of fibrosarcoma is one of ultimate immunohistologic exclusion. Tumor cells in FSL generally stain only for vimentin, a primitive intermediate filament protein, and they lack all epithelial, myogenous, neural, and endothelial markers.^172,174,175

Therapy and Prognosis

Although resection is the treatment of choice, many surgically treated fibrosarcomas of the lungs do recur, and survival after this event is short, with patient fatality usually occurring within 2 years.¹⁶⁸ Three cases seen at the Mayo Clinic between 1980 and 1990 occurred in young women whose lesions all recurred within 15 months following surgical excision.¹⁷¹ In contrast, primary bronchopulmonary fibrosarcomas in children appear to have a relatively favorable prognosis and behave only as low-grade malignancies.^172,173 The five patients with pediatric FSL reported by Pettinato and colleagues all had complete surgical removal of their tumors, and four were disease-free after 4 to 9 years. The fifth case in that series had insignificant follow-up.¹⁷² The efficacy of adjunctive chemotherapy and irradiation has not yet been proven.

Primary Pulmonary Hyalinizing Spindle Cell Tumor with Giant Rosettes

A rare lesion that is probably biologically related to FSL is one called hyalinizing spindle cell tumor with giant rosettes (HSCT). This entity was originally documented as a low-grade sarcoma in the deep soft tissues of adults,¹⁷⁶ but at least two cases have been reported as primary pulmonary examples.^177,178 HSCT has a distinctive morphologic appearance, featuring the multifocal presence of large rosette-like structures amid a bland spindle cell proliferation (Fig. 14-20). The lesion has infiltrative borders, with no necrosis and only limited mitotic activity.

Figure 14-20 A, So-called spindle cell tumor (low-grade fibrosarcoma) with giant rosettes primarily arising in the lung. B, Other areas of this neoplasm show a virtual identity to fibromyxoid sarcoma of Evans, and those two tumor types have an identical cytogenetic profile.

HSCT has a partial kinship with Evans tumor (low-grade fibromyxoid sarcoma)¹⁷⁹ of soft tissue, on behavioral, morphologic, and cytogenetic grounds. Both of those tumors manifest a t(7;16) (q33;p11) chromosomal translocation, producing fusion of the FUS and CREB3L2 genes.¹⁷⁸ Unlike FSL, HSCT demonstrates some immunophenotypic variability, often labeling for alpha-isoform actin in its spindle cell population. The cells in the giant rosettes may manifest immunoreactivity for S100 protein and CD45RO,¹⁷⁶ the latter of which is more typically a hematopoietic determinant. The precise biologic potential of HSCT in the lung is uncertain, because of the anecdotal nature of reported cases.

Clinical Summary

A series of 19 PPLMSs seen at the AFIP was divided into those neoplasms that were predominantly endobronchial and others that were intraparenchymal, in analogy to pulmonary fibrosarcomas.¹⁶⁸ The majority of these tumors in children are endobronchial in nature,^180,181 whereas those in adults are not. In contrast to leiomyosarcomas of the soft tissue, which occur most commonly in women, patients in the aforementioned report from the AFIP were almost exclusively men. However, another survey that reviewed 92 cases of PPLMS in the literature found a male-to-female ratio of 2.5, suggesting that the paramilitary study just cited was biased demographically by its affiliation with the armed services.¹⁸² In contrast to carcinoma of the lung, leiomyosarcoma is not associated with cigarette smoking or other potential inhalant carcinogens. Most patients with PPLMS (particularly its endobronchial form) are symptomatic, often complaining of cough, hemoptysis, or chest pain. However, intraparenchymal lesions may be discovered incidentally on chest radiographs. Roentgenographically, PPLMS usually takes the form of a discrete mass (Fig. 14-21), sometimes with cavitation or cyst formation that is best seen by CT of the thorax.^168,183,184

Figure 14-21 Computed tomogram of the thorax showing primary leiomyosarcoma of the lung.

Pathologic Findings

Parenchymal tumors range from 3 to 15 cm in maximum dimension. They are well circumscribed, white to yellowish tan, and variably firm. Cut surfaces of these neoplasms commonly show hemorrhagic and necrotic areas. Endobronchial tumors are often smaller than the intraparenchymal lesions, presumably because of confinement by the bronchial walls.¹⁸⁵

Microscopy discloses histologic features that mirror those of leiomyosarcomas elsewhere in the body. On low-power magnification, there are interlacing fascicles of spindled cells arranged haphazardly, yielding a “whorled” appearance (Fig. 14-22). The neoplastic cells have cigar-shaped nuclei with blunt ends, a moderate amount of cytoplasm, and indistinct cell borders (Fig. 14-23). Fascicles cut in cross section demonstrate characteristic intracellular perinuclear lucencies.^185–188 Prominent myxoid stromal change may be observed.¹⁸⁹

Figure 14-22 Leiomyosarcoma of the lung (A) shows fascicular growth of atypical spindle cells with blunt-ended nuclei, fibrillary cytoplasm, and dense cellularity (B and C).

Figure 14-23 Cytologic details are clearly seen in this primary pulmonary leiomyosarcoma.

The differential diagnosis of PPLMS includes fibrosarcoma and malignant peripheral nerve sheath tumor, as well as SC. Electron microscopy and immunohistochemistry are again helpful in confirming the smooth muscle nature of a spindle cell neoplasm.¹⁸⁷ Ultrastructural features of leiomyogenous differentiation include cytoplasmic dense bodies punctuating skeins of thin filaments, subplasmalemmal dense plaques, plasmalemmal pinocytotic vesicles, and pericellular basal lamina (Fig. 14-24). Immunoreactivity for desmin, muscle-specific actin, calponin, caldesmon, or smooth muscle actin is also characteristic of the tumor cells in PPLMS.¹⁹⁰

Figure 14-24 Electron photomicrograph of pulmonary leiomyosarcoma demonstrating cytoplasmic thin filaments, pericellular basal lamina, and cytoplasmic dense bodies.

Transthoracic fine needle aspiration of possible PPLMS can be attempted if the lesion is large and peripherally located. The cytologic preparations from that procedure typically show a dyshesive population of relatively monotonous spindle cells, with blunt-ended fusiform nuclei. Mitotic figures and nuclear pleomorphism are variably seen; some lesions also may exhibit a more epithelioid cytologic image^191–193 (Fig. 14-25).

Figure 14-25 Fine needle aspiration biopsy of primary pulmonary leiomyosarcoma showing loosely cohesive tumor cells with blunt-ended fusiform nuclei.

Therapy and Prognosis

The natural history of PPLMS and its responses to various therapeutic regimens are difficult to predict because of the rarity of this neoplasm. However, there is generally a consensus that surgical resection is the treatment of choice^{182,185–187} and that it produces a survival rate of 45% to 50% at 5 years. Survival for as long as 15 to 30 years has been documented in PPLMS cases.^168,170 However, pulmonary leiomyosarcomas appear to be relatively resistant to irradiation and chemotherapy.^182,188 Various prognostic variables have been discussed in connection with these lesions.^168,170 Endobronchial tumors are thought to be less aggressive than parenchymal neoplasms, largely because the former tend to be smaller and are diagnosed earlier. It follows, therefore, that tumor size is an important indicator of biologic behavior for all pulmonary leiomyosarcomas. The scope of mitotic activity may affect prognosis as well. In an AFIP series on PPLMS, a mitotic rate of 8 or less per 10 high-power fields was associated with infrequent metastasis and a generally favorable clinical outcome.¹⁶⁸

Clinical Summary

EH of the lung is a neoplasm that arises predominantly in female patients; women account for roughly 80% of all cases.^195,199,200 It primarily occurs in young adults, with approximately 50% of affected individuals being younger than 40 years of age; only 10% are older than 50 years of age at diagnosis.^198,201 Many affected persons are asymptomatic, and their tumors are detected incidentally on chest radiographs. Patients who have tumor-related complaints usually present with pleuritic pain, dyspnea, and cough. Case reports have also documented alveolar hemorrhage as a presenting sign of pulmonary EH,^202,203 and it may simulate thromboembolic disease symptomatically as well.²⁰⁴ Chest radiographs commonly show numerous, small nodular lesions throughout both lung fields (Fig. 14-26). Therefore, EH enters the roentgenographic differential diagnosis of multiple pulmonary nodules in asymptomatic young women, together with metastatic germ cell tumors, chondroid pulmonary hamartomas, multiple arteriovenous malformations of the lung, deposits of “benign metastasizing leiomyoma,” and malignant lymphoma.²⁰⁵

Figure 14-26 Multiple nodular densities are seen throughout both lung fields on plain film radiography (A) and computed tomography (B) in this case of primary pulmonary epithelioid hemangioendothelioma. C, Gross photograph of epithelioid hemangioendothelioma of the lung, in a wedge-excision specimen.

Pathologic Findings

The pathologic diagnosis of EH is almost always made by open lung biopsy, inasmuch as transbronchial biopsy is usually ineffectual because of sampling constraints. Most nodules of EH are discrete and usually measure less than 2 cm. They are grayish-white to tan and have a chondroid macroscopic consistency. More nodules are typically seen on histologic examination than are apparent grossly. Microscopically, EH is typified by multiple oval or round nodules with hypocellular, sclerotic, or necrotic centers^195,199 (Fig. 14-27). These are surrounded by rims of viable, more cellular tissue that is associated with a myxohyaline fibrous stroma; exceptionally, metaplastic bone formation may be apparent.²⁰⁶ The neoplastic cell population is composed of plump, epithelioid cells, which are the histologic hallmark of EH (Fig. 14-28). They have centrally located, round-to-oval nuclei, with ample amounts of eosinophilic cytoplasm. Often, intracytoplasmic vacuoles are evident, which should raise the possibility of endothelial differentiation on light microscopy. Saqi and colleagues have described “rhabdoid” cellular differentiation in EH as well.²⁰⁷

Figure 14-27 A and B, Epithelioid cells are set in a sclerotic and myxofibrous stroma in this case of epithelioid hemangioendothelioma of the lung. C, The tumor grows in a lepidic fashion through the alveolar pores of Kohn, yielding a micronodular image. Low-grade forms (previously known as intravascular bronchioloalveolar tumor) may be paucicellular and dominated by an eosinophilic extracellular matrix in the alveolar space. Secondary alveolar pneumocytic proliferation is also evident.

Figure 14-28 A, The epithelioid nature of the tumor cells in pulmonary epithelioid hemangioendothelioma (PEH), as well as the myxofibrous stroma, is clearly seen in these photographs. B, The neoplastic cells in PEH are bland cytologically, and some have intracytoplasmic lumina. C, This example of PEH demonstrates a greater degree of nuclear atypia. Such tumors may show mitotic activity as well. D, Immunoreactivity for CD31 indicating the endothelial nature of PEH.

Tumoral involvement of arterioles, venules, and lymphatics is variable within the tumor nodules as well as other distant sites. EH commonly shows an intra-alveolar pattern of growth secondary to tumor extension through the pores of Kohn, and surgical margins may be, therefore, difficult to ascertain on gross examination if a limited resection of the lesion is attempted.

Ultrastructural and immunohistochemical evaluation can be of great assistance in confirming the endothelial origin of EH.^{196,198,208–211} Briefly, ultrastructural features of this tumor include cytoplasmic vacuoles, Weibel-Palade bodies (Fig. 14-29), cell membranous pinocytotic vesicles, and pericellular basal lamina.²¹⁰ Histochemical and immunologic markers of endothelial differentiation—such as Ulex europaeus I lectin, anti-CD31, anti-FLI-1, and anti-CD34—are helpful in labeling the neoplastic cells in virtually all examples of EH.^206,212 Weinreb and coworkers have also described labeling for CD10 in a majority of EH cases.²¹³

Figure 14-29 A and B, Numerous Weibel-Palade bodies, which have the appearance of lysosomal-like inclusions with internal striations, are present in epithelioid hemangioendothelioma in these electron photomicrographs. These organelles are the intracellular packaging sites for von Willebrand factor.

Fine needle aspiration biopsy of EH yields a loosely cohesive population of epithelioid cells that may be binucleated or multinucleated. Variably sized cytoplasmic vacuoles are demonstrable in a proportion of the tumor cells (Fig. 14-30).²¹⁴

Figure 14-30 Fine needle aspiration biopsy of epithelioid hemangioendothelioma shows dispersed polygonal tumor cells (A), some of which contain cytoplasmic vacuoles (B).

Therapy and Prognosis

Surgery is usually not feasible as effective treatment for EH because of its tendency to show intrapulmonary multicentricity. Unfortunately, irradiation and chemotherapy likewise have been of little benefit.^195,199 Nevertheless, EH is generally an indolent neoplasm that is classified as a borderline malignancy. It is associated with a protracted clinical course and potential survival of several years after diagnosis.²⁰⁸ Most patients do eventually succumb to the tumor and die of respiratory failure secondary to progressive parenchymal replacement; in one series reported by Einsfelder and Kuhnen, 36% of patients were dead or likely to die of their tumors after 52 months’ follow-up.²⁰⁶ Adverse prognostic factors that predict a more rapid decline in pulmonary function include prominent symptoms at the time of presentation; radiographic demonstration of extensive intravascular, endobronchial, or pleural spread of the tumor;¹⁹⁵ and the presence of fusiform tumor cells.²⁰⁰

A particularly vexing clinical problem is represented by those patients who have EH synchronously in several organs, including the lungs. In such cases, one is never certain whether tumor multifocality or metastasis is operative. Pragmatically, each involved organ is usually treated as if it harbors an independent primary tumor in this scenario.²¹⁵

The general predilection of EH for women, a reported association of primary hepatic EH with oral contraceptives, and the lack of effective therapy for this tumor have prompted some investigators to explore the possibility of treatment involving hormonal modulation. These tumors have been examined for possible expression of estrogen and progesterone receptor proteins as well as other estradiol-binding moieties. Ohori and colleagues analyzed five cases of pulmonary EH for steroid hormone receptors by immunohistochemical methods, using paraffin-embedded material.²¹⁶ Only one case showed apparent binding of estradiol. Our own unpublished experience with the immunohistologic characteristics of pulmonary EH has disclosed no reactivity with monoclonal antibodies against estrogen and progesterone receptor proteins. Thus, we believe that hormonal therapies are unlikely to produce significant results in this setting.

Clinical Summary

Pulmonary HPC-SFT affects men and women equally, and most commonly arises in middle adulthood. The peak incidence of this lesion is in the fifth decade of life, although individuals as young as 4 years of age and as old as 73 years of age have been reported.^222,223 Some tumors are detected incidentally on radiographic studies without causing pulmonary symptoms; 6 of 18 cases in one series fit this scenario.²²⁴ Alternatively, presenting symptoms may include hemoptysis, chest pain, cough, and dyspnea, and, more rarely, pulmonary osteoarthropathy.²²⁴

Various radiographic imaging studies have been used in studying this neoplasm. Although angiography has usually not been performed, vascular contrast studies of HPC-SFT generally show a characteristic intralesional “blush.”²²⁵ No other pathognomonic features are evident in chest x-rays, CT scans, and MRIs of the lung.^223,226 Plain film x-rays typically show a discrete, homogeneously dense mass with lobulated contours. On CT images, however, HPC-SFT is heterogeneous. Central low-density areas are evident that correspond to necrotic foci, and an apparent capsule may be seen at the interface with surrounding lung parenchyma. MRIs also show intratumoral heterogeneity with respect to tissue density and are apparently more sensitive in depicting intralesional hemorrhage. These images were found to be the most useful in delineating the potential plane of surgical separation between an HPC-SFT and surrounding soft tissue in one report.²²⁷ In summary, a radiologic diagnosis of pulmonary HPC-SFT may be suspected in a middle-aged person lacking pulmonary symptoms, but whose radiographic imaging studies reveal a large, lobulated, sharply marginated, variably dense mass (Fig. 14-31) that does not cause compression atelectasis.²²⁶

Figure 14-31 Chest radiograph of primary pulmonary hemangiopericytoma/solitary fibrous tumor, represented by a nondescript large globoid mass in the right upper lung field.

Pathologic Findings

HPC-SFTs of the lung can attain large sizes, and lesions measuring up to 18 cm have been documented. The typical gross appearance of this tumor is that of a well-circumscribed, yellow to tan-brown mass with a pseudocapsule, as well as areas of internal necrosis and hemorrhage. Histologic sections typically show a relatively monomorphous cellular proliferation surrounding thin-walled, anastomosing vascular channels lined by a single endothelial layer. These blood vessels often (but not always) assume gaping, “staghorn,” or “antler-like” configurations (Figs. 14-32 and 14-33). The population of neoplastic cells is uniform, with oval compact nuclei and ill-defined cytoplasm.¹⁸⁵ Mitotic activity and areas of necrosis and hemorrhage are noted frequently. Vascular invasion of large pulmonary vessels, however, is uncommon. With regard to the latter features, some pathologists have, in the past, rendered a diagnosis of benign hemangiopericytoma if necrosis, hemorrhage, and mitoses were absent. In our view, this approach is highly inadvisable. We have seen cases of pulmonary HPC-SFT with exceedingly bland histologic profiles in which metastasis nonetheless supervened. Accordingly, it is advised that each report on this tumor should carry the statement that HPC-SFT is at least potentially malignant behaviorally.^219,224

Figure 14-32 Pulmonary hemangiopericytoma showing ill-defined clusters of bluntly fusiform tumor cells and prominent stromal blood vessels.

Figure 14-33 A, “Staghorn”-shaped blood vessels in primary pulmonary hemangiopericytoma (HPC). B, Individual tumor cells are invested by reticulin fibers in HPC (reticulin stain method).

Pulmonary HPC-SFT has sometimes been overdiagnosed because other neoplasms may show foci that resemble the former lesion. In this regard, it is notable that in their seminal report, Stout and Murray admonished others to make the diagnosis of hemangiopericytoma by ultimate exclusion.²¹⁷ The histologic differential diagnosis includes SC, SS, fibrous histiocytomas, leiomyosarcoma, and mesenchymal chondrosarcoma.²¹⁹ Distinctions among these neoplasms are best made by ancillary studies.

Electron microscopy can confirm the pericytic nature of HPC through the demonstration of polygonal cells with cytoplasmic processes, pinocytotic vesicles, basal lamina, and a paucity of other organelles.^174,219 HPC-SFT is a neoplasm that demonstrates a relatively restricted group of immunoreactants; these include vimentin, collagen type IV, CD34, CD99, CD57, and bcl-2 protein^54,228 (Fig. 14-34). Endothelial stains such as Ulex europaeus I, CD31, and FLI-1 highlight the lining of intralesional vascular spaces but do not label the surrounding tumor cells. Silver impregnation techniques highlight a complex reticulin matrix with individual cell investment.

Figure 14-34 Immunoreactivity for CD99 is seen in pulmonary hemangiopericytoma-solitary fibrous tumor. CD34 and bcl-2 protein are usually present in this tumor as well.

Therapy and Prognosis

As in the management of soft tissue HPC-SFT, complete surgical excision is the mainstay of therapy for primary pulmonary tumors of this type. However, it is known that intraoperative rupture of pulmonary HPC-SFT may occur (especially those tumors that are adherent to the chest wall). As expected, this complication results in early local recurrence, as reported by Van Damme and associates, and should therefore be avoided at all costs.²²³ Chemotherapy and irradiation have not been shown to be consistently effective adjuvant modalities, but they may have some role to play in management.^229,230 A study by Jha and coworkers on the general role of radiation therapy in treating HPC-SFT showed that postoperative irradiation was useful for local tumor control, salvage therapy after local recurrence, and palliation.²³¹ Tumors less than 5 cm in maximum dimension exhibit a better response than those that are larger than 10 cm.²³²

As mentioned above, hemangiopericytomas in general are well known for their unpredictable biologic behavior. Postoperative survival has ranged from 10 weeks to 18 years.^223,232 Even with apparently complete surgical resection, HPC-SFT recurs locally within 2 years in approximately 50% of cases,^224,227,233 and later recurrences are seen as well; distant metastasis, however, is uncommon.²²⁸

Clinical and histologic features that have been cited as prognostically useful^219,222,227 include the presence of symptoms at presentation, mitotic activity of four or more mitoses per 10 high-power microscopic fields, spontaneous tumor necrosis, vascular invasion, and tumor size greater than 5 cm. In one series, metastases were seen in one third of tumors that measured greater than 5 cm, and in two thirds of those greater than 10 cm.²²² However, Yousem and Hochholzer did not find any single histologic or clinical feature that was statistically significant in reliably predicting the clinical course of primary pulmonary HPC-SFT.²²⁴

Clinical Summary

In general, MFH is a neoplasm of patients who are in late middle age, with a median of 54 years. However, its occasional occurrence in children and young adults has also been reported.^235,244 No consistent predilection for either gender is seen. Previous irradiation is a pathogenetic risk factor for tumors arising in soft tissue, and the literature similarly contains sporadic reports of PPMFH presenting in patients who have received radiation therapy previously. Clinical and radiographic features of this tumor are nonspecific, and a distinction from the much more common epithelial tumors of the lungs absolutely requires tissue examination. The majority of patients present with symptoms of cough, chest pain, hemoptysis, or dyspnea. Chest x-rays generally show a solitary mass with a nondescript appearance and a relatively homogeneous density on CT or MRI studies.²⁴³

Pathologic Findings

Most examples of PPMFH are intraparenchymal, but occasional endobronchial lesions have also been observed.²³⁵ There is apparently no predilection for any particular lobe of either lung. These tumors are usually large, ranging up to 25 cm in maximum dimension,²⁴⁶ with an average size of 6 to 7 cm. They are well circumscribed, lobular, and white-tan, and not uncommonly they contain central necrosis or cavitation on macroscopic examination.

Histologically, PPMFH is characterized by fusiform and pleomorphic elements that are arranged in storiform, fascicular, or medullary patterns (Fig. 14-35). As the name “MFH” implies, this tumor was originally thought to be composed of malignant fibroblast-like and the histiocytoid cells; however, it now appears that there is little if any relationship between the neoplastic elements and true histiocytes. Fusiform tumor cells contain elongated nuclei and relatively scant cytoplasm, and the histiocytoid cells have round-to-oval nuclei with a moderate quantity of amphophilic cytoplasm (Fig. 14-36). A hallmark of most lesions in this category is the presence of large, bizarre, often multinucleated cells with irregular contours. Mitoses, including atypical forms, are easily found and number from 5 to 30 per 10 high-power microscopic fields.¹⁷⁴

Figure 14-35 A, Primary pulmonary malignant fibrous histiocytoma showing a disorganized proliferation of atypical spindle cells and pleomorphic elements that entraps alveolar airspaces. B, Marked nuclear pleomorphism and multinucleation are focally present in the lesion.

Figure 14-36 This example of primary pulmonary malignant fibrous histiocytoma shows a more epithelioid cell population that could cause diagnostic confusion with poorly differentiated carcinoma.

The differential diagnosis of PPMFH by light microscopy includes primary or secondary pleomorphic sarcomas (e.g., dedifferentiated leiomyosarcoma and pleomorphic rhabdomyosarcoma), metastatic malignant melanoma, and SC.¹³ Immunohistochemical and electron microscopic studies can be used to separate these pathologic entities.^{236–240,246} Ultrastructurally, PPMFH shows fibroblastic and histiocyte-like differentiation, with abundant rough endoplasmic reticulum, numerous lysosomes, and a variable number of small cytoplasmic lipid droplets. Desmosomes, tonofibrils, elongated cell processes, myogenous filament skeins, and cytoplasmic dense bodies are absent. PPMFH expresses vimentin but is devoid of other specialized markers of myogenous, neural, or epithelial differentiation on immunohistologic analyses.¹⁷⁴

Therapy and Prognosis

The rarity of PPMFH again serves as an impediment to assessments of optimal treatment for this tumor. Surgical resection is currently the recommended treatment of choice, even if the lesion in question shows limited extrapulmonary spread to the intrathoracic great vessels or soft tissue.²⁴⁷ Adjunctive chemotherapy and irradiation have not proven to be effective in the few published cases of PPMFH in which these treatments have been used.^235,245,246 In one series of 22 examples,²³⁵ 7 of 15 patients who underwent radical surgical resection suffered relapses and died from metastatic disease. There was recurrence in the lungs and pleura, as well as metastasis to the liver and brain; almost all of these events occurred within 12 months of diagnosis. However, survival for as long as 5 to 10 years has been documented in a few patients with PPMFH.^235,237

Potential adverse prognostic factors include an advanced clinical or pathologic stage at presentation (with mediastinal, chest wall, or carinal involvement), prominent symptoms at diagnosis, incompleteness of excision, and tumor recurrence. Histologic findings have not been found to affect behavior.

Clinical Summary

To date, there are less than 30 well-documented examples of bona fide, “pure” intrapulmonary rhabdomyosarcoma in the pertinent literature. They all occurred in patients who were in the first two decades of life, and most were in children younger than 10 years of age.^248–251 At least one lesion, documented by Choi and colleagues, was seen in a child with neurofibromatosis.²⁵² Symptoms and signs of RMSL may be nonspecific, including cough, wheezing, and dyspnea, or the patient may present with spontaneous pneumothorax.²⁵³ The latter relates to a peculiar tendency of RMSL to associate itself with cystic lesions of the lungs, particularly as one component of a PPB (see subsequent discussion).^249,250,254 When these cysts rupture, pneumothorax results. The underlying lesions in such cases of RMSL have included not only PPB, but also congenital cystic adenomatoid malformations and peripheral bronchogenic cysts.²⁵⁴

Roentgenographic studies may demonstrate a single, nondescript, intraparenchymal mass that is homogeneous on CT or MRI analysis, or they may reveal the presence of a mass in the wall of a cyst. The second of these scenarios is much more likely to result in a correct diagnosis by the radiologist.

Pathologic Findings

As mentioned above, RMSL may be associated with preexisting cystic lesions of the lung. Hence, the cyst walls should always be examined microscopically for a malignant component, despite the contextual rarity of the latter complication.

Pulmonary rhabdomyosarcomas have most often assumed an embryonal or an alveolar growth pattern^249,250 (Figs. 14-37 and 14-38), although pleomorphic tumors, which are usually encountered in the soft tissues of adults, have been reported in the lung as well.²⁵⁵ These neoplasms are typically composed of small round cells that are configured in one of three ways. These include “solid” sheetlike clusters with no further distinguishing morphologic attributes, dyscohesive groups with internal pseudolumina or alveoli, and “botryoid” proliferations in which a polypoid lesion (usually within a bronchial lumen) shows a zonation into hypocellular and hypercellular cellular strata (so-called “cambium” layers).²⁵⁶ In contradistinction to other small round cell tumors of children, RMSL demonstrates a moderate degree of cellular pleomorphism and anisonucleosis. Nuclear chromatin is usually coarse and clumped, cytoplasm is scanty and amphophilic or eosinophilic, and mitoses and apoptotic cells are easily found. Small foci of spontaneous necrosis are also present.

Figure 14-37 A, Embryonal rhabdomyosarcoma (ERMS) of the lung, which presented as an endobronchial lesion in a child. The tumor comprises hyperchromatic small cells with modestly irregular nuclear outlines, set in a myxoid stroma. B, Immunoreactivity for desmin is intense in another example of ERMS.

Figure 14-38 A, Alveolar rhabdomyosarcoma (ARMS) of the lung, composed of undifferentiated small round cells that lack cohesion and form cleftlike or alveolar spaces. B, Another example of ARMS is the solid variant, without appreciable intercellular spaces. It may be confused with several other small round-cell tumors of childhood. C, Desmin-immunoreactivity is present in solid ARMS.

Particularly in those lesions that have an embryonal “solid” appearance histologically, special pathologic studies are nearly always necessary to procure a definitive diagnosis. Moreover, these analyses should also be done in all putative cases in adults, for reasons mentioned earlier. Histochemical stains show that striated muscle tumors contain abundant glycogen, as determined with the periodic acid/Schiff (PAS) method with and without diastase digestion. Electron microscopically, rhabdomyosarcoma is characterized by the focal presence of intermediate filament whorls in the cytoplasm, sometimes with the addition of thick filaments in aggregates that resemble primitive muscular Z-bands (Fig. 14-39). Furthermore, cytoplasmic glycogen is present, and pericellular basal lamina can be visualized. This constellation of fine structural attributes excludes other small cell tumors from diagnostic consideration.²⁵⁷ By immunohistology, RMSL is found to express one or more myogenous determinants, such as desmin, tropomyosin, titin, muscle-specific actin, “fast” myosin, myo-D1, myogenin (Fig. 14-40), or Z-band protein.^258–260 Vimentin is also uniformly found, but markers of epithelial differentiation, such as keratin and EMA, must be absent in order to make the diagnosis of RMSL.

Figure 14-39 Electron photomicrograph of pulmonary rhabdomyosarcoma showing cytoplasmic sarcomeric differentiation with formation of Z-bands.

Figure 14-40 Nuclear immunoreactivity for Myo-D1, shown here, is another general feature of rhabdomyosarcoma.

Therapy and Prognosis

The great majority of reported cases of RMSL have been treated surgically, with the usual addition of postoperative irradiation and standard chemotherapy such as that used by the InterGroup Rhabdomyosarcoma Study.^248–255 However, there are no controlled studies to determine whether this protocol is the optimal approach to management. Once again, the extreme rarity of the lesion in question interferes with the design of the most efficacious therapeutic regimen.

Prognostically, the fact that RMSL is a visceral manifestation of rhabdomyosarcoma is an adverse clinical variable, along with the probability that such tumors may attain a size of several centimeters before coming to clinical attention. Pathologic features that have been associated with unfavorable tumoral behavior include the focal or global presence of an alveolar growth pattern and the existence of areas that resemble adult-type pleomorphic rhabdomyosarcoma.²⁶¹

Clinical Summary

Patients with PPCS are adults, with no predilection of the tumor for either gender. They may present with slowly evolving stridor, wheezing, cough, vague chest pain, or episodes of hemoptysis.^264,265 Systemic complaints are not encountered. Tracheobronchoscopy usually demonstrates a smooth, nodular, glistening mass that stretches and attenuates the overlying mucosa but does not ulcerate it. Attempted biopsy of the mass through the bronchoscope is usually unsuccessful because of the firm consistency of the tumor and difficulty of sampling submucosal lesions in general.²⁶²

Radiographically, there may be no visible abnormalities on plain films if the neoplasm is predominantly or exclusively intraluminal in a large airway. Other examples of PPCS are manifested simply as sharply circumscribed, lobulated masses (Fig. 14-41) that may contain flecks of central calcification or cystic change.²⁶⁷ The latter findings are more graphically displayed in CT or MRI studies.²⁶⁵

Figure 14-41 Plain chest film showing chondrosarcoma arising from the carina represented by a rounded mass that projects into the left lung field.

Pathologic Findings

Chondrosarcomas of the lung differ significantly from pulmonary chondroid hamartomas on macroscopic and microscopic grounds. The latter of those two lesions are sharply marginated grossly; they typically entrap small tubular airways and are composed of extremely well-differentiated chondrocytes. In contrast, a PPCS has an irregular peripheral macroscopic interface with the lung (Fig. 14-42); it exhibits at least modest nuclear pleomorphism, nuclear crowding, and cellular binucleation; and it does not contain respiratory epithelial profiles^262,264 (Fig. 14-43). Despite the statements just made, most chondrosarcomas of the lung are well-differentiated tumors. Hence, a striking degree of nondescript spindle cell growth or cellular anaplasia in a cartilage-forming tumor should instead invoke concerns over a probable diagnosis of SC with divergent chondroid areas.^1,4 Mesenchymal chondrosarcomas,²⁶³ represented by small cell neoplasms of childhood with a resemblance to Ewing sarcoma (see later discussion) (Fig. 14-44) are rare and special variants that differ from the descriptions just given. They comprise sheets of small lymphocyte-like cells, often punctuated by hemangiopericytoid blood vessels, with interposed islands of embryonal-type cartilage. Another singular subtype of chondrosarcoma is the dedifferentiated form, in which low-grade chondroid tissue is juxtaposed to a highly anaplastic pleomorphic tumor component (Fig. 14-45). It has been reported only rarely as a primary pulmonary lesion.^268,269

Figure 14-42 Excisional gross specimen of carinal chondrosarcoma demonstrating obvious bluish foci of cartilaginous differentiation.

Figure 14-43 Low-grade chondrosarcoma of the carina. A to C, The constituent neoplastic chondrocytes are minimally atypical, but this particular lesion grossly demonstrated obvious destruction of the wall of the airway and justified a malignant diagnosis. D, Fine needle aspiration biopsy of the tumor shows dyshesive ovoid cells, some of which contain cytoplasmic vacuoles. The stroma is amorphous.

Figure 14-44 A and B, Mesenchymal chondrosarcoma of the lung showing a juxtaposition of chondroid islands and undifferentiated small round tumor cells.

Figure 14-45 Dedifferentiated chondrosarcoma of the lung demonstrating a low-grade “parent” component (top) and an abruptly juxtaposed anaplastic sarcomatous derivative thereof (bottom).

With these features in mind, there are few other differential diagnostic considerations in cases of PPCS. Thus, special histochemical, ultrastructural, and immunohistochemical assessments are not usually needed to establish a confident diagnosis.

Therapy and Prognosis

Primary chondrosarcomas of the airway are best treated by surgical ablation. Because these are, in most cases, slowly growing and generally low-grade malignancies, such intervention carries with it a good chance of long-term survival if the tumor can be completely extirpated.²⁶⁵ Chemotherapy and irradiation are ineffectual in treating PPCS and probably incur more morbidity than is acceptable in the treatment of an indolent sarcoma. On the other hand, those interventions would be appropriate to consider for examples of dedifferentiated PPCS.

In extrapolation from bone tumor pathology, there are only three features that correlate with a risk of recurrence or metastasis of chondrosarcoma: tumor size greater than 5 cm, vascular invasion by the neoplastic cells, and a dedifferentiated microscopic image. There is no evidence that preemptive adjuvant treatment of patients with the first two risk factors in any way improves the clinical outlook. Indeed, it is our opinion that reoperation to remove any recurrent masses is the most sensible approach to patient management in this context.

Clinical Findings

The basic symptoms and signs that are associated with primary pulmonary SS are no different than those attending bronchogenic carcinomas, except they are seen in a younger age group (mean, 38.5 years). Chest pain, cough, shortness of breath, and hemoptysis may be encountered, but, in one series, one fourth of all patients were asymptomatic.²⁷⁰ Men and women are relatively equally likely to develop SS of the lung. Roentgenographically, there is usually little to point the radiologist toward a specific diagnosis of SS in the lung (Fig. 14-46), which may arise in any segment of any pulmonary lobe. However, some cases show flocculent or particulate calcification on plain film radiographs or CT scans. Cystic change may also be noted, and a minority of lesions is clearly associated with a major bronchus.^270–277

Figure 14-46 Computed tomography scan of primary pulmonary synovial sarcoma showing a large mass in the right hemithorax.

Pathologic Findings

The gross and microscopic spectrum of SS of the lung parallels that seen in similar tumors of peripheral soft tissue.²⁷⁹ Macroscopically, one sees a fleshy, ill-circumscribed mass in virtually any intrapulmonary location (Fig. 14-47). Classically, biphasic SS is composed of fascicles of compact spindle cells arranged in interweaving or “herringbone” fascicles, punctuated by clefts or overtly glandlike spaces that are lined by cuboidal to low columnar tumor cells (Fig. 14-48). The latter inclusions may contain mucoid matrical material and may also demonstrate squamous or goblet cell metaplasia. Nuclei of the neoplastic cells in both components are generally monomorphic, with dispersed chromatin and inconspicuous nucleoli. Cytoplasm is sparse in the fusiform cellular elements. In contrast, a moderate quantity of amphophilic, eosinophilic, or vacuolated cytoplasm is apparent in glandlike foci. Mitotic activity is greatly variable, may be surprisingly scant, and only rarely features the presence of “atypical” division figures. Intercellular calcifications (sometimes with a psammomatous configuration) may be scattered randomly throughout the tumor (Fig. 14-49), be clustered in discrete foci, or be lacking altogether. The finding of necrosis is likewise highly variable. Tumoral stroma can be overtly collagenous, delicate and fibrovascular, or myxoid. Besides the prototypic form of biphasic SS, another with an admixture of solid polygonal cell clusters and spindle cell zones (Fig. 14-50) is recognized.²⁷⁹

Figure 14-47 Grossly, primary pulmonary synovial sarcoma exhibits a fleshy tan-gray cut surface.

Figure 14-48 A, Photomicrograph of biphasic synovial sarcoma of the lung. The tumor contains glandlike epithelial structures punctuating a neoplastic spindle cell proliferation. Diagnostic confusion with biphasic sarcomatoid carcinoma is possible. B, Immunostaining for pankeratin highlights the overtly epithelial glandular component of this neoplasm.

Figure 14-49 Stromal calcification is present in this pulmonary synovial sarcoma.

Figure 14-50 Another variant of biphasic synovial sarcoma of the lung contains solid epithelial cell nests, admixed with spindle cell areas.

The existence of monophasic SS is now undeniable. This variant may be composed entirely of fusiform elements, epithelioid polygonal cells that may or may not demonstrate obvious glandlike differentiation, or sheets of small round cells.²⁷⁰ Monophasic spindle cell SS is more common by far (Fig. 14-51), and recognition of it as a distinct entity has resulted in reclassification of many fibrosarcomas of the soft tissues and other sites. It is now realized that the great majority of sarcomas with a “herringbone” spindle cell constituency are actually synovial rather than fibroblastic, as traditionally taught.²⁵⁸ Another key feature to the recognition of monophasic spindle cell SS is the presence of a “staghorn” pattern of intratumoral vascularity.²⁷⁹ Divergent differentiation, simulating osteogenic, neural, or squamous lesions, is another pathologic facet of monophasic SS that may cause diagnostic consternation.²⁷⁰

Figure 14-51 A to C, Monophasic spindle cell synovial sarcoma (MSS). The images shown here overlap with those of sarcomatoid carcinomas as well as other sarcoma morphotypes. D, Fine needle aspiration biopsy of MSS shows loosely cohesive and blunt-ended spindle cells with no other distinguishing cytologic features.

Electron microscopy and immunohistology have shown that SS is actually an epithelial proliferation, with ultrastructurally well-formed junctional complexes between the tumor cells.^258,279 Reticulin stains are often useful in outlining epithelioid cell clusters when they are present but indistinct. Immunostains for keratin and EMA (Fig. 14-52) can be used to similar advantage; these determinants are also commonly seen together with vimentin in the spindle cells of biphasic or monophasic SS. CD99, calretinin, and bcl-2 protein are often observed in SS as well.²⁷⁹ Another extremely useful marker is TLE-1; it is a nuclear protein that is observed in virtually all cases of SS^141–144 (Fig. 14-53); there is some sharing of reactivity for TLE1 with neural neoplasms,¹⁴³ but, when used in an immunohistochemical panel setting, that should not pose a diagnostic problem. It is clear that SS shows a characteristic t(X;18) (p11.2;q11.2) chromosomal translocation (Fig. 14-54), which can be assessed using traditional cytogenetic techniques or fluorescence or chromogenic in situ hybridization.^272,273 This karyotypic aberration produces a selective fusion transcript known as SYT-SSX, and the polymerase chain reaction can be used to detect it diagnostically, using suitable primer pairs of nucleotides.^144,277

Figure 14-52 Immunoreactivity for epithelial membrane antigen (A) and pankeratin (B) is potentially seen in monophasic synovial sarcoma (MSS). C, Electron microscopy of MSS demonstrates well-formed junctional complexes between the fusiform tumor cells, consistent with their epithelial nature.

Figure 14-53 Nuclear immunoreactivity for TLE1 is a selective marker for synovial sarcoma of both monophasic and biphasic types, among all sarcoma morphotypes.

Figure 14-54 Fluorescent in situ hybridization preparation from primary pulmonary synovial sarcoma showing the t(X;18) chromosomal translocation that typifies this neoplasm. The green signal (white in this image) corresponds to a segment of chromosome 18; the red signal corresponds to a segment on the X chromosome.

The major differential diagnostic alternatives to primary SS in the lung are metastatic SS from soft tissue sites, HPC-SFT, fibrosarcoma, mesothelioma, and SC. Among these possibilities, only SS shows the aforementioned t(X;18) chromosomal abnormality, making cytogenetic evaluation, with or without other adjunctive studies, highly desirable in this context. A decision tree that can be used in the differential diagnosis of SS is shown in Figure 14-55.

Figure 14-55 Decision tree for the immunohistochemical diagnosis of synovial sarcoma. (+), positive; (–), negative; EMA, epithelial membrane antigen; Indeterm, immunohistologically indeterminate category (requires molecular characterization for diagnosis); Meso, mesothelioma; Sarc CA, sarcomatoid carcinoma; SFT, solitary fibrous tumor; Syn Sarc, synovial sarcoma.

Therapy and Prognosis

The long-term outlook for patients with SS of the lung is guarded at best. In a series reported by Zeren and associates, 14 of 18 patients had died of their tumors or were likely to do so at a mean follow-up period of 12.5 years.²⁷⁰ In general, this neoplasm has the ability to recur locally or demonstrate distant metastasis many years after its initial diagnosis; indeed, follow-up shows that tumor-related mortality continues to accrue up to 20 years after presentation.²⁷⁹

Essary and coworkers²⁸⁰ also reported that primary pulmonary SS is a more aggressive lesion than its soft tissue counterpart. They posited that this was due to its usual large size at diagnosis and because of a common difficulty in resecting the tumor completely.

Recommended therapy for primary pulmonary SS is predicated on radical surgical extirpation. The efficacy of adjuvant radiation treatment and chemotherapy is somewhat controversial.

Clinical Summary

The ages of reported patients with PMML have ranged from 29 to 80 years. Because of the rarity of this lesion, no meaningful statements can be made regarding gender-related incidence figures. Some patients with bronchopulmonary melanoma have been asymptomatic, whereas others have presented with hemoptysis, dyspnea, or cough.^293–301 A location in the lumen of the trachea may be associated with asthma-like symptoms. Plain film radiographic examinations generally have shown abnormalities only if the tumors were in the pulmonary parenchyma; in other words, endobronchial tumors are visible only on CT or MRI.

Pathologic Findings

In several reported cases of PMML, the lesions have been centered in large airways, including the trachea and major bronchi.^{293,299,301,309–311} Grossly, these tumors are generally polypoid, endoluminal masses that are partially or completely obstructing, or they present as nodules within the lung parenchyma, which range from 1 to 4.5 cm in greatest dimension. In addition, they are characteristically colored, in shades of brown or black, but may occasionally be amelanotic (tan-gray).

Histologically, PMMLs are composed of heterogeneously pigmented and variably pleomorphic cells that range from epithelioid to fusiform in configuration with occasional gigantiform figures; overtly sarcoma-like lesions are certainly part of the repertoire of these neoplasms (Fig. 14-59). Indeed, divergent differentiation into chondro-osseous–like tissue has been reported in melanomas.³¹²

Figure 14-59 A and B, Apparently primary malignant melanoma of the lung represented by an amelanotic proliferation of pleomorphic tumor cells within a bronchus. Immunohistologic studies were necessary to support the presence of melanocytic differentiation in this case.

Several times over the years, we have made mistakes in the microscopic interpretation of melanoma (usually metastatic) in the lungs. If pigment is absent or sparse in the tumor cells, no meaningful historical data are supplied by the surgeon, and the lesion being studied is solitary; the stage is set for a possible error. Maeda and colleagues³¹³ and Yamada and associates³¹⁴ have discussed the particular resemblance of amelanotic melanoma to large cell undifferentiated lung carcinoma, and we concur with their conclusions. It is certainly not a necessary step to subject all undifferentiated pulmonary neoplasms to immunohistologic evaluations. Nonetheless, if such studies are obtained, and there is no reactivity in the tumor cells for pankeratin (often used as an “internal control” in carcinoma cases), the alternative possibility of melanoma should be considered.

An important microscopic feature that supports a primary origin in the respiratory tract is the presence of a cytologically atypical in situ melanocytic proliferation in adjacent bronchial mucosa, which may be metaplastic^293,296 (Fig. 14-60). To confirm the presence of melanocytic differentiation²⁹³ and exclude the differential diagnoses of anaplastic carcinoma or sarcoma, electron microscopic studies showing the presence of cytoplasmic premelanosomes (Fig. 14-61) or immunohistochemical negativity for keratin and labeling for S100 protein, HMB-45 antigen, Melan-A/MART-1, PNL2, or tyrosinase are useful.

Figure 14-60 In situ malignant melanoma of the bronchial mucosa. The tumor cells are scattered throughout the epithelium randomly.

Figure 14-61 Electron photomicrograph of malignant melanoma demonstrating the presence of cytoplasmic premelanosomes. These inclusions are diagnostic.

Therapy and Prognosis

Before assigning a diagnosis of probable PMML, one must undertake a thorough dermatologic examination, as well as extensive radiologic and endoscopic assessments.^315–317 Those measures are designed to detect an occult primary mucocutaneous melanoma in another location. De Wilt and coworkers also have considered the scenario in which pathologists confront a possible diagnosis of intrapulmonary melanoma in intraoperative consultation.³¹⁸ If the tumor being analyzed is amelanotic, it will likely resemble a high-grade carcinoma in frozen sections and touch preparations. Even if the patient has a known history of melanoma, the surgeon should be counseled to perform a conservative—but adequate—excisional procedure that would be appropriate for primary lung cancer under those circumstances.

In most documented cases of PMML, patients have fared extremely poorly, with the majority dying within 1 year of diagnosis.^{293,296–298,300} Reid and Mehta reported one individual who survived 11 years after surgery²⁹⁹; however, there was no mention in the latter study of clinical evaluations that were designed to exclude other primary sites of origin, and no in situ melanocytic proliferation was found in the pulmonary resection specimen. Thus, the latter case is doubtful as a verifiable PMML. Most patients have undergone surgical resections of their tumors, although a few have received irradiation or chemotherapy.²⁹⁴ In extension of therapeutic results obtained in cases of other primary melanomas of the viscera, it must be concluded that long-term survival of patients with PMML is an idiosyncratic and unlikely event.

Clinical Summary

Patients with PTS are adults in middle life or beyond, with no predilection for either gender. They present with a panoply of potential symptoms and signs, the most common of which simulate the findings of right-sided cardiac failure or pulmonary thromboembolic disease.³²³ Patients often complain of intractable cough, progressive dyspnea, and dull chest pain that may increase with exertion; cardiac tamponade has rarely been observed.³²¹ Neck veins may be distended, a loud precordial systolic heart murmur may be audible at the upper left sternal border, and the patient may manifest the complete clinical scenario of anasarca.^324,325 However, cardiac imaging studies demonstrate no evidence of ventricular hypokinesis or perfusion abnormalities.³⁰⁹

In the era before modern angiography, echocardiography, CT, and specialized radionuclide scans, the diagnosis of PTS was usually made for the first time at autopsy.³¹⁹ However, current imaging modalities are now capable of revealing the tumor in question rather easily³⁰⁹ (Fig. 14-62). It takes the form of a partially obstructing, endoluminal mass at the level of the right ventricular outlet or above it, and it may extend over a span of several centimeters. Attachment of the lesion to the arterial wall is variable in character and may be sessile or pedunculated. The neoplasm is typically somewhat heterogeneous in density and greatly heterogeneous in size, from case to case.

Figure 14-62 A, Computed tomogram showing a mass within the pulmonary trunk, representing pulmonary trunk sarcoma. B, Another pulmonary trunk sarcoma, as seen at autopsy.

Pathologic Findings

The preoperative diagnosis of PTS is typically one that may not involve the pathologist, inasmuch as biopsy of an intravascular mass in the right ventricular outlet is a challenging procedure. Thus, his or her first encounter with such lesions may be in the frozen section laboratory during a definitive surgical procedure. In this context, it is important to realize that a firm diagnosis of a particular sarcoma type (or even of a malignancy) may not be an easy proposition. Some PTSs take the form of rather paucicellular myxoid proliferations with surprisingly bland cytologic characteristics (Fig. 14-63), whereas others are anaplastic tumors that defy easy classification under the microscope³¹⁹ (Fig. 14-64). The proffered pathologic interpretations in the literature on PTS include such diagnoses as undifferentiated sarcoma, angiosarcoma, leiomyosarcoma, rhabdomyosarcoma, fibromyxosarcoma, fibrosarcoma, chondrosarcoma, osteosarcoma, hemangioendothelioma, malignant fibrous histiocytoma, and malignant mesenchymoma. ^325–335 What one is able to glean from this apparently confusing list is that the histologic spectrum and pathologic grades of PTS are broadly distributed, such that no two individual lesions look quite the same under the microscope. Beyond that, pathologists take a great deal of interest in speculating on the mechanistic reasons for this diversity, but this issue has admittedly little clinical import at the present time.

Figure 14-63 This pulmonary trunk sarcoma has a low-grade fibromyxoid image.

Figure 14-64 These microscopic images of a case of pulmonary trunk sarcoma demonstrate one area (A) that resembles malignant fibrous histiocytoma histologically, whereas another focus in the lesion (B) shows obvious formation of osteoid. The exact nosologic classification of such tumors is often difficult.

With respect to differential diagnosis, the majority of PTSs have the characteristics of high-grade spindle cell or pleomorphic sarcomas, which, in current parlance, would usually be grouped together under the rubric “MFH.” However, some low-grade fibromyxoid variants can closely simulate an intracardiac myxoma or organizing mural thrombus.³¹⁹ Close attention to morphologic detail is the only certain method for distinguishing between such possibilities.

With particular regard to cytologic preparations of thoracic sarcomas, including PTS, the relative lack of architectural detail seen in fine needle aspiration biopsies has an “equalizing” effect. With the exception of biphasic synovial sarcoma, spindle cell sarcomas of various lineages (Fig. 14-65), pleomorphic sarcomas (Fig. 14-66), and small round cell tumors (Fig. 14-67) have superimposable microscopic images in such preparations. Thus, ancillary diagnostic methods are necessary to make specific diagnoses in those neoplastic categories.

Figure 14-65 Generic fine needle aspiration biopsy image of a spindle cell sarcoma.

Figure 14-66 Generic fine needle aspiration biopsy image of a pleomorphic sarcoma.

Figure 14-67 Generic fine needle aspiration biopsy image of a small round cell sarcoma.

Therapy and Prognosis

Because of the dominance of autopsy reports in the earliest literature on PTS, the recommended therapy for this tumor must still be considered evolutionary. At the present time, providing that a firm radiologic diagnosis can be made or a frozen section interpretation of sarcoma can be rendered, the surgeon may perform an en bloc resection of the pulmonary trunk and its luminal tumor contents, followed by interposition of a synthetic graft.³¹⁰ This is probably the most definitive approach to operative therapy, inasmuch as it is difficult to determine the boundaries of intramural tumor growth by visual inspection. The latter point makes more limited vascular resections and reconstructions a tenuous enterprise.

Extension of the tumor through the wall of the pulmonary artery is the single most important piece of pathologic information in cases of PTS, inasmuch as histologic grading generally does not appear to correlate with tumor behavior in a consistent fashion.^319,325 An exception to the latter statement is embodied in a report by Tavora and colleagues, who suggested that low-grade myofibroblastic PTS had a distinctly better prognosis than other histotypes.³³⁶ In addition, the surgeon’s or radiologist’s estimation of whether the lesion is pedunculated or sessile has considerable importance. Tumors with a narrow stalk tend to “flutter” in the stream of ejected blood in the ventricular outflow tract, and pieces of the neoplasm may be embolized into the lungs.³³⁷ This phenomenon is not as common with lesions that assume a broadly based sessile macroscopic growth pattern.

Cases demonstrating metastasis or obvious extravascular spread of PTS may be managed with irradiation or chemotherapy. However, there are no unified recommendations for the use of these treatments, and their implementation has produced discouraging results thus far.

Clinical Summary

Regardless of histologic subtype—sarcomatoid or otherwise—the clinical features of intrathoracic mesothelioma are the same.^338–340 Malignant mesothelioma (MM) of the pleura typically affects adult men, although women and children are certainly represented in the patient population with this neoplasm.^340,341 The most common presenting symptoms and signs are pleuritic-type chest pain and progressive shortness of breath, with a pleural effusion on chest radiographs. An influenza-like syndrome is occasionally reported in association with pleural mesothelioma. The lesion most commonly takes the form of multiple nodules and plaques in the serosal surfaces but may occasionally be represented by a solitary localized mass (Fig. 14-68). Later in the clinical course, encasement of the lung by confluent neoplastic tissue is seen (Fig. 14-69).

Figure 14-68 Computed tomogram (A) and gross photograph (B) of localized sarcomatoid mesothelioma.

Figure 14-69 In this case, an extrapleural pneumonectomy specimen demonstrates circumferential encasement of the lung by tumor tissue, as well as extension into the interlobar septa.

Like examples of peritoneal mesothelioma that have been linked causally to chronic recurrent peritonitis in the context of familial Mediterranean fever,³⁴² the authors have observed several pleural tumors that arose in the background of chronic pleuritis in patients with a connective tissue disease (e.g. lupus erythematosus). Roughly 50% to 70% of pleural mesotheliomas can be objectively related to prior occupational-level asbestos exposure.³⁴³ In those instances, 85% to 90% of patients show the presence of (1) pleural plaques or pleural calcifications or (2) quantitative pulmonary asbestos fiber burdens clearly in excess of the background, serving as tangible markers of such exposure.^344–350 Those findings are vastly more reliable than patients’ historical accounts of occupational conditions and should be sought in all instances before concluding objectively that a given mesothelioma is indeed asbestos-related etiologically.

Other accepted pathogenetic factors in mesothelioma cases include inhalation exposure to erionite, chronic infection of the pleural spaces (e.g., in tuberculous pleuritis), and prior therapeutic irradiation of the thorax.^351,352 Substantial recent interest has centered on the potential role of simian virus-40 in this setting,³⁵³ but conclusions about whether this agent is indeed causative in any way are premature. At least 30% of pleural mesotheliomas are idiopathic.³⁴³

Pathologic Findings

In considering the pathologic appearances of overtly malignant mesothelial tumors, a surprising variety of patterns has emerged over time, and these have expanded the traditional categorical outline, which previously included “epithelioid,” “biphasic,” and “sarcomatoid” mesotheliomas.^340,354,355 The epithelioid subgroup has now been enlarged to include mesothelial malignancies that have a wholly clear cell, oncocytoid (“deciduoid”) or granular cell, tubulopapillary, large polygonal cell, polyhedral stromal mucin-producing, “medullary” epithelioid, or even small cell appearance (see Chapter 20).³⁵⁴ The differential diagnostic potentialities raised by such images are numerous, including metastatic non–small cell carcinomas of various primary origins, metastatic melanoma, pleural sarcomas with an epithelioid or small round cell appearance, and even metastatic small cell neuroendocrine carcinoma. In reference to biphasic MM—with epithelioid and sarcoma-like elements—primary SS of the pleura is an important diagnostic alternative.³⁵⁶ Indeed, in the absence of data showing the characteristic t(X;18) chromosomal translocation of SS, which is associated with production of SYT-SSX fusion transcripts,³⁵⁷ or immunoreactivity for TLE1 (see earlier discussion), its separation from MM can be extremely challenging. This is so because the immunophenotypes of the two tumors are so similar.³⁵⁸

Monophasic sarcomatoid mesothelioma potentially simulates a range of spindle cell sarcoma morphotypes that may affect the pleura (Figs. 14-70 and 14-71), again including monophasic SS, but also fibrosarcoma, MFH, rhabdomyosarcoma, chondrosarcoma, osteosarcoma, leiomyosarcoma, and malignant peripheral nerve sheath tumor.^1,359–363 Pseudomesotheliomatous secondary pleural carcinomas with a sarcomatoid phenotype also enter the differential diagnosis in a meaningful fashion, as referenced earlier in this discussion. The histomorphologic findings in that particular differential diagnostic group of tumors have been summarized previously.

Figure 14-70 A and B, Microscopic images of sarcomatoid malignant mesothelioma showing a disorganized proliferation of highly atypical spindle cells, surrounding a nerve (N). Metastatic or pleurotropic sarcomatoid carcinoma and true sarcomas of the pleura are differential diagnostic alternatives.

Figure 14-71 Another example of sarcomatoid mesothelioma is more anaplastic cytologically (A), simulating the appearance of pleomorphic sarcomas. This attribute is also visible in a fine needle aspiration biopsy specimen (B).

In specific reference to sarcomatoid mesotheliomas, the basic histologic image of such lesions is virtually identical to that associated with SC of the lung.^364–369 Indeed, cases in which a tumor mass involves both the peripheral lung and the pleura require immunohistologic or molecular evaluation in order for a distinction to be made with definition between those tumor types.³⁷⁰ As such, sarcomatoid mesotheliomas are composed exclusively by overtly malignant spindle cells and pleomorphic elements, with or without such heterotopic tissue as osteoid, cartilage, muscle, or osteoclast-like giant cells.

Lymphohistiocytic mesothelioma^371,372 was formerly classified as a sarcomatoid subtype, but that lesion is now generally considered to be a form of epithelioid mesothelioma with a lymphoepithelioma-like image. Another special variant of sarcomatoid mesothelioma merits further consideration: namely, desmoplastic mesothelioma.^373–379 That tumor is characterized by relatively bland neoplastic spindle cells that are set in a densely collagenized fibrohyaline matrix with a so-called “patternless pattern” of growth (Fig. 14-72). Differential diagnosis of that tumor type is with fibrous (or fibrohyaline) pleuritis (“fibrous pleurisy”); the presence of focally dense and atypical cellular growth, necrosis, obvious invasion of lung or soft tissue, or metastasis points to a diagnosis of mesothelioma.³⁷⁸ On the other hand, lymphohistiocytoid mesotheliomas may be confused with malignant lymphoma, inflammatory myofibroblastic (pseudo)tumor of the pleura, or metastatic lymphoepithelioma-like carcinoma.^371,372

Figure 14-72 A and B, Desmoplastic sarcomatoid malignant mesothelioma composed of minimally atypical spindle cells set in a densely hyalinized collagenous stroma. A distinction from fibrous pleurisy is often difficult.

This information brings one to a consideration of adjunctive pathologic studies in the objectification of a diagnosis of MM. In regard to this important topic, it should be remembered that there are definite roles for a number of laboratory analyses, including but not limited to histochemistry, immunohistology, electron microscopy, fluorescent or chromogenic in situ hybridization, the polymerase chain reaction using appropriately chosen primers, and traditional cytogenetic evaluations.338–350,^380,381

Although most attention has been paid in recent years to the immunohistochemical separation of epithelioid MM from metastatic adenocarcinoma,^382,383 the panel of markers used for that purpose is generally not helpful in the differential diagnosis of nonepithelioid (i.e., sarcomatoid) MM variants, with selected exceptions. Standard approaches to separating MM from adenocarcinoma include immunostains for keratin (either “pankeratin,” or keratin 5/6, or both), EMA, thrombomodulin, HBME-1, calretinin, Wilms tumor gene product 1 (WT1), podoplanin,¹⁴⁶ tumor-associated glycoprotein-72 (recognized by B72.3), carcinoembryonic antigen, CD15, Ber-EP4, BG8, and MOC-31, with expected reactivity in MM primarily including any of the first seven of those determinants.³⁸⁴ Electron microscopy is still extremely useful in this particular context, inasmuch as the long, branching, bushy microvilli that one associates with mesothelial cells are best represented in epithelioid MM.³⁸⁵

Neither immunohistology nor electron microscopy is nearly as helpful in the realm of biphasic or sarcomatoid tumors, and an entirely different set of morphologic and immunophenotypic variables must be assessed in those lesions. For example, keratin, WT1, podoplanin, and calretinin assume much greater value in the differential diagnosis of sarcomatoid MM (Fig. 14-73).^146,384,386 The principal interpretative alternatives are those of true sarcoma, sarcomatoid pseudomesotheliomatous carcinoma, or malignant solitary fibrous tumor; sarcoma-like mesothelioma differs from the latter two entities in that it may divergently express specialized mesenchymal markers such as desmin and muscle actin isoforms.^387,388

Figure 14-73 Diffuse immunoreactivity is seen in this sarcomatoid mesothelioma for podoplanin, with antibody D2-40.

Fluorescent in situ hybridization or polymerase chain reaction for SYT-SSX transcripts may be necessary to separate some examples of SS (which are also reactive for keratin and potentially for calretinin) from MM with certainty.^357,358 Electron microscopic analyses are likewise not very helpful in the differential diagnosis of sarcomatoid MM, because that variant of mesothelioma tends to lose specialized ultrastructural features of epithelial cells (Fig. 14-74).^369,389 Rarely, localized sarcomatoid mesotheliomas also may resemble solitary fibrous tumors of the pleura³⁹⁰; in those cases, immunoreactivity for CD34, or CD99, or both, tends to exclude a diagnosis of MM.³⁹¹

Figure 14-74 This electron photomicrograph of sarcomatoid mesothelioma shows an intercellular attachment plaque (left center), but there are otherwise no specialized markers of epithelial differentiation.

Therapy and Prognosis

The natural history of malignant pleural mesothelioma is an adverse one. The usual survival of patients with that tumor is less than 15 months, with death occurring because of cardiorespiratory embarrassment or pulmonary superinfection.^338,339,392 A peculiarity of this neoplasm is its tendency to grow through surgical defects in the chest wall, either represented by thoracotomy incisions or thoracostomy sites. Metastases outside the thorax are relatively rare, although they have been reported in a small minority of cases in such sites as liver, bones, and skin.³⁹³ Treatment is generally supportive, inasmuch as irradiation and chemotherapy produce little survival benefit.³⁹⁴ Extrapleural pneumonectomy is still a controversial surgical approach to mesothelioma; its proponents claim a definite decrease in mortality in the operative group compared with stage-matched and age-matched controls managed by other means.³⁹⁵ However, those observations have not been supported by other studies.³⁹⁶

Clinical Summary

Pleural fibrosarcoma and MSFT arise in adult patients over a wide range of ages (15–75 years), with a male-to-female ratio of 3:1. They may be associated with dull or pleuritic chest pain, dyspnea, cough, systemic flu-like symptoms, and digital clubbing.^414,415 In addition, a small proportion of patients may manifest paraneoplastic hypoglycemia (Doege-Potter syndrome) because of the production of an insulin-like peptide by the tumor cells.^415,416 It appears that pleural sarcomas have no association with prior asbestos exposure (in contradistinction to a proportion of MMs).³⁶⁷ Other potential etiologies of these lesions are unsettled at the present time, but some authors have reported a putative pathogenetic linkage to chronic tuberculous pleuritis and prior pyothorax.^417,418

Radiographic studies in cases of PPFS commonly demonstrate the presence of a unilateral pleural effusion, which may be massive.^415,419 In addition, a dominant mass and diffuse but irregular thickening of the pleura are usually evident, and are especially visible with CT or MRI studies.⁴¹⁹ Based on clinical data, it is not possible to distinguish PPFS from diffuse MM, and tissue procurement is mandatory for this purpose. On the other hand, MSFT are typically well-circumscribed, pleural-based masses on chest x-rays; they usually show rounded contours, but may occasionally be lobulated⁴¹⁵ (Fig. 14-77). Most measure between 1 and 10 cm in maximal dimension. In contrast to benign solitary fibrous pleural tumors, MSFTs are less often pedunculated and usually attain a larger size. Moreover, the latter lesion has a higher likelihood of involving the parietal pleura or mediastinum, or of demonstrating “inverting” growth into the subjacent lung parenchyma.^408,415

Figure 14-77 Computed tomogram showing a left pleural-based mass, which proved to be a malignant solitary fibrous tumor.

Pathologic Findings

The macroscopic appearance of PPFS is virtually identical to that of diffuse MM (i.e., as a “rind” of solid tissue that encases the lung and restricts its movement). These tumors commonly extend into interlobar fissures and intrapulmonary interstitial septa as well.^404–416 On the other hand, MSFTs are sessile or pedunculated localized masses that are most often seen in the upper portions of either hemithorax. They have bosselated, fleshy, tan-gray cut surfaces, usually with foci of spontaneous necrosis and hemorrhage^408,415 (Fig. 14-78).

Figure 14-78 Gross photograph of excised malignant solitary fibrous tumor of the pleura demonstrating internal foci of necrosis.

Microscopically, one sees a dense proliferation of spindle cells with high nuclear-to-cytoplasmic ratios, coarse chromatin, nuclear irregularity, and prominent nucleoli. Mitotic activity is typically brisk, and foci of spontaneous hemorrhage and necrosis may be evident as well (Fig. 14-79). The neoplastic cells may be arranged in a storiform fashion and show moderate-to-marked pleomorphic cytologic features, calling to mind the histologic attributes of MFH (see earlier discussion).^404,415 In other cases, they are aligned in a fascicular “herringbone” configuration, as in pulmonary fibrosarcomas (Fig. 14-80). The subjacent lung is involved by tumor only if it extends downward from the pleura via the intrasegmental fibrous septa, and there is no association with pleural fibrohyaline plaques, the presence of intraparenchymal asbestos fibers, or asbestosis. MSFT may contain areas that resemble benign solitary fibrous pleural tumors, in which more bland spindle cell aggregates are enmeshed in hyalinized, keloidal-type collagen.⁴¹⁵ A “staghorn” stromal vascular pattern is common in such areas as well.

Figure 14-79 A, Microscopic image of malignant solitary fibrous tumor (MSFT) of the pleura showing an atypical spindle cell proliferation. B, Another MSFT is more pleomorphic in appearance.

Figure 14-80 A, A “herringbone” pattern of densely cellular growth and mitotic activity are present in this malignant solitary (localized) fibrous tumor (MSFT) of the pleura. B, The lesion is immunoreactive for CD34, although a proportion of MSFTs lose that marker.

Electron microscopy shows only primitive, fibroblast-like characteristics of the neoplastic cells. They are loosely apposed and surrounded in part by collagen fibers. Cytoplasmic contents are rudimentary and include the basic metabolic organelles as well as abundant free polyribosomes and rough endoplasmic reticulum (Fig. 14-81). There is no ultrastructural evidence of epithelial or myogenous differentiation. Similarly, immunohistologic assessment of PPFS and MSFT demonstrates reactivity for vimentin alone, to the exclusion of actin, desmin, keratin, and EMA.^404–409 In contrast, true mesotheliomas (including sarcomatoid variants) uniformly express epithelial markers.³⁸⁶ In contrast to benign SFTs, some MSFTs may lack immunoreactivity for CD34, bcl-2 protein, and CD99.⁴¹³

Figure 14-81 Fibrosarcoma-like malignant solitary fibrous tumor of the pleura (A), comprising cells that ultrastructurally resemble fibroblasts (B).

Therapy and Prognosis

PPFS is not often treatable by surgical means because of its diffuse nature. The only operative procedure that can be attempted in such circumstances is extrapleural pneumonectomy, which generally is associated with a very high level of morbidity and mortality. Radiotherapy and chemotherapy (including intrapleural instillation of pharmaceuticals) may play a role in palliation of symptoms, but unfortunately they are not curative treatments. Death is due to progressive respiratory compromise, and PPFS also may involve the pericardium and produce cardiac embarrassment.⁴²⁰ Actuarial 1-year survival was only 39% in one series where multimodality therapy was used.⁴¹⁴

MSFT, on the other hand, is amenable to complete surgical resection in a high proportion of cases; in a series from the AFIP, 45% of such lesions were cured by excision alone.⁴¹⁵ Most of these were pedunculated, well-localized masses that involved only a small area of the pleural surface, and the authors of the latter report therefore suggested that resectability was the single most favorable prognostic feature in MSFT cases. Those lesions that do go on to recur may seed the ipsilateral pleural surfaces or involve the contralateral pleura, the lung parenchyma, and other viscera. Interestingly, relapses often still take the form of localized masses, and even patients with persistent tumor may go on to survive for extended periods of time.³⁶⁷ Irradiation and chemotherapy do not appear to offer any benefits in this setting, and they may even shorten the survival of patients with MSFT.⁴¹⁵

Clinical Summary

Patients with primary pleural leiomyosarcoma present in a similar fashion to those with mesothelioma, except that a greater proportion have had asymptomatic lesions. Radiographically, pleural effusions have not been observed consistently in association with such tumors, the majority of which appeared as solitary, solid, unilateral masses measuring up to 18 cm in greatest dimension (Fig. 14-82).⁴²³ Some examples have encased the lung completely, simulating malignant mesothelial tumors.⁴²¹

Figure 14-82 Gross photograph of primary pleural leiomyosarcoma showing a localized lesion with a “fleshy,” white-gray cut surface.

Pathologic Findings

As in other anatomic sites, pleural leiomyosarcomas are characterized by fascicles and whorls of atypical spindle cells, featuring fusiform nuclei, fibrillary eosinophilic cytoplasm, nuclear pleomorphism, and mitotic activity (Fig. 14-83). Necrosis is also frequently encountered as well. The tumors invade the lung parenchyma, or the soft tissues of the chest wall, or both.

Figure 14-83 Fascicular spindle cell growth is evident in this primary pleural leiomyosarcoma.

Ultrastructural analyses have shown typical findings of smooth muscle differentiation in such tumors, including plasmalemmal dense plaques, pinocytotic vesicles, cytoplasmic thin filaments punctuated by dense bodies, and pericellular basal lamina (Fig. 14-84). Immunohistologically, pleural leiomyosarcomas are reactive for vimentin, desmin, muscle-specific actin, caldesmon, calponin, and alpha-isoform actin (Fig. 14-85),⁴²¹ yielding potential immunophenotypic overlap with SC or mesothelioma. However, in our experience, keratin, EMA, and calretinin are uniformly absent, providing points of difference from the latter two epithelial tumors.

Figure 14-84 Cytoplasmic skeins of thin filaments, punctuated by dense bodies, are seen in this electron photomicrograph of primary pleural leiomyosarcoma.

Figure 14-85 Immunoreactivity for caldesmon is apparent in primary pleural leiomyosarcoma.

Therapy and Prognosis

Because of the rarity of these lesions, only anecdotal information is available on the biology of primary pleural leiomyosarcomas. Moran and associates advocated surgical ablation but found that two of five such lesions they studied could not be resected completely.⁴²¹ The merits of adjuvant therapeutic modalities are as yet unstudied.

Clinical Summary

Askin tumor and DSRCT demonstrate a peak incidence during the second decade of life (mean age, 15 years), and they show a slight male predilection. Isolated cases of TPNETs in infants and in older adults have also been documented.^438–443 These neoplasms may present as asymptomatic masses in the chest wall or produce symptoms of cough, unilateral chest pain, and dyspnea or tachypnea. Pleural effusion is a common complication and may be detected on physical examination or by radiography of the thorax.⁴²⁵ Although Askin tumors and DSRCTs have been confused with classic neuroblastoma in some reports, they are not associated with elevations of catecholamine metabolite levels in the urine or blood, and they do not produce the opsoclonus-myoclonus syndrome.^433,441

Chest x-rays and other imaging studies typically show a large mass that may be pleural-based or centered in the thoracic soft tissue, with secondary extension into the pleural space (Fig. 14-86). TPNETs and DSRCTs often reach greater than 10 cm at the time of initial diagnosis, and they demonstrate ill-defined interfaces with the subjacent lung or surrounding tissues.⁴⁴⁴

Figure 14-86 Askin tumor (primitive neuroectodermal tumor) of the right hemithorax in a young child, as seen in a computed tomography scan.

Pathologic Findings

Askin tumor is one of the prototypical small round cell neoplasms of children and may be confused with several other tumor entities by the pathologist.⁴³³ At a macroscopic level, TPNET is lobulated with fleshy, relatively soft, tan-gray cut surfaces (Fig. 14-87) that may show foci of hemorrhage and necrosis.⁴²⁴ Microscopically, it exhibits cellular monomorphism, with round-to-oval nuclei, even distribution of chromatin, indistinct nucleoli, and variable mitotic activity (Fig. 14-88). Stromal blood vessels are numerous and form a discernible network within the tumor mass; matrical hemorrhage also may be manifest.^424–441 One of the most characteristic findings of TPNET on conventional microscopy is the presence of neural-type cellular “rosettes,” wherein tumor cells are disposed radially around small virtual tissue spaces^424,425 (Fig. 14-89). Histochemically, Askin tumor may or may not contain abundant glycogen with the PAS method (Fig. 14-90), although in the original series on this lesion, only PAS-negative neoplasms were accepted to facilitate separation from classic Ewing sarcoma.

Figure 14-87 Partial excision of the lesion yielding a fleshy mass demonstrating internal foci of necrosis.

Figure 14-88 A, Microscopic image of primitive neuroectodermal tumor showing a densely cellular proliferation of monomorphic small round cells. B, The neoplastic cells have scant cytoplasm and dispersed nuclear chromatin. C, An electron micrograph of the lesion showing primitive cytoplasmic extensions that contain neurosecretory-type or synaptic vesicles. D, Immunoreactivity for CD99 (MIC2 protein) is also present.

Figure 14-89 Primitive intercellular rosettes are present in this Askin tumor (primitive neuroectodermal tumor).

Figure 14-90 Diffuse reactivity is seen with the periodic acid/Schiff stain in the Askin tumor, reflecting the presence of abundant cytoplasmic glycogen.

DSRCT differs from the description just given in that it features aggregates of small monomorphic tumor cells that are set in a much more fibrogenic stroma than that seen in Askin tumor (Fig. 14-91). The growth pattern is also more organoid than in conventional TPNET.^438–440 Although no obvious evidence of myogenous differentiation is apparent at a conventional morphologic level, immunostains typically show coreactivity for vimentin, desmin, and keratin in DSRCT (Fig. 14-92),⁴³⁹ and ultrastructural studies also support the presence of bifid epithelial-myogenic differentiation.

Figure 14-91 A and B, Desmoplastic small round cell tumor of the pleura, in which angular cell groups composed of cells like those of “ordinary” primitive neuroectodermal tumor (see Figs. 14-88 and 14-89) are set in a markedly fibrous stroma. They are dyshesive and monomorphic in a fine needle aspiration biopsy specimen (C).

Figure 14-92 The neoplastic cells in desmoplastic small round cell tumor of the pleura are concurrently immunoreactive for keratin (A) and desmin (B).

Special studies of biopsy or resection specimens are mandatory to recognize TPNET and DSRCT properly and exclude other diagnostic possibilities. Those include mesenchymal chondrosarcoma, small cell synovial sarcoma, hemangiopericytoma, and metastatic small cell neuroendocrine carcinoma; the last of these possibilities is unlikely in the usual patient group with TPNET. Along with other peripheral neuroepithelial neoplasms, TPNET and DSRCT demonstrate characteristic t(11:22) chromosomal translocations^425,445 (Fig. 14-93). By electron microscopy, they demonstrate blunt cytoplasmic processes that contain dense-core granules or microtubules; these characteristics are seen in classic neuroblastoma as well, but not in other small round cell tumors.⁴³³

Figure 14-93 The characteristic t(11;22) chromosomal translocation of primitive neuroectodermal tumor is seen in a spectral karyotypic preparation (A) and a fluorescent in situ hybridization preparation, using “break-apart” probes (B).

Immunohistochemically, TPNET is related to classic Ewing tumor–PNET in that it shows consistent reactivity for synaptophysin as well as for CD99.⁴⁴⁶ DSRCT is more variable with regard to its positivity for both of those markers.^447,448 Askin tumor may be distinguished from classic neuroblastoma immunophenotypically; the former lesion is reactive for both beta₂-microglobulin and CD99,⁴³⁹ whereas the latter tumor is not. Among primitive neuroectodermal tumor, DSRCT, and neuroblastoma, only DSRCT labels for WT1 (Fig. 14-94).^449,450

Figure 14-94 Nuclear immunoreactivity for Wilms tumor gene product 1 protein is apparent in pleural desmoplastic small round cell tumor.

Therapy and Prognosis

The most important prognostic procedure in cases of TPNET or DSRCT is that of accurate staging. Using a scheme devised by the National Cancer Institute, stage I tumors are defined as those measuring less than 5 cm in maximum diameter that can be completely excised, stage II lesions are less than 5 cm and are grossly resectable but show positive microscopic margins, stage III neoplasms are greater than 5 cm and are nonresectable, and stage IV primitive neuroectodermal tumors have metastasized to extrapleural sites.⁴²⁵ Low stage has shown a direct correlation with long-term survival after surgical removal and intensive cyclical postoperative treatment with irradiation and chemotherapy, using protocols similar to those used for Ewing sarcoma.^426,451 Stage III and IV TPNETs and DSRCTs are probably best managed nonsurgically, because there are no data to support a role for debulking surgery in such circumstances.⁴²⁵

A sobering aspect of the therapy for TPNET and DSRCT is that it undeniably subjects patients who become survivors to the risk of a second malignancy. Intensive radiation to the chest wall may be followed years later by a postradiation sarcoma (or mesothelioma) in approximately 1% of cases, and Farhi and coworkers have described several examples of postchemotherapy myelodysplastic syndrome and acute leukemia in this context.⁴⁵²

Clinical Summary

PPBs arise most often in the first decade of life, without a distinct preference for males or females. However, isolated examples have been reported in adult patients as well.74–80,^453–463 Cough, chest pain, weight loss, dyspnea or tachypnea, and spontaneous pneumothorax are the most common presenting complaints.^74,459 Evidence of a pleural effusion may also be found on physical examination, and a small subset of patients present with acute, rapidly progressive respiratory embarrassment.⁴⁶⁴ It is clear that this neoplasm may be part of certain “cancer families,” in which other soft tissue sarcomas, variants of Wilms tumor, and cystic nephromas may be seen in other members of the kindred.^{78,79,459,460} Other familial and patient-specific associations have been noted between PPB and sex-cord stromal tumors of the gonads, seminomatous germ cell tumors, intestinal polyps, and thyroid hyperplasia.⁴⁶⁵ The operative gene defect that ultimately yields PPB has now been identified. It is represented by a constitutive mutation in the DICER1 gene on chromosome 12, which encodes an endoribonuclease that is critical to the generation of small regulatory ribonucleic acid molecules.⁴⁶⁶

Radiologic studies typically demonstrate the presence of a large, irregularly outlined mass in the thorax, which may have its epicenter in the pleura, the mediastinal soft tissue, or the peripheral lung parenchyma. These lesions can be massive—sometimes effacing an entire hemithorax—and they demonstrate internal variation in density on CT or MRI (Fig. 14-95). Some examples may show focal internal calcification, and types I and II PPB (see subsequent discussion) demonstrate obvious internal cyst formation (Fig. 14-96).^{74,459,461,462}

Figure 14-95 Computed tomogram of pleuropulmonary blastoma in a young adult showing partial effacement of the right hemithorax.

Figure 14-96 Multilocular internal cystic change is apparent in this pleuropulmonary blastoma, as seen in a high-resolution computed tomography scan.

Pathologic Findings

PPB is grossly cystic or fleshy and tan-pink-gray on prosection, with frequent foci of internal hemorrhage and punctate necrosis; overt cystification is also seen in many cases. Chondroid areas may be apparent on macroscopic examination of the mass, and areas of calcification may be manifest as “grittiness” that is encountered when sectioning the lesion.

Dehner and associates^77,459 have subclassified PPBs into three groups, based on the extent of cystic change that they demonstrate. Type I tumors are predominantly cystic, type II lesions are mixed solid and cystic, and type III PPBs are predominantly solid (Figs. 14-97 to 14-99). Cystic foci are lined by modified respiratory epithelium that is typically bland cytologically, and the surrounding stroma is variably myxoid and relatively hypocellular. It is now believed that PPB is associated with “type 4” cystic congenital adenomatoid malformations (CCAMs) of the lung, whereas bronchioloalveolar carcinoma of the lung in children is linked to CCAM type 1^467,468 (see Chapter 4).

Figure 14-97 A and B, Gross photographs of type I pleuropulmonary blastoma demonstrating extensive cystic change in the lesions. The cyst walls contain primitive mesenchymal tissue (C), as well as elements with rhabdomyoblastic features (D and E), which are immunoreactive for desmin (F).

Figure 14-98 Gross photograph of type II pleuropulmonary blastoma (A), the solid areas of which (B) resemble the microscopic image of pleomorphic sarcoma.

Figure 14-99 A, Type III pleuropulmonary blastoma, represented by a solid mass. B, This particular tumor has a nondescript spindle cell constituency.

(Courtesy of Dr. D. Ashley Hill, Washington, DC.)

Microscopically, one sees a heterogeneous mixture of growth patterns that are admixed with one another in various solid regions of these tumors. Some foci resemble MFH (Fig. 14-100); others take on a rhabdomyosarcomatous appearance; and still other areas have the features of fibrosarcoma, liposarcoma, chondrosarcoma, or osteosarcoma.^74,459 In the past, some observers applied the term “malignant mesenchymoma” to PPB, but such a designation has generally fallen from favor in current nosology. Importantly, epithelial foci are absent in PPB, in contrast to their dominance in so-called “adult pulmonary blastoma.”^74,77,459 Immunohistochemical and ultrastructural studies demonstrate findings that are in accord with the aforementioned microscopic features, and they again fail to reveal epithelial characteristics in these lesions.^74,469

Figure 14-100 Another type III pleuropulmonary blastoma.

Fine needle aspiration biopsies typically show dyshesive, pleomorphic cells from PPBs (Fig. 14-101). Immunohistologic studies are required to assess the presence of lineage-related markers in such elements.

Figure 14-101 Bizarre, large, dyshesive spindle cells are seen in this fine needle aspiration biopsy specimen of type III pleuropulmonary blastoma.

Hill and coworkers have suggested that cystic type I PPB evolves into types II or III over time in a sizable proportion of cases. Type I tumors show the presence of primitive mesenchymal tissues mantling intralesional cysts, beneath a cytologically bland lining of respiratory epithelium. Rhabdomyosarcoma-like and chondrosarcoma-like elements are present in 49% and 40% of cases, respectively (Figs. 14-102 and 14-103). The latter elements become even more common in types II and III PPB.⁴⁷⁰

Figure 14-102 Solid, alveolar rhabdomyosarcoma-like growth in type III pleuropulmonary blastoma (A), showing immunoreactivity for fast muscle myosin (B).

Figure 14-103 A chondroid area is present in this pleuropulmonary blastoma.

The pathologic differential diagnosis of PPB concerns SC of the lung and pleura, sarcomatoid mesothelioma with divergent differentiation, and rhabdomyosarcoma arising in congenital pulmonary cysts or teratoid tumors involving the pleura. The absence of keratin in PPB excludes pulmonary blastoma, other forms of carcinoma, mesothelioma, and germ cell tumors from further consideration.

Therapy and Prognosis

PPB is a rare tumor; therefore, organized protocol studies of therapy are still in evolution. In general, however, it is obvious that this neoplasm is a highly aggressive lesion that requires every effort at surgical extirpation, followed by intensive radiation and chemotherapy.^459,465 Because of the histologic characteristics of the tumor, which are like those of de novo soft tissue sarcomas, it would seem appropriate to use drug combinations that are directed toward the various histologic components of PPB (e.g., rhabdomyosarcoma, MFH, osteosarcoma). Surgical debulking of the tumor mass should also be considered in individual cases where complete resection is not thought to be feasible. Dehner and colleagues have related morphologic findings in PPBs to prognosis; predominantly cystic lesions have the best outlook, whereas type II and type III neoplasms are aggressive and often prove fatal within 2 years of diagnosis.⁴⁵⁹ Interestingly, Wright has also reported a case wherein successive recurrences of a PPB showed progressive transformation from type I to type III morphology.⁴⁶³ Priest and associates have reported a singular tendency for PPB to demonstrate metastases to the brain (Fig. 14-104). That complication is observed in 11% of type II cases and 54% of type III cases.⁴⁷¹

Figure 14-104 Metastasis of pleuropulmonary blastoma to the brain, as seen in a magnetic resonance image of the head.